PHYSIOLOGIC ANATOMICAL PECULIARITIES OF THE BLOOD SYSTEM IN CHILDREN OF DIFFERENT AGE GROUPS.
SEMIOTICS OF MAIN SYMPTOMS (ANAEMIC, HEMORRHAGIC, HAEMOLYTIC) AND BLOOD SYSTEM DISEASES (ACUTE AND CHRONIC LEUKAEMIA, HAEMOPHILIA, HEMORRHAGIC VISCOSITIES)
The primary function of blood is to supply oxygen and nutrients as well as constitutional elements to tissues and to remove waste products. Blood also enables hormones and other substances to be transported between tissues and organs. Problems with blood composition or circulation can lead to downstream tissue malfunction. Blood is also involved in maintaining homeostasis by acting as a medium for transferring heat to the skin and by acting as a buffer system for bodily pH.
The blood is circulated through the lungs and body by the pumping action of the heart. The right ventricle pressurizes the blood to send it through the capillaries of the lungs, while the left ventricle re-pressurizes the blood to send it throughout the body. Pressure is essentially lost in the capillaries, hence gravity and especially the actions of skeletal muscles are needed to return the blood to the heart.
Blood circulation from the heart to the lungs.
Gas Exchange
Oxygen (O2) is the most immediate need of every cell and is carried throughout the body by the blood circulation. Oxygen is used at the cellular level as the final electron acceptor in the electron transport chain (the primary method of generating ATP for cellular reactions). Oxygen is carried in the blood bound to hemoglobin molecules within red blood cells. Hemoglobin binds oxygen when passing through the alveoli of the lungs and releases oxygen in the warmer, more acidic environment of bodily tissues, via simple diffusion.
Carbon dioxide (CO2) is removed from tissues by blood and released into the air via the lungs. Carbon dioxide is produced by cells as they undergo the processes of cellular respiration (particularly the Kreb’s Cycle). The molecules are produced from carbons that were originally part of glucose. Most of the carbon dioxide combines with water and is carried in the plasma as bicarbonate ions. An excess of carbon dioxide (through exercise, or from holding ones breath) quickly shifts the blood pH to being more acidic (acidosis). Chemoreceptors in the brain and major blood vessels detect this shift and stimulate the breathing center of the brain (the medulla oblongata). Hence, as CO2 levels build up and the blood becomes more acidic, we involuntarily breathe faster, thus lowering CO2 levels and stabilizing blood pH. In contrast, a person who is hyperventilating (such as during a panic attack) will expire more CO2 than being produced in the body and the blood will become too alkaline (alkalosis).
Blood Composition
Blood is a circulating tissue composed of fluid plasma and cells (red blood cells, white blood cells, platelets). Anatomically, blood is considered a connective tissue, due to its origin in the bones and its function. Blood is the means and transport system of the body used in carrying elements (e.g. nutrition, waste, heat) from one location in the body to another, by way of blood vessels.
Blood is made of two parts:
1. Plasma which makes up 55% of blood volume.
2. Formed cellular elements (red and white blood cells, and platelets) which combine to make the remaining 45% of blood volume.
Plasma makeup
Plasma is made up of 90% water, 7-8% soluble proteins (albumin maintains bloods osmotic integrity, others clot, etc), 1% electrolytes, and 1% elements in transit. One percent of the plasma is salt, which helps with the pH of the blood. The largest group of solutes in plasma contains three important proteins to be discussed. There are: albumins, globulins, and clotting proteins.
Albumins are the most common group of proteins in plasma and consist of nearly two-thirds of them (60-80%). They are produced in the liver. The main function of albumins is to maintain the osmotic balance between the blood and tissue fluids and is called colloid osmotic pressure. In addition, albumins assist in transport of different materials, such as vitamins and certain molecules and drugs (e.g. bilirubin, fatty acids, and penicillin).
Globulins are a diverse group of proteins, designated into three groups: gamma, alpha, and beta. Their main function is to transport various substances in the blood. Gamma globulins assist the body’s immune system in defense against infections and illness.
Clotting proteins are mainly produced in the liver as well. There are at least 12 substances, known as “clotting factors” that participate in the clotting process. One important clotting protein that is part of this group is fibrinogen, one of the main components in the formation of blood clots. In response to tissue damage, fibrinogen makes fibrin threads, which serve as adhesive in binding platelets, red blood cells, and other molecules together, to stop the blood flow. (This will be discussed in more detail later on in the chapter.)
Plasma also carries Respiratory gases; CO2 in large amounts(about 97%) and O2 in small amounts(about 3%), various nutrients(glucose, fats), wastes of metabolic exchange(urea, ammonia), hormones, and vitamins.
Red Blood Cells
Overview
Red blood cell (erythrocyte) also known as “RBC’s”. RBC’s are formed in the myeloid tissue or most commonly known as red bone marrow, although when the body is under severe conditions the yellow bone marrow, which is also in the fatty places of the marrow in the body will also make RBC’s. The formation of RBC’s is called erythropoiesis ( erythro / red; poiesis / formation). Red blood cells lose nuclei upon maturation, and take on a biconcave, dimpled, shape. They are about 7-8 micrometers in diameter. There are about 1000x more red blood cells than white blood cells. RBC’s live about 120 days and do not self repair. RBC’s contain hemoglobin which transports oxygen from the lungs to the rest of the body, such as to the muscles, where it releases the oxygen load.The hemoglobin gets it’s red color from their respiratory pigments.
Shape
RBC’S have a shape of a disk that appears to be “caved in” or almost flattened in the middle; this is called bi-concave. This bi-concave shape allows the RBC to carry oxygen and pass through even the smallest capillaries in the lungs. This shape also allows RBCs to stack like dinner plates and bend as they flow smoothly through the narrow blood vessels in the body. RBC’s lack a nucleus (no DNA) and no organelles, meaning that these cells cannot divide or replicate themselves like the cells in our skin and muscles. RBC’s have a short life span of about 120 days, however, as long as our myeloid tissue is working correctly, we will produce about 2-3 million RBC’s per second. That is about 200 billion a day! This allows us to have more to replace the ones we lose.
Main Component
The main component of the RBC is hemoglobin protein which is about 250 million per cell. The word hemoglobin comes from hemo meaning blood and globin meaning protein. This is the protein substance of four different proteins: polypeptide globin chains that contain anywhere from 141 to 146 amino acids. Hemoglobin also is responsible for the cell’s ability to transport oxygen and carbon dioxide. This hemoglobin + iron + oxygen interact with each other forming the RBC’s bright red color. You can call this interaction by product oxyhemoglobin. Carbon Monoxide forms with hemoglobin faster that oxygen, and stays formed for several hours making hemoglobin unavailable for oxygen transport right away. Also a red blood cell contains about 200 million hemoglobin molecules. If all this hemoglobin was in the plasma rather than inside the cells, your blood would be so “thick” that the heart would have a difficult time pumping it through. The thickness of blood is called viscosity. The greater the viscosity of blood, the more friction there is and more pressure is needed to force blood through.
Functions
The main function is the transportation of oxygen throughout the body and the ability of the blood to carry out carbon dioxide which is called carbamino – hemoglobin. Maintaining the balance of blood is important. The balance can be measured by the acid and base levels in the blood. This is called pH. Normal pH of blood ranges between 7.35-7.45; this normal blood is called Alkaline (less acidic then water). A drop in pH is called Acidic. This condition is also called Acidosis. A jump in pH higher then 7.45 is called “Alkalosis“. To maintain the homeostasis (or balance,) the blood has tiny molecules within the RBC that help prevent drops or increases from happening.
From left to right diagram of Erythrocyte, Thrombocyte, and Leukocyte
Destruction
Red blood cells are broken down and hemoglobin is released. The globin part of the hemoglobin is broken down into amino acid components, which in turn are recycled by the body. The iron is recovered and returned to the bone marrow to be reused. The heme portion of the molecule experiences a chemical change and then gets excreted as bile pigment (bilirubin) by the liver. Heme portion after being broken down contributes to the color of feces and your skin color changing after being bruised.
White Blood Cells
Shape
White blood cells are different from red cells in the fact that they are usually larger in size 10-14 micrometers in diameter. White blood cells do not contain hemoglobin which in turn makes them translucent. Many times in diagrams or pictures white blood cells are represented in a blue color, mainly because blue is the color of the stain used to see the cells. White blood cells also have nucleii, that are some what segmented and are surrounded by electrons inside the membrane.
Functions
White blood cells (leukocytes) are also known as “WBC’s”. White blood cells are made in the bone marrow but they also divide in the blood and lymphatic systems. They are commonly amoeboid (cells that move or feed by means of temporary projections, called pseudopods (false feet), and escape the circulatory system through the capillary beds. The different types of WBC’s are Basophils, Eosinophils, Neutrophils, Monocytes, B- and T-cell lymphocytes. Neutrophils, Eosinophils, and Basophils are all granular leukocytes. Lymphocytes and Monocytes are agranular leukocytes. Basophils store and synthesize histamine which is important in allergic reactions. They enter the tissues and become “mast cells” which help blood flow to injured tissues by the release of histamine. Eosinophils are chemotoxic and kill parasites. Neutrophils are the first to act when there is an infection and are also the most abundant white blood cells. Neutrophils fight bacteria and viruses by phagocytosis which mean they engulf pathogens that may cause infection. The life span of a of Neutrophil is only about 12-48 hours. Monocytes are the biggest of the white blood cells and are responsible for rallying the cells to defend the body. Monocytes carry out phagocytosis and are also called macrophages. Lymphocytes help with our immune response. There are two Lymphocytes: the B- and T- cell. B-Lymphocytes produce antibodies that find and mark pathogens for destruction. T-Lymphocytes kill anything that they deem abnormal to the body.
WBCs are classified by phenotype which can be identified by looking at the WBCs under a microscope. The Granular phenotype are able to stain blue. The Agranular phenotype are able to stain red. Neutrophils make up 50-70% of Granular cells Eosinophils make up 2-4%, and Basophils 0-1%. Monocytes make up 2-8% of Agranular cells. B and T Lymphocytes make up 20-30%. As you can see, there is a great deal of differentiation between WBCs. These special cells help our bodies defend themselves against pathogens. Not only do they help our immune system but they remove toxins, wastes, and abnormal or damaged cells. Thus, we can say that WBCs’ main function is being Phagocytic which means to engulf or swallow cells.
Platelets
A 250 ml bag of newly collected platelets.
Platelets, also called thrombocytes, are membrane-bound cell fragments. Platelets have no nucleus,they are between one to two micrometers in diameter, and are about 1/10th to 1/20th as abundant as white blood cells. Less than 1% of whole blood consists of platelets. They result from fragmentation of large cells called Megakaryocytes – which are cells derived from stem cells in the bone marrow. Platelets are produced at a rate of 200 billion per day. Their production is regulated by the hormone called Thrombopoietin. The circulating life of a platelet is 8–10 days. The sticky surface of the platelets allow them to accumulate at the site of broken blood vessels to form a clot. This aids in the process of hemostasis (“blood stopping”). Platelets secrete factors that increase local platelet aggregation (e.g., Thromboxane A), enhance vasoconstriction (e.g., Serotonin), and promote blood coagulation (e.g., Thromboplastin).
Hemostasis (Coagulation or Clotting)
Hemostasis is the natural process of stopping blood flow or loss of blood following an injury. (hemo = blood; stasis = standing). It has three stages: (1) vascular spasm, vasoconstriction, or intense contraction of blood vessels, (2) formation of a platelet plug and (3) blood clotting or coagulation. Once the flow of blood has been stopped, tissue repair can begin.
Vascular spasm or Vasoconsriction: In a normal individual, immediately after a blood vessel has been cut and endothelial cells are damaged, vasoconstriction occurs, thus slowing blood flow to the area. Smooth muscle in the vessel wall goes through spasms or intense contractions that constrict the vessel. If the vessels are small, spasms compress the inner walls together and may be able to stop the bleeding completely. If the vessels are medium to large-sized, the spasms slow down immediate outflow of blood, lessening the damage but still preparing the vessel for the later steps of hemostasis. These vascular spasms usually last for about 30 minutes, long enough for the next two stages of hemostasis to take place.
Formation of a Platelet Plug: Within 20 seconds of an injury, coagulation is initiated. Contrary to popular belief, clotting of a cut on the skin is not initiated by air or drying out, but by platelets adhering to and activated by collagen in the blood vessels endothelium. The activated platelets then release the contents of their granules, which contain a variety of substances that stimulate further platelet activation and enhance the hemostatic process.
When the lining of a blood vessel breaks and endothelial cells are damaged, revealing collagen proteins in the vessel wall, platelets swell, grow spiky extensions, and start clumping together. They start to stick to each other and the walls of the vessel. This continues as more platelets congregate and undergo these same transformations. This process results in a platelet plug that seals the injured area. If the injury is small, a platelet plug may be able to form and close it within several seconds. If the damage is more serious, the next step of blood clotting will take place. Platelets contain secretory granules. When they stick to the proteins in the vessel walls, they degranulate, thus releasing their products, which include ADP (adenosine diphosphate), serotonin, and thromboxane A2.
A Blood Clot Forms: If the platelet plug is not enough to stop the bleeding, the third stage of hemostasis begins: the formation of a blood clot. First, blood changes from a liquid to a gel. At least 12 substances called clotting factors take part in a series of chemical reactions that eventually create a mesh of protein fibers within the blood. Each of the clotting factors has a very specific function. We will discuss just three of the substances here: prothrombin, thrombin, and fibrinogen. Prothrombin and fibrinogen are proteins that are produced and deposited in the blood by the liver.
- Prothrombin: When blood vessels are damaged, vessels and nearby platelets are stimulated to release a substance called prothrombin activator, which in turn activates the conversion of prothrombin, a plasma protein, into an enzyme called thrombin. This reaction requires calcium ions.
- Thrombin: Thrombin facilitates the conversion of a soluble plasma protein called fibrinogen into long insoluble fibers or threads of the protein fibrin.
- Fibrin: Fibrin threads wind around the platelet plug at the damaged area of the blood vessel, forming an interlocking network of fibers and a framework for the clot. This net of fibers traps and helps hold platelets, blood cells and other molecules tight to the site of injury, functioning as the initial clot. This temporary fibrin clot can form in less than a minute, and usually does a good job of reducing the blood flow. Next, platelets in the clot begin to shrink, tightening the clot and drawing together the vessel walls. Usually, this whole process of clot formation and tightening takes less than a half hour.
The use of adsorbent chemicals, such as zeolites, and other hemostatic agents, are also being explored for use in sealing severe injuries quickly.
ABO Group System
The ABO blood group is represented by substances on the surface of red blood cells (RBCs). These substances are important because they contain specific sequences of amino acid and carbohydrates which are antigenic. As well as being on the surface of RBCs, some of these antigens are also present on the cells of other tissues. A complete blood type describes the set of 29 substances on the surface of RBCs, and an individual’s blood type is one of the many possible combinations of blood group antigens. Usually only the ABO blood group system and the presence or absence of the Rhesus D antigen (also known as the Rhesus factor or RH factor) are determined and used to describe the blood type. Over 400 different blood group antigens have been found, many of these being very rare. If an individual is exposed to a blood group antigen that is not recognized as self, the individual can become sensitized to that antigen; the immune system makes specific antibodies which binds specifically to a particular blood group antigen and an immunological memory against that particular antigen is formed. These antibodies can bind to antigens on the surface of transfused red blood cells (or other tissue cells) often leading to destruction of the cells by recruitment of other components of the immune system. Knowledge of a individual’s blood type is important to identify appropriate blood for transfusion or tissue for organ transplantation.
Surface Antigens
Several different RBC surface antigens stemming from one allele (or very closely linked genes) are collectively labeled as a blood group system (or blood group). The two most important blood group systems were discovered during early experiments with blood transfusion, the ABO group in 1901 and the Rhesus group in 1937 . These two blood groups are reflected in the commoomenclature A positive, O negative, etc. with letters referring to the ABO group and positive/negative to the presence/absence of the RhD antigen of the Rhesus group. Development of the Coombs test in 1945 and the advent of transfusion medicine led to discovery of more blood groups.
Compatibility of blood types.
Blood Group A individuals have the A antigen on the surface of their RBCs, and blood serum containing IgM antibodies against the B antigen. Therefore, a group A individual can only receive blood from individuals of groups A or O (with A being preferable), and can donate blood to individuals of groups A or AB.
Blood Group B individuals have the B antigen on their surface of their RBCs, and blood serum containing IgM antibodies against the A antigen. Therefore, a group B individual can only receive blood from individuals of groups B or O (with B being preferabe), and can donate blood to individuals of groups B or AB.
Blood group O individuals do not have either A or B antigens on the surface of their RBCs, but their blood serum contains IgM antibodies against both A and B antigens. Therefore, a group O individual can only receive blood from a group O individual, but they can donate blood to individuals of any ABO blood group (ie A, B, O or AB). O blood is also know as “Universal donor.”
Inheritance
Blood types are inherited and represent contributions from both parents. The ABO blood type is controlled by a single gene with three alleles: i, IA, and IB. The gene encodes an enzyme that modifies the carbohydrate content of the red blood cell antigens.
IA gives type A, IB gives type B, i give types O
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Blood group inheritance |
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Mother/Father |
O |
A |
B |
AB |
|
O |
O |
O, A |
O, B |
A, B |
|
A |
O, A |
O, A |
O, A, B, AB |
A, B, AB |
|
B |
O, B |
O, A, B, AB |
O, B |
A, B, AB |
|
AB |
A, B |
A, B, AB |
A, B, AB |
A, B, AB |
IA and IB are dominant over i, so ii people have type O, IAIA or IAi have A, and IBIB or IBi have type B. IAIB people have both phenotypes because A and B are codominant, which means that type A and B parents can have an AB child. Thus, it is extremely unlikely for a type AB parent to have a type O child (it is not, however, direct proof of illegitimacy): the cis-AB phenotype has a single enzyme that creates both A and B antigens. The resulting red blood cells do not usually express A or B antigen at the same level that would be expected on common group A or B red blood cells, which can help solve the problem of an apparently genetically impossible blood group.
Rh Factor
Many people have the Rh Factor on the red blood cell. Rh carriers do not have the antibodies for the Rh Factor, but can make them if exposed to Rh. Most commonly Rh is seen when anti-Rh antibodies cross from the mothers placenta into the child before birth. The Rh Factor enters the child destroying the child’s red blood cells. This is called Hemolytic Disease.
Compatibility in Blood/Plasma Transfusions
Blood transfusions between donor and recipient of incompatible blood types can cause severe acute immunological reactions, hemolysis (RBCT destruction), renal failure, shock, and sometimes death. Antibodies can be highly active and can attack RBCs and bind components of the complement system to cause massive hemolysis of the transfused blood.
A patient should ideally receive their own blood or type-specific blood products to minimize the chance of a transfusion reaction. If time allows, the risk will further be reduced by cross-matching blood, in addition to blood typing both recipient and donor. Cross-matching involves mixing a sample of the recipient’s blood with a sample of the donor’s blood and checking to see if the mixture agglutinates, or forms clumps. Blood bank technicians usually check for agglutination with a microscope, and if it occurs, that particular donor’s blood cannot be transfused to that particular recipient. Blood transfusion is a potentially risky medical procedure and it is vital that all blood specimens are correctly identified, so in cross-matching labeling is standardized using a barcode system known as ISBT 128.
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Plasma compatibility table |
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Donor |
Recipient |
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|
O |
A |
B |
AB |
|
O |
OK |
OK |
OK |
OK |
|
A |
|
OK |
|
OK |
|
B |
|
|
OK |
OK |
|
AB |
|
|
|
OK |
When considering a plasma transfusion, keep in mind that plasma carries antibodies and no antigens. For example you can’t give type O plasma to a type A, B or AB, because a person with type O blood has A and B antibodies and the recipient would have an immune response. On the other hand an AB donor could give plasma to anyone, since they have no antibodies.
The table to the right is for plasma transfusions, and it’s just the opposite for RBC transfusions. It doesn’t take the Rh factor into effect, though, because most people don’t have antibodies for the Rhesus factor (it only happens upon exposure).
Age peculiarities of blood system:
Erythrocite lewel 6-7-10
Anisocytosis
Short life of erythrocytes (12-40days
Hemoglobin lewel 180-240 gr L
Color index (CI)-1,1-1,3 (degree of saturation of Hb in one erythrocyte
Lewelof HbF-70%
Erythrocyte sedimentation vale-0-2 mm hour
Leucocytosis 11-33#10 9 Liter
Peculiarities of blood from 1 month till 1 year
Precense of extramedullary sources of hemopoesis
High lewel of Hb (90% and more)
Increased lewel of yong cells
Developing of the early anemia of premature newborns at the age 1.5-2.0 month
Developing of the late anemia of prematures at the age 4-5 month
Leucocytosis is not very high
Absence of first cross in white blood
Peculiarities of blood from 1 month till 1 year
Decreasing Hb lewel to 120-110 gr l
Erythrocyte level decreases as well 4-3.5 10 12 L
Colour index is less than 1:0.8-0.7
Leucocytosis 10-12 10 9 L appears after adding new food in menu <during crying<emotions
Trombocytes have gygant forms
Monocytosis 9-11%
Peculiarities of bllod –children elder 1 year
Increasing Hb lewel to 130-140 dr l till 15 years
Erythrocyte lewel 4,5-5,0-10 12 L
Riticulocytes about 0,5-5%
Leucocyte lewel
Second cross in 5 years age
Hemorragic syndrome
Hemorrhagic spots in surface of the skin petechiae, urpura teleangiectasis, emorragies are present in the skin,in subcutaneous fat,in muscles,in brain.for example
Inherited thrombocytopenic purpureas, neonatal thrombocytopenic purpuras,other sings of bleeding;include hematuria,upper and lower gastrointestinal tract hemorrage prolonged bleeding from the umbilical stump or from venipunctures,intracranial hemorrage.
Laboratory evaluation;
Initial investigation should include a platelet count,blood smear,routine blood count,detection of antibodies of platelets
Anemic syndrome
Decreasing Hb level (lower 100gr per liter
Decreasing erythrocite level (lower 4 10 12 L
Painless of the skin and muscles membranes
Headache
In the area of the heart-systolic murmur
Children first 3 years of life have iron deficiency anemias
Hemolytic anemias
Joundance,fever enlargement of liver and spleen,
One can see different form of erythrocytosis: microspherocytes, anisocytosis.
Syndrome of leycocytosis
Increasing leucocyte lewel more than 10 10 9 per liter
Neutrophils leucocytosis develops during inflammation processes (sepsis meningitis,pyelonephritis).Very high level of leucocytes we have in children with leucosis.
Type and Crossmatch
Blood typing determines the ABO and Rh blood groups of a blood sample. A crossmatch tests for agglutination reactions between donor and recipient blood.
Complete Blood Count
The complete blood count consists of the following: red blood cell count, hemoglobin measurement (grams of hemoglobin per 100 ml of blood), hematocrit measurement (percent volume of erythrocytes), and white blood cell count.
White Blood Cell Differential Count
The white blood cell differential count determines of. percentage of each type of leukocyte.
Erythrocytes and hemoglobin
Neonatal period
-5.4×10 12/l-7.2×10 12/l (at the beginning of the period)
-4.7×10 12 (by the end of the period)
Breast feeding period-14 years 4.2×1012/l
Older than 14 years -in boys-5.2×10 12/l
-in girls-4.8×1012/l
Critical number of erythrocytes is 1.0×1012/l
Hemoglobin
Newborn period- 220-180 g/l -150g/l(till the end of the period)
1 month-5 months -120-150 g/l
1 months-5 years -on average 120-140g/l (but not less than 110 g/l)
Older than 5 years -on average 130-150 g/l (but not less than 120 g/l)
Critical number-20 g/l
Pathological changes
Eythropenia (=erythrocytopenia)-reduction in quantity of erythrocytes in children of 1 month of age below 3.5×10 12/l
Reduction in the quantity of hemoglobin (below the special level)
-Anemia of different genesis
-Malignant diseases of blood (leucosis)
-Hyperhydratation, when pseudo-anemia is observed
Osmotic fragility of erythrocytes
MIN.OFE-0.48-0.44%
Max.OFE-0.36-0.28%
Exponents of newborn are
Min.OFE-0.52-0.48%
Max.OFE-0.30-0.24%
Pathological changes
The decrease in OFE is a sign of congenital and acquired genesis
Erythrocyte sedimentation rate (ESR) iorm is equal to
Newborn period- 0-2 mm/hour
Breast-feeding age-2-4 mm/hour
Further on -4-10 mm/hour
The increase in ESR
-inflammatory process of any system
-Allergic reaction
-malignancy
The reduction in ESR is observed rather seldom
-exsiccosis
-Anaphylactic shock
-hypotrophy,exhaustion
-peptic ulcer
-decompensated heart diseases
-can be in acute viral hepatitis
Thrombocytes 150-300×109/l
Critical number is 30 G/l
Thrombocytosis higher than 400G/l
It is observed that thrombocytosis occurs in the postoperative period of splenectomy,
Bad prognosis of chronic myeloid leucosis
Thrombocytopenia lower than 100×109/l
3xHbg/l
Color index of blood ——————————————————————
First three digits in the number of erythrocytes per one million
(without the point)
Normochromia– the figure is within the limits of the specified norm that indicates normal satiation of erythrocytes with hemoglobin
Hypochromia-the figure is below normal which indicates incomplete satiation of erythrocytes with hemoglobin or microcytosis,or both impairments together
Hyperchromia- the figure is higher than normal-it is only a sign of increased volume of erythrocytes, macrocytic hyperchromia
Reticulocytes absolutely non mature forms of erythrocytes with the substance,their predecessors
Newborn period- 10-30%
Breast-feeding age- 5-10%
After 1 year – 2.5-5%
Reticulocytes-
It is a positive index of the efficiency of treatment in bleeding and anemia
Indicates the hemolytic character of disease
Sometimes is a diagnostic criterion of latent bleeding
1– Leuko-erythroblastic index (L\E) – percentage ratio of cellular elements of leuko- and erythroblastic stem cells.iorm L\E=3-4:1;deviations are possible
.increase in cells to the side of leukoblastic stem cells is a sympotom of leucosis, ha
Eavy intoxication.
.significant shift of erythroblastic stem cells, which specifies its hyperplasia , arises during loss
Of blood ,hemolytic syndrome. Erythremia (see below).
.simultaneous decrease iumber of leucopoiesis and aplasia of hemopoiesis condition in the whole.
2- partial myelogram is a ratio between young and more mature cellar elements in all three columns of hemopoiesis .(erythroblastic, leukoblastic and megakaryocytic);on the average their
Normative amount aquals to.
IMMATURE CELLS – 20%
Mature cells – 80%
The increase in the number of immature cells is a main a symptom of malignant pathology
( leukosis=leukemia)
DISEASES OF BLOOD AND HEMOPOESIS SYSTEM
Anemia
Anemia (anaemia. From the Greek negative prefix an and haima-blood) is a condition for which the reduction of erythrocytes quantity and hemoglobin content (separately or bothbsigns )
In the unit of blood volume ischaracteristic.
There are 3 main groups of anemia according to the etiologic factor.
1- Anemia caused by bleeding (posthemorrhagic). The reduction of erythrocytes and hemoglobin quantity ,normochromia , reticulocytosis after a while is detected in general blood count.
2- Anemia as a result of hemopoietic disorder:
(a) Asiderotic \ iron-deficiency\anemia ( the pathogenetic cause is in the name itself-this is the anemia which is caused by the deficiency of iron in the body connected with disorders of its intake , absorption or the increased losses). The reasone are:
. Exogenous deficiency of iron with the child does not receive the necessary amount of iron
With food- nutritive (=alimentary) anemia.
. Exogenous deficiency of iron during the increased requirement of it by the body (at infectious diseases).
. Endogenous deficiency of iron because of its malassimilation (disease of the gastrointestinal tract).
The degree of anemia is usually specified depending on the amount of hemoglobin:
I= m ld – 110-90 g\l
II= moderate- -90-70 g\l
III= severe -lass than 70 g\l
The following changes take place simultaneously in blood at different degrees of anemia with
Shortage in supply of iron:
Degree Erythrocytes Erythrocetes MCHC Reticulocytes
Anemia count (T\l) diameter(Um) (%)
I 3.5-3.0 6.8 0.8-0.7 10
II 3.0-2.5 6.7 0.7-0.6 18
III <2.5 6.1 <0.6 25
Laboratory criteria of an anemia ieonatal period are the following :
0-14 days -< 145 g\l
15_28 days -<120 g\l
The basic complaints and clinical attributes of iron deflciency anemia ;
. Weakness , fast fatigue or irritability.
. Headache , dizziness, tinnitus (=ear noise)- are characteristic for significant anemia.
. The decrease of visual acuity and disorders in the form of myiodesopsia.
. The decreas of appetite (sometimes to anorexia );the pervertion of taste (pica)- the
Child eats chalk,sand,clay,the ground,raw meat.
. A short breath and the increase of heart rate during physical over load.
. Pallor ,the dryness of skin and mucous membranes.
. The fragility of hair .
. Quite often: involuntary incontinence of urine during laughter,sneezing; the night enuresis ;dyspepsia.
. The delay of physical and psychological development (about 40%).
. Heart auscultation-systolic murmur,tachycardia,the weakening of heart tones.just remember
The murmur is of function character.
. The decrease of blood pressure.
. Hepatolienal syndrome in severe cases.
. Subfebrile condition can be observed.
. The decrease in immunity –often inflammatory processes, ie, anemia is an attribute of the aggravation of pre-morbid conditions.
The laboratory data-see :
.Reduction of erythrocytes quantity and hemoglobin contents.
. Poikilocytosis.
. Anisocytosis ,microcytosis.
. Immature erythrocytes (erythroblasts,normoblasts,megaloblasts)can be found.
. After some time reticulocytosis (I)can be observed – a positive sign that points out to good
Regenerative ability of the bone marrow in reply to anemia .
B 12(folic) deficiency(=pemicious)anemia:
. Exogenous deficiency of vitamin B12 \folic acid ;in pediatrics the often reason is the feeding of the child with goat s milk or dry milk-nutritive(alimentary)B12-folate deficient anemia.
. Quite often occurs at long reception of Phenobarbital , prescribed for treating convulsive syndrome-durg (-induced) (phenobarbltal) B 12-folate deficient anemia.
. Endogenous deficiency of vitamin B12\folic acid as a result of disorders of digestion and absoption of vitamin B12 in the gastrointestinal tract (in prematurely born child,at celiac disease, helminthiasis, gastritis), etc…
HEMOLYTIC SYNDROME
Hemolysis (Greek lysis_destruction) (=erythrocysis)in the process of destruction of erythrocytes after which hemoglobin releases from them into plasma.
To the future researchers: there are scientific data according to which the violation of the integrity of erythrocytes are not necessary ,and there can be only their functional change in the form of as a stretching of the cell-membrane also and increasing of its permeability.
Hemolysis also occurs in blood as a normal phenomenon,which is known as physiological hemolysis,arising at natural ageing of erythrocytes.
Hemolysis of pathological genesis can arise under influence of different factors.
Exoerythrocytal hemolytic factors are:
(a) Hemolytic poisons and toxins:
. snakes .
.worms.
.Insects-bese, scorpions.
. Salts of arsenic ,derivatives of benzene.
. Many bacterial forms can produce hemotoxin.
. Recently it is established that in ecologically adverse territories.
Anemias
Anemia is defined as reduction of red cell volume or hemoglobin concentration to levels below normal. It is an indication or manifestation of an underlying pathologic process or disease. The anemias are the most common hema-tologic disorders of infancy and childhood. This discussion is primarily concerned with an overview of the classification of anemia. Specific anemic conditions such as iron-deficiency anemia and aplastic anemia are discussed elsewhere. Later in this chapter the hemoglobinopathies sickle cell anemia and thalassemia are discussed.
Classification
The basic cause of anemia is either
(1) an increased loss or destruction of red blood cells
(2) an impaired or decreased rate of production. An etiologic classification is based on the various conditions that can lead to either of these results.
Blood loss. Acute or chronic hemorrhage results in loss of plasma and all formed elements of the blood. After acute hemorrhage the body replaces plasma within 1 to 3 days, maintaining blood volume. However, this results in a low concentration of red blood cells, which are gradually replaced within 3 to 4 weeks. During this period there is usually a normocytic (normal size), normochromic (normal color) anemia, provided there are sufficient iron stores for hemoglobin synthesis.
In chronic blood loss the actual number of red blood cells may be normal because of continual replacement. However, insufficient iron is available to form hemoglobin as quickly as it is lost. As a result, erythrocytes are usually small in size (microcytic) and pale in color (hypochromic).
Excessive destruction. Excessive destruction or hemo-lysis of erythrocytes can occur from a variety of causes. One of the most common is a result of a defect within the red blood cell (intracorpuscular) that shortens the life span of the cell so that production cannot keep pace with destruction. The two examples discussed in this chapter, sickle cell anemia and thalassemia, have decreased erythrocyte life spans because of a defect in hemoglobin synthesis.
Extracorpuscular factors are those conditions that cause hemolysis in otherwise normal red blood cells. A classic example is erythroblastosis fetalis.Other causes can be toxic drugs, transfusion reactions, burns, poisonings (such as from lead), infections such as malaria, and splenic sequestration (hypersplenism).Impaired or decreased production.
Production of red
blood cells can occur as a result of either bone marrow failure or deficiency of essential nutrients. Bone marrow failure may be caused by (1) replacement of bone marrow by fibro-sis or by neoplastic cells, such as in leukemia, (2) depression of marrow activity from irradiation, chemicals, or drugs, or (3) interference with bone marrow activity from other systemic diseases, such as severe infection, chronic renal disease, widespread malignancy (without marrow infiltration), collagen diseases, or hypothyroidism.
The reason for various systemic disorders affecting eryth-rocyte production varies according to the condition. For example, in severe chronic infection there is evidence that depression of erythropoiesis is caused by a defect in the conversion of protoporphyrin into hemoglobin. In addition, there is some degree ofhemolysis, although the exact mechanism is not known.
The most common childhood anemia is a result of deficient iron supply .Besides iron as an essential component of hemoglobin synthesis, red blood cell production is dependent on amino acids, vitamins B6, Bu, and C, folic acid, copper, and possibly cobalt. Chronic malnutrition results in anemia as a result of generalized protein, mineral, and vitamin deficiencies.
Pernicious anemia develops when the gastric mucosa fails to secrete sufficient amounts of intrinsic factor, which is essential for absorption of vitamin Biz. This type of anemia is common in the elderly as a result of physiologically decreased gastric secretions. Deprived of vitamin Biz, the bone marrow produces fewer but larger (macrocytic) red blood cells. The erythrocytes are usually immature and because of their extremely fragile cell membranes, are more rapidly destroyed during circulation.
Classification based on morphology.
A second classification has been made that is based on the morphologic changes within the red blood cell. The major categories are
(1) normocytic,
(2) microcytic,
(3) macrocytic.
In addition, each category may be subdivided according to the amount of hemoglobin in the cell. Since hemoglobin gives the cell its characteristic red color, the usual classifications are
(1) normochromic
(2) microchromic.
Pathophysiology and clinical manifestations
The basic physiologic defect caused by anemia is a decrease in the oxygen-carrying capacity of blood and consequently a reduction in the amount of oxygen available to the tissues. Most of the clinical manifestations are directly attributable to tissue hypoxia. Muscle weakness and easy fati-gability are common, although children seem to have a remarkable ability to function quite well despite low levels of hemoglobin.
The skin is usually pale to a waxy pallor in severe anemia. Cyanosis is typically not evident, because it is the result of the quantity of deoxygenated hemoglobin in arterial blood. Hemoglobin levels generally must exceed 5 g/dl before cyanosis is evident. Anemia is caused by decreased hemoglobin and/or red blood cells, not inadequate oxygen saturation of existing hemoglobin. The nurse should also keep in mind that skin pigmentation can alter one’s assessment of skin pallor.
Central nervous system manifestations include headache, dizziness, light-headedness, irritability, slowed thought processes, decreased attention span, apathy, and depression. Growth retardation resulting from decreased cellular metabolism and coexisting anorexia is a common finding in chronic severe anemia. It is frequently accompanied by delayed sexual maturation in the older child.
The effects of anemia on the circulatory system can be profound. A reduction in hemoglobin concentration that results in decreased oxygen-carrying capacity of the blood is associated with a compensatory increase in heart rate and cardiac output. Initially this greater cardiac output compensates for the lower oxygen-carrying capacity of the blood, since blood replenished with oxygen returns to the tissues at a faster thaormal rate. However, if the body’s demand on the pumping action of the heart increases, such as during exercise, infection, or emotional stress, cardiac failure may ensue. valuate the morphologic and quantitative changes resulting from anemia
Diagnostic evaluation
Several tests can be used to e arizes these routine hematologic laboratory procedures. Other tests used to diagnose the underlying cause of anemia are included elsewhere in the discussion of the particular disorder.
Therapeutic management
The objective of medical management is to reverse the anemia by treating the underlying cause. For example, iutritional anemias the specific deficiency is replaced. In blood loss caused by hemorrhage, packed red blood cells or whole blood is given. In cases of severe anemia supportive medical care may include oxygen therapy, restoration of adequate blood volume, intravenous fluids, and bed rest.
Nursing considerations
Since anemia is not a disorder but a symptom of some underlying problem, nursing care is related to determining the cause, fostering appropriate supportive and therapeutic treatments, and decreasing tissue oxygen requirements.
Assist in establishing a diagnosis. Although the physical examination yields valuable evidence regarding the severity of the anemia and some indication of its possible etiology, diagnosis primarily rests on hematologic blood studies and a careful history. In interviewing parents the nurse stresses the following areas that include tentative information regarding common causes of childhood anemia:
Prepare child for laboratory tests .Explain to older childreeed forrepeated venipunctures or fingersticks for blood analysis,particularly why a sequence of tests is required Allow children to play with laboratory equipment and/or participate with test Older children may enjoy looking at blood smears under a microscope or at pictures of blood cells
Observe for signs of shock and hypoxia from repeated blood samples Explain to parents reason for replacing withdrawn blood and necessity of performing tests.
Decrease tissue oxygeeeds
Minimize physical exertion. Assess child’s level of hysical tolerance
Anticipate and assist child in those activities of daily living that may be beyond his tolerance Provide diversional play activities that promote rest and quiet but prevent boredom and withdrawal Choose an appropriate roommate of similar age and interests and one who requires restricted activity
Minimize emotional stress Anticipate child’s irritability, short attention span, and fretfulness by offering to assist him in activities rather than waiting for him to ask. Assess parents’ awareness of child’s need for dependency to conserve strength Explain to older children and parents reason for behavioral changes caused by anemia. Encourage parents to remain with child
Prevent and observe for infec tion Place child in room with noninfectious children; restrict visitors with active illnesses Advise visitors (and hospital personnel) to practice good hand washing Report any temperature elevation to physician . Observe for leukocytosis Maintain dequate nutrition.
Implement safety precautions Alert ancillary hospital personnel regarding hild’s physical tolerance and need for assistance during activity. Keep side rails raised and use safety restraints when applicable
Observe for complications
Cardiac decompensation Be alert to signs of heart failure from excessive cardiac demands or from cardiac overload during blood transfusion
Transfusion reaction Practice all precautions
Check blood with another nurse and physician to ensure correct blood group/type with that of child. Run blood slowly and remain with child for infusion of initial 50 ml Stop blood immediately if any untoward reaction occurs Attach blood to piggyback setup with normal saline or other intravenous solution to maintain open venous line. Observe for signs and symptoms of reaction.
Oxygen therapy. Monitor for benefit of oxygen but avoid prolonged use. Therefore, the child is monitored closely for evidence of kle cell disease includes all those hereditary disorders, the decreasing benefit from oxygen. One of the first signs of clinical, hematologic, and pathologic features of which are hypoxia is restlessness.
1. Idiopathic thrombocytopenic purpura.
2. Hemorrhagic vasculitis (Schönlein-Henoch disease).
3. Hemophilia.
Introduction: All hemorrhagic diatheses are divided into 3 groups, depending on the type and cause of hemorrhagic syndrome: vasopathies, thrombopathias, coagulopathies.
Idiopathic thrombocytopenic purpura.
Immune Thrombocytopenic Purpura (idiopathic thrombocytopenic purpura, autoimmune thrombocytopenic purpura, primary thrombocytopenic purpura)
Background: Immune thrombocytopenic purpura (ITP) is a clinical syndrome in which a decreased number of circulating platelets (thrombocytopenia) present as a bleeding tendency, easy bruising (purpura), or extravasation of blood from capillaries into skin and mucous membranes (petechiae).
Pathophysiology: An abnormal autoantibody, usually immunoglobulin G (IgG) with specificity for one or more platelet membrane glycoproteins, binds to circulating platelet membranes.
Immunoglobulin-coated platelets induce receptor–mediated phagocytosis by mononuclear macrophages, primarily but not exclusively in the spleen. The spleen is the key organ in the pathophysiology of ITP, not only because platelet autoantibodies are formed in the white pulp, but also because the immunoglobulin-coated platelets are destroyed by mononuclear macrophages in the red pulp.
If bone marrow megakaryocytes are not able to increase production and maintain a normal number of circulating platelets, thrombocytopenia and purpura develop.
Frequency: The annual incidence of chronic ITP has been estimated to be
Mortality/Morbidity: The most frequent cause of death in ITP is spontaneous or accidental, trauma-induced intracranial bleeding in patients whose platelet counts are less than 10,000 per µL. This situation occurs in 1-2% of cases.
Sex: In children, the incidence is the same among males and females.
Age: Children may be affected at any age, but the peak incidence occurs in children aged 3-5 years.
Causes:
1. Postviral illness. In children, most cases of ITP are acute, and onset seems to occur within a few weeks of recovery from a viral illness. Thrombocytopenia is a recognized complication following Ebstein-Barr virus infection; varicella virus; cytomegalovirus; rubella virus; hepatitis A, B or C; or more typically, a vaguely defined, viral, upper respiratory infection or gastroenteritis. Transient thrombocytopenia often follows recent immunization with attenuated live-virus vaccines.
2. Human immunodeficiency virus (HIV). Thrombocytopenia may occur during the acute retroviral syndrome coincident with fever, rash, and sore throat.
3. Drug-induced thrombocytopenia. Persons who have been sensitized (by prior exposure) to quinidine or quinine may develop immune-mediated drug purpura within hours to days of subsequent exposure. ther drugs that have been associated with drug purpura include antibiotics (eg, cephalothins, rifampicin), gold salts, analgesics, neuroleptics, diuretics, antihypertensives, eptifibatide (Integrilin), and, more recently, abciximab (ReoPro), a chimeric monoclonal fragment antigen binding (Fab) antibody fragment directed against the platelet GPIIb/IIIa receptor.
CLINICAL Physical:
1. Skin and mucous membranes. The presence of widespread petechiae and ecchymoses, oozing from a venepuncture site, gingival bleeding, or hemorrhagic bullae indicates that the patient is at risk for a serious bleeding complication (Fig. 1). If the patient’s blood pressure was taken recently, petechiae may be observed under and distal to the area where the cuff was placed and inflated (Fig. 2). Similarly, suction-type ECG leads may induce petechiae.
2. Abdomen. The spleen is palpable in less than 10% of children with ITP. In children with acute ITP, the presence of a readily palpable spleen is not typical.
Fig. 1. Haemorrhagic rush in idiopathic thrombocytopenic purpura.
Fig. 2. “Cuff” symptom in thrombocytopenic purpura.
Lab Studies:
Complete blood count. The hallmark of ITP is isolated thrombocytopenia.
Peripheral blood smear
1. The morphology of red cells and leukocytes is normal.
2. The morphology of platelets is typically normal, with varying numbers of large platelets.
3. Clumps of platelets on a peripheral smear prepared from ethylenediaminetetraacetic acid (EDTA)-anticoagulated blood are evidence of pseudothrombocytopenia.
Antiplatelet antibody. Assays for platelet antigen-specific antibodies, platelet-associated immunoglobulin, or other antiplatelet antibodies are available in some medical centers and certain mail-in reference laboratories.
Imaging Studies:
Computer-assisted tomographic (CT) scanning or magnetic resonance imaging (MRI) Use them promptly when the medical history or physical examination suggests serious internal bleeding.
Procedures: The primary diagnostic evaluation is the bone marrow aspirate and biopsy. In ITP, a normal-to-increased number of megakaryocytes exist in the absence of other significant abnormalities.
Spleen. No specific findings exist in the spleen.
Medical Care:
1. The goal of medical care is to increase the platelet count to a safe level, permitting patients with ITP to live normal lives while awaiting spontaneous or treatment-induced remission. After 6 months, if the platelet count cannot be maintained at a safe level or it cannot be maintained at a safe level with medication without serious treatment-related toxicity, consider splenectomy.
2. Corticosteroids (oral prednisone, IV methylprednisolone) are the drugs of choice for initial management of ITP.
3. Intravenous immune globulin (IVIG) has been the drug of second choice for many years. However, recent studies indicate that for patients who are Rh(D) positive with ITP, intravenous
4. The limitation of using IV RhIG is the lack of efficacy in patients who are Rh(D) negative or splenectomized. Also, IV RhIG induces immune hemolysis in persons who are Rh(D) positive and should not be used when the hemoglobin concentration is less than 8.0 g/dL.
Medical care in children
1. The initial treatment of ITP depends on whether the risk of severe hemorrhage, such as intracranial bleeding, is estimated to be low, moderate, or high.
2. Children whose platelet count is greater than 30,000/L typically only have mild purpura, and the risk of a severe hemorrhage is low. They may be managed as outpatients without specific treatment.
3. Children whose platelet count is less than 20,000/L may have more significant purpura and mucosal bleeding. Oral prednisone is conservative treatment, and the addition of IV RhIG for patients who are Rh(D) positive or IVIG for patients who are Rh(D) negative is a more aggressive treatment.
4. Children whose platelet count is less than 10,000/L are likely to have a significant bleeding tendency and a high risk of serious hemorrhage. Initial treatment with IV methylprednisolone and either IV RhIG or IVIG is appropriate.
5. Platelet transfusions may be required for overt bleeding but are not recommended for prophylaxis.
Chronic or treatment-resistant ITP
1. For those patients whose platelet counts do not or no longer respond to treatment with tolerable doses of corticosteroids, IV RhIG, IVIG, or splenectomy, other treatments are available.
2. Data supporting these options are based on relatively few case studies and response rates are comparatively lower.
3. Before concluding that a patient has failed both medical management and splenectomy, necessitating treatment with alternative options, perform an imaging study to ensure that the problem is not associated with the presence of an accessory spleen.
4. Among the medical treatment options in these circumstances are cyclophosphamide, azathioprine, and danazol.
5. Interventions of uncertain efficacy include vinblastine, vincristine, ascorbic acid, colchicine, or interferon-alpha, for which conflicting reports of efficacy in the medical literature exist.
Surgical Care: In acute ITP, splenectomy usually results in a rapid, complete, and lifelong clinical remission. In chronic ITP, the results of splenectomy typically are less predictable. Platelet counts may not revert to fully normal values, and relapses are not uncommon. Splenectomy results in a lifelong increased risk of sepsis from infection by encapsulated bacteria. In children, the risk of bacterial sepsis after splenectomy is estimated to be 1-2%. Many pediatricians recommend delaying splenectomy until children are aged 5 years.
MEDICATION
Prednisone 4-8 mg/kg/d PO; however, a reduced dose of 1.5-2.0 mg/kg/d may be adequate for management of nonurgent situations or when risk of adverse effects is high because of predisposing factor, such as diabetes or psychiatric illness
Methylprednisolone (Solu-Medrol) 30 mg/kg/d IV for initial management of a severe bleeding tendency in ITP. IV methylprednisolone recommended when most rapid and reliable treatment of ITP is required. In this situation, combine methylprednisolone with IV RhIG in qualified patients who are Rh(D) positive or IVIG in patients who are Rh(D) negative or unqualified patients who are Rh(D) positive.
Intravenous Rho immune globulin (WinRho SDF) — Specialized immunoglobulin product manufactured from pools of plasma from persons who are Rh(D) negative and have been alloimmunized to the D blood group antigen. A single infusion of 50 µg/kg, followed by a second dose, if required, of 20-40 µg/kg, is recommended; an off-label dose of 75 µg/kg in patients whose hemoglobin concentration is at least 8.0 g/dL may increase efficacy without adverse effect Not recommended for persons whose Rh blood type is Rh(D)-negative or who have had a splenectomy; IV RhIG should not be used for persons whose hemoglobin concentration is <8.0g/dL; persons with known IgA deficiency and anti-IgA are at risk of an anaphylactic/anaphylactoid reaction to all plasma-containing biologicals, including IV RhIG
Immune globulin intravenous (IVIG, Gamimune, Gammagard, Sandoglobulin) Begin with 1.0 g/kg infused IV at starting rate of 0.5 mL/kg/h (5% solution) to a maximum rate of 4.0 mL/kg/h; repeat dose at 3-4 wk intervals when indicated by decreasing platelet count
Immunosuppressive antimetabolite — Used in patients with ITP to reduce production of abnormal autoantibody. Azathioprine (Imuran) — May be effective in some patients with ITP who do not or no longer respond to corticosteroids, IV RhIG, or IVIG. May be used in conjunction with prednisone to reduce dose of prednisone, or it may be used as another oral medication to delay splenectomy. Adult Dose 2 mg/kg/d PO/IV Pediatric Dose 50mg/daily
Synthetic antineoplastic drugs (chemically related to nitrogen mustards) — Inhibit cell growth and proliferation. Cyclophosphamide (Cytoxan) — May be useful in some patients who do not or no longer respond to corticosteroids, IV RhIG, IVIG, or splenectomy. Induces less of a decrease in platelet count compared to other immunosuppressive alkylating agents. 2 mg/kg/d
Prognosis: More than 80% of children with untreated ITP had a spontaneous recovery with completely normal platelet counts in 2-8 weeks. Fatal bleeding occurred in 0.9% on initial presentation. Fatal intracerebral hemorrhage occurs rarely in children who have been treated with prednisone and IV RhIG or IVIG for at least 2 days.
Thrombocytopenia-Absent Radius Syndrome
Thrombocytopenia-absent radius (TAR) syndrome is a rare association of thrombocytopenia and bilateral radial aplasia first described in 1951. With some families having more than one member affected, an autosomal recessive inheritance pattern was proposed. TAR was defined as a syndrome in 1969 and further classified as the association of hypomegakaryocytic thrombocytopenia and absent of radii (forearms). The expression varies and includes abnormalities in skeletal, gastrointestinal, hematologic, and cardiac systems.
Frequency: Frequency is 0.42 cases per 100,000 live births in
Mortality/Morbidity: The major cause of mortality in TAR is hemorrhage.
History:
1. Thrombocytopenic episodes begin in the neonatal period.
2. Fifty percent of affected infants are symptomatic in the first week of life, and 90% are symptomatic by age 4 months.
3. Episodes may be precipitated by nonspecific stress, infection, and diet (eg, cow’s milk allergy).
4. Symptoms include purpura, petechiae, epistaxis, melena, hemoptysis, hematuria, and hematemesis.
5. Mental retardation has been associated with intracranial hemorrhage in patients with TAR. Symptoms of acute intracranial hemorrhage in an infant would be associated with poor feeding, lethargy, irritability, and fluctuating level of consciousness.
Physical:
1. Upper extremity abnormalities range from isolated absent radii to phocomelia.
2. Lower extremity anomalies occur in 46% of patients and vary from clinically undetectable to phocomelia. They are usually less severe than those of the upper limbs.
3. Cardiac anomalies occur in 33% of patients and include the following: Tetralogy of Fallot
4. Atrial septal defect Ventricular septal defect
5. Facial anomalies include the following: Micrognathia (in 3-30%) Facial hemangiomas Hypertelorism
Lab Studies: CBC findings: Platelets 15-30 X 109/L, Eosinophilia in 50%, Leukocytosis – WBC greater than 35 X 109/L with left shift, leukemoid reaction, Anemia secondary to bleeding
Imaging Studies: Characteristic skeletal involvement (ie, absent radii) is detectable by prenatal ultrasonography as early as 16 weeks’ gestation, when sufficient fetal skeletal ossification is present.
Other Tests: Bone marrow sampling reveals the following findings: Decreased or absent megakaryocytes; Small, basophilic, vacuolated megakaryocytes; Erythroid hyperplasia;
Procedures: Cordocentesis can be performed to confirm known genetic conditions. TREATMENT Medical Care: General thrombocytopenic precautions during times of significant thrombocytopenia with platelet count less than 80 X 109/L (usually during the first year of life) should include avoidance of trauma (soft helmet if needed), avoidance of certain antiplatelet medications (eg, aspirin, NSAIDs), and prolonged pressure on injection sites (especially after intramuscular injections).
· The mainstay of hospital treatment is supportive care, and by far the most significant treatment is platelet transfusion.
· Treatment of patients who are refractory or do not respond to transfusion is difficult but may include the use of HLA-matched platelets from family members.
· Splenectomy is usually effective for the treatment of thrombocytopenia in adults.
· Bone marrow transplantation (BMT) is an option for patients who continue to remain thrombocytopenic with bleeding despite platelet transfusions.
Antifibrinolytic agents Aminocaproic acid (Amicar) — Competitively inhibits activation of plasminogen to plasmin. Pediatric Dose 100-200 mg/kg PO/IV loading dose; followed by 200-400 mg/kg/d
Synthetic antidiuretic hormones Desmopressin acetate (DDAVP) — Increases plasma factor VIII levels, promoting platelet aggregation. Pediatric Dose 0.3 mcg/kg IV over 15-30 min
Complications arise from hemorrhage and hemorrhagic insults, especially intracranial hemorrhage.
Thrombasthenia Glanzmann thromboasthenia, Glanzmann disease, constitutional thrombopathy, hereditary hemorrhagic thrombopathy
Background: Glanzmann initially described thrombasthenia in 1918 when he noted purpuric bleeding in patients with platelet counts within the reference range. Glanzmann thrombasthenia is one of several inherited disorders of platelet function.
athophysiology: Glanzmann thrombasthenia is an autosomal recessive trait whereby the production and assembly of the platelet membrane glycoprotein (GP) IIb-IIIa is altered, preventing the aggregation of platelets and subsequent clot formation.
Mortality/Morbidity: The probability of death following bleeding is estimated at approximately 5%. ]
Age: Patients with Glanzmann thrombasthenia are typically diagnosed in infancy; all individuals with the disorder are recognized by age 5 years.
Physical: Most patients with thrombasthenia present with signs of purpura or bleeding.
The diagnosis is made in patients with refractory hemorrhage and appropriate findings on the diagnostic laboratory studies
Causes: Trauma and pressure remain the most frequent causes of bleeding in persons with thrombasthenia.
Lab Studies:
1. A history of prolonged bleeding, a prolonged bleeding time, and failure of platelets to aggregate in response to any of the usual agonists are diagnostic of thrombasthenia.
2. A CBC may also suggest the degree of bleeding. Patients who are thrombasthenic have platelet counts within the reference range and, on blood smear, normal platelet morphology.
3. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are within reference ranges.
4. A urinalysis may demonstrate proteinuria and microscopic hematuria.
5. The diagnosis is confirmed by documenting the absence of GP IIb-IIIa via sodium dodecyl sulfate-polyacrylamide gel electrophoresis of radiolabeled platelet proteins.
Medical Care:
1. Refractory bleeding in individuals with thrombasthenia requires the transfusion of normal platelets.
2. E-aminocaproic acid may be useful in controlling bleeding after dental extraction.
3. Corticosteroids are not helpful in persons with acute bleeding.
4. Other more rare therapies cited were bone marrow transplants and recombinant factor VIIa.
Surgical Care: Patients with severe menorrhagia may require hysterectomy.
Vasculitis and Thrombophlebitis
Vasculitis is a descriptive term associated with a heterogeneous group of diseases that results in inflammation of blood vessels. Arteries and veins of any size in any organ may be affected, leading to ischemic damage to organs. The pattern of vessel involvement is highly variable, leading to innumerable clinical presentations. The most common vasculitides of childhood are Henoch-Schцnlein purpura and
For the clinician, diagnosing the cause of vasculitis is a difficult task that involves distinguishing disease entities with possibly overlapping clinical presentations. Classification criteria have been established for a number of distinct clinical syndromes, but these are less useful in making a diagnosis in patients who do not meet all the criteria of any one disease. While groups of patients with unifying features can be identified, a patient with vasculitis often presents initially with nonspecific constitutional findings. Various classification schemes for vasculitis have been proposed, most recently by an international consensus conference in
Large-sized vessel vasculitis
1. Temporal arteritis – Granulomatous arteritis of the aorta and major branches, especially the extracranial branches of the carotid artery that usually occurs in patients older than 50 years
2. Takayasu arteritis – Granulomatous arteritis of the aorta and major branches that usually occurs in patients younger than 50 years
Medium-sized vessel vasculitis
1. Polyarteritis nodosa – Necrotizing vasculitis of medium- or small-sized arteries without involvement of large arteries, veins, or venules; renal involvement without glomerulonephritis
2.
Small-sized vessel vasculitis
1. Wegener granulomatosis – Granulomatous inflammation of small- to medium-sized vessels involving the respiratory tract; necrotizing glomerulonephritis common
2. Churg-Strauss syndrome – Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis of small- to medium-sized vessels; associated with asthma and eosinophilia (Under the classification of the American College of Rheumatology and traditional classifications, Wegener granulomatosis and Churg-Strauss syndrome are grouped together with polyarteritis nodosa under medium-sized vessel vasculitis.)
3. Microscopic polyangiitis (MPA) – Pauci-immune necrotizing vasculitis involving small- and medium-sized vessels; necrotizing glomerulonephritis common; pulmonary capillaritis frequent
4. Schönlein-Henoch disease: Small-vessel vasculitis with immunoglobulin A (IgA) immune accumulation; involvement of skin, gut, and glomeruli typical; associated with arthritis or arthralgia
5. Essential cryoglobulinemic vasculitis – Vasculitis with cryoglobulin immune accumulation affecting arterioles and venules; associated with serum cryoglobulins; skin and glomeruli often involved
6. Cutaneous leukocytoclastic vasculitis – Isolated cutaneous vasculitis without systemic vasculitis or glomerulonephritis
7. Possible thrombophlebitis, or superficial venous thrombosis – Resulting from vasculitic lesions with endothelial activation; in children, more often due to hypercoagulable states or catheter instrumentation
Hemorrhagic vasculitis (Schönlein-Henoch disease).
Frequency: Henoch-Schцnlein purpura occurs in 10,000 children per year, with an estimated incidence of 13.5 cases per 100,000 children.
Sex: Schönlein-Henoch disease – Male-to-female ratio of 1.5:1
Age: Schönlein-Henoch disease: Peak age of onset is 5-15 years.
Etiology: Schönlein-Henoch disease is an immunocomplex disease. Suspected though not proved inciting agents (antigens) include: group A β-hemolytic streptococci and other bacteria, viruses, drugs, foods, insect bites.
Pathogenesis: antigen influence → immunoglobulin G, M, A hyperproduction → antigen-antibody-complement complex in the blood → skin, kidney, intestine, joints precipitation → lesion → new autoantigens production → autoimmune damage of small vessels.
CLINICAL
Schönlein-Henoch disease: Up to 50% of patients may report a history of preceding upper respiratory tract infection or pharyngitis. The triad of abdominal pain, palpable purpura, and periarticular inflammation, swelling, or both may be incomplete at presentation
Clinical Findings
1. The skin rash is often urticarial initially and progresses to a macular-papular appearance, which transforms into a diagnostic symmetric purpuric rash distributed on the ankles, buttocks, elbows (Fig. 3, Fig. 4). Purpuric areas of a few millimeters in diameter may progress to larger hemorrhages. The rash usually begins on the lower extremities, but the entire body may be involved. New lesions can continue to appear for 2–4 weeks.
2. Approximately two-thirds of patients develop migratory polyarthralgia and polyarthritis, primarily of the ankles and knees.
3. Edema of the hands, feet, scalp and periorbital region may occur.
4. Abdominal colic – due to hemorrhage and edema primarily of the small intestine – occurs in about 50% of those affected. Abdominal symptoms include severe colicky abdominal pain, nausea, vomiting, and hematochezia or diarrhea.
5. 25–50% of those affected develop renal involvement, with hematuria, proteinuria or nephrotic syndrome. Renal symptoms manifest in the second to third week of illness. Nephritis is a late finding, but if present initially, it portends a worse renal outcome.
6. Testicular torsion may occur.
7. Neurologic symptoms are possible.
Fig. 3. Purpuric rash on the ankles.
Fig. 4. Purpuric rash on the buttocks.
Laboratory findings:
1. CBC reveals normochromic normocytic anemia of chronic disease; leukocytosis and thrombocytosis are associated with inflammatory process.
2. The Westergren sedimentation rate is elevated.
3. The platelet count, platelet function test, and bleeding time are usually normal.
4. Blood coagulation studies are normal.
5. Urinalysis frequency reveals hematuria, proteinuria, but casts are uncommon.
6. The ASO (antistreptolizin-O) titer is frequently elevated and the throat culture positive for group A beta-hemolytic Streptococci.
7. Serum Ig A may be elevated.
Histologic Findings: Leukocytoclastic vasculitis observed in Henoch-Schцnlein purpura, is characterized by focal segmental necrotizing full-thickness lesions of varying stages in small vessels. Fibrinoid necrosis is present. The cellular infiltrate is predominantly polymorphonuclear neutrophils. Lymphocytes and eosinophils may be present. Henoch-Schцnlein purpura reveals a leukocytoclastic vasculitis with IgA immune deposits.
Medical Care:
Treatment goals are to decrease acute inflammation of blood vessels and to maintain adequate perfusion of skin and vital organs, while limiting the side effects of potentially toxic therapies.
Individualize treatment based on the organs affected and the overall condition of the patient. In general, corticosteroids are administered to control acute symptoms and laboratory evidence of systemic inflammation. After control is achieved, attempts may be made to taper over a month.
Treatment:
1. Corticosteroids therapy may provide symptomatic relief for severe gastrointestinal or joint manifestations, but doesn’t alter skin or renal manifestations.
2. Aspirin is useful for the pain associated with arthritis.
3. If culture for group A beta-hemolytic Streptococci is positive or if the ASO titer is elevated, penicillin should be given in full therapeutic doses for 10 days.
4. Heparin should be administrated to treat Henoch-Schönlein purpura in case of: large, repeated rush with ulcerating; renal syndrome; abdominal syndrome.
Heparin Pediatric Dose Initial dose: 50-100 U/kg IV Maintenance infusion: 15-25 U/kg/h IV; increase dose by 2-4 U/kg/h q6-8h prn using aPTT results
Hemophilia A and B factor VIII deficiency, factor IX deficiency
Hemophilia A and B are inherited bleeding disorders caused by deficiencies of clotting factor VIII (F VIII) and factor IX (F IX), respectively. They account for 90-95% of severe congenital coagulation deficiencies. The 2 disorders are considered together because of their similar clinical pictures and similar patterns of inheritance.
Hemophilia is one of the oldest described genetic diseases. An inherited bleeding disorder in males was recognized in Talmudic records of the second century. The modern history of hemophilia began in 1803 with the description of hemophilic kindred by John Otto, followed by the first review of hemophilia by Nasse in 1820. Wright demonstrated evidence of laboratory defects in blood clotting in 1893; however, FVIII was not identified until 1937 when Patek and Taylor isolated a clotting factor from the blood, which they called antihemophilia factor (AHF). A bioassay of FVIII was introduced in 1950.
Pathophysiology: F VIII and F IX circulate in an inactive form. When activated, these 2 factors cooperate to cleave and activate factor X, a key enzyme that controls the conversion of fibrinogen to fibrin. Therefore, the lack of either of these factors may significantly alter clot formation and clinical bleeding.
Frequency: Hemophilia has a worldwide distribution.
Sex: Both Hemophilia A and B are X-linked recessive disorders; therefore, they affect males almost exclusively.
Physical: Only 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. At birth, other neonates may present with severe hematoma and prolonged bleeding from the cord or umbilical area.
After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers. When trauma-related soft-tissue hemorrhage occurs, young children may have oral bleeding when their teeth are erupting. Bleeding from gum and tongue lacerations often is troublesome because the oozing of blood may continue for a long time despite local measures. As physical activity increases in children, hemarthrosis and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a serious life-threatening complication that requires urgent diagnosis and intervention.
Hemophilia is classified according to the clinical severity as mild, moderate, or severe. Patients with severe disease usually have less than 1% factor activity. It is characterized by spontaneous hemarthrosis and soft tissue bleeding in the absence of precipitating trauma. Patients with moderate disease have 1-5% factor activity and bleed with minimal trauma. Patients with mild hemophilia have more than 5% FVIII activity and bleed only after significant trauma or surgery.
Lab Studies:
Usually, the activated partial thromboplastin time (aPTT) is prolonged.
Bleeding times, prothrombin times, and platelet counts are normal.
The diagnosis is based on functional assay results for FVIII and FIX.
It is usual to also measure von Willebrand factor which, when combined with low factor VIII, may indicate vWF deficiency as the primary diagnosis.
TREATMENT
Ambulatory replacement therapy for bleeding episodes is essential for preventing chronic arthropathy and deformities. Home treatment and infusion by the family or patient is possible in most cases. Prompt and appropriate treatment of hemorrhage is important to prevent long-term complications and disability. For most mild hemorrhages, dose calculations are directed toward achieving an FVIII activity level of 30-40% or FIX activity levels of 30% and clotting factor activity of at least 50% in severe bleeds (eg, major dental surgery, major surgery or trauma), and 80-100% activity in life-threatening hemorrhage.
Hospitalization is reserved for severe or life-threatening bleeds, such as large soft tissue bleeds; retroperitoneal hemorrhage; and hemorrhage related to head injury, surgery, or dental work. Patients are treated with prophylaxis or intermittent therapy (demand) for bleeding events. Prophylaxis has been shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints.
In most countries with access to recombinant product, prophylaxis is primary recommended beginning as early as 1 year of age and continuing into adolescence. A cost benefit analysis indicates that this approach reduces overall factor use and significantly reduces morbidity. In situations in which this is not feasible, secondary prophylaxis, ie, therapy after a target joint has been established to prevent worsening of the joint, is instituted for a defined period. Dosing is designed to maintain levels greater than 2% at the trough. This requires thrice weekly factor VIII or twice weekly factor IX to achieve.
The treatment of hemophilia may involve the management of hemostasis, management of bleeding episodes, use of factor replacement products and medications, and treatment of patients with factor inhibitors.
Management of hemostasis Hemostasis is achieved with replacement therapy aimed at correcting the coagulation factor deficiency.
Management of bleeding episodes
Musculoskeletal bleeding
Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain.
Early infusion upon the recognition of pain often may eliminate the need for a second infusion by preventing the inflammatory reaction in the joint. Cases in which treatment begins late or causes no response may require repeated infusions for 2-3 days.
Do not aspirate hemarthroses unless they are severe and involve significant pain and synovial tension.
Infusion must be aimed at maintaining a normal level of FVIII or FIX.
Other interventions include elevation of the affected part to enhance venous return and, rarely, surgical decompression.
Oral bleeding
Oral bleeding from the frenulum and bleeding after tooth extractions are not uncommon. Bleeding is aggravated by the increased fibrinolytic activity of the saliva.
Combine adequate replacement therapy with an antifibrinolytic agent (e-aminocaproic acid [EACA]) to neutralize the fibrinolytic activity in the oral cavity.
GI bleeding Manage GI hemorrhage with repeated or continuous infusions to maintaiearly normal circulating levels of FVIII coagulant or FIX.
Intracranial bleeding If CNS hemorrhage is suspected, immediately begin an infusion prior to radiologic confirmation. Maintain the factor level in the normal range for 7-10 days until a permanent clot is established.
FVIII products A variety of products are available for replacement therapy. Fresh frozen plasma and cryoprecipitate no longer are used in hemophilia A and B because of the lack of safe viral elimination and concerns regarding volume overload. Many plasma-derived FVIII concentrates are commercially available.
Many recombinant FVIII concentrates are now available. The advantage of such products is the elimination of viral contamination. The effectiveness of these products appears comparable to that of plasma-derived concentrates. Concerns regarding higher incidences of the presence of inhibitor appear to be unwarranted.
The indications for this approach include intracranial hemorrhage, vascular compromise, iliopsoas bleeding, and preparation for surgery.
Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP)
DDAVP is considered the treatment of choice for mild and moderate hemophilia A. It is not effective in the treatment of severe hemophilia.
It stimulates a transient increase in plasma FVIII levels and results in sufficient hemostasis to stop a bleeding episode or to prepare patients for dental and minor surgical procedures.
It can be administered intravenously at a dose of 0.3 mcg per kilogram of body weight.
Its peak effect is observed in 30-60 minutes.
Several doses of DDAVP may need to be infused every 12-24 hours before tachyphylaxis is observed.
Treatment in patients with factor inhibitors Inhibitors to FVIII develop in 25-35% of children with severe hemophilia A, and inhibitors to FIX develop in 1-3% in children with hemophilia B. Inhibitors develop in relatively young children, usually within their first 50 exposures to FVIII.
In the treatment of patients with low-titer FVIII inhibitors (<5 Bodansky units [BU]), bleeding can be controlled with human FVIII administered at standard or higher doses. In patients with high-titer inhibitors, immune tolerance induction (ITI) may be used to reduce or suppress the inhibitor. Therapeutic options include standard or activated prothrombin complex concentrate (PCC); recombinant factor VIIa (NovoSeven); and porcine FVIII (Hyate:C), if no cross-reacting antibodies are present. In patients with high-titer FIX inhibitors, ITI usually is less successful compared with that in patients with FVIII inhibitors. Therapeutic options are the same for these patients as for those with FVIII inhibitors, with the same doses. Patients with hemophilia B and inhibitors can have anaphylactic reactions to FIX infusions.
Antihemophilic factor Dose 20-50 U/kg/dose IV q12-24h; higher doses may be used (eg, 50-75 U/kg with high inhibitor titers); individualize doses according to clinical situation; may administer more frequently in special circumstances
FIX Complex Dose 20-50 U/kg IV; individualize doses according to clinical situation; may administered higher doses and qd or more frequently in special cases Patients with FVIII: 75-100 U/kg IV q6-12h
Recombinant factor VII (NovoSeven, NiaStase) — Indicated for the treatment for bleeding episodes in patients with hemophilia A or B and inhibitors. Dose 90 mcg/kg IV q2h until hemostasis is achieved or treatment is judged inadequate; for patients with or without inhibitors; may use 35-120 mcg/kg, depending on the severity of the clinical situation; duration of administration has not been well established
Hemophilia C
Hemophilia C can be distinguished from hemophilias A (deficiency of factor VIII) and B (deficiency of factor IX) by the absence of bleeding into joints and muscles and by its occurrence in individuals of either sex. Unlike hemophilias A and B in which the bleeding tendency clearly is related to factor level, the bleeding risk in hemophilia C is not always influenced by the severity of the deficiency, especially in individuals with partial deficiency. This unpredictable nature of the disease makes it more difficult to manage than hemophilia A or B.
Causes: Congenital deficiency of factor XI clotting activity is caused by mutations in the factor XI gene.
Pathophysiology: The severity of the deficiency is based on plasma factor XIC (clotting) activity.
Frequency: Hemophilia C has a high prevalence among Ashkenazi Jews (in
Sex: The inheritance of factor XI is autosomal, affecting males and females equally.
History: Bleeding after surgery or after injury is the usual presenting symptom in individuals prone to bleeding.
The following presentations have been reported:
· Massive hemothorax
· Cerebral hemorrhage
· Subarachnoid hemorrhage
· Spinal epidural hematoma with the Brown-Sequard syndrome
· Hematuria and spontaneous hemarthrosis are rare.
· In women, menorrhagia is an important finding.
Physical: Physical examination usually is normal except when bleeding occurs. Bruising may occur at unusual sites. The patient may have signs of pallor, fatigue, and tachycardia with excessive bleeding.
Lab Studies: Prothrombin time (PT), aPTT, and thrombin time (TT): The aPTT is prolonged in factor XI deficiency, whereas the PT and TT are normal.
Genetic analysis for the mutation in factor XI is helpful in determining which mutation has caused the deficiency.
Medical Care: The basic principle of management consists of altering the balance between bleeding and clotting. This would consist of replacing the deficient factor and using other measures, such as fibrin glue and antifibrinolytics.
Soft tissue bleeding may not require treatment. When therapy is required, therapeutic products are available to treat patients with factor XI deficiency, including fresh frozen plasma (FFP), solvent-detergent–treated FFP, and factor XI concentrates (available in Europe, but not in the
Adjunctive measures include the use of fibrin glue, antifibrinolytic agents, and desmopressin (DDAVP).
Fresh frozen plasma — Product of choice when factor XI concentrates are not available. Dose 15-20 mL/kg IV loading dose, followed by 3-6 mL/kg q12h until hemostasis is achieved
Factor XI concentrates. The typical dose of these products is up to 30 U/kg.
Prognosis is excellent in patients with partial deficiency who do not have bleeding manifestations. In patients with bleeding tendencies, hemorrhage and bleeding into organs may be life threatening.
Von Willebrand Disease Although referred to as a single disease, von Willebrand disease (vWD) is in fact a family of bleeding disorders caused by an abnormality of the von Willebrand factor (vWF). vWD is the most common hereditary bleeding disorder.
First described by Erik Adolf von Willebrand in 1926, vWD is characterized by a lifelong tendency toward easy bruising, frequent epistaxis, and menorrhagia.
Pathophysiology: vWD is due to an abnormality, either quantitative or qualitative, of the vWF, which is a large multimeric glycoprotein that functions as the carrier protein for factor VIII (FVIII). vWF also is required for normal platelet adhesion. As such, vWF functions in both primary (involving platelet adhesion) and secondary (involving FVIII) hemostasis.
vWD can be classified into 3 main types, of which 70-80% are considered to be type 1.
1. Type 1 vWD is characterized by a partial quantitative decrease of qualitatively normal vWF and FVIII.
2. vWD type 2 is a variant of the disease with primarily qualitative defects of vWF.
3. type 3 vWD is characterized by marked deficiencies of both vWF and FVIIIc in the plasma, the absence of vWF from both platelets and endothelial cells, and a lack of the secondary transfusion response and the response to DDAVP
Frequency: Prevalence worldwide is estimated at 0.9-1.3%.
Sex: vWD affects males and females in equal numbers.
History: Many children with vWD are asymptomatic and are diagnosed as a result of a positive family history or during routine preoperative screening (eg, prolonged bleeding time). Importantly, remember that a wide variation in clinical manifestations exists, even for members of the same family.
The history may reveal the following:
· Increased or easy bruising
· Recurrent epistaxis
· Menorrhagia
· Postoperative bleeding (particularly after tonsillectomy or dental extractions)
· Family history of a bleeding diathesis
· Bleeding from wounds
· Gingival bleeding
· Postpartum bleeding
Medical Care: Minor bleeding problems, such as bruising or a brief nosebleed, may not require specific treatment. For more serious bleeding, medications that can raise the vWF level and, thereby, limit bleeding are available. The goal of therapy is to correct the defect in platelet adhesiveness (by raising the level of effective vWF) and the defect in blood coagulation (by raising the FVIII level). In recent years, desmopressin (1-deamine-8-D-arginine vasopressin, DDAVP) has become a mainstay of therapy for most patients with mild vWD.
Pediatric Megaloblastic Anemia
Background
Megaloblastic anemia is an uncommon problem in childhood that is most frequently associated with vitamin deficiency or gastrointestinal disease. The megaloblastic effect is characterized by an aregenerative macrocytic anemia with nuclear dysmaturity, where the nucleus appears immature relative to the cytoplasm because of impaired DNA synthesis. See image below.
Bone marrow aspirate from a patient with untreated pernicious anemia. Megaloblastic maturation of erythroid precursors is shown. Two megaloblasts occupy the center of the slide with a megaloblastic normoblast above. Photo courtesy of Marcel E Conrad, MD.
DNA synthesis is impaired in these cases because of inadequate amounts of metabolically active folate derivatives necessary for DNA base synthesis. Megaloblastic changes affect all 3 hematopoietic cell lines. Thrombocytopenia, leukopenia, and anemia are all observed to varying extents.
The 2 most common causes of megaloblastic anemia are vitamin B-12 (cobalamin) deficiency and folic acid deficiency. Although their clinical settings differ considerably, no hematologic finding can distinguish between the 2 conditions; specific testing is necessary (see Workup). Other less common causes include the use of metabolic inhibitors such as methotrexate and 6-mercaptopurine and certain rare inborn errors such as thiamine-responsive megaloblastic anemia,Lesch-Nyhan syndrome, and hereditary orotic aciduria (see Etiology).
Treatment of megaloblastic anemia depends on the underlying cause. Supplemental folate or vitamin B-12 may be indicated (see Treatment).
Go to Pediatric Chronic Anemia, Anemia of Prematurity, Donath-Landsteiner Hemolytic Anemia, Pediatric Acute Anemia, and Fanconi Anemia for complete information on these topics.
Vitamin B-12 deficiency
Vitamin B-12 is commonly ingested with meat or fish. It binds to salivary haptocorrins, which are digested in the stomach, allowing the cobalamin to bind to intrinsic factor (IF). IF is produced by the parietal cells of the stomach. The IF-B12 complex makes its way to the terminal ileum, where it binds to receptors on the enterocyte. It is transported across the cell and enters the circulation bound to a transport molecule, TC II. The B12-TC II complex is absorbed into cells by endocytosis. In the cell, cobalamin acts as a coenzyme in several reactions, including the synthesis of methionine from homocysteine during the reduction of dihydrofolate to tetrahydrofolate and the conversion of methylmalonyl CoA to succinyl CoA. It is the role of vitamin B-12 in the reduction of folic acid derivatives that results in the megaloblastic changes seen clinically.
Vitamin B-12 deficiency can be caused by decreased ingestion (eg, poor dietary intake), impaired absorption (eg, failure to release B-12 from protein, IF deficiency, chronic pancreatic disease, competitive parasites, intrinsic intestinal disease), or impaired use (eg, congenital enzyme deficiencies, lack of transcobalamin II, administration of nitrous oxide).
Inadequate vitamin B-12 dietary intake is rare in children, though it may be seen in breastfed infants whose mothers are themselves deficient. Pernicious anemia, a common cause of vitamin B-12 deficiency in adults, is rare in childhood. Deficiency of vitamin B-12 activity is usually due to malabsorption or a congenital deficiency of one of the vitamin B-12 carrier proteins. In recent years, vitamin B-12 deficiency has been described in patients with human immunodeficiency virus (HIV) infection, with or without acquired immunodeficiency syndrome (AIDS).
In addition to the hematologic manifestations of vitamin B-12 deficiency, abnormalities of the GI tract and nervous system may also be present. The underlying cause of megaloblastic anemia must be determined in each case. Failure to recognize B-12 deficiency, even in the presence of concomitant folate deficiency, may result in permanent neurologic damage. Treatment with folate alone in these cases may reverse anemia but may allow neurologic damage to progress.
Folate deficiency
Folate is ingested in the diet in many different types of food. It enters the enterocyte and is transported into the portal circulation by a carrier molecule. It circulates in the plasma mostly as 5-methyl tetrahydrofolate (THF). It enters the cell via a carrier (methotrexate competes with this carrier). In the cell, folate binds to and acts as a coenzyme with enzymes responsible for single carbon metabolism.
Folate deficiency can be caused by any of the following:
- Decreased ingestion (eg, poor dietary intake, alcoholism, infancy)
- Impaired absorption (eg, intestinal short circuits, celiac sprue, congenital malabsorption, certain drugs such as sulfasalazine)
- Impaired use (eg, use of folic acid antagonists such as antiepileptic medications, sulfa antibiotics, or methotrexate)
- Increased requirements (eg, pregnancy, infancy, hyperthyroidism, chronic hemolytic disease, cancer)
- Increased loss (eg, hemodialysis)
Folic acid is available in a wide variety of food groups. Approximately one third of dietary folate is estimated to come from cereals and grains, another third from fruits and vegetables, and another third from meats and fish. Folic acid deficiency is commonly observed in children who are fed a severely restricted diet. This usually occurs with a diet restricted to goat’s milk, which is deficient in folic acid. It may also be observed in children with celiac sprue and other malabsorption disorders that affect the proximal small intestine.
Deficiency of metabolically active folate metabolites is frequently observed in patients who receive antifolate drugs, such as sulfa antibiotics and methotrexate. A relative deficiency of metabolically active folate metabolites may also be observed in patients who are experiencing increased red cell destruction. These patients require a greater amount of folate than is usually present in the diet and develop macrocytic changes in their erythrocytes. Increased folate intake is also important during pregnancy, in which deficiencies have been associated with neural tube defects.
Pathophysiology
Megaloblastic anemia is caused by various DNA synthesis defects. In folate deficiency, purine biosynthesis is affected because folic acid is essential in this process.
Folic acid is essential for purine biosynthesis. Folic acid absorbed from the diet must be activated to produce active tetrahydrofolic acid (THF). THF is necessary for single carbon transfers in the synthesis of pyrimidine nucleotides. Without adequate levels of biologically active THF, the ability to repair and replicate DNA is decreased. Vitamin B-12 is a cofactor for the activation of folic acid in a step that also converts homocysteine to methionine.
In the case of inadequate folic acid intake, THF production is depleted, and DNA synthesis is slowed. The effect on hematopoiesis is to reduce the rate of cell production, resulting in pancytopenia. In the cells that are produced, the effect created is an arrest of nuclear maturation. In other words, the cells that are produced have immature nuclei compared with the degree of maturation of the cytoplasm.
Etiology
Megaloblastic anemia is most often caused by an acquired lack of vitamin B-12 or lack of folic acid. Inherited abnormalities of the metabolism of these nutrients may be the cause.
Acquired causes of insufficient vitamin B-12 include the following:
- Inadequate intake in diet
- Inadequate absorption (deficient IF; deficient absorption from ileum)
- Impaired transport from the intestine
Acquired causes of insufficient folate include inadequate dietary intake and inadequate absorption from the proximal small intestine. Medications associated with folate deficiency include the following:
- Sulfonamide antibiotics may interfere with folate metabolism, particularly when they are used on a long-term basis
- Other antifolate antimetabolite drugs may also cause megaloblastic changes
- Megaloblastic changes are observed with some frequency with antineoplastic agents, such as methotrexate; azathioprine (Imuran) may also cause megaloblastic changes
Increased metabolic demand (eg, chronic hemolysis, such as in sickle cell disease) or increased loss may also result in insufficient folate.
Congenital absence or deficiency of carrier proteins can cause vitamin B-12 deficiency. These deficiencies occur most commonly as autosomal recessive enzymopathies. These conditions often manifest during infancy and early childhood and are rare but important causes of megaloblastic anemia.
The Imerslund-Grasbeck syndrome of proteinuria and excretion of cobalamin and IF is a rare disorder that arises in early childhood. However, it is an important cause of B-12 deficiency
Epidemiology
The prevalence of megaloblastic anemia in childhood has not been established. Vitamin B-12 deficiency is a worldwide problem, however, particularly in the newborn period, due to the combined effects of poor maternal diet and congenital deficiencies of transcobalamin.
Pernicious anemia is a common cause of megaloblastic anemia, especially in persons of European or African descent. Dietary vitamin B-12 deficiency is a serious problem in India, Mexico, Central America, South America, and some areas of Africa. The increase in vegetarianism is related to an increase in vitamin B-12 deficiency and is a particular concern in breastfed infants of vitamin B-12–deficient mothers.
Megaloblastic anemia is observed in all racial and ethnic groups and in both sexes. It is rarely observed in infants, but may occur in infants who breastfeed from mothers who are themselves deficient in vitamin B-12 or in infants with a congenital deficiency of one of the carrier proteins.
Prognosis
Prognosis depends on the underlying cause of the megaloblastic anemia and the degree of compliance with therapy. Folic acid deficiency is relatively easy to treat; patients usually respond to added folate in their diet. Vitamin B-12 deficiency may be a more significant concern because some patients may require vitamin B-12 injections, with which they may not readily comply. In addition, vitamin B-12 deficiency may be associated with severe neurologic abnormalities that may be long lasting and persist even with appropriate vitamin B-12 therapy.
Morbidity in megaloblastic anemia may include CNS toxicity, including dementia and loss of dorsal column function. Deficiency of vitamin B-12 is usually at the root of this. CNS dysfunction has been described in adult patients who have deficient vitamin B-12 levels in the absence of anemia. Megaloblastic anemia in pregnancy is associated with persistent learning deficits in children.Hyperpigmentation may also be seen.
Decreased numbers of CD4 cells and abnormal CD4/CD8 ratios as well as natural killer (NK) cell numbers have been documented in patients with pernicious anemia. These numbers normalize with cobalamin administration.
Pediatric Methemoglobinemia
Background
Methemoglobinemia is a condition in which the iron within hemoglobin is oxidized from the ferrous (Fe) state to the ferric (Fe) state. Because iroeeds to be in the ferrous state to allow hemoglobin-to-oxygen binding, methemoglobinemia results in variable degrees of deficiencies of oxygen transport. Clinically, this condition causes cyanosis, often posing a diagnostic dilemma.
Methemoglobinemia in children usually results from exposure to oxidizing substances (such as nitrates or nitrites; aniline dyes; or medications, including lidocaine, prilocaine, phenazopyridine hydrochloride [Pyridium], and others) or is the result of inborn errors of metabolism (especially glucose-6-phosphate dehydrogenase [G6PD] deficiency and cytochrome b5 oxidase deficiency) or severe acidosis, which impairs the function of cytochrome b5 oxidase. This is particularly evident in young infants with diarrhea,in whom excessive stool bicarbonate loss leads to metabolic acidosis, which exacerbates the relatively immature cytochrome b5 oxidase system.
Note the chocolate brown color of methemoglobinemia. Tube 1 and tube 2 have a methemoglobin concentration of 70%; tube 3, a concentration of 20%; and tube 4, a normal concentration.
Pathophysiology
Hemoglobin molecules are tetrameric and contain iron within a porphyrin heme structure. The iron moiety in hemoglobin is normally in the ferrous state (Fe) in both oxyhemoglobin and deoxyhemoglobin and is capable of reversibly binding with oxygen only in this (ferrous) state. The oxidation of iron to the ferric state (Fe) results in the formation of methemoglobin, which alters absorption and causes a brownish discoloration of the blood.
In healthy children, the ferric iron in methemoglobin is readily reduced to the ferrous state, primarily through the function of cytochrome b5 oxidase (also referred to as methemoglobin reductase), which is present in erythrocytes and other cells. Patients who are deficient in cytochrome b5 reductase are particularly prone to methemoglobinemia, especially when exposed to oxidizing medications and other chemicals, including nitrates, nitrites, prilocaine and lidocaine, nitric oxide, and aniline dyes. Because methemoglobin is incapable of reversibly binding and transporting oxygen or carrying carbon dioxide, if it is present in significant amounts, methemoglobinemia can result in impaired oxygen delivery to (and carbon dioxide removal from) all tissue beds.
Cyanosis is commonly caused by either an excess of deoxygenated hemoglobin (usually in amounts >5 g/dL) or significant amounts of abnormal hemoglobins such as methemoglobin (>1.5 g/dL) or sulfhemoglobin (>0.5 g/dL), resulting in a grayish-bluish coloration of the skin and mucous membranes. Because the absolute amount of deoxygenated or abnormal hemoglobin (rather than its percentage) is required for cyanosis to be clinically evident, patients with moderate-to-severe anemia may not appear cyanotic, even with elevated percentages of deoxygenated or abnormal hemoglobins.
In healthy individuals, ongoing RBC exposure to various oxidizing agents produces small amounts of methemoglobin; however, the concentration of methemoglobin (as a fraction of total hemoglobin) is maintained below 1% by a reduction enzyme system (mainly cytochrome b5 along with nicotinamide adenine dinucleotide [NADH] reductase), with additional protection provided by other systems, including glutathione reductase and G6PD. Methemoglobinemia occurs if the rate of oxidation is significantly increased and overwhelms the protective and reductive capacities of the cells, if the structure of hemoglobin is altered and is resistant to reduction, or if the rate of reduction of methemoglobin is decreased. Methemoglobinemia may be acquired or congenital.
Acquired methemoglobinemia
Acquired methemoglobinemia is more common than congenital forms. Exposure to oxidant drugs and toxins in amounts that exceed the enzymatic reduction capacity of RBCs precipitates symptoms of methemoglobinemia.
Acquired methemoglobinemia is more frequent in premature infants and infants younger than 4 months. The following factors may have a role in the higher incidence in this age group:
- Fetal hemoglobin may more easily (auto) oxidize than adult hemoglobin.
- The level of NADH reductase is low at birth and increases with age; it reaches reference range limits by age 4 months.
- Higher gastric pH in infants may facilitate bacterial proliferation, resulting in increased conversion of dietary nitrates to nitrites.
- An association between methemoglobinemia and acute gastroenteritis in infants has beeoted in several studies and may be due to acidosis from stool bicarbonate loss impairing the already immature function of the methemoglobin reductase system in these young patients.
Congenital (ie, hereditary) methemoglobinemia
Hereditary methemoglobinemias may be divided into 2 categories: methemoglobinemia due to an altered form of hemoglobin (hemoglobin M) and enzyme deficiency (NADH reductase deficiency) that decreases the rate of reduction of iron in the hemoglobin molecule.Four types of hereditary methemoglobinemias are secondary to deficiency of NADH cytochrome b5 reductase. All types are autosomal recessive disorders. Heterozygotes have 50% enzyme activity and no cyanosis. Homozygotes that have elevated methemoglobin levels above 1.5% have clinical cyanosis.
- Type I: This is the most common variant, and the enzyme deficiency is limited to the erythrocytes causing cyanosis.
- Type II: Widespread deficiency of the enzyme occurs in various tissues, including erythrocytes, liver, fibroblasts, and brain. It is associated with severe CNS symptoms, including encephalopathy, microcephaly, hypertonia, athetosis, opisthotonus, strabismus, mental retardation, and growth retardation. Cyanosis is evident at an early age.
- Type III: Although the hemopoietic system (platelets, RBCs, white cells including lymphocytes and granulocytes) is involved, the only clinical consequence is cyanosis.
- Type IV: Similar to type I, this type has isolated involvement of the erythrocytes but results in chronic cyanosis.
Deficiency of nicotinamide adenine dinucleotide phosphate (NADPH)–flavin reductase can also cause methemoglobinemia.
An amino acid substitution in or near the heme pocket affects the heme-globin bond, and the hemoglobin molecule becomes more stable in the oxidized form, resisting reduction. Several variants of hemoglobin M have been described, including hemoglobin Ms, hemoglobin MIwate, hemoglobin MBoston, hemoglobin MHydePark, and hemoglobin MSaskatoon. These are usually autosomal dominant iature. Alpha chain substitutions cause cyanosis at birth, whereas those in the beta chain become clinically apparent in infants aged 4-6 months.
Epidemiology
Frequency
United States
Theexact incidence is unknown.
International
The exact incidence is unknown.
Mortality/Morbidity
Patients with congenital methemoglobinemia are generally asymptomatic other than cyanosis. Life expectancy is normal, unless the methemoglobin level is above 25-40%. Acquired methemoglobinemia is usually mild but may be severe and rarely fatal, depending on the cause. Mild-to-moderate transient methemoglobinemia may be present but may escape clinical detection; a high index of suspicion must be maintained.
Race
Congenital methemoglobinemia is more prevalent among populations with endemic cytochrome b5 reductase deficiency, including Alaskan and Native American Indian populations.
As G-6-PD deficiency is a risk factor for acquired methemoglobinemia, so populations endemic for G-6-PD deficiency, including populations of Mediterranean and African descent, are at higher risk for acquired methemoglobinemia.
Sex
There is no association between sex and congenital methemoglobinemia. However, because G-6-PD deficiency is X-linked, there is a higher risk of acquired methemoglobinemia in males with G-6-PD deficiency when they are subjected to oxidative stress.
Age
Hereditary forms appear early in life. Young infants, especially infants aged 3-4 months, are more susceptible to acquired methemoglobinemia, as the ability to reduce methemoglobinemia is not well developed at birth, but reaches reference range limits by age 4 months. Free iron deposition in the brains of sudden fetal and infant death victims has been identified as a possible catabolic product of maternal methemoglobinemia and may be a marker of maternal nicotine exposure.
Pediatric Polycythemia
Background
Polycythemia is characterized by an increase in absolute quantity of red cells or total RBC volume. In contrast, relative polycythemia (pseudoerythrocytosis) is secondary to fluid loss or decreased fluid intake resulting in hemoconcentration. Two basic categories of polycythemia are recognized:
- Primary polycythemias due to factors intrinsic to red cell precursors, including primary familial and congenital polycythemia (PFCP), idiopathic erythrocytosis, and polycythemia vera (PV).
- Secondary polycythemias are caused by factors extrinsic to red cell precursors and include a physiologic-approproriate erythropoietin (epo) production in response to tissue hypoxia and physiologic-inappropriate erythropoietin productioot in response to tissue hypoxia.
Iormal hematopoiesis, myeloid stem cells give rise to erythrocytes, platelets, granulocytes, eosinophils, basophils, and monocytes. The production of each lineage is a function of cell proliferation, differentiation, and apoptosis. These various stages of differentiation rely on multiple interrelated processes. Protein growth factors, known as cytokines, stimulate proliferation of the multilineage cells (eg, interleukin [IL]-3, granulocyte-macrophage colony-stimulating activity [GM-CSF]). Other factors primarily stimulate the growth of committed progenitors (eg, GM-CSF, macrophage colony-stimulating factor [M-CSF], erythropoietin [Epo]).
Erythropoiesis is a carefully ordered sequence of events. See the image below.
Bone marrow film at 400X magnification demonstrating dominance of erythropoiesis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Initially occurring in fetal hepatocytes, the process is taken over by the bone marrow in the child and adult. Although multiple cytokines and growth factors are dedicated to the proliferation of the RBC, the primary regulator is Epo. Red cell development is initially regulated by stem cell factor (SCF), which commits hematopoietic stem cells to develop into erythroid progenitors. Subsequently, Epo continues to stimulate the development and terminal differentiation of these progenitors. In the fetus, Epo is produced by monocytes and macrophages found in the liver. After birth, Epo is produced in the kidneys; however, Epo messenger RNA (mRNA) and Epo protein are also found in the brain and in RBCs, suggesting that some paracrine and autocrine function is present as well.
Erythropoiesis escalates as increased expression of the EPO gene produces higher levels of circulating Epo. EPO gene expression is known to be affected by multiple factors, including hypoxemia, transition metals (Co, Ni, Mn), and iron chelators. However, the major influence is hypoxia, including factors of decreased oxygen tension, RBC loss, and increased oxygen affinity of hemoglobin. In fact, Epo production has been observed to increase as much as 1000-fold in severe hypoxia.
Pathophysiology
Primary polycythemia is due to factors intrinsic to red cell precursors caused by acquired and inherited mutations. It includes the diagnoses of primary familial and congenital polycythemia, idiopathic erythrocytosis, and polycythemia vera.
Polycythemia vera, also known as polycythemia rubra vera, is a chronic clonal myleoproliferative disorder characterized by clonal proliferation of myeloid cells. Currently, the diagnosis of polycythemia vera is based on the 2008 World Health Organization (WHO) criteria, which has integrated molecular diagnostics into the evaluation and screening for polycythemia vera.A diagnosis of polycythemia vera is made when both major and one minor criterion are present or when the first major criterion is present with any two minor criteria. The current criteria include the following:
- Major criteria
1. Hemoglobin level of more than 18.5 g/dL in men (>16.5 g/dL in women) or other evidence of increased red cell volume
2. or
3. Hemoglobin or hematocrit level higher than 99th percentile of method-specific reference range for age, sex, altitude, of residence
4. or
5. Hemoglobin level of more than 17 g/dL in men (>15 g/dL in women) if associated with a documented and sustained increase of at least 2 g/dL from an individual’s baseline value that caot be attributed to correction of iron deficiency
6. or
7. Elevated red cell mass greater than 25% above meaormal predicted value
8. Presence of JAK2or similar mutation (eg, JAK2 exon 12 mutation)
- Minor criteria
1. Bone marrow trilineage myeloproliferation
2. Subnormal serum Epo levels
3. Endogenous erythroid colony growth
Earlier diagnostic criteria for polycythemia vera included the following (based on the Polycythemia Vera Study Group Diagnostic Criteria):
- Red cell mass greater than 36 mL/kg for men and greater than 32 mL/kg for women
- Arterial oxygen saturation greater than 92%
- Splenomegaly or 2 of the following:
- Thrombocytosis greater than 400 X 10/L
- Leukocytosis greater than 12 X 10/L
- Leukocyte alkaline phosphatase activity greater than 100 U/L in adults (reference range, 30-120 U/L) without fever or infection
- Serum vitamin B-12 greater than 900 pg/mL (reference range, 130-785 pg/mL)
- Unsaturated vitamin B-12 binding capacity greater than 2200 pg/mL
Polycythemia vera is considered to be a form of the myeloproliferative syndromes that include polycythemia vera, essential thrombocythemia, and myelofibrosis (agnogenic myeloid metaplasia). The clonality of polycythemia vera is well established and was first demonstrated by Adamson et al in 1976.Subsequent studies suggest hypersensitivity of the myeloid progenitor cells to growth factors, including Epo, IL-3, SCF, GM-CSF, and insulinlike growth factor (IGF)–1, whereas other studies show defects in programmed cell death.
Until recently, the pathophysiology of polycythemia vera was unclear. In 2005, significant progress in the understanding of polycythemia vera was made with the discovery of a gain of function mutation in the tyrosine kinase JAK2 (JAK2), which now appears to cause most primary cases in adults.. JAK2is detectable in more than 95% of patients diagnosed with polycythemia vera.Several other mutations of JAK2 have since been described (eg, exon 12, JAK2).The JAK2 mutations cause the enzyme to be constitutively active allowing cytokine independent proliferation of cell lines that express Epo receptors causing these cells to be hypersensitive to cytokines.
Familial clustering suggests a genetic predisposition. Whether these mutations are responsible for the development of polycythemia vera in pediatric patients is unclear. Some groups have reported lower rates of JAK2 mutations in children compared with adults,whereas other groups have seen similar rates with complete or near complete presence of JAK2and other JAK2 mutations.. The prevalence of familial cases of chronic myeloproliferative disease is thought to be at least 7.6%, and the pattern of inheritance is consistent with an autosomal dominant pattern with decreased penetrance. Evidence of disease anticipation is noted in the second generation, presenting at a significantly younger age. However, clinical and hematological features in familial cases have not been shown to differ from those of sporadic mutations.
Primary familial and congenital polycythemia is caused by a mutation in the Epo receptor resulting in hypersensitivity to Epo. Several mutations (approximately 14) have been identified in the Epo receptor (EPOR) gene; however, EPOR mutations have not been identified in all PFCP kindreds. Most identified EPOR mutations (11) cause truncation of the c-terminal cytoplasmic receptor domain of the receptor. These truncated receptors have heightened sensitivity to circulating Epo due to a lack of negative feedback regulation.This autosomal dominant trait does not necessarily carry an adverse prognosis in early life but is associated with an increased risk of thrombotic and vascular mortality in later life.
Chuvash polycythemia, a congenital polycythemia first recognized in an endemic Russian population, is a variant of primary familial and congenital polycythemia and has mutations in the von Hippel-Lindau (VHL) gene, which is associated with a mutation in the oxygen-sensing pathway that regulates Epo synthesis. Polycythemia outside of Russia found to have a similar mechanism is referred to as primary proliferative polycythemia.
Secondary polycythemia may result from functional hypoxia induced by lung disease, heart disease, increased altitude (hemoglobin increase of 4% for each 1000-m increase in altitude), congenital methemoglobinemia, and other high–oxygen affinity hemoglobinopathies stimulating increased Epo production. Secondary polycythemia may also result from increased Epo production secondary to benign and malignant Epo-secreting lesions.
High altitude erythrocytosis is evident within the first week of high-altitude exposure. A sharp increase in Epo production is noticeable, with associated mobilization of iron stores with evidence of iron-deficient erythropoiesis.
Abnormal high-affinity hemoglobin mutations characterized by left shift in the oxygen-hemoglobin dissociation curves lead to erythrocytosis. In most cases, no treatment is indicated for these patients because the erythrocytosis is compensatory. Similarly, in familial polycythemia with defects in 2,3-DPG metabolism, a left shift in the oxygen-hemoglobin curve is noted with a physiological response of polycythemia.
Secondary polycythemia of the newborn is fairly common and is seen in 1-5% of all newborns in the United States. It results from either chronic or acute fetal hypoxia or delayed cord clamping and stripping of the umbilical cord.
Aberrant erythropoietin production is seen with various renal, liver, CNS disorders and leads to physiologically inappropriate secondary polycythemia. Renal disorders frequently associated with polycythemia include renal cell carcinoma, Wilms tumor, polycystic kidneys, and renal transplantation. Erythrocytosis has also been documented in patients with hepatocellular carcinoma.
Epidemiology
Frequency
United States
Primary polycythemia is rare; the overall prevalence of polycythemia vera is 22 cases per 100,000 people.The annual incidence of polycythemia vera is 2 cases per 100,000 people. The median age is 70 years,with only 0.1% of cases of polycythemia vera observed in individuals younger than 20 years. Fewer than 50 cases of pediatric polycythemia vera have been reported in the literature. Polycythemia vera is less likely in blacks than in individuals of European ancestry, with a higher incidence in Ashkenazi Jews.
International
Polycythemia vera has a similar incidence in Western Europe as in the United States, and occurrence rates are very low in Africa and Asia (as low as 2 cases per million per year in Japan).
Mortality/Morbidity
Death rates for children are unavailable. The complications found in polycythemia vera are related to 2 primary factors. The first includes complications related to hyperviscosity. The second involves bone marrow–related complications. Untreated, the median survival time for these patients is 18 months. However, if patients are treated, survival is greatly extended, as many as 10-15 years with phlebotomy alone. The causes of death in adults are as follows:
- Thrombosis/thromboembolism (30-40%) -Myocardial infarctions, deep vein thrombosis, pulmonary embolus, portal splenic and mesenteric vein thrombosis
- Acute myelogenous leukemia (19%)
- Other malignancies (15%)
- Hemorrhage (2-10%)
- Myelofibrosis/myeloid metaplasia (4%)
- Other (25%)
In the neonatal period, polycythemia-induced hyperviscosity can lead to altered blood flow and subsequently affect organ function. Infants with polycythemia are at increased risk for necrotizing enterocolitis, renal dysfunction, hypoglycemia, and increased pulmonary vascular resistance with resultant hypoxia and cyanosis. Although initially thought to cause neurologic dysfunction, the decrease in cerebral blood flow seen in newborns with polycythemia is a physiologic response and does not appear to cause cerebral ischemia.
Race
In the United States, higher rates of polycythemia vera are observed in the Ashkenazi Jewish population, and lower rates are seen in blacks.
Sex
The male-to-female ratio is 1.2-2.2:1 in adults and 1:1 in children.
Age
The median age for polycythemia vera is 70 years.Only 0.1% of polycythemia cases occur in people younger than 20 years.
Pediatric Splenomegaly
Background
Splenomegaly in childhood is generally first suspected upon physical examination. One third of newborns and 10% of children may normally have a palpable spleen. The tip of the normal, palpable spleen is soft, smooth, nontender and less than 1-2 cm below the left costal margin. A pathologically enlarged spleen is often firm, may have an abnormal surface, and is frequently associated with signs and symptoms of the underlying disease. When any of these features are noted, or if the tip of the spleen is enlarged more than 1-2 cm below the costal margin, further evaluation should be considered.
Pathophysiology
Anatomy
The spleen is the largest lymphoid organ in the body. The spleen and the lymph nodes are the major components of the mononuclear-phagocyte system (MPS). They serve as filters that remove damaged cells, microorganisms, and particulate matter and deliver antigens to the immune system. The MPS, originally called the reticuloendothelial system, consists of fixed phagocytic cells in different organs. These phagocytes locally interact with lymphocytes and play an essential role in the recognition of antigens and their interaction with immunocompetent cells.
The splenic tissue consists of red and white pulp lying in a capsule. Blood enters the spleen through the splenic artery, a branch of the celiac artery. It then travels into the smaller arterioles and approaches the white pulp. The white pulp, rich in T and B lymphocytes, receives plasma for antigen processing. Splenic macrophages efficiently ingest these antigens and deliver them to the immunocompetent cells of the spleen for antibody production and stimulation of T-lymphocyte immune responses. The remaining hemoconcentrated blood continues into the contiguous red pulp, the sinuses and cords of which are also lined with macrophages.
The red pulp forms most of the splenic tissue and consists of splenic cords, the circulation of which is designated as open because no well-defined endothelial lining is present. To exit the cords, blood must pass through 1-µm to 5-µm slits in this fenestrated basement membrane to reach the venous sinusoids. The circulation through the cords is slow and congested. This delay provides prolonged exposure of blood cells, bacteria, and particulate matter to the dense mononuclear-phagocyte elements in the red pulp.
After reaching the sinuses, blood from the red pulp empties into the splenic vein, which joins the superior mesenteric vein to form the hepatic portal vein. Because no valves are present in the splenic venous system, the pressure in the splenic vein reflects the pressure in the portal vein.
Function
One of the primary functions of the spleen is the filtration of defective cells. Erythrocytes slowly pass through the hypoxic and acidotic environment of the splenic cords and then squeeze through narrow slits into the sinusoids. Although healthy erythrocytes readily accomplish this passage, aged and abnormal red cells, such as spherocytes and sickle cells, remain behind to be ingested by the macrophages lining the cords. Fc receptors on splenic macrophages also bind to IgG antibody-coated erythrocytes or platelets, which are mainly cleared by the spleen.
The spleen is also critical for clearing circulating, particularly encapsulated, bacteria. The amorphous polysaccharide coat of encapsulated bacteria greatly impairs their clearance in the absence of antibody, and only the spleen’s highly efficient phagocytic cords can effectively clear them. The splenic white pulp processes these intravenous antigens and produces antibody that, during subsequent exposures, allows for efficient clearance by the rest of the MPS.
The splenic cords are uniquely capable of removing erythrocytic inclusions, such as nuclear remnants (ie, Howell-Jolly bodies) or precipitated globin (ie, Heinz bodies), without destroying the cell. The spleen also serves as a reservoir for platelets and produces blood components (extramedullary hematopoiesis) if the bone marrow is unable to meet demands.
Epidemiology
Frequency
United States
A 1-cm to 2-cm splenic tip is palpable in 30% of full-term neonates and in as many as 10% of healthy children. Approximately 3% of healthy college freshmen have palpable spleens. Initial and follow-up studies confirm that these college freshmen are not at high risk for subsequent serious disease.
International
Malaria, schistosomiasis, and other infections in endemic areas are frequent causes of splenomegaly.
In malaria-endemic areas, the prevalence of splenomegaly (ie, spleen rate) is a measure of malaria exposure. In hyperendemic areas (eg, Papua New Guinea), the spleen rate in children exceeds 50%.Such hyperendemic areas have a prevalence of massive splenomegaly (hyperreactive malarial splenomegaly) of 1-2% in children.
Mortality/Morbidity
Splenic rupture may occur in acute splenomegaly associated with infectious mononucleosis. The incidence is 1:1000, and it usually occurs in the first 3 weeks of illness.
Splenectomy is uncommonly performed in children with splenomegaly. Nevertheless, should it be clinically indicated, the overall risk of postsplenectomy sepsis is approximately 2%, with increased incidence and mortality in young children.
Hypersplenism is the occurrence of thrombocytopenia, and occasionally leukopenia and anemia, in the context of significant splenomegaly.The cytopenias are usually mild but may contribute to overall morbidity.
Race
Specific causes of splenomegaly are most common in certain racial groups. Examples include splenic sequestration as a complication of sickle cell disease in patients of African or Mediterranean ancestry and noncirrhotic portal fibrosis in patients of Iranian, South Asian, or Japanese ancestry.
Age
The etiology of splenomegaly varies with age. For example, splenic sequestration in sickle cell disease occurs early in life, before the splenic involution that ultimately occurs in most patients with sickle cell disease.
Pediatric Thalassemia
Practice Essentials
Signs and symptoms
The clinical picture of the thalassemias varies widely, depending on the severity of the condition and the age at diagnosis. In the more severe forms of the disease (eg, β-thalassemia major), symptoms vary from extremely debilitating in patients who are not receiving transfusions to mild and almost asymptomatic in those receiving regular transfusion regimens and closely monitored chelation therapy.
Signs and symptoms of different types of thalassemia include the following:
- More severe forms: Some pallor, slight scleral icterus, enlarged abdomen
- Rare types of β-thalassemia trait: Severe hemolytic process requiring management, such as thalassemia intermedia or thalassemia major
- Hb E/β thalassemia: May have severe symptoms and clinical course identical to that of β-thalassemia major
- Heterozygous/homozygous Hb E: Usually slightly anemic and usually asymptomatic
- Α-Thalassemia: Clearly evident hematologic abnormalities in newborns with mild or moderate forms of the disease
- Β-Thalassemia: Extreme pallor, swollen abdomen due to hepatosplenomegaly
- Severe bony changes due to ineffective erythroid production (eg, frontal bossing, prominent facial bones, dental malocclusion)
- Hypermetabolism from ineffective erythropoiesis
- Gout due to hyperuricemia (occasionally)
- Iron overload: One of the major causes of morbidity in all patients with severe forms of thalassemia
- Growth retardation, failure to thrive
- Metabolic symptoms that suggest diabetes, thyroid disorder, or other endocrinopathy
- Neuropathy/paralysis in patients with severe anemia not receiving transfusion therapy
Diagnosis
The diagnosis of thalassemia is made through studies such as bone marrow examination, hemoglobin electrophoresis, and iron count. The CBC count and peripheral blood film examination results are usually sufficient to suspect the diagnosis. Hb evaluation confirms the diagnosis in β-thalassemia, Hb H disease, and Hb E/β thalassemia.
Classification of thalassemia
Although there are many types of thalassemic syndromes, each involves decreased production of one globin chain or more, which form the different Hbs normally found in RBCs. In clinical practice, the most important types affect either α- or β-chain synthesis.
The most common forms of α-thalassemia are as follows:
- Silent carrier α-thalassemia: The diagnosis cannot be confirmed based on Hb electrophoresis results, which are usually normal in all α-thalassemia traits
- Α-Thalassemia trait: Characterized by mild anemia and low RBC indices
- Hb H disease: Represents α-thalassemia intermedia, with mildly to moderately severe anemia, splenomegaly, icterus, and abnormal RBC indices
- Α-Thalassemia major: Results in the severe form of homozygous α-thalassemia
Some of the more common forms of β-thalassemia are as follows:
- Silent carrier β-thalassemia: Patients are asymptomatic, except for possible low RBC indices
- Β-Thalassemia trait: Patients have mild anemia, abnormal RBC indices, and abnormal Hb electrophoresis results with elevated levels of Hb A2, Hb F, or both
- Thalassemia intermedia: Patients have anemia of intermediate severity
- Β-thalassemia associated with β-chain structural variants: The most significant condition in this group of thalassemic syndromes is the Hb E/β thalassemia
- Thalassemia major (Cooley anemia): This condition is characterized by transfusion-dependent anemia, massive splenomegaly, bone deformities, growth retardation, and peculiar facies in untreated individuals, 80% of whom die within the first 5 years of life from complications of anemia
Staging
- Stage I patients: Received fewer than 100 units of packed red blood cells; usually asymptomatic
- Stage II patients: Received 100-400 units of blood; may report slight fatigue
- Stage III patients: Have symptoms ranging from palpitations to CHF
The Lucarelli classification is used for patients with severe disease who are candidates for hematopoietic stem cell transplantation.
Laboratory studies
- CBC count
- Hb electrophoresis
- Peripheral blood smear
- Iron studies (ie, levels of serum iron, serum ferritin)
- Complete RBC phenotype
- Hepatitis screen
- Folic acid level
- level of urinary excretion of iron after deferoxamine challenge
- HLA typing before initiation of blood transfusion therapy
- Renal function tests during chelation therapy
Imaging studies
- Skeletal survey: Reveals classic bony changes in patients who are not regularly transfused
- Chest radiography: To evaluate cardiac size and shape
- MRI or CT scanning of affected areas: To diagnose complications (eg, bony deformities, compression fractures)
- R2 MRI: For noninvasive measurement of liver and cardiac iron overload and to monitor response to iron chelation therapy (eg, FerriScan)
- ECG, echocardiography: To monitor cardiac function
Procedures
- Bone marrow examination: To exclude other conditions that may manifest as thalassemia major
- Liver biopsy: To assess iron deposition and the degree of hemochromatosis
Management
Patients with thalassemia traits do not require medical or follow-up care after the initial diagnosis is made. Do not initiate iron therapy unless a definite deficiency is confirmed.
Patients with severe thalassemia require medical treatment. Regular blood transfusion combined with well-monitored chelation therapy is the standard therapy.
Pharmacotherapy
- Antipyretics, analgesics (eg, acetaminophen)
- Antihistamines (eg, diphenhydramine)
- Chelating agents (eg, deferoxamine, deferasirox)
- Corticosteroids (eg, hydrocortisone)
- Antibacterial combinations (eg, TMP/SMX, gentamicin, penicillin V)
- Vitamins (eg, ascorbic acid, alpha-tocopherol, folic acid)
- Vaccines (eg, polyvalent pneumococcal; 7-valent pneumococcal conjugated; H influenzae type B; meningitis group A, C, Y, and W-135)
- Antineoplastics (eg, hydroxyurea)
- Growth hormone (eg, somatropin)
The FDA has expanded the approved use of deferasirox to treat children aged 10 years and older with chronic iron overload due to nontransfusion-dependent thalassemia (NTDT). The agency recommends administration of deferasirox in such children who have a hepatic iron concentration of at least 5 mg of iron per gram of dry liver weight. Previously, deferasirox was approved for managing chronic iron overload due to blood transfusions in patients ages 2 years and older.
Surgical options
- Splenectomy: Principal surgical procedure for many patients with thalassemia
- Placement of central line: For the ease and convenience of administering blood transfusions, chelation therapy, or both in patients with severe thalassemia on transfusion therapy
Background
The thalassemias are inherited disorders of hemoglobin (Hb) synthesis. Their clinical severity widely varies, ranging from asymptomatic forms to severe or even fatal entities. The name Mediterranean anemia, which Whipple introduced, is misleading because the condition can be found in any part of the world. As described below, different types of thalassemia are more endemic to certain geographic regions.
In 1925, Thomas Cooley, a Detroit pediatrician, described a severe type of anemia in children of Italian origin. He noted abundant nucleated red blood cells (RBCs) in the peripheral blood, which he initially thought was erythroblastic anemia, an entity that von Jaksh described earlier. Before long, Cooley realized that erythroblastemia is neither specific nor essential in this disorder and that the term erythroblastic anemia was nothing but a diagnostic catchall. Although Cooley was aware of the genetic nature of the disorder, he failed to investigate the apparently healthy parents of the affected children.
In Europe, Riette described Italian children with unexplained mild hypochromic and microcytic anemia in the same year Cooley reported the severe form of anemia later named after him. In addition, Wintrobe and coworkers in the United States reported a mild anemia in both parents of a child with Cooley anemia. This anemia was similar to the one that Riette described in Italy. Only then was Cooley’s severe anemia recognized as the homozygous form of the mild hypochromic and microcytic anemia that Riette and Wintrobe described. This severe form was then labeled as thalassemia major and the mild form as thalassemia minor. The word thalassemia is a Greek term derived from thalassa, which means “the sea” (referring to the Mediterranean), and emia, which means “related to blood.”
These initial patients are now recognized to have been afflicted with β thalassemia. In the following few years, different types of thalassemia that involved polypeptide chains other than β chains were recognized and described in detail.
In recent years, the molecular biology and genetics of the thalassemia syndromes have been described in detail, revealing the wide range of mutations encountered in each type of thalassemia, depicted in the image below.
β thalassemia alone can arise from any of more than 150 mutations.
Pathophysiology
The thalassemias are inherited disorders of Hb synthesis that result from an alteration in the rate of globin chain production. A decrease in the rate of production of a certain globin chain or chains (α, β, γ, δ) impedes Hb synthesis and creates an imbalance with the other, normally produced globin chains.
Because 2 types of chains (α and non-α) pair with each other at a ratio close to 1:1 to form normal Hbs, an excess of the normally produced type is present and accumulates in the cell as an unstable product, leading to the destruction of the cell. This imbalance is the hallmark of all forms of thalassemia. For this reason, most thalassemias are not considered hemoglobinopathies because the globin chains are normal in structure and because the defect is limited to a decreased rate of production of these normal chains. However, thalassemic hemoglobinopathies are recognized, as discussed below.
The type of thalassemia usually carries the name of the underproduced chain or chains. The reduction varies from a slight decrease to a complete absence of production. For example, when β chains are produced at a lower rate, the thalassemia is termed β+, whereas β-0 thalassemia indicates a complete absence of production of β chains from the involved allele.
The consequences of impaired production of globin chains ultimately result in the deposition of less Hb into each RBC, leading to hypochromasia. The Hb deficiency causes RBCs to be smaller, leading to the classic hypochromic and microcytic picture of thalassemia. This is true in almost all anemias caused by impairment in production of either of the 2 main components of Hb: heme or globin. However, this does not occur in the silent carrier state, since both Hb level and RBC indices remaiormal.
In the most common type of β thalassemia trait, the level of Hb A2 (δ2/α2) is usually elevated. This is due to the increased use of δ chains by the excessive free α chains, which results from a lack of adequate β chains with which to pair. The δ gene, unlike β and α genes, is known to have a physiologic limitation in its ability to produce adequate δ chains; by pairing with the α chains, δ chains produce Hb A2 (approximately 2.5-3% of the total Hb).
Some, but not all, of the excessive α chains are used to form Hb A2 with the δ chains, whereas the remaining α chains precipitate in the cells, reacting with cell membranes, intervening with normal cell division, and acting as foreign bodies, leading to destruction of RBCs. The degree of toxicity caused by the excessive chains varies according to the type of such chains (eg, the toxicity of α chains in β thalassemia is more prominent than the toxicity of β chains in α thalassemia).
β thalassemia is mostly related to a point mutation in the β globin gene. However, large deletions that may involve the entire β gene, or even extend to delete the neighboring δ gene, have been previously reported. Four new such mutations were identified in French patients. In 3 of these mutations, the deletion has extended to involve the δ gene, resulting in failure to produce any Hb A2. In such cases, the β/δ thalassemia is to be differentiated from the phenotypically similar condition known as hereditary persistence of fetal hemoglobin (HPFH). The importance of differentiating the conditions is reflected in prenatal and newborn screening for hemoglobinopathy.
In the severe forms, such as β thalassemia major or Cooley anemia, the same pathophysiology applies with substantial exaggeration. The significant excess of free α chains caused by the deficiency of β chains causes destruction of the RBC precursors in the bone marrow (ie, ineffective erythropoiesis).
Globin chain production
To understand the genetic changes that result in thalassemia, one should be familiar with the physiologic process of globin chain production in the healthy individual. The globin chain as a unit is a major building block for Hb: together with heme, it produces the Hb molecule (heme plus globin equals Hb). Two different pairs of globin chains form a tetrameric structure with a heme moiety in the center. All normal Hbs are formed from 2 α-like chains and 2 non-α chains. Various types of Hb are formed, depending on the types of chains pairing together. Such Hbs exhibit different oxygen-binding characteristics, normally related to the oxygen delivery requirement at different developmental stages in human life.
In embryonic life, ζ chains (α-like chains) combine with γ chains to produce Hb Portland (ζ2/γ2) and with ε chains to produce Hb Gower-1 (ζ2/ε2).
Subsequently, when α chains are produced, they form Hb Gower-2, pairing with ε chains (α2/ε2). Fetal Hb is composed of α2/γ2 and the primary adult Hb (Hb A) of α2/β2. A third physiologic Hb, known as Hb A2, is formed by α2/δ2 chains, as in the image below.
Alpha chain genes in duplication on chromosome 16 pairing with non-alpha chains to produce various normal hemoglobins.
Genetic changes
All the genes that control the production of globin chains lie within 1 of 2 clusters located on 2 different chromosomes. Chromosome 11 is the site of 5 functional b-like globin genes arranged in a link cluster over 60 kilobases (kb). From left to right (5′-3′), they are ε/γ-G/γ-A/δ/β. γ-G and γ-A differ by only one amino acid (alanine vs glycine).
A critical control region of the d-globin gene (promoter) is known to be defective; it inhibits messenger RNA (mRNA) processing, resulting in only a small amount of Hb A2 (α2/δ2) production, which thus accounts for less than 3% of total Hb in adult RBCs.
The α-like globin gene cluster is located on chromosome 16 and consists of 3 functional genes. From left to right (5′-3′), the genes are α/α2/α1.
Understanding the structure of the globin genes, how they are regulated to produce globin chains, and how the chains pair together to produce the various Hbs is critical for appreciating the different pathologic changes of this process that result in thalassemia.
Molecular biology
Each globin gene consists of a string of nucleotide bases divided into 3 coding sequences, termed exons, and 2 noncoding regions, known as introns or intervening sequences (IVS). See the image below.
Three other regions, known as regulatory regions, are also present in the 5′ noncoding or flanking region of each globin gene.
The first is the promoter, which plays a major role in the transcription of the structural genes. The second region is the enhancer, which has an important role in promoting erythroid-specific gene expression, as well as in coordinating the changes in globin gene activity at different stages of development (embryonal, fetal, adult). Enhancers can influence gene expression, despite being located some distance away from the gene itself, and, unlike the promoter, they can stimulate transcription irrespective of their orientation relative to the transcription start site. Finally, master regulatory sequences, known as locus control regions (in the β-globin gene family) and HS40 (in the α gene complex), are responsible for activating the genes in erythroid cells.
Each of these regulatory sequences has a modular structure that consists of short nucleotide motifs that act as binding sites for transcriptional activator or suppressor molecules. Such molecules activate or suppress gene expression in different cell types at different stages of development. A certain gene is transcribed by an initiation complex formed of certain proteins and a number of transcription factors, which interact with binding sites on the promoters and other regulatory sequences of the relevant genes.
When a gene is transcribed, mRNA is synthesized from one of the gene’s DNA strands by the action of RNA polymerase. The initial product is a large mRNA precursor. Both exons and introns are initially present on this mRNA precursor; the introns are ultimately subsequently eliminated, and the exons are spliced together in the nucleus. At this stage, the mRNA, which has also been modified at both 5′ and 3′ ends, moves to the cytoplasm to act as a template for the production of globin chains.
Carrier molecules (transfer RNA [tRNA]) transport amino acids to the mRNA template. Each amino acid has a specific tRNA, which also contains 3 bases (anticodon), complimentary to the mRNA codons for that amino acid. The position of each amino acid in the globin chain is thus established by its corresponding triplet code (codon) in the globin gene. The cytidine, uridine, and guanosine (CUG) codon, for example, encodes the amino acid leucine, while the adenosine, adenosine, and adenosine (AAA) codon encodes lysine. When a tRNA molecule carries the initial amino acid to the template, directed by codon-anticodon base pairing, globin chain synthesis begins.
Once the first tRNA is in place, a complex is formed between several protein initiation factors and the subunit of the ribosome that is to hold the growing peptide chains together on the mRNA as it is translated. A second tRNA moves in alongside, and a new amino acid is bound to the first with a peptide bond, resulting in a peptide chain 2 amino acids long. This process continues from left to right until a specific codon for termination is reached. At this point, the completed peptide chain drops off the ribosome-mRNA complex and the ribosomal subunits are recycled. The globin chain is now ready to join a heme molecule and 3 other globin chains to form an Hb molecule.
The developmental switches from embryonic to fetal and then to adult Hb production are synchronized throughout the different organs of hematopoiesis (yolk sack, liver, bone marrow), which function at various stages of development. Even though the mechanism of such switches is not clearly understood, the globin gene promoter is known to contain information that specifies developmental stages of transcription.
Molecular pathology
To date, more than 1000 inherited mutations that affect either the structure or synthesis of the α- and β-globin chains are known. Mutations that result in β or α thalassemia are similar in principle but different in their patterns. Presently, more than 200 molecular defects known to downregulate the expression of β globin have been characterized. Such defects result in various types of β thalassemia.
Major deletions in β thalassemia are unusual (in contrast to α thalassemia), and most of the encountered mutations are single base changes, small deletions, or insertions of 1-2 bases at a critical site along the gene, as in the image below.
These mutations occur in both exons and introns. For example, in a nonsense mutation, a single base change in the exon generates a stop codon in the coding region of the mRNA, resulting in premature termination of globin chain synthesis. This termination leads to the production of short, nonviable β chains.
Conversely, in the frame shift mutation, one or more bases on the exon are lost or inserted, resulting in a change in the reading frame of the genetic code or the production of a new stop codon.
RNA-splicing mutations are fairly common and represent a large portion of all mutations that result in β thalassemia. These mutations corrupt the splicing process. The importance of precise splicing in the quantitative production of stable functional mRNA cannot be overemphasized.
Slippage by even one nucleotide changes the reading frame of the mRNA. Both ends of the RNA introns (at the junction with the exons) have specific consensus sequences; these motifs include GT in the 5′ (left end or donor site) consensus sequence and AG in the 3′ (right end or acceptor site) consensus sequence. Such sequences are obligatory for correct splicing, and a single substitution at the invariant GT or AG sequence prevents splicing altogether and results in β-0 or α-0 thalassemia. Mutations in the other members of the consensus sequences, although still highly conserved, result in variable degrees of ineffective β-globin production, causing milder types of β thalassemia.
Mutations in exon sequences may activate a cryptic splice site. For example, in exon 1 of the β-globin gene, a consensus sequence that resembles a sequence in IVS-1 has been identified as the site for several distinct mutations, resulting in a gene that carries the features of both thalassemia and hemoglobinopathy simultaneously (quantitatively and qualitatively abnormal Hb production). This type of mutation represents a clear link between the thalassemias and the hemoglobinopathies, and, accordingly, these are labeled thalassemic hemoglobinopathies.
Thus, mutations at codon 19 (A to G), 26 (G to A), and 27 (G to T)—all in exon 1—result in reduced production of mRNA (thalassemia) because of inefficient splicing and an amino acid substitution encoded by the mRNA that is spliced and translated (albeit inefficiently) into protein. The resulting abnormal Hbs are Malay, E, and Knossos, respectively.
The flanking regions of the β-globin gene are also sites for various mutations. A single base substitution that involves the promoter element, for example, can downregulate β-globin gene transcription, resulting in a mild form of β thalassemia. Conversely, a mutation that affects the 3′ end of the β-globin mRNA can interfere with its processing, resulting in a severe form of β thalassemia.
Clearly, many different β thalassemia mutations exist, and compound heterozygosity is frequently encountered. The resulting laboratory findings may lead to confusion. An example is the patient who manifests symptoms of β thalassemia major without an elevated Hb A2 level. The explanation for such a situation is often co-inheritance of β and δ thalassemia. δ/β thalassemia further is divided into δ/β+ or δ/β-0.
In the first type, a misalignment in the δ/β genes during meiosis results in the production of fused δ/β genes, a process responsible for the production of an Hb variant termed Hb Lepore.
The fused δ/β gene is under the control of a δ-globin gene promoter region (the β gene promoter is deleted in the process). Because the δ gene promoter carries mutations that lead to ineffective transcription, the fused δ/β chains are produced in limited amounts, resulting in thalassemia. This is in addition to the hemoglobinopathy.
Conversely, in d/β-0 thalassemia, a large deletion occurs in the β-globin gene cluster, removing both the δ and the β genes, which can also extend to involve all globin genes on chromosome 11, thus producing ε, γ, δ, and β-0 thalassemia.
Cellular pathophysiology
The basic defect in all types of thalassemia is imbalanced globin chain synthesis. However, the consequences of accumulation of the excessive globin chains in the various types of thalassemia are different. In β thalassemia, excessive α chains, unable to form Hb tetramers, precipitate in the RBC precursors and, in one way or another, produce most of the manifestations encountered in all of the β thalassemia syndromes; this is not the situation in α thalassemia.
The excessive chains in α thalassemia are γ chains earlier in life and β chains later in life. Because such chains are relatively soluble, they are able to form homotetramers that, although relatively unstable, nevertheless remain viable and able to produce soluble Hb molecules such as Hb Bart (4 γ chains) and Hb H (4 β chains). These basic differences in the 2 main types of thalassemia are responsible for the major differences in their clinical manifestations and severity.
α chains that accumulate in the RBC precursors are insoluble, precipitate in the cell, interact with the membrane (causing significant damage), and interfere with cell division. This leads to excessive intramedullary destruction of the RBC precursors. In addition, the surviving cells that arrive in the peripheral blood with intracellular inclusion bodies (excess chains) are subject to hemolysis; this means that both hemolysis and ineffective erythropoiesis cause anemia in the person with β thalassemia.
The ability of some RBCs to maintain the production of γ chains, which are capable of pairing with some of the excessive α chains to produce Hb F, is advantageous. Binding some of the excess a chains undoubtedly reduces the symptoms of the disease and provides additional Hb with oxygen-carrying ability.
Furthermore, increased production of Hb F, in response to severe anemia, adds another mechanism to protect the RBCs in persons with β thalassemia. The elevated Hb F level increases oxygen affinity, leading to hypoxia, which, together with the profound anemia, stimulates the production of erythropoietin. As a result, severe expansion of the ineffective erythroid mass leads to severe bone expansion and deformities. Both iron absorption and metabolic rate increase, adding more symptoms to the clinical and laboratory manifestations of the disease. The large numbers of abnormal RBCs processed by the spleen, together with its hematopoietic response to the anemia if untreated, results in massive splenomegaly, leading to manifestations of hypersplenism.
If the chronic anemia in these patients is corrected with regular blood transfusions, the severe expansion of the ineffective marrow is reversed. Adding a second source of iron would theoretically result in more harm to the patient. However, this is not the case because iron absorption is regulated by 2 major factors: ineffective erythropoiesis and iron status in the patient.
Ineffective erythropoiesis results in increased absorption of iron because of downregulation of the HAMP gene, which produces a liver hormone called hepcidin. Hepcidin regulates dietary iron absorption, plasma iron concentration, and tissue iron distribution and is the major regulator of iron. It acts by causing degradation of its receptor, the cellular iron exporter ferroportin. When ferroportin is degraded, it decreases iron flow into the plasma from the gut, from macrophages, and from hepatocytes, leading to a low plasma iron concentration. In severe hepcidin deficiency, iron absorption is increased and macrophages are usually iron depleted, such as is observed in patients with thalassemia intermedia.
Malfunctions of the hepcidin-ferroportin axis contribute to the etiology of different anemias, such as is seen in thalassemia, anemia of inflammation, and chronic renal diseases. Improvement and availability of hepcidin assays facilitates diagnosis of such conditions. The development of hepcidin agonists and antagonists may enhance the treatment of such anemias.
By administering blood transfusions, the ineffective erythropoiesis is reversed, and the hepcidin level is increased; thus, iron absorption is decreased and macrophages retain iron.
Iron status is another important factor that influences iron absorption. In patients with iron overload (eg, hemochromatosis), the iron absorption decreases because of an increased hepcidin level. However, this is not the case in patients with severe β thalassemia because a putative plasma factor overrides such mechanisms and prevents the production of hepcidin. Thus, iron absorption continues despite the iron overload status.
As mentioned above, the effect of hepcidin on iron recycling is carried through its receptor “ferroportin,” which exports iron from enterocytes and macrophages to the plasma and exports iron from the placenta to the fetus. Ferroportin is upregulated by iron stores and downregulated by hepcidin. This relationship may also explain why patients with β thalassemia who have similar iron loads have different ferritin levels based on whether or not they receive regular blood transfusions.
For example, patients with β thalassemia intermedia who are not receiving blood transfusions have lower ferritin levels than those with β thalassemia major who are receiving regular transfusion regimens, despite a similar iron overload. In the latter group, hepcidin allows recycling of the iron from the macrophages, releasing high amounts of ferritin. In patients with β thalassemia intermedia, in whom the macrophages are depleted despite iron overload, lower amounts of ferritin are released, resulting in a lower ferritin level.
Most nonheme iron in healthy individuals is bound tightly to its carrier protein, transferrin. In iron overload conditions, such as severe thalassemia, the transferrin becomes saturated, and free iron is found in the plasma. This iron is harmful since it provides the material for the production of hydroxyl radicals and additionally accumulates in various organs, such as the heart, endocrine glands, and liver, resulting in significant damage to these organs.
By understanding the etiology of the symptoms in thalassemia, one can appreciate that certain modifiers may result in the development of milder types of thalassemia. Factors that may reduce the degree of globin chain imbalance are expected to modify the severity of the symptoms; co-inheritance of α thalassemia, the presence of higher Hb F level, or the presence of a milder thalassemia mutation all typically ameliorate the symptoms of thalassemia.
Malaria hypothesis
In 1949, Haldane suggested a selective advantage for survival in individuals with the thalassemia trait in regions where malaria is endemic. He argued that lethal RBC disorders such as thalassemia, sickle cell disease, and G-6-PD deficiency are present almost exclusively in tropical and subtropical regions of the world. The incidence of these genetic mutations in a certain population thus reflects the balance between the premature death of homozygotes and the increased fitness of heterozygotes.
For instance, in β thalassemia, the frequency of the gene is greater than 1% in the Mediterranean Basin, India, Southeast Asia, North Africa, and Indonesia; it is very uncommon in other parts of the world. α thalassemia may be the most common single gene disorder in the world (5-10% in the Mediterranean, 20-30% in West Africa, approximately 68% in the South Pacific); however, the gene prevalence in Northern Europe and Japan is less than 1%.
The mechanism of protection against malaria is not clear. Hb F in cells has been demonstrated to retard the growth of the malaria parasite, and, by virtue of its high level in infants with β thalassemia trait, the fatal cerebral malaria known to kill infants in these areas may be prevented. The RBCs of patients with Hb H disease have also shown a suppressive effect on the growth of the parasites. This effect is not observed in α thalassemia trait.
Classification of thalassemia
A large number of thalassemic syndromes are currently known; each involves decreased production of one globin chain or more, which form the different Hbs normally found in RBCs. The most important types in clinical practice are those that affect either α or β chain synthesis.
α thalassemia
Several forms of α thalassemia are known in clinical practice. The most common forms are as follows:
- Silent carrier α thalassemia
- This is a fairly common type of subclinical thalassemia, usually found by chance among various ethnic populations, particularly African American, while the child is being evaluated for some other condition. As pointed out above, 2 α genes are located on each chromosome 16, giving α thalassemia the unique feature of gene duplication, see the image below. This duplication is in contrast to only one β-globin gene on chromosome 11. Alpha and beta globin genes (chromosomes 16 and 11, respectively).
- In the silent carrier state, one of the α genes is usually absent, leaving only 3 of 4 genes (aa/ao). Patients are hematologically healthy, except for occasional low RBC indices.
- In this form, the diagnosis cannot be confirmed based on Hb electrophoresis results, which are usually normal in all α thalassemia traits. More sophisticated tests are necessary to confirm the diagnosis. One may look for hematologic abnormalities in family members (eg, parents) to support the diagnosis. A CBC count in one parent that demonstrates hypochromia and microcytosis in the absence of any explanation is frequently adequate evidence for the presence of thalassemia.
- α thalassemia trait: This trait is characterized by mild anemia and low RBC indices. This condition is typically caused by the deletion of 2 α (a) genes on one chromosome 16 (aa/oo) or one from each chromosome (ao/ao). This condition is encountered mainly in Southeast Asia, the Indian subcontinent, and some parts of the Middle East. The ao/ao form is much more common in black populations because the doubly deleted (oo) form of chromosome 16 is rare in this ethnic group.
- Hb H disease: This condition, which results from the deletion or inactivation of 3 α globin genes (oo/ao), represents α thalassemia intermedia, with mildly to moderately severe anemia, splenomegaly, icterus, and abnormal RBC indices. When peripheral blood films stained with supravital stain or reticulocyte preparations are examined, unique inclusions in the RBCs are usually observed. These inclusions represent b chain tetramers (Hb H), which are unstable and precipitate in the RBC, giving it the appearance of a golf ball. These inclusions are termed Heinz bodies, depicted below.
Supra vital stain in hemoglobin H disease that reveals Heinz bodies (golf ball appearance).
- α thalassemia major: This condition is the result of complete deletion of the a gene cluster on both copies of chromosome 16 (oo/oo), leading to the severe form of homozygous α thalassemia, which is usually incompatible with life and results in hydrops fetalis unless intrauterine blood transfusion is given.
β thalassemia
Similar to α thalassemia, several clinical forms of β thalassemia are recognized; some of the more common forms are as follows:
- Silent carrier β thalassemia: Similar to patients who silently carry α thalassemia, these patients have no symptoms, except for possible low RBC indices. The mutation that causes the thalassemia is very mild and represents a β+ thalassemia.
- β thalassemia trait: Patients have mild anemia, abnormal RBC indices, and abnormal Hb electrophoresis results with elevated levels of Hb A2, Hb F, or both. Peripheral blood film examination usually reveals marked hypochromia and microcytosis (without the anisocytosis usually encountered in iron deficiency anemia), target cells, and faint basophilic stippling, as depicted below. The production of β chains from the abnormal allele varies from complete absence to variable degrees of deficiency.
Peripheral blood film in thalassemia minor.
- Thalassemia intermedia: This condition is usually due to a compound heterozygous state, resulting in anemia of intermediate severity, which typically does not require regular blood transfusions.
- β thalassemia associated with β chain structural variants: The most significant condition in this group of thalassemic syndromes is the Hb E/β thalassemia, which may vary in its clinical severity from as mild as thalassemia intermedia to as severe as β thalassemia major.
- Thalassemia major (Cooley anemia): This condition is characterized by transfusion-dependent anemia, massive splenomegaly, bone deformities, growth retardation, and peculiar facies in untreated individuals, 80% of whom die within the first 5 years of life from complications of anemia. Examination of a peripheral blood preparation in such patients reveals severe hypochromia and microcytosis, marked anisocytosis, fragmented RBCs, hypochromic macrocytes, polychromasia, nucleated RBCs, and, on occasion, immature leukocytes, as shown below.
Peripheral blood film in Cooley anemia.
Frequency
United States
Because of immigration to the United States from all parts of the world and the intermarriages that have taken place over the years, all types of thalassemia occur in any given part of the country. However, until recently, the number of patients with severe forms of both β and α thalassemia has been very limited. For this reason, finding more than 2-5 patients with the very severe forms in any pediatric hematology center is unusual (except for in the few referral centers in the United States).
However, this situation is changing rapidly in certain parts of the country. In the last 10 years, Asian immigration has been steadily increasing. According to the Federal Census Bureau, in 1990, 6.9 million Asians were in the United States, twice that reported in the 1980 Census count. The prevalence of various thalassemia syndromes in this population is very high. β and α thalassemia, as well as Hb E/β thalassemia, are currently on the rise in the state of California as a result of the large concentration of Asian immigrants in that part of the country.
The interaction between Hb E (a β chain variant) and β thalassemia (both very common among Southeast Asians) has created the Hb E/β thalassemia entity, which is now believed to be the most common thalassemia disorder in many regions of the world, including coastal North America, thus replacing β thalassemia major in frequency. For this reason, the cord-blood screening program for detection of hemoglobinopathy in California has been modified to include the detection of Hb H disease. In California alone, 10-14 new cases of β thalassemia major and Hb E/β thalassemia and 40 cases of neonatal Hb H disease are detected annually.
International
Worldwide, 15 million people have clinically apparent thalassemic disorders. Reportedly, disorders worldwide, and people who carry thalassemia in India alone number approximately 30 million. These facts confirm that thalassemias are among the most common genetic disorders in humans; they are encountered among all ethnic groups and in almost every country around the world.
Certain types of thalassemia are more common in specific parts of the world. β thalassemia is much more common in Mediterranean countries such as Greece, Italy, and Spain. Many Mediterranean islands, including Cyprus, Sardinia, and Malta, have a significantly high incidence of severe β thalassemia, constituting a major public health problem. For instance, in Cyprus, 1 in 7 individuals carries the gene, which translates into 1 in 49 marriages between carriers and 1 in 158 newborns expected to have β thalassemia major. As a result, preventive measures established and enforced by public health authorities have been very effective in decreasing the incidence among their populations. β thalassemia is also common in North Africa, the Middle East, India, and Eastern Europe. Conversely, α thalassemia is more common in Southeast Asia, India, the Middle East, and Africa.
Mortality/Morbidity
α thalassemia major is a mortal disease, and virtually all affected fetuses are born with hydrops fetalis as a result of severe anemia. Several reports describe newborns with α thalassemia major who survived after receiving intrauterine blood transfusions. Such patients require extensive medical care thereafter, including regular blood transfusions and chelation therapy, similar to patients with β thalassemia major. Morbidity and mortality remain high among such patients. In the rare reports of newborns with α thalassemia major born without hydrops fetalis who survived without intrauterine transfusion, high level of Hb Portland, which is a normally functioning embryonic Hb, is thought to be the cause for the unusual clinical course.
Patients with Hb H disease also require close monitoring. They may require frequent or only occasional blood transfusions, depending on the severity of the condition. Some patients may require splenectomy. Morbidity is usually related to the anemia, complications of blood transfusions, massive splenomegaly in some patients, or the complications of splenectomy in others.
In patients with various types of β thalassemia, mortality and morbidity vary according to the severity of the disease and the quality of care provided. Severe cases of β thalassemia major are fatal if not treated. Heart failure due to severe anemia or iron overload is a common cause of death in affected persons. Liver disease, fulminating infection, or other complications precipitated by the disease or by its treatment are some of the causes of morbidity and mortality in the severe forms of thalassemia.
Morbidity and mortality are not limited to untreated persons; those receiving well-designed treatment regimens also may be susceptible to the various complications of the disease. Organ damage due to iron overload, chronic serious infections precipitated by blood transfusions, or complications of chelation therapy, such as cataracts, deafness, or infections with unusual microorganisms (eg, Yersinia enterocolitica), are all considered potential complications.
Race
Although thalassemia occurs in all races and ethnic groups, certain types of thalassemia are more common in some ethnic groups than in others (see Frequency). β thalassemia is common in southern Europe, the Middle East, India, and Africa. α thalassemia is more common in Southeast Asia; nevertheless, it is also seen in other parts of the world. Furthermore, specific mutations of the same type of thalassemia are more common among certain ethnic groups than others; this facilitates the screening and diagnostic processes because certain probes for the more common mutations in a particular region are usually readily available.
The α thalassemia trait in Africa is usually not of the cis deletion on chromosome 16, unlike the condition in Southeast Asia, which is associated with complete absence of the α gene on one chromosome. When both parents have the cis deletion, the fetus may develop hydrops fetalis. For this reason, hydrops fetalis is not a risk in the African population, although it remains a risk for Southeast Asian population.
Sex
Both sexes are equally affected with thalassemia.
Age
Despite thalassemia’s inherited nature, age at onset of symptoms varies significantly. In α thalassemia, clinical abnormalities in patients with severe cases and hematologic findings in carriers are evident at birth. Unexplained hypochromia and microcytosis in a neonate, depicted below, are highly suggestive of the diagnosis.
Peripheral blood film in hemoglobin H disease in a newborn.
However, in the severe forms of β thalassemia, symptoms may not be evident until the second half of the first year of life; until that time, the production of γ-globin chains and their incorporation into fetal Hb can mask the condition.
Milder forms of thalassemia are frequently discovered by chance and at various ages. Many patients with an apparent homozygous β thalassemia condition (ie, hypochromasia, microcytosis, electrophoresis negative for Hb A, evidence that both parents are affected) may show no significant symptoms or anemia for several years. Almost all such patients’ conditions are categorized as β thalassemia intermedia during the course of their disease. This situation usually results when the patient has a milder form of the mutation, is a compound heterozygote for β+ and β-0 thalassemia, or has other compound heterozygosity.
References
а) Basic
1. Manual of Propaedeutic Pediatrics / S.O. Nykytyuk, N.I. Balatska, N.B. Galyash, N.O. Lishchenko, O.Y. Nykytyuk – Ternopil: TSMU, 2005. – 468 pp.
2. Kapitan T. Propaedeutics of children’s diseases and nursing of the child : [Textbook for students of higher medical educational institutions] ; Fourth edition, updated and translated in English / T. Kapitan –
3. Nelson Textbook of Pediatrics /edited by Richard E. Behrman, Robert M. Kliegman; senior editor, Waldo E. Nelson – 19th ed. – W.B.Saunders Company, 2011. – 2680 p.
b) Additional
1. www.bookfinder.com/author/american-academy-of-pediatrics
2. www.emedicine.medscape.com
3. http://www.nlm.nih.gov/medlineplus/medlineplus.html
