HEMORRHAGIC DIATHESIS
Haemophilia is a group of hereditary genetic disorders that impair the body’s ability to control blood clotting or coagulation, which is used to stop bleeding when a blood vessel is broken. Haemophilia A (clotting factor VIII deficiency) is the most common form of the disorder, occurring at about
Haemophilia B (factor IX deficiency) occurs at about
Like most recessive sex-linked, X chromosome disorders, haemophilia is more likely to occur in males than females. This is because females have two X chromosomes while males have only one, so the defective gene is guaranteed to manifest in any male who carries it. Because females have two X chromosomes and haemophilia is rare, the chance of a female having two defective copies of the gene is very low, so females are almost exclusively asymptomatic carriers of the disorder. Female carriers can inherit the defective gene from either their mother or father, or it may be a new mutation. Only under rare circumstances do females actually have haemophilia.
Haemophilia lowers blood plasma clotting factor levels of the coagulation factors needed for a normal clotting process. Thus when a blood vessel is injured, a temporary scab does form, but the missing coagulation factors prevent fibrin formation, which is necessary to maintain the blood clot. A haemophiliac does not bleed more intensely than a normal person, but can bleed for a much longer time. In severe haemophiliacs even a minor injury can result in blood loss lasting days or weeks, or even never healing completely. In areas such as the brain or inside
joints, this can be fatal or permanently debilitating.
Signs and symptoms
Characteristic symptoms vary with severity. In general symptoms are internal or external bleeding episodes, which are called “bleeds”. Patients with more severe haemophilia suffer more severe and more frequent bleeds,while patients with mild haemophilia typically suffer more minor symptoms except after surgery or serious trauma. Moderate haemophiliacs have variable symptoms which manifest along a spectrum between severe and mild forms.Prolonged bleeding and re-bleeding are the diagnostic symptoms of haemophilia. Internal bleeding is common in
people with severe haemophilia and some individuals with moderate haemophilia. The most characteristic type of internal bleed is a joint bleed where blood enters into the joint spaces.
This is most common with severe haemophiliacs and can occur spontaneously (without evident trauma). If not treated promptly, joint bleeds can lead to permanent joint damage and disfigurement. Bleeding into soft tissues such as muscles and subcutaneous tissues is less severe but can lead to damage and requires treatment.
Children with mild to moderate haemophilia may not have any signs or symptoms at birth especially if they do not undergo circumcision. Their first symptoms are often frequent and large bruises and haematomas from frequent bumps and falls as they learn to walk. Swelling and bruising from bleeding in the joints, soft tissue, and muscles may also occur. Children with mild haemophilia may not have noticeable symptoms for many years. Often, the first sign in very mild haemophiliacs is heavy bleeding from a dental procedure, an accident, or surgery. Females who are carriers usually have enough clotting factors from their one normal gene to prevent serious bleeding problems, though some may present as mild haemophiliacs.
Complications
Severe complications are much more common in severe and moderate haemophiliacs. Complications may be both directly from the disease or from its treatment:
• Deep internal bleeding, e.g. deep-muscle bleeding, leading to swelling, numbness or pain of a limb.
• Joint damage from haemarthrosis, potentially with severe pain, disfigurement, and even destruction of the joint and development of debilitating arthritis.
• Transfusion transmitted infection from blood transfusions that are given as treatment.
• Adverse reactions to clotting factor treatment, including the development of an immune inhibitor which renders factor replacement less effective.
• Intracranial haemorrhage is a serious medical emergency caused by the buildup of pressure inside the skull. It can cause disorientation, nausea, loss of consciousness, brain damage, and death.
Life expectancy
Like most aspects of the disorder, life expectancy varies with severity and adequate treatment. People with severe haemophilia who don’t receive adequate, modern treatment have greatly shortened lifespans and often do not reach maturity.
Today with appropriate treatment, males with haemophilia typically have a near normal quality of life with an average lifespan approximately 10 years shorter than an unaffected male.
Since the 1980s the primary leading cause of death of people with severe haemophilia has shifted from haemorrhage to HIV/AIDS acquired through treatment with contaminated blood products. The second leading cause of death related to severe haemophilia complications is intracranial haemorrhage which today accounts for one third of all deaths of patients with haemophilia. Two other major causes of death include: hepatitis infections causing cirrhosis and, obstruction of air or blood flow due to soft tissue haemorrhage.
Causes
• Haemophilia A is a recessive X-linked genetic disorder involving a lack of functional clotting Factor VIII and
represents 80% of haemophilia cases.
• Haemophilia B is a recessive X-linked genetic disorder involving a lack of functional clotting Factor IX. It comprises approximately 20% of haemophilia cases.
• Haemophilia C is an autosomal genetic disorder (i.e. not X-linked) involving a lack of functional clotting Factor
XI. Haemophilia C is not completely recessive: heterozygous individuals also show increased bleeding.
Genetics
X-linked recessive inheritance Females possess two X-chromosomes, males have one X and one Ychromosome. Since the mutations causing the disease are X-linked, a
woman carrying the defect on one of her X-chromosomes may not be affected by it, as the equivalent allele on her other chromosome should express itself to produce the necessary clotting factors, due to X inactivation. However, the Y-chromosome in men has no gene for factors VIII or IX. If the genes responsible for production of factor VIII or factor IX present on a male’s X-chromosome are deficient there is no equivalent on the Y-chromosome to cancel it out, so the deficient gene is not masked and he will develop the illness. Since a male receives his single X-chromosome from his mother, the son of a healthy female silently carrying the deficient gene will have a
50% chance of inheriting that gene from her and with it the disease; and if his mother is affected with haemophilia, he will have a 100% chance of being a haemophiliac. In contrast, for a female to inherit the disease, she must receive two deficient X-chromosomes, one from her mother and the other from her father (who must therefore be a haemophiliac himself). Hence haemophilia is far more common among males than females. However, it is possible for female carriers to become mild haemophiliacs due to lyonisation (inactivation) of the X chromosomes. Haemophiliac daughters are more common than they once were, as improved treatments for the disease have allowed more haemophiliac males to survive to adulthood and become
parents. Adult females may experience menorrhagia (heavy periods) due to the bleeding tendency. The pattern of inheritance is criss-cross type. This type of pattern is also seen in colour blindness. A mother who is a carrier has a 50% chance of passing the faulty X chromosome to her daughter, while an affected father will always pass on the affected gene to his daughters. A son cannot inherit the defective gene from his father. Genetic testing and genetic counselling is recommended for families with haemophilia. Prenatal testing, such as amniocentesis, is available to pregnant women who may be carriers of the condition. As with all genetic disorders, it is of course also possible for a human to acquire it spontaneously through mutation,
rather than inheriting it, because of a new mutation in one of their parents’ gametes. Spontaneous mutations account for about 33% of all cases of haemophilia A. About 30% of cases of haemophilia B are the result of a spontaneous gene mutation.
If a female gives birth to a haemophiliac child, either the female is a carrier for the disease or the haemophilia was the result of a spontaneous mutation. Until modern direct DNA testing, however, it was impossible to determine if a female with only healthy children was a carrier or not. Generally, the more healthy sons she bore, the higher the probability that she was not a carrier.
If a male is afflicted with the disease and has children with a female who is not even a carrier, his daughters will be carriers of haemophilia. His sons, however, will not be affected with the disease. The disease is X-linked and the father cannot pass haemophilia through the Y chromosome. Males with the disorder are theo more likely to pass on the gene to their children than carrier females, though all daughters they sire will be carriers and all sons they father will not have haemophilia (unless the mother is a carrier).
Severity
There are numerous different mutations which cause each type of haemophilia. Due to differences in changes to the genes involved, patients with haemophilia often have some level of active clotting factor. Individuals with less than 1% active factor are classified as having severe haemophilia, those with 1-5% active factor have moderate
haemophilia, and those with mild haemophilia have between 5-40% of normal levels of active clotting factor.
Diagnosis
Haemophilia A can be mimicked by von Willebrand disease.
• von Willebrand Disease could significantly affect as many as
• von Willebrand Disease type 2A, where decreased levels of von Willebrand Factor can lead to premature proteolysis of Factor VIII. In contrast to haemophilia, vWD type 2A is inherited in an autosomal dominant fashion.
• von Willebrand Disease type 2N, where von Willebrand Factor cannot bind Factor VIII, autosomal recessive inheritance. (i.e.; both parents need to give the child a copy of the gene).
• von Willebrand Disease type 3, where lack of von Willebrand Factor causes premature proteolysis of Factor VIII. In contrast to haemophilia, vWD type 3 is inherited in an autosomal recessive fashion.
Additionally, severe cases of vitamin K deficiency can present similar symptoms to haemophilia. This is due to the fact that vitamin K is necessary for the human body to produce several protein clotting factors. This vitamin deficiency is rare in adults and older children but is common iewborns. Infants are born with naturally low levels
of vitamin K and do not yet have the symbiotic gut flora to properly synthesize their own vitamin K. Bleeding issues due to vitamin K deficiency in infants is known as “haemorrhagic disease of the newborn”, to avoid this complication newborns are routinely injected with vitamin K supplements.
Though there is no cure for haemophilia, it can be controlled with regular infusions of the deficient clotting factor, i.e. factor VIII in haemophilia A or factor IX in haemophilia B. Factor replacement can be either isolated from human blood serum, recombinant, or a combination of the two. Some haemophiliacs develop antibodies
(inhibitors) against the replacement factors given to them, so the amount of the factor has to be increased or non-human replacement products must be given, such as porcine factor VIII.
If a patient becomes refractory to replacement coagulation factor as a result of circulating inhibitors, this may be partially overcome with recombinant human factor VII (NovoSeven), which is registered for this indication in many countries.
Preventive exercises
It is recommended that people affected with haemophilia do specific exercises to strengthen the joints, particularly the elbows, knees, and ankles. Exercises include elements which increase flexibility, tone, and strength of muscles, increasing their ability to protect joints from damaging bleeds. These exercises are recommended after an internal bleed occurs and on a daily basis to strengthen the muscles and joints to prevent new bleeding problems.
Many recommended exercises include standard sports warm-up and training exercises such as stretching of the calves, ankle circles, elbow flexions, and quadriceps sets.
Contraindications
Anticoagulants such as Heparin and Warfarin are contraindicated for people with haemophilia as these can aggravate clotting difficulties. Also contraindicated are those drugs which have “blood thinning” side effects. For instance,
medications which contain aspirin, ibuprofen, or naproxen sodium should not be taken because they are well known to have the side effect of prolonged bleeding.
Also contraindicated are activities with a high likelihood of trauma, such as motorcycling and skateboarding. Popular sports with very high rates of physical contact and injuries such as American football, hockey, boxing, wrestling, and
rugby should be avoided by people with haemophilia. Other active sports like soccer, baseball, and basketball also have a high rate of injuries, but have overall less contact and should be undertaken cautiously and only in consultation with a doctor.
Epidemiology
Haemophilia is rare, with only about 1 instance in every 10,000 births (or
Idiopathic thrombocytopenic purpura is a bleeding disorder in which the immune system destroys platelets, which are necessary for normal blood clotting. Persons with the disease have too few platelets in the blood.
Prehospital Care
Rapid transport to definitive care is the mainstay of prehospital care. Prehospital care providers should do the following:
· Apply aggressive hemostatic techniques
· Assist patients capable of self-administered factor therapy
· Gather focused historical data if the patient is unable to communicate
Emergency Department Care
Before a patient with hemophilia is treated, the following information should be obtained:
· The type and severity of factor deficiency
· The nature of the hemorrhage or the planned procedure
· The patient’s previous treatments with blood products
· Whether inhibitors are present and if so, their probable titer
· Any previous history of desmopressin acetate (DDAVP) use (mild hemophilia A only), with the degree of response and clinical outcome.
Use aggressive hemostatic techniques. Correct coagulopathy immediately. Include a diagnostic workup for hemorrhage, but never delay indicated coagulation correction pending diagnostic testing. If possible, draw blood for the coagulation studies (see Workup), including 2 blue-top tubes to be spun and frozen for factor and inhibitor assays.
If admission is indicated, disposition (ICU vs floor) should be based on severity of hemorrhage and potential for morbidity and death. Choose attending service based on etiology of hemorrhage. Hematology/ blood bank/pathology consultation is mandatory.
Patients whose condition and bleeding are stabilized should be transferred to a specialized center for further treatment and monitoring because a multidisciplinary approach by specialists experienced in hemophilia may be required.
Further outpatient care for patients with minor hemorrhage (not life threatening) consists of continued hemostatic measures (eg, brief joint immobilization, bandage). Hematologist or primary care physician follow-up care is indicated. The patient should continue factor replacement and monitoring.
If a patient has HIV seroconversion, arrange appropriate outpatient care at a specialty infectious disease clinic, monitor the patient’s CD4 count, observe the patient for adverse effects of anti-HIV treatment, and monitor for and treat possible opportunistic infections.
Factor VIII Concentrates
Various FVIII concentrates are now available to treat hemophilia A. Fresh frozen plasma and cryoprecipitate are no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload.
Various purification techniques are used in plasma-based FVIII concentrates to reduce or eliminate the risk of viral transmission, including heat treatment, cryoprecipitation, and chemical precipitation. These techniques inactivate viruses such as hepatitis B virus, hepatitis C virus, and HIV. However, the transmission of nonenveloped viruses (eg, parvovirus and hepatitis A virus) and poorly characterized agents (eg, prions) is still a potential problem.
Many recombinant FVIII concentrates are now available. The advantage of such products is the elimination of viral contamination. Third-generation products without any exposure to animal proteins are now available to further decrease this risk. 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.
With wider availability of improved products (ie, better stability, purity), use of continuous infusion of factors has incrementally increased. Continuous administration of antihemophilic factors prevents the peaks and valleys in factor concentrations that occur with intermittent infusion; this benefit is particularly important when treatment is required for prolonged periods.
Besides improved hemostasis, continuous infusions decreases the amount of factor used, which can result in significant savings. The indications for this approach include intracranial hemorrhage, vascular compromise, iliopsoas bleeding, and preparation for surgery.
In most minor-to-moderate bleeding episodes, intermittent boluses are adequate. Intermittent boluses can also be used prophylactically, especially in the treatment of recurrent bleeding in target joints.
Doses of FVIII concentrate are calculated according to the severity and location of bleeding. Guidelines for dosing are provided in Table 2 below. As a rule, FVIII 1 U/kg increases FVIII plasma levels by 2%. The reaction half-time is 8-12 hours. Target levels by hemorrhage severity are as follows:
· Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding): Maintain an FVIII level of 30%
· Major hemorrhages (ie, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination): Maintain an FVIII level of 50%
· Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent hemarthrosis): Maintain an FVIII level of 80-90%. Plasma levels are maintained above 40-50% for a minimum of 7-10 days.
ITP – IMMUNE THROMBOCYTOPENIC PURPURA.
Causes
ITP occurs when certain immune system cells produce antibodies against platelets. Platelets help your blood clot by clumping together to plug small holes in damaged blood vessels.
The antibodies attach to the platelets. The spleen destroys the platelets that carry the antibodies.
In children, the disease sometimes follows a viral infection. In adults, it is more often a chronic (long-term) disease and can occur after a viral infection, with use of certain drugs, during pregnancy, or as part of an immune disorder.
ITP affects women more frequently than men, and is more common in children than adults. The disease affects boys and girls equally.
Symptoms
· Abnormally heavy menstruation
· Bleeding into the skin causes a characteristic skin rash that looks like pinpoint red spots (petechial rash)
· Easy bruising
· Nosebleed or bleeding in the mouth
Exams and Tests
Laboratory tests will be done to see how well your blood clots and to check your platelet count.
· A complete blood count (CBC) shows a low number of platelets.
· Blood clotting tests (PTT and PT) are normal.
· Bleeding time is prolonged.
· Platelet associated antibodies may be detected.
A bone marrow aspiration or biopsy appears normal or may show a greater thaormal number of cells called megakaryocytes. These cells are an early form of platelets.
Treatment
In children, the disease usually goes away without treatment. Some children, however, may need treatment.
Adults are usually started on an anti-inflammatory steroid medicine called prednisone. In some cases, surgery to remove the spleen (splenectomy) is recommended. This will increase the platelet count in about half of all patients. However, other drug treatments are usually recommended instead.
If the disease does not get better with prednisone, other treatments may include:
· A medicine called danazol (Danocrine) taken by mouth
· Injections of high-dose gamma globulin (an immune factor)
· Drugs that suppress the immune system
· Filtering antibodies out of the blood stream
· Anti-RhD therapy for people with certain blood types
People with ITP should not take aspirin, ibuprofen, or warfarin because these drugs interfere with platelet function or blood clotting, and bleeding may occur.
Outlook (Prognosis)
With treatment, the chance of remission (a symptom-free period) is good. Rarely, ITP may become a long-term condition in adults and reappear, even after a symptom-free period.
Possible Complications
Sudden and severe loss of blood from the digestive tract may occur. Bleeding into the brain may also occur.
When to Contact a Medical Professional
Go to the emergency room or call the local emergency number (such as 911) if severe bleeding occurs, or if other new symptoms develop.
Prevention
The causes and risk factors are unknown, except in children when it may be related to a viral infection. Prevention methods are unknown.
Medication Summary
Glucocorticoids and IVIg are the mainstays of medical therapy. Indications for use, dosage, and route of administration are based on the patient’s clinical condition, the absolute platelet count, and the degree of symptoms. Consultation with a hematologist may be needed prior to starting therapy.
Children who have platelet counts >30,000/mm3 and are asymptomatic or have only minor purpura do not require routine treatment. Children who have platelet counts < 20,000/mm3 and significant mucous membrane bleeding and those who have platelet counts < 10,000/mm3 and minor purpura should receive specific treatment.
Adults with platelet counts >50,000/mm3 do not require treatment. Treatment is indicated for adults with counts < 50,000/mm3 with significant mucous membrane bleeding. Treatment also is indicated for those adults with risk factors for bleeding (eg, hypertension, peptic ulcer disease, vigorous lifestyle) and in patients with a platelet count < 20,000-30,000/mm3.
IV anti-(Rh)D, also known as IV Rh immune globulin (IG), was not recommended by the 1996 American Society of Hematology practice guidelines. However, recent studies using higher dosages of IV RhIG in acute ITP in children and adults show platelet count increases at 24 hours faster than medicating with steroids and at 72 hours similar to IVIg. Although generally less toxic than IV steroids, IV RhIG is more expensive than IV steroids. Studies in children with chronic ITP show that escalating or elevated doses of IV RhIG have comparable responses to those of high-dose IVIg therapy in children. This therapy is not appropriate for patients who have undergone splenectomy. Acute intravascular hemolysis after infusing IV RhIG has been reported, with an estimated incidence of
Steroid use and immunosuppressives and splenectomy may be undesirable because of their associated complications. For long-term steroid use, this includes osteoporosis, glaucoma, cataracts, loss of muscle mass, and an increased risk of infection. For immunosuppressive therapy and splenectomy, risks include worsening immunosuppression and infection or sepsis. Studies of the use of multiagent therapies in refractory patients are ongoing. Some small studies have shown limited success. According to one study, using a combination of weekly vincristine, weekly methylprednisolone, both until platelet counts reached 50,000/mm3, and cyclosporine orally twice daily until the platelet count is normal for 3-6 months seems promising, though larger prospective studies are needed.
Other therapies, such as cyclophosphamide, danazol, dapsone, interferon alfa, azathioprine, vinca alkaloids, accessory splenectomy, and splenic radiation have been studied. Many case series discussing these treatments are too small to show sufficient evidence of a clinically significant reduction in bleeding or mortality rate; however, they serve as additional therapeutic measures in ITP refractory-to-primary therapy (eg, glucocorticoids, IVIg immunoglobulin, splenectomy). Newer studies on rituximab suggest that this agent is an effective treatment option in splenectomized refractory or relapsed ITP patients.
Clinical trials have shown promise for agents that directly stimulate platelet production, such as thrombopoietin (TPO) receptor-binding agents. Two new agents, eltrombopag and romiplostim, are available to patients with chronic ITP who have failed other therapies. Both of these agents require registration in a database. While they show promise for raising platelet counts, there are potential safety concerns such as thrombocytosis and rebound thrombocytopenia. It is unlikely that emergency physicians should be prescribing these agents without being under the recommendation of a hematologist.
