CM 3(1)
DISTURBANCES OF GENERAL BLOOD VOLUME. BLOOD LOSS
ALTERATION OF HEMOSTASIS SYSTEM. DIC-SYNDROME. HEMOPHILIA
ANEMIA
Disturbances of general blood volume. Blood loss
The pathological changes of blood system can arise in any functional part of it, which are closely connected and not strictly isolated. The main components of blood system violations are changes of the blood volume, quantity, structure and function of the blood cells, hemostasis, biochemical, and physical-chemical blood properties.
Changes of total blood volume
The normal quantity of blood is 5-6 liters or 6-8 % of body weight. This volume can change, but its rate does not exceed 5 % of its initial volume. There is 20-25 % of blood volume in the pulmonary circulation; heart receives 8-10 % of it, and lungs – 12-15%. The systemic blood circle contains 75-80 % of blood. 15-20 % of blood circulates in the arterial system, 70-75 % – in the venous system, and 5-7% – in capillaries one. The main blood volume is intended for the maintenance of movement constancy, and for duly heart filling. Normal volume of circulatting blood can be characterized by concept normovolemia. The violations of blood volume develop into hypervolemia and hypovolemia.
Normovolemia, hypervolemia, hypovolemia are distinguished, depending on rate of hematocrite parameter (norm is 0,36-0,48 L/L) as simple, olygocytemic and polycytemic. The normal condition of blood, which is characterized by normal volume and normal hematocrite parameter, is named the simple normovolemia.
Olygocytemic normovolemia is characterized by the decrease of hematocrite index and arises at posthemorrhagic anemia, when blood volume is supplied with extravascular liquid, and the quantity of erythrocytes is not restored yet; the similar state arises at massive hemolysis, cachexia.
Polycytemic normovolemia can occur in the conditions high-altitude hypoxia, at lungs emphysema and heart disease, after the transfusion of erythrocyte mass or blood small quantities.
Hypervolemia is a pathological state, which is characterized by the increase of circulating blood volume. Simple hypervolemia (hematocrite index is normal) can be the consequence of plenty blood transfusion, of intensive physical work and heart failure (in those conditions the deposited blood comes into vessels).
Olygocytemic hypervolemia (hematocrite index is lower thaorm, and the blood quantity is increased at the expense of plasma) arises as the result of water excees in the organism at the disorder of renal function after injections of physiological solution or blood-substitutes.
Polycytemic hypervolemia (hematocrite index is higher than norm, and the blood quantity is increased at the expense of erythrocytes) occur as the result of deep hypoxia of the organism at the atmospheric pressure drop, at cardiac defect, at chronic lungs diseases as the compensatory reaction and also as the result of the malignant stimulation of erythrocytes growth (erythrismal). The fast-development hypervolemia can provoke the blood circulation violations, stagnant phenomena in the pulmonary circulation. Besides that, the increase of the circulating blood volume promotes the vessels over-expansion, the decrease of their tonus and permeability, the blood condensation, and this in its turn worsens the heart work.
Hypovolemia is a pathological state, which is characterized by the volume circulating blood reduction. The simple hypovolemia (hematocrite index is normal) can be the result of blood losses, when the blood volume is not restored, of shock states (in this case the significant part of blood does not participate in the circulation).
Olygocytemic hypovolemia (hematocrite index is lower thaorm) arises after the acute bleeding, when the blood volume began to be restored, with the extravessel liquid, at malignant Addisone-Birmer’s anemia (in this case the quantity of plasma is not changed and the quantity of erythrocytes is much lower than norm).
Polycytemic hypovolemia (hematocrite index is higher thaorm) is characterized by the relative increase of the erythrocytes amount in blood. Such state can develop at dehydratation caused by diarrhea, vomiting, burns, hyperthermia, and also at shock (the vessels permeability increase and the output of plasma through their limits are characteristic). At that state blood becomes dense, viscous, and that worsens hemodynamic processes.
Blood loss
Blood loss is a pathological state of the organism arising in the reply to the significant blood loss from vessels and is characterized by the development of number compensatory and pathological reactions. Depending on an anatomic type of the damaged vessels there are arterial, venous, capillary and parenchymal bleedings. Arterial bleeding is characterized by massivity and intensity. The bleedings from big vessels are dangerous, when from the damaged vessel blood is streaming by a pulsing jet and the irreversible consequences blood loss can arise within several minutes. The difference between the arterial and venous blood pressure disappears, the right atrium blood inflow diminishes and blood circulation becomes impossible.
Venous bleeding is characterized by blood outflow from the damaged vessel by a continuous jet. Venous bleeding more often than arterial ends with independent hemostasis due to the formation of hematoma and vessel compression, and slowing down of blood flow speed.
The capillary bleedings in the condition of normal blood coagulation are the insignificant and usually stop owing wound filling. The bleeding from capillaries is the mostly widespread at injuries of skin, muscles, mucous membranes and bones. Blood follows from smallest capillaries by a thin jet. In such cases the whole wounds surface bleeds.
Parenchymal bleedings are caused by damage of liver, spleen, kidneys and pancreas. These bleedings can become profuse as the result of plenty microvessels damage of parenchymal tissue. In the absence of large arteries and veins damage the spontaneous stop of the bleeding is possible due to blood clot, which is formed in the area of damaged organ.
Depending on time of occurrence there are primary and secondary bleedings. Primary bleedings arise at the moment of blood vessels damage; the secondary bleedings can develop a bit later after a trauma, as the result of wounds infection development or the repeated trauma of the damaged vessel.
Depending on the localization of bleeding source and the places of blood receipt there are internal, external and mixed bleedings. The internal bleedings can be intracavital, intratissual and mixed. Intracavital bleeding (into abdominal and pleural cavities) are characterized by the violation of clots formation owing to the defibrination of blood by pleura, peritoneum and synovial joint membrane. Intratissual bleedings arise in skin, fat tissue, muscles and interfascial spaces. The reason of the mixed bleedings can be simultaneous damage of abdominal cavity’s organs and retroperitoneal space ones. The external bleedings arise because of skin and mucous membranes damages.
Profuse external bleedings arise in the result of limbs big vessels damage, at penetrating thorax wounds and abdominal cavity ones. The mixed bleedings are characterized by combination of internal and external signs. First they arise as internal, when blood gets to a hollow body, for example, digestive tract, bladder uterine cavity, then after some time the signs of external bleeding (bloody vomiting, hematuria, metrorrhagia) appear.
The pathogenic principle of bleedings classification includes three types of them: mechanical origin bleedings, erosive bleedings, and bleedings developing as a result of vessels permeability violation. The mechanical origin bleedings are caused by the effect of blunt trauma (bruises, compressions, pressings, breaks) and wounds caused by cold and fire arms. Incisive wounds cause the most intensive bleedings, when edges of vessels are smooth and the minimum quantity of thromboplastin is formed in tissue. Fragmentary and bruised-compressed wounds are accompanied with less expressed blood loss as the interposition of intimae and fast formation of thrombi occur due to formation of plenty thromboplastin in wound, acidosis and erythrocytes aggregation.
Erosive bleedings are the result of vessel wall disorder at various diseases of internal organs. At the result of necrobiotic processes prevalence and the destruction in tissues of the affected organ the erosion of different caliber vessels and the occurrence of latent bleedings are possible (stomach and duodenum ulcer disease, malignant and benign tumors, portal hypertension, ulcerous colitis, cavernous tuberculosis). The bleedings developing due to the violation of vessels wall permeability arise under the influence of toxic substances, allergic and infectious agents. They occur in the patients suffering a scurvy, hemorrhagic vasculitis, arterial hypertension, acute and chronic leucosis.
Depending on the clinical characteristic of the patient state there are mild blood loss (the quantity of the lost blood doesn’t exceed 10 %), middle serious blood loss (30 %), and heavy (dangerous) blood loss (the quantity of the lost blood doesn’t exceed 30-50 % ). The loss of over 50 % of blood is very dangerous for patient’s life and can be fatal, and the decrease of the circulating blood volume by 60 % is fatal the patient.
Blood loss is divided into acute and chronic in clinical practice. The degree of patient stability to blood loss depends on many factors: blood lost volume, bleeding speed, patient’s age and sex, accompanying diseases, the state of regulator systems. Pathogenesis of organism changes is very complex, but it is possible to divide all reactions, which arise at bleeding into pathological and compensatory. The conditional character of this division is stipulated by the fact that at certain stages of organism struggle with the consequences of a bleeding the compensatory reaction can strengthen the pathological displays and worsen the organs and tissues condition.
Hemodynamic disturbances. Hypovolemia starts the mechanisms of complex hemodynamic disorder. Blood loss is stress, which activates of hypothalamus-hypophisis-adrenal system due to the barroreceptor irritation (in aorta and carotid arteries, where are located the richest receptor zone) because the arterial pressure decreases. In addition to catecholamines, which make vessels spasm, the secretion of glucocorticoids and aldosterone from cortical layer of adrenal gland increase.
First of all the contraction of vessels smooth muscles of the capacitor department venous system arise, because these vessels are more sensitive to catecholamines, than the resistance vessels. 10 % of the lost blood without any change of heart emission can be compensated due to capacitor vessels contraction of skin, lungs and abdominal organs.
The redistribution of blood stream, which is promoted also by the opening of artery-venous anastomosis, increases the blood supply of vital organs, that is heart and brain due to ischemia of other organs. First vasoconstriction of all the organs, and then the systems develops.
This compensation mechanism is urgent; its main result is the reflectory spasm of peripheral vessels, which promotes the centralization blood circulation and the maintenance of normal blood pressure level. The bleeding continuation causes the inclusion of additional adaptation mechanisms – the transition of extravessel liquid into vessels; it’s the so-called hydremic phase of compensation. This is possible due to increase of precapillar resistance under the influence cateholamines and aldosteron.
The precapillar resistance arise due to the contraction of vessels smooth muscles (there are two mechanisms: strengthening of basal myogenic tonus due to the vasopressor nerves activity increase and strengthening of basal myogenic tonus of vessels), and also due to the short-term increase of blood viscosity. Postcapillar resistance also increases, but to a lesser degree. As the result of such changes, the average capillary hydrostatic pressure reduces, and the colloid-osmotic pressure still remains at a sufficient level, that promotes the amplified extravessel liquid inflow into the vessels.
The consequence of this compensatory mechanism is the circulating blood volume increase and the maintenance of normal heart and brain functions. But further blood loss can cause the decompensation and the organs functions violations. Generally this is conditioned by the state of vasoconstriction and depends on its duration. The state of vasoconstriction has phase character of its development. It is conditioned by the division of vessel system into departments with primary function of resistance and capacity and depends on sympathetic-adrenal activity and on tissue metabolism state. The narrowing of the capacitor vessels can be related to the first phase of vasoconstriction state, this compensatory reaction (centralization of blood flow) doesn’t promote organs damage.
The second phase of vasoconstriction is characterized by the system narrowing of vessels directed on the maintenance of arterial pressure at a normal level, but in this case some organs damages owing to microcirculation decompensation arise because blood circulates only in large (central) vessels.
The bleeding results in progressive decrease of heart emission. This changes baroreceptors activity promotes the reflectory tachycardia, and also the spread of diffused vasoconstriction state. The decrease of circulating blood volume reduces the average blood pressure; it promotes the reduction of the difference blood pressure between right atrium and vanae cavae, the venous inflow and the heart emission decrease. This changes lead to the decrease of organ’s blood circulation (at first of kidneys, liver, stomach, intestine, and then of lungs and adrenal glands).
There is blood stream redistribution from cortical layer into medullar one in kidneys. It is carried out according to the type of juxta glomerular shunt due to interlobular arteries and afferent arterioles of cortical glomerules spasm with preservation intensive blood flow in the cortical-medullar zone. Artery-venous anastomoses of kidneys don’t function almost iorm. The blood stream redistribution promotes the renal filtration reduction. The kidneys oxygen consumption decreases because the number of open capillaries decreases. The kidney ischemia strengthens the rennin secretion, the angiotensin-2 synthesis, which in its turn stimulates the secretion of aldosteron from adrenal glands. All these humoral substances strengthen vasoconstriction (in kidneys too). The acute renal insufficiency arises in the result of prolonged vessels spasm.
The liver’s vessels spasm reduces of portal blood flow and promotes change of liver’s metabolism. The carbons metabolism violation is characterized by the hyperglycemia, lactic and piruvate acids accumulation, metabolic acidosis, violation of glycogen synthesis.
Electrolyte metabolism violations are manifested by the increase of Na, Ca and the decrease of K, Mg and inorganic pH blood.
The protein metabolism violations are characterized by the urea synthesis reduction, the protein synthesis decrease (reduction of albumens, globulins, fibrinogen and prothrombin). Hypoproteinemia and dysproteinemia are the main signs of these violations. Heavy blood loss can cause dystrophy or necrosis of hepatocytes. Mesenteries blood flow is closely connected with the hepatic one because common portal channel containing unites them. The mesenteries blood flow violations in mesenteries come earlier, than in kidneys and brain. The increase of sympathetic-adrenal system activity results in strengthening of intrahepatic sphincters spasm, the portal and mesenteries pressure increase.
The venous vessels tonus reduces, the blood stagnation in abdominal cavity organs arises. The microcirculation violations (contraction of arterioles, venules and capillaries, the stasis, the increase of plasmatic capillaries quantity, the blood cells aggregation) provoke of intestine and stomach ischemia. Synthesis and secretion of vasodilatators into blood (histamine and histamine -similar substances, acetylcholine, kinines, lactic and piruvate acids), and also of intestine toxins are the result of intestine hypoxia. The danger of this state consists in the derivation of stomach and intestine trophic ulcers, which can become complicated by a bleeding and perforations.
Breath plays the important role in the development at first of compensating and then decompensation reactions. The circulating blood volume reduction causes hypoxia. The pulmonary blood flow decreases parallel with heart output lessening. Compensatory reactions (the increase of O2 tissues supply) promote the development of hyperventilation (due to the chemoreceptors and partially baroreceptors activation) and the more effective О2 utilization.
It results in the increase of arterial рН and the decrease of СО2 partial pressure in arterial blood. Such changes promote the reduction of brain blood flow, and brain ischemia strengthens vasoconstriction, from which lungs suffer too.
The lungs blood flow limitation promotes the decrease of lungs elasticity, the increase of air ways resistance, the cells aggregations formation in pulmonary capillaries, bleedings in alveoluses and small-sized bronchi, the damage of vascular endothelium and alveoluses epithelium, the decrease of surphactant synthesis, the increase of respiratory dead space and leads to ventilation insufficiency.
The 1/3 part of minute blood volume is spent for the maintenance of brain blood circulation. Brain vessels are exposed to constant vasodilatation influences from the synocarotid receptor zone. The sympathetic stimulation renders vasopressor influences but of lesser degree, than on other organs vessels. Brain vessels are very sensitive to СО2 and O2 blood level; they extend at СО2 surplus and at О2 lack and contract due to the increase of СО2 and the decrease of О2 blood level. Moderate blood loss (up to 20 % of volume) promotes the expansion a brain arteries and the increase of brain blood flow (the effect of blood flow centralization).
But the decrease of circulating blood volume lower than 20 % worsens the brain blood supply, causes the infringement of the central nervous system activity because the arterial blood рН increases, the СО2 concentration decreases, arteries extend and the blood flow insufficiency progresses.
Peripheral compensatory vasoconstriction causing the skin cooling causes the hypothalamic reaction, which is manifested by the strengthening of vessels constriction. The subsequent development of metabolic acidosis reduces cerebral blood flow, brain ischemia strengthens the system vasoconstriction and limits the hydremic compensation mechanism. The heart activity depends on a degree of acute blood loss and the deficiency of circulating blood volume.
Blood loss up to 10 % of volume does not reduce the heart output. The further reduction of blood volume reduces the minute blood flow volume, infringes myocardium metabolism, and reduces heart output. The lasting bleeding exhausts all compensatory capacities of the organism.
Vessels capacity cannot be decrease by vasoconstriction, and the decrease of heart output is not compensated by the tachycardia. On the contrary, tachycardia reduces a diastolic interval and on the background of the reduced gradient of pressure between the right atrium and central veins worsens the heart filling; the arterial pressure is lowered, the heart and vessels insufficiency develops.
Blood loss more than 10 % of blood worsens the microcirculation and its signs arise much earlier, than in macrocirculatory channel. The microcirculation disorders have some stages: vasoconstriction stage; the stage of duplicated violations (arterioles spasm, venules and capillaries dilatation); the stage of all vessels dilatation. The microcirculation violations are the result of prolonged vasoconstriction, of the disclosure of arterial-venous shunts, of the increase of plasmatic capillaries quantity, of the increase of blood viscosity and erythrocytes aggregation, of the intravessels thrombosis, of vessels damage by vasotoxic substances.
Microvessels sensitivity to endogen pressor amines reduces and gradually the capillaries disclosure appears, and as the result of this the blood stagnation up to stasis, especially in small-sized venules, develops. Such changes aggravate the decrease of arterial pressure, the decrease of О2 blood concentration, the increase of capillary blood hematocrite index, the infringements of capillary hemodillution, the decrease of tissues perfusion and cells metabolism disorder, the development of secondary heart failure, violations of the central nervous system activity, and shock condition. The tissues metabolism disorders depend on the degree of blood loss and hypovolemia, the changes of macro- and microcirculation.
Arterial hypoxemia and the reduced peripheral blood flow results in the total hypoxia. Blood loss of easy and mild seriousness due to start of compensatory reactions save the O2 consumption. Heavy blood loss amplifies the aorta-venous shunting and tissues perfusion sharply reduces.
Hypoxia reduces aerobic metabolism and macroergic substances synthesis, but promote the activation of anaerobic reactions. The carbons metabolism changes are manifested with hyperglycemia, lactic and pyruvate acids accumulation, metabolic acidosis development because the mobilization glycogen from depot takes place catecholamines, glucocorticoids and thyroxin influence. The glycogen and macroergic substances stocks are rapidly exhausted and anaerobic glycolysis is activated. In the conditions of heavy blood loss and the decrease of pancreas’s blood supply the insulin synthesis is decreased, the cells glucose contents reduces and diabetes-like state develops (despite of hyperglycemia, the cells keep the requirement in glucose, which caot penetrate through their membrane).
Lipid metabolism in conditions of sympathetic system activation and pancreas insufficiency is characterized by lipolysis activation. The fatty acids and triglycerides concentration increases, and this can promote the fatty infiltration of organs, ketone bodies accumulation and ketoneacidosis development.
Plasmal hyperlipemia violates blood viscosity and provokes the erythrocytes aggregation and the decreases of O2 blood capacity. The disorders of protein metabolism are mainly provoked by the insufficiency of liver protein-synthesis function and are manifested by hypoproteinemia, dysproteinemia. Oncotic (osmotic) blood pressure lowers and this promotes the infringement of transcapillar liquid flow. Heavy blood loss is characterized by the reserve protein catabolism activation, which are used in the reactions gluconeogenesis (formation of tricarbonic acids from proteins and lipids), the losses irreplaceable aminoacids (leucine, izoleucine, metionine), infringement of nitrogen balance, and reduction of fibrinogen and prothrombine blood concentration.
Blood loss violates the acid-base balance, but the blood рН changes are characterized by phases, which are determined by the inclusion of certain compensatory reactions. At first hyperventilation, which arises during development of hypoxia, provokes the gas alkalosis, and then subsequent pathological changes in lungs and disorder ventilation provokes gas acidosis. The tissues blood perfusion violations and anaerobic metabolism activation promote the organic acids accumulation and metabolic acidosis.
Tissue acidosis increases the permeability of capillaries, the liquid leaves vessels, secondarily the circulating blood volume is reduced thus volume of blood inflow and heart emission decreases. Heavy blood losses can become complicated by metabolic alkalosis of aldosteron secretion activation (for Na setback in kidneys and hypovolemia compensation).
The changes of blood structure and its functions are characterized by the decrease of hemoglobin level, of hematocrite index (in capillaries it is increased), of blood oxygen capacity. Blood viscosity and erythrocytes aggregation on the contrary increases and this promotes the blood sequestration, the microcirculation violation and amplification of hemic and tissue hypoxia.
Red bone marrow cells formation at blood loss is one of the main protective factors, which promotes the restoration of blood mass and structure. The red bone marrow depends on erythropoietins quantity, which are formed in reply to blood loss and hypoxia. Blood cells formation at blood loss of an easy degree proceeds as regeneratory normoblast type and is accompanied with moderate hyperregeneration and occurrence of big reticulocytes quantity in the peripheral blood. This is promoted by moderate hypoxia of kidneys, which intensively produce erythropoietins. The newly formed erythrocytes restore the cellular balance within 14-20 days, but their accelerated maturing cause the lowered saturation with hemoglobin and the development of hypochromic anemia.
A blood loss of average gravity is characterized by regeneratory normoblastic type of blood poem, but attributes of erythropoiesis oppression appear (insignificant reticulocytes quantity) owing to blood flow violation in kidneys and red bone marrow (the result of peripheral vasoconstriction). The normoblastic type of blood cells formation is still preserved at grave blood losses, however, the maturing process and the washing away of blood cells are infringed.
The bleeding can be complicated by hemorrhagic shock. Acute decrease of circulating blood volume, of heart emission and tissues perfusion, the exhaust of protective reactions, pathological changes in organism are the main attributes of this state. An initial link of shock is the infringement of biological balance between the capacity of vessels channel and the mass of circulating blood, which the organism cannot support at a normal level due to compensatory reactions.
Clinics consider that main signs of hemorrhagic shock development are the symptoms of microcirculation infringement (the decrease of arterial pressure, tachycardia, venous hypotonia, dyspnoe, oliguria, infringement of consciousness, cooling of limbs, cold sweat). The pathological changes in the organism develop much earlier, than the signs of blood circulation insufficiency and the determination of hemorrhagic shock stages is a little bit conditional (1-st stage – compensated shock; 2-nd stage – decompensated shock; 3-d stage – irreversible shock).
Alteration of hemostasis system. DIC-syndrome. Hemophilia
The hemostasis violations are classificated acording to: the etiology, the directivity of variations and the mechanism of progressing. The directivity of variations there are hypocogulation and hypercoagulation, acording to the mechanism of violations progressing there are vessel-throbocyte hemostasis disorder and coagulative hemostasis disorder. Hypocogulation is characterized by the reduced of blood capacity to coagulate. All reasons of hypocoagulation are united in four groups: thrombocytopenia, thrombocytopathy, angiopathy, coagulopathy.
Hypocoagulation
Thrombocytopenia includes a diseases groups, which are characterised by the decrease of thrombocytes blood level less than 150×109/l. There are the congenital and acquired forms of thrombocytopenias. The congenital thrombocytopenias are mostly followed by the changes of thrombocytes functional properties, that makes it possible to refer these illnesses to thrombocytopathies group.
The aquired thrombocytopenias are the result of immune and mechanical damages, the depression of thrombocytes forming, and increased thrombocytes using.
There are four groups of immune thrombocytopenias:
a) alloimmune- thrombocytes distruction is the result of noncompatibility at one of blood group systems;
b) transimmune- thrombocytes demage can be carried out by mother autoantibodies, who suffers from autoimmunal thrombocytopenia, and these immunoglobulins penetrate through placenta and cause the thrombocytes amount decrease in infant;
c) heteroimmune-thrombocytes damage is the result of their injury by antigenic pattern under the influence of viruses or the appearance of a new antigene or gapten;
d) autoimmune-thrombocytes destruction of is a result antibodies synthesis against own thrombocytic antigene.
Heteroimmune thrombocytopenia are mostly common for children’s age, and autoimmune one – for adult. Werlhof’s disease (so-called idiopathic purpura) is the one example of the autoimmune thrombocytopenia, the main reason of it is the decrease of immune tolerance to own antigenes. T-suppressors deficit predetermines B-lymphocytes activation and autoimmune process beginning. The reason of suppression function lymphocytes failure at the idiopathic autoimmune thrombocytopenia isn’t know so far, may be this is T-suppressors genetic trouble.
Figure. Acute idiopathic thrombocytopenic purpura
The possible mechanism provoking autoagression is the alteration of thrombocytes antigene under the influence of drugss, viruses, bacterias. In some cases the bacterial antigenes, probably, have similarity with the thrombocytic antigenes determinants. Macrophages of the spleen plays the main role in pathogenesis of autoimmune thrombocytopenias, they kill of thrombocytes and decrease their number. At heteroimmune thrombocytopenias, the antibodies are synthesized against alien antigene, which are fixed on thrombocytes surface and which have stipulated the alteration of antigenic pattern (this antigene there can be medicines: quinidine, digitoxinum, sulfonilamid drugs, rifampicinum, hypothiazidum, viruses of rubella, chickenpox, influenza and adenoviral infection, vaccine). Thrombocytopenia is dangerous with progressing hematencephalons, gastrointestinal tract bleedings, hematuria
Thrombocytopathies is characterised by hemostasis disorder in the result of platelets dysfunction. The first group is congenital desaggregative thrombocytopathies without any failures of reaction of granules release. This group consist of Glantsman’s thrombasthenia (absence of thrombocytes glycoproteins 2а and 3b complex in shells, which are indispensable components of thrombocytes adhesion stimulators and fibrinogen interaction), essential athrombia, May-Heglin’s anomaly, partial desaggregative thrombocytopathies. Signs of this group diseases are the petechias, frequent nose bleedings, menorrhagia, hematencephalon.
The second group is characterized by the failure of granules release, which leads to absence of thrombocytes aggregation during their contact with collagen fibers of basal mambrane and the absence of the second surge aggregation, and as the result thromboxan А2 synthesis, ADP, serotonin, adrenaline, Са2+ disengagement is violated. The key role in the pathogeny of this defect is played by cyclogenase and thromboxan-synthetase deficit, decrease of membrane phospholypase activity. Clinical signs are petechias, mild appearance of ecchymoses, nose and gem bleedings are possible.
The third group are the result of thrombocytes disability to store and to select granules content (ADP, serotonin, adrenaline, factor IV) at hemostasis. One of examples is the Herdimansky’s-Pudlac’s disease, which is characterized by not dangerous bleeding. Another example is TAR-syndrome (pathology of megacaryocytic-thrombocytes with bones anomalies).
The fourth group of thrombocytopathies are caused by failures of adhesive and agregational thrombocytes (different variants of Willebrand’s and Willebrand’s-Urgens’ diseases – thrombocytes disfunction is the result of Willebrand’s factor deficit; Bernar’s-Syle’s syndrome, which is the result of megacaryocytes and thrombocytes anomaly, suhc as the increase blood platelets sizes, the absence of glycoprotein 1 in megacaryocytes and thrombocytes cytoplasmic membrane, that being indispensable for the interaction with Willebrand’s, V and XI factors. Severe danger even of mild of this disease arises during sexual maturation of the girl (juvenile menorrhagias arise) and at labours.
The fifth group are caused by the deficit and the decrease accessibility of factor III (Boye’s and Oven’s thrombocytopathies). The thrombocytes pathology is characterized by the deficit of membrane phospholipids, that activate of factor III, so normal structural modification of membranes doesn’t take place during adhesion and aggregation of thrombocytes.
Wiscott-Oldridge’s syndrome is the example of the sixth group thrombocytopathies. A reason of thrombocytes pathology is the low content of dense and alpha granules, the small conservation of ATP, ADP, serotonin and reductants of alpha granules, decrease of thrombocytes adhesive properties.
The prognosis for life thus is unfavorable. The majority of the aquired thrombocytopathies are characterized by the complication of pathogeny. Only some medicines and toxins (conditioned by aspirin) have legible and stable functional marker. Aquired thrombocytopathies arise at acute leukoses (blastal surrounding provokes disorder of thrombocytes maturation). Thrombocytes dysfunction and hemorrhagic syndrome can be immune inhibition. Immune thrombocytopathies are coused by the capacity of antibodies to damage cytoplasmic membrane and to lock up the receptors. The В12-deficient anemia is also called thrombocytopathy, which is characterized by the disorders of granules release reaction.
Thrombocytopathies can arise at uremia, diseases of the liver. Very often the applying of medical drugs can be the reason of the thrombocytes functions disorder. However the mechanism of many medicines action is well studied and this enables to distinguish the following links of pathogeny of thrombocytes activity disorders: 1) suppression of thromboxan А2 synthesis, such operating mechanism is characterized for phospholypase inhibitors, which violate the arachidonic acid synthesis (сhinacrinum, glucocorticoids), for cyclogenase inhibitors (acetylsalycilic acid, indomethacinum, butadionum, ibuprofenum, naproxenum), for thromboxan-synthetase inhibitors (prostacyclinum, imidazole); 2) the decrease of thrombocytes cAMP level, such mechanism of action is characterized for stimulators adenilatcyclase (prostacyclinum, prostaglandinum Е), for inhibitors of phosphodieterase, which conduce the cAMP degradation (dipiridamolum, papaverine, euphilinum, flavonoids), for stimulators of prostocycline synthesis, (anabolic steroids, niacin); 3) infringement of Ca2+ transportation (verapamilum, corinfarum).
Vassopathies (angiopathies) are the diseases, which are characterized by the bleeding in the result of vascular wall pathology. All congenital vassopathies, despite their variety, are united by the same pathology – congenital inferiority and improper development of the connective tissue, including vessels subendothelium. Congenital angiopathies are presented by heritable hemorrhagical teleangioectazias, diffusal trunk angiokeratoma, heritable thrombocytopenic microangiomatosis etc.
Bleeding is the basic performance of this disease and is conditioned by the low resistance and easy vunurability of a vascular wall, by very gentle stimulation in these adhesion sections by both the thrombocytes aggregation and blood coagulation. Most often bleedings nose start, however possible are profuse and sometimes fatal bleedings from teleangioectazias of bronchi and gastrointestinal truck, sometimes brain and internal organs hemorrhages are registered.
The group of acquired (secondary) angiopathies (vascular purpuras) includes mostly dermal bleedings, which arise in the result of exogenic or endogenic vessels injuries. There are idiopathic, stagnant (orthostatic), atrophic (dystrophic), neurogenic, mechanical and other acquired vassopathies. The etiology of idiopathic angiopathies is not known (example is the idiopathic hemorrhagic Caposhi’s sarcoma – reticulihystiocytic system malignant tumor with skin bleeding in the result of vessels hemostasis failure). The stagnant angiopathies can be caused by chronic heart failure, local venous insufficiency (Klots’ haemostatic dermatitis, Favr-Racusho’s dermatitis) and are the result of long-time tissues hypoxia and vassal dystrophy.
Figure. Skin rashes in patients with hemorrhagic vasculitis (Shenlyayn-Henoch disease)
Steroid purpura is the example of atrophic-dystrophic angiopathies, it arises after the durable treatment by glucocorticoids, which suppress the fibroblasts proliferation, decrease the collagen and mucopolysaccharides synthesis that predetermines the dot hemorrhages.
Vessels dystrophy and the following bleeding can be the result of vascular walls damage by immune complexes (Shanline-Genokh’s hemorrhagical vasculitis). The vit. C deficit (scorbutus) also promotes the infringement of collagen fibres synthesis (they ensure the continuity of capillary endothelial covering) and is the reason of bleeding in pericappilar spaces (in fascia, aponeurosis, fatty tissue, muscles, joint cavities, in very severe cases the hemothorax and hemopericardium can develops.
Coagulopathy is the example of hypocoagulation in the result of coagulative blood system pathology development. There are primary (hereditary) and secondary (aquired).
The primary coagulopathies are divided on such group as:
1) failure of internal mechanisms prothrobinase activity forming (hemophilia A – procoagulant unit of factor-VIII deficit, hemophilia B – factor-IX deficit and hemophilia C – factor-XI deficit, Willebradn’s disease, Hageman’s defect – factor-XII deficit),
2) failure of external mechanisms prothrombinase activity forming (hypoproconvertinaemia – factor – VII deficit),
3) the combined failure of external and internal mechanisms prothrombinase activity forming (parahemophilia – factor-V deficit),
4) failure of final stage blood coagulation (hypofibrinogenemia, dysfibrinogenemia).
The patients’ number, which suffer hemophilia A, B, C and Willebrand’s disease occur more often in clinical practice. The hemophilia A is the result of heritable deficit or molecular anomaly of VIII-factors’ procoagulative part, and is characterized by the coagulative hemostasis failure. Normally factor-VIII circulates in blood in the large molecular protein form and consists of a subunits series: glucoprotein having procoagulative property (VШ:К); glucoprotein with property to cause of thrombocytes adhesion (Willebrand’s factor – VШ:W), ristomicine-cofactor (VIII:R-cоf.), and also antigenic markers of VIII:K and VIII:R-cof.. Activity of both factor VIII:K and VШ:W is being decreased at the decrease of complex structure mass. Synthesis of factor-VIII all components is controlled by X-chromosome.
The gene of hemophilia is recessive, thus men are suffered mostly (woman, having the second normal X-chromosome, as a rule, don’t suffer from bleeding, but the VIII-factor activity is reduced in twice and this fact should be taken into consideration surgical operations referring to mothers, sisters and especially daughters the person, which is ill with hemophilia. The hemophilia A сan be caused by poor synthesis of VIII:K factor, thus it’s antigen isn’t discovered in patients plasma (so-called antigeegative hemophilia or hemophilia A–). In other cases antigen activity of VIII:K factor prevails the activity of this component, as the result of abnormal VIII:K factor synthesis (so-called antigen positive hemophilia A or hemophilia A).
Clinically the hemophilia A is manifested by hemorrhages in major joints of finitenesses, deep hypodermic, intermuscular and intramuscular hematomas, massive and prolonged posttraumatic bleedings. Man, who have cariotype 46,ХhУ and women, who have cariotype 46,ХhХh or 45,ХhО suffer with hemophilia A, but woman, who have cariotype 46,ХХh are the carriers only.
Figure. Acute knee hemarthrosis in hemophilia patients Hematoma in hemophilia patients
The Willebrand’s disease is the example of autosomal heritable coagulopathy. This is not single disease, but a group of related of hemorrhagic diathesises, which are caused by the infringement of synthesis or the quality anomalies of VIII: factor. The great number of Willebrand’s disease variations is the proof of factor-VIII structure complication. The patients frequently have hypodermic hematomas, parent bleedings with women can be last 15-25 days, are hardly treated, the hemorrhages in large joints are possible. The heritable factor-IX deficit is called hemophilia B or Cristmas’ disease; it is inherited by the recessive type and is joined with X-chromosome, however the structural gene of the factor-IX is localized in the other end of this chromosome and isn’t connected with the gene of VIII: K factor.
Hemophilia B is antigene positive (hemophilia B+) and antigene negative one (hemophilia B–). Such patients have caryotypes 46,XhY, 46,ХhХh, 45,ХhО or 46,XX/45,XhO). Hemophilia B is identical to hemophilia A by clinical developments, by gravity and complications. These hemophilias are distinguished only by the results of laboratory studies. The hemophilia C is the example of autosomal heritable coagulopathies, which caused by the factor-XI deficit.
Figure. Hematoma in a newborn child with hemophilia Figure. Hematoma in a child with hemophilia after injection
The acquired coagulopathies, as a rule, are caused by the complex infringement in the coagulative system and have much more complicated pathogeny, than the heritable ones. The insulated deficit of the some coagulation factors occurs not often (amiloidosis provokes factor-X deficit, factor-VIII deficit may be result of its immune inhibition at the antigenic noncompatibility of the mother and the fetus. The simultaneous deficit of several factors is frequent in clinical practice.
Hemorrhagic syndrome, as a result of of K-vitamin dependent coagulation factors deficit, is characterized by the disorder of synthesis in hepatocytes and the decrease of factors VII, X, IX and II blood concentrations. Reasons of hemostasis violations and poor vitamin K synthesis can be dysbacteriosis, profusal diarrhea, enteropathies, failures of this liposoluble vitamin suction at bile deficit (mechanical icterus), failure of the final stage vitamin-K dependent coagulation factors synthesis (process of their decarboxilation) due to displacement of vitamin K from the metabolism by competitive antagonists anticoagulants of the indirect action, dangerous liver destructions. The depression of the VII, X, IX, XII factors activity arises thus in succession, this depends on the different lifetime of these factors in blood. the medical drugs using can be complicated by coagulopathies. This happens if the drugs have the anthithrombical activity and are overdosed (heparin especially).
Hypercoagulation is the organism state characterized by excessive activation of coagulative blood systems. The examples are thrombosis and dessiminative intravascular blood coagulation syndrome (DIC-syndrome). Most often DIC-syndrome arises at the development of infections (especially generalized one); at septic states coused by bacteriemia or virusemia, including at abortions, after labors, at a long-term vessels catheterization; at shock (traumatic, hemorrhagical, anaphylactic, cardiogenic, septic, in conditions of septic shock the acute DIC-sindrome is registered in 100 % of cases); at traumatic surgical operations; at long-term usage of an artificial blood circulation apparatus; at all terminal states the DIC-syndrome (in 100 % of cases); at acute hemolysis; at anticipatory flaking-off of placenta, at thermal and chemical burns, at immune diseases, at allergic reactions.
The main DIC-syndrome mechanisms are the following:
1) the activation of thrombocytic and coagulative hemostasis components by the endogenenic factors – tissues thromboplastin, factors of tissues and blood cells disintegration, leukocytic proteases, factors of endothelium injured;
2) the activation of hemostasis system by such exogenic factors as bacterias, viruses, medicines, snake poisons;
3) the injure of vascular endothelium, followed by the decrease its antithrombical potential;
4) the dissipated intravascular blood coagulation, thrombocytes and erythrocytes aggregation with the formation of many microclots and the block of microcirculation;
5) deep dystrophic failures in organs-targets, the failures of their function;
6) circulatory disturbances which predetermine tissues hypoxia, hemocoagulational shock, acidosis, microcirculation failure caused by the disability of the organism to promote the capillary hemodilution process, and stop blood flow;
7) the development of the consumption coagulopathy followed by complete disability of blood to coagulate, the exhaustion of anticoagulative mechanisms (deficit of antithrombin III and protein С), component of fibrinolytic and calicrein-kinin systems;
8) the secondary high-gravity endogene intoxication by toxic substances of proteolysis and tissues destruction.
The key role in a pathogeny of a DIC-syndrome is given to the increase of thrombinum concentrationin (hypethrombinemia), to the exhaustion of hemocoagulational potential.
The main initiator of the coagulation process is the tissues thromboplastin, that comes into the blood from the injured tissues and endothelium. Activated monocytes provoke to produce tissues thromboplastin and this mechanism plays an important role in DIC-syndrome pathogeny at virusemia, at endotoxemia, at immune diseases (activated monocytes start to produce partially activated such factors as VII, X, IX, II.
The thrombocytes aggregation and their using for the thrombforming is the obligatory component of DIC-syndrome pathogeny. The erythrocytes at DIC-syndrome are injured, their lifetime in blood is shortened and the intravascular hemolysis appears. This process activates the blood coagulation because much ADP and other agents from injured erythrocytes came into the blood, promotes thrombocytes aggregation, conduces the DIC-syndrome progressing, and microcirculation disorder in tissues.
The very important pathogenetic link of this pathology is the activatioot only the system of blood coagulation, but also of such plasma proteolytic systems, as fibrinolytic, calicrein-kinin and complement ones. There of the imagination about the acute DIC-syndrome as about the “humoral protease detonating” was developed in the result of which the patients’ blood is filled up with the great amount of proteins disintegration metabolites. These substances can damage a vascular wall; promote bleeding and secondarilly strendhen blood coagulation. DIC-syndrome progressing provokes the decrease of anticoagulants concentration, especially antithrombin III, which is the coagulation enzyme factors inhibitor and protein C, which is the not enzyme factors (f.-VIII and f.-V) inhibitor. Similarly the fibrinolytic components (precallicrein, kininogene) are utilized.
The hemorrhagic syndrome at these conditions is the result of coagulative blood properties failure, namely:
1) the anticoagulative action of toxic substances,
2) usage of the factors VIII and V;
3) failure of thrombocytic hemostasis in the result of hypoxia;
4) toxic influence on a vascular wall of proteolysis products;
5) the decrease in blood of the most active thrombocytes and their block by the fibrin dissociation products.
Thrombocytopenia and thrombocytopathy, which arise at this condition, is the important bleeding factor.
Gravity of DIC-syndrome depends on infringement of microcirculation in organs. Constant satellites of DIC-syndrome are shock lung, acute renal insufficiency and other organ failures. Their development is the result of massive capillary block by fibrin clots and blood cells aggregates. Hematocrite capillary blood index increases until 0,45 – 0,55 l/l at DIC-syndrome. The indicated failure and microvessels thrombosis plays the key role in the development of stasis, hypoxia and organs dystrophy. The current of DIC-syndrome can be acute, lingering, the relapsing, chronic, and latent.
Stages of DIC-syndrome are following: the first stage – hypercoagulation and thrombocytes aggregation; the second stage – consumption coagulopathy and thrombocytopathia; the third stage – hypocoagulation; the fourth stage – recovery or consequences and complications (at the unfavorable current the death of the patient is possible). By the gravity of the current DIC-syndrome may be acute, subacute and chronic.
The main signs of DIC-syndrome are hemocoagulative or mixed shock (at acute form), failure of hemostasis (thrombosis and hemorrhagia), hypovolemia, anemia, disfunction and dystrophy of organs, metabolic disorders. Hemocoagulative shock is the result of microcirculation violations in organs and tissuel hypoxia, the formation of proteolysis toxic substances. This is characterised by the decrease of arterial and central venous pressure, by organs microcirculation violations and acute organs functional insufficiency (acute renal or hepatorenal insufficiency, shock lung). The development of profusal bleeding promotes the transformation of hemocoagulative shock into the hemorrhagic one.
There are different phases at hemostasis failure – from hypercoagulation up to hypocoagulation (at first we can observe massive thrombogenesis, but then thrombogenesis depression and bleeding). The thrombocytopenia and thrombocytopathy in this condition is the result of great number microthrombuses forming, of the thrombocytes injury and returning to circulation of degranulated thrombocytes. Hemorrhagic syndrome (bleeding) mostly arises at acute DIC-syndrome in hypocoagulation stage. The main pathogenetic mechanisms of bleeding are pathological influence on vessels of toxic proteolysis substances, the failure of thrombocytes angiothrophical function, thrombocytopenia, thrombocytopathy of consumption, fibrinolytic system activation.
Figure. DIC-syndrome at case of septicemia
The microcirculation block predetermines the disfunction and dystrophy of organs. The organs-targets (lung, kidneys, intestine) suffer mostly. The combined forms of organ violations are more difficult, for example, the combination of pulmonary and renal insufficiencies. The stomach and intestine also belong to the group of organs, which are frequently damaged at a DIC-syndrome. Microcirculation violations provoke mucous membrane dystrophy and profusal bleedings. In complicated cases the failures of cerebral circulation, of paranephroses, of pituitary body, and liver are possible.
Anemia
The anemia is decrease of erythrocytes amount and hemoglobin maintenances in unit of blood volume which is accompanied by qualitative changes of erythrocytes.
Hematological attributes of anemias are subdivided on quantitative and qualitative.
The quantitative displays include:
1) reduction of the maintenance of erythrocytes in unit of blood volume – in men is lower than 4×1012, in women is lower than 3,5×1012 in 1L of blood;
2) reduction of hemoglobin concentration – in men is lower than 130 g/l, in women is lower than 120 g/l;
3) reduction of hematocrit – in men is lower than 0,43 l/l, in women is lower than 0,40 l/l;
4) change of a color index – is not lower than0,85 and not higher than 1,15.
Qualitative attributes of anemias are presence in blood of:
1) regenerative, but not mature forms of erythrocytes;
2) degenerative changes of erythrocytes;
3) cells of pathological regeneration.
Regenerative forms of erythrocytes (cells of physiological regeneration) are young immature cells of red blood sprout appearance of which in peripheral blood testifies to amplification of regeneration of cells erythroid lines in red bone marrow or increase of medullar barrier permeability.
Regenerative forms include:
а) reticulocytes. They are found in smear of blood after supravital staining. Represent denuclearized cells dirty – staining colouring with black inclusions as granules (substantia granulofilamentosa). Iorm their contents in blood is 0,2-2 %. At the strengthened regeneration of cells red sproud blood their quantity may increase to 50 %.
b) polychromatophils. They are found in blood smear colored as in the method bu Romanovsky-Gimza. They are denuclearized cells cytoplasm of which shows property to perceive both acid, and the basic dye-stuffs. Therefore polychromatophils different from mature erythrocytes by cyanotic shade of the colouring. In essence reticulocytes and polychromatophils are cells of an identical degree of maturity – direct predecessors of erythrocytes. Different names are connected with their different properties which come to light at different ways of staining.
c) normocytes (basophilic, acidophilic, polychromatophilic). They are nuclear predecessors of erythrocytes. Iorm its absent in peripheral blood, and contain only in a red bone marrow. At the intensification of regeneration of cells erythroid lines they may occur in blood as acidophilic and polychromatophilic rarely as basophilic normocytes. Sometimes, erythroblasts can be found in blood (predecessors of normocytes) during hyperregenerative anemias.
Changes of erythrocytes, which testify about inferiority of these cells, named degenerative. Such changes are characterized by the following phenomena:
а) anisocytosis – change in the size of the erythrocytes. Occurrence of macrocytes and microcytes;
Figure. Anisocytosis
b) poikilocytosis – change in the form of the erythrocytes. In conditions of a pathology may occur pear-shaped, extended, sickle-cell, oval erythrocytes, and also erythrocytes with the spherical form (spherocytes);
c) change in the staining of the erythrocytes, that depends on the contents of hemoglobin in them. Erythrocytes, intensively colored, are named hyperchromatic, with pale staining – hypochromatic.
d) presence of pathological inclusions. They include Jolly’s bodies – are the rests of nuclear substance; Cabot’s rings – the rests of nuclear environment having the form of ring or eight; basophilic granularity – the rests basophilic substances of cytoplasm significative of toxic defeat of red bone marrow.
Cells of pathological regeneration occur when there is changed of erythropoesis from erythroblastic to megaloblastic:
а) megaloblasts are big cells with basophilic, polychromatophilic or acidophilic cytoplasm, containing large, located usually eccentrically nucleus with soft chromatin grid;
b) megalocytes – denuclearized cells which are formed during maturing of megaloblasts. They usually intensively stained, some the oval form, non an brighten up in the central part.
Occurrence of the specified cells in red bone marrow and blood is typical for megaloblastic anemias, in particular of the B12-deficiency anemia.
Classifications of anemias.
І. According to color index:
а) normochromic (the color index is within the limits of 0,85-1; for example, acute posthemorrhagic anemia during first days after hemorrhage);
b) hypochromic (the color index is lower than 0,85; for example, irondeficiency anemia);
c) hyperchromic (the color index is higher than 1,0; for example, B12-deficiency anemia).
ІІ. Pathogenetic classification:
А. posthemorrhagic anemias:
a) acute posthemorrhagic anemia;
b) chronic posthemorrhagic anemia.
B. hemolytic anemias.
1. acquired:
а) toxic-hemolytic;
b) immune;
c) mechanical;
d) acquired membranopathy.
2. hereditary:
а) hereditary membranopathy;
b) enzymopathy;
c) hemoglobinopathy.
C. Anemias as a result of erythropoiesis disorders.
1. deficient:
а) irondeficient;
b) B12-deficient;
c) proteindeficient.
2. hypo-, aplastic.
3. metaplastic.
4. Dysregulative
Posthemorrhagic anemia is an anemia which develops as a result of hemorrhage. There are two types of anemias of this group according to the character of hemorrhage: 1) acute posthemorrhagic and 2) chronic posthemorrhagic anemia.
Acute posthemorrhagic anemia arises after fast massive hemorrhage as a result wounding of vessels or their damage by pathological process.
Chronic posthemorrhagic anemia develops after repeated hemorrhages, caused by injury of blood vessels during number diseases (dysmenorrhea, ulcer of stomach, hemorrhoids etc.)
The picture of blood of acute posthemorrhagic anemias depends on time which has passed after hemorrhage. Depending on it it is possible pick out three periods, each of them is characterized by the certain picture of peripheral blood.
1. The first several hours after acute hemorrhage. At this period of time the total amount of blood, and also total number of erythrocytes in an organism decreases. However in unit of blood volume the contents of erythrocytes and concentration of hemoglobin do not vary.
2. The period of time from several hours untill several days after acute hemorrhage. Dillution of blood takes place as a result of transition of liquid from interstitial spaces into blood vessels. As a result of it the quantity of erythrocytes and hemoglobin in unit of volume of blood decreases, as well as hematocrit. A color index stays without changes (normochromic anemia). Qualitative changes of erythrocytes in blood smear are not found yet.
3. The period of time from several days untill 1-2 weeks after acute hemorrhage. The most typical feature of picture of blood in this period is occurrence of plenty regenerative forms of erythrocytes, due to amplification of erythropoiesis in red bone marrow. Because young unripe erythrocytes contain less hemoglobin in comparison with mature cells, the color index decreases also and anemia becomes hypochromic.
Figure. Reticulocytosis in acute posthemorrhagic anemia
During chronic posthemorrhagic anemia after the loss of iron hematologic attributes of irondeficiency anemia develop: concentration of hemoglobin and color index decrease, in blood smear there are degenerate forms of erythrocytes (micro- and poikilocytosis, hypochromy). Quantity of erythrocytes and hematocrit may remain without changes.
Figure. Chronic posthemorrhagic anemia – blood
The characteristic of hemolytic anemias. Anemias which arise after destruction (hemolysis) of erythrocytes are called hemolytic. According to the mechanism of development hemolysis anemias may be: 1) anemias with intravascular hemolysis; 2) anemias with endocellular hemolysis.
Intravascular hemolysis arises in blood vessels under the action of factors that damage erythrocytes. These factors are called hemolytic. They include:
а) Factors of physical nature (mechanical trauma, ionizing radiation, ultrasound, temperature);
b) Chemical agents (hemolytic poisons);
c) Biological factors (causative agents of infectious diseases, toxins, enzymes);
d) Immune factors (antibodies).
Intravascular hemolysis it is accompanied by an output of hemoglobin from cells to blood plasma where it partially connects with protein haptoglobin.
Endocellular hemolysis develops after absorption and digestion of erythrocytes by macrophages. In its basis the following reasons may lay: а) occurrence of defective erythrocytes. b) occurrence on surface of erythrocytes the chemical groups capable to cooperate specifically with receptors of macrophages. In this case antibodydependent phagocytosis of erythrocytes is activated; c ) hypersplenism – increase of phagocytic activity of spleen macrophages.
Acquired hemolytic anemias. Depending on the reasons of development is allocated the following kinds of acquired hemolytic anemias.
1. Toxic hemolytic anemias.
2. Immune hemolytic anemias.
3. The anemias caused by mechanical damage of erythrocytes.
4. Acquired membranopathy.
Mechanical hemolysis of erythrocytes arises at prosthetics vessels or valves of heart traumas of erythrocytes in capillaries of foot during a long march (marching hemoglobinuria), at their collision with strings of fibrin (microangiopathic hemolytic anemia of DIC-syndrome).
Immune hemolytic anemias arise due to participation of specific immune mechanisms. They are caused by interaction of humoral antibodies with the antigenes fixed on a surface of erythrocytes. Their reason may be: а)receipt from the outside antibodies against own of erythrocytes (hemolytic desease of newborn); b)receipt into organism of erythrocytes which in plasma there are antibodies (the blood transfusion, not compatible on groups AB0 or Rh); c)fixing on a surface of erythrocytes foreing antigenes (haptens), in particular, medical products (antibiotics, sulfanilamides), viruses; d)formation of antibodies against own erythrocytes.
Toxic hemolytic anemia may be caused by:
а) exogenous chemical agents: phenylhydrasin, lead, copper salts, arsenous hydrogen etc.;
b) endogenous chemical factors: bile acids, products formed at burn desease, uraemia;
c) poisons of biological origin: snake, beer, poison of some kinds of spiders, aumber of infectious agents, in particular, hemolytic streptococcus, malarial plasmodium, toxoplasma, leishmania.
Acquired membranopathy arise due to the acquired defects of erythrocytes membranes. As an example may be paroxysmal noctural hemoglobinuria. This disease as a results of a somatic mutation erythropoietic cells with defects of membrane. It is considered that disorders of membranes are connected with changes of ratio of fat acids which are part of their phospholipids. Erythrocytes of abnormal population get ability to fix complement and hemolyse.
The picture of blood of acquired hemolytic anemias is characterized by reduction of erythrocytes quantity and hemoglobin. The color index iorm, however may be higher than 1 unit that is connected with extraerythrocytic hemoglobin. In blood smear the significant amount regenerative forms of erythrocytes is found out: reticulocytes, polychromatophils, normocytes.
Figure. Reticulocytes
Hereditary hemolytic anemias
All hereditary caused hemolytic anemias are subdivided into three groups.
1. Membranopathies. Defects of erythrocytes membranes are in basis of this anemias group.
2. Enzymopathies. Anemias of this group are caused by disorder of erythrocytes enzymes.
3. Hemoglobinopathies. Arise after qualitative changes of hemoglobin.
Hereditary membranopathies may be caused by two groups of defects erythrocytic membranes:
1) membranopathies, caused by disorders of membrane proteins: а) microspherocytic anemia Minkovsky-Shoffar’s; b) ovalocytic hemolytic anemia;
Anemia Minkovsky-Shoffar’s is hereditary, endoerythrocytic (membranopathy) hemolytic anemia with endocellular hemolysis. Type of inheritance – autosomal dominant. Hereditary defect mentions membrane proteins of erythrocytes, in particular spectrin. Therefore permeability of erythrocytic membranes for ions sodium is considerably increased. Sodium and water pass from plasma inside of erythrocytes. In spleen they lose part of erythrocytes membrane and turn into microspherocytes. Life expectancy of erythrocytes decreases untill 8-12 days instead of 120.
Figure. Membranopathia. Inherited microspherocytosis – blood
The group also includes hereditary membranopathias: hereditary eliptocytosis, hereditary piropoykilocytosis, hereditary stomatocytosis, hereditary akantocytosis, and hereditary ehinocytosis.
Figure. Membranopathia. Hereditary eliptocytosis – blood
Figure. Membranopathia. Hereditary piropoykilocytosis – blood
Figure. Membranopathia. Hereditary stomatocytosis – blood
Figure. Membranopathia. Hereditary akantocytosis – blood
Figure. Membranopathia. Hereditary ehinocytosis – blood
Hereditary enzymopathias arise due to defect of erythrocytes enzymes systems:
1) deficiency of enzymes pentose cycle. The most widespread enzymopathy is glucose-6-phosphatedehydrogenase deficiency anemia, caused by absence or significant decrease(reduction) of glucose-6-phosphatedehydrogenase activity;
2) deficiency of enzymes of glycolysis. The most widespread is deficiency of pyruvatekinase which results to disorders of energy provision Na-K-pumps of plasmatic membranes. Erythrocytes thus turn into spherocytes which are exposed to phagocytosis by macrophages;
3) deficiency of enzymes of glutathion cycle (glutathionsynthetase, glutathionreductase, glutathionperoxidaza) results in oppression antioxidant systems of erythrocytes, barrier properties of erythrocytic membranes to ions and osmotic hemolysis;
4) deficiency of utilization АТP enzymes. An example is deficiency of albuminous components Na-K-pump of erythrocytic membranes. Thus concentration of sodium that results them to hemolysis is increased in a cell.
Qualitative and quantitative changes of hemoglobin lay in basis of development of hereditary hemoglobinopathies. The most widespread clinical form is sickle-cell anemia at which in β-chain of a molecule of hemoglobin glutamine acid is replaced on valine (HbS.) HbS is crystallized easily, erythrocyte loses its shape and cells of red blood get the sickle-like form.
Figure. Scanning electron micro photo of oxygenated (A) and dezoxyhenated (B)
erythrocytes of patient with sickle cell anemia.
Н.F.Bunn et al. (1977).
Figure. Sickle cell anemia – blood
Figure. Sickle cell anemia – blood on the left – sickle-shaped red blood cells,
on the right – test hypoxia
Macrophages phagocytose and hemolyse them, especially when hypoxia is present.
Quantitative hemoglobinopathies are characterized by disorder of hemoglobin chains synthesis. An example of this group is α- and β-thalassemia.
Figure. Small (heterozygous) thalassemia – blood
Thalassemias are hereditary caused hemolytic anemias with endocellular hemolysis. Pathological forms of hemoglobin which can easily drop out in deposit are appeared in the erythrocytes during α-thalassemia and erythrocytes look like targets (target cell anemia). Macrophages phagocytose and hemolyse the erythrocytes.
Synthesis of β-chains of hemoglobin molecule is broken during β- thalassemia (disease of Cooley).
Anemias as a result of erythropoiesis disorder
The reasons of anemias with disorders of erythropoiesis may be:
1) disorder of formation of erythrocytes: deficiency of hemopoietic cells due to their damage or replacement, disorder of cells maturation of hemopoiesis (disorders of DNA resynthesis), defects of erythrocytes maturing and their output(exit) into blood flow (deficiency erythropoiesis);
2) disorders of hemoglobin synthesis: deficiency of iron, disorder of synthesis porphyrines (hereditary disorders of enzymes, poisonings by lead, deficiency of vitamin B6, frustration of albuminous chains synthesis of hemoglobin molecules).
Deficiency anemias
Irondeficiency anemia arises as a result of:
1) Insufficient receipt of iron with organism: а) an alimentary anemia in the infants (feeding with cow or goat milk); b) disorder of iron absorbtion (resection of stomach, intestines, gastritises, enteritis);
2) Hemorrhage. It is the most widespread reason of iron deficiency in organism;
3) Strengthened use of iron – pregnancy, lactation.
Figure. Irondeficiency anemia – blood
Figure. Irondeficiency anemia – blood
Insufficiency of iron in organism results in disorder of ferriferous proteins synthesis and consequently to the following disorders:
1) disorder of heme synthesis,
2) disorder of cytochromes formation and tissue hypoxia,
3) decrease of catalase activity hemolysis of erythrocytes and development of dystrophic changes in cells,
4) reduction of synthesis myoglobin and decrease(reduction) of resistance to hypoxia.
Decrease of hemoglobin concentration in peripheral blood and reduction of color index are typical for iron deficiency anemia. The quantity of erythrocytes decreases a little.
In blood smear the quantity regenerative forms of erythrocytes (reticulocytes, polychromatophils) decreases and their degenerative forms (anulocytes, microcytosis, poikilocytosis).
Iron refractory anemia results from disorder of iron inclusion in heme at decrease of enzymes activity, which catalase synthesis of porphyrines and heme. The reasons may be:
1) genetic down turn of decarboxylase activity of coproporphyrinogen – the enzyme providing one of final stages of heme synthesis (it is inherited recessively, is linked to the X-chromosome);
2) reduction of the maintenance pyridoxalphosphate – the active form of vitamin B6 and as a result of this iron is not taken from mitochondria of erythroblasts and is not included in heme;
3) lead blockade of sulfhydryl groups of the enzymes participating in synthesis of heme.
B12-(folate)deficiency anemia. The reasons of vitamin B12 insufficiency in an organism:
1. Exogenous (alimentary) insufficiency – insufficient receipt in an organism with food stuffs. May develop in small children as a result feeding goat milk or dry dairy mixes.
2. Disorders of vitamin B12 absorbtion:
а) Disorder of formation and secretion of gastromucoprotein (internal Castle’s factor). It happens at hereditary caused disorders, an atrophy of a mucous membrane of stomach, autoimmune damages of parietal cells of stomach mucous, due to gastrectomy or removal of more than two thirds of stomach;
b) Disorder of small intestine function: chronic diarrheas (celiac disease, sprue), resection of the big parts of intestine;
c) Competitive use of vitamin B12 by helmints and microflora of intestines (diphyllobothriasis).
3. Disorder of transcobalamines formation in liver.
4. Disorder of vitamin B12 deposition in liver.
5. Increased use of vitamin B12 (at pregnancy).
Deficiency of vitamin B12 results in development of the frustration connected with formation disorder of its two coenzyme forms: methylcobalamine and 5-desoxyadenosilcobalamine. In a red bone marrow erythroblastic type of hemopoiesis is replaced on megaloblastic, inefficient erythropoesis increases, life expectancy of erythrocytes is shortened. The anemia with the expressed degenerate shifts not only in a bone marrow, but also in blood develops. Changes in cells of myeloid and megacariocytic lines are shown by reduction of leukocytes quantity and thrombocytes, expressed by atypia of cells (huge neutrophils, megacaryocytes with degenerative changes in a nucleus). Occurrence of atypic mitosis and huge cells of epithelium digestive tract results in development of inflammatory-atrophic processes in mucous membrane of its parts (glossitis, stomatitis, esophagitis, achylic gastritis, enteritis).
As a result of the second coenzyme forms insufficiency of vitamin B12-5-desoxyadenosilcobalamine in organism propionic and methylmalonic acids, which are toxic for nervous cells. Besides fatty acids with the changed structure are synthesised iervous fibres results in disorder formation of myeline and to damage of axones. The degeneration of back and lateral columns of a spinal cord develops (funicular myelosis), cranial and peripheral nerves are damaged.
Occurrence in blood and red bone marrow of pathological regeneration cells – megaloblasts, megalocytes is the most typical feature of this anemia. the color index is increased, that is explained by the big saturation of cells by hemoglobin. The phenomenon of degeneration erythrocytes is typical: anisocytosis (macrocytosis), poikilocytosis (occurrence of the oval form cells), pathological inclusions (Jolly’s bodies, Cabot’s rings). The maintenance granulocytes (especially neutrophils) and thrombocytes in blood is reduced. Huge neutrophils with the hypersegmented nucleus are found out.
Figure. B12-deficiency anemia – bone marrow. Megaloblasts and megalocytes
Figure. Jolly’s bodies Figure. Cabot’s rings
Such syndromes are observed for B12-(folate)deficiency anemia:
1. hematologic syndrome: а) anemia; b) leukopenia; c) thrombocytopenia.
2. Damages of the digestive tract which are shown by development inflammatory –atrophic changes in mucous membrane.
3. Damages of the central and peripheral nervous system: funicular myelosis, degeneration of peripheral nerves.
Hypoplastic (аplastic) anemia is characterized by oppression hemopoietic functions of red bone marrow and shown by insufficient formation of erythrocytes, granulocytes and throrombocytes or only erythrocytes.
There are acquired and is hereditary caused forms of hypoplastic anemia. The type of hereditary is autosomal-recessive type of inheritance concerns.
The acquired forms may be caused by the following reasons:
1) physical factors (ionizing radiation);
2) chemical agents (benzene, lead, steams of mercury, medical products: cytostatic agents, chloramphenicol, sulfanilamids);
3) biological factors (virus of hepatites).
Essential forms of anemia, which reason is not established belongs to acquired anemias.
Reduction of erythrocytes maintenance and concentration of hemoglobin when color index is within the limits of norm is characterised for the peacture of peripheral blood. Regenerative of erythrocytes (reticulocytes, polychromatophils) as a role are not found in a blood smear. The maintenance of granulocytes (especially neutrophils) and thrombocytes decreases. The quantity of lymphocytes may remain without changes.
In a red bone marrow the quantity of hemopoietic cells decreases with increase of maintenance of fatty tissue (picture of devastation red bone marrow). Because of iron is not used for the purposes hemopoiesis, its maintenance in erythroblasts and extracelulary is increased.
Appearence of hypoplastic anemias are connected with reduction of three kinds formation of form blood elements: erythrocytes, granulocytes and thrombocytes. It results in development of the following clinical syndromes:
1. the anemia and connected to it hypoxic syndrome.
2. hemorrhagic syndrome.
3. the inflammatory processes caused by infectious agents (pneumonia, otitis, pyelitis etc.).
The metaplastic anemia is the result of hemopoietic tissue replacement on tissues: leucosis cells, connective tissue (fibrosis), metastasises of tumor.
Dysregulative anemias. Dysregulative anemias arise as a result of erythropoiesis regulation disorders (infringement of ratio between erythropoietins and inhibitors of erythropoiesis due to insufficiency of kidneys, damage of strome elements – microenvironments of erythropoietins cells, hypofunction of hypophysis, thyroid gland).
