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COAGULOPATHIES

COAGULOPATHIES. COAGULATION PATHWAY. A deficiency of each of the thirteen known plasma coagulation factors has been reported. Inherited or acquired. The plasma coagulation defects manifest more often in the form of large ecchymoses haematomas

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COAGULOPATHIES

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  1. COAGULOPATHIES

  2. COAGULATION PATHWAY

  3. A deficiency of each of the thirteen known plasma coagulation factors has been reported. • Inherited or acquired

  4. The plasma coagulation defects manifest more often in the form of • large ecchymoses • haematomas • bleeding into muscles, joints, body cavities, GIT and urinary tract • Prolonged bleeding after laceration or surgical procedures

  5. Disorders of plasma coagulation factors • Hereditary • Acquired

  6. HEREDITARY COAGULATION DISORDERS • Most are due to qualitative or quantitative defect in a single coagulation factor. • Two of the most common inherited coagulation disorders are 1. Sex-(X)- linked disorders • classic haemophilia or haemophilia A (deficiency of factor VIII) • Christmas disease or haemophilia B (deficiency of factor IX) 2. von Willebrand’s disease (defect of vWF)

  7. ACQUIRED COAGULATION DISORDERS • Characterised by deficiencies of multiple coagulation factors. • Most common acquired clotting abnormalities are: • Vitamin K deficiency • Coagulation disorder in liver diseases • Fibrinolytic defects • Disseminated intravascular coagulation (DIC)

  8. CLASSIC HAEMOPHILIA (HAEMOPHILIA A) • Second most common hereditary coagulation disorder next to von Willebrand’s disease • Occurrs due to deficiency or reduced activity of factor VIII (anti-haemophilic factor) • Inherited as a sex-(X-) linked recessive trait • Manifests clinically in males, females are usually the carriers

  9. Incidence • Highest incidence in populations of Britain, Northern Europe and Australia • 1 in 10,000 male births • Another interesting facet  this disorder is seen in the blood of royal families in Great Britain and some European countries

  10. Pathogenesis • Factor VIII is synthesised in hepatic parenchymal cells and regulates the activation of factor X in intrinsic coagulation pathway. • Factor VIII circulates in blood complexed to another larger protein, von Willebrand’s factor (vWF). • Quantitative reduction of factor VIII - 90% of cases • Normal or increased level of factor VIII with reduced activity - 10% cases • Normal haemostasis requires 25% factor VIII activity • Most symptomatic haemophilic patients have factor VIII levels below 5%

  11. Clinical features • Clinical severity of the disease correlates well with plasma level of factor VIII activity • Bleeding for hours or days after the injury • Involve any organ but occurs most commonly as • recurrent painful haemarthroses • muscle haematomas • Haematuria • Most feared complications: • spontaneous intracranial haemorrhage • oropharyngeal bleeding

  12. Laboratory findings 1. Whole blood coagulation time - prolonged (severe cases) 2. Prothrombin time - normal 3. Activated partial thromboplastin time - prolonged 4. Specific assay for factor VIII - lowered activity • Diagnosis of female carriers is made by the findings of about half the activity of factor VIII.

  13. Treatment • Factor VIII replacement therapy consisting of factor VIII concentrates or plasma cryoprecipitates

  14. CHRISTMAS DISEASE (HAEMOPHILIA B) • Inherited deficiency of factor IX (Christmas factor or plasma thromboplastin component) • Rarer than haemophilia A • Incidence - 1 in 100,000 male births • Inheritance pattern and clinical features of factor IX deficiency are indistinguishable from those of classic haemophilia

  15. Laboratory diagnosis: • Screening tests for coagulation: BT, CT, PT, APTT • Bioassay of factor IX - lowered activity

  16. Treatment • Infusion of either fresh frozen plasma or • Plasma enriched with factor IX • Complications of hepatitis, chronic liver disease, AIDS & activate the coagulation system  cause thrombosis and embolism.

  17. VON WILLEBRAND’S DISEASE • Most common hereditary coagulation disorder • Qualitative or quantitative defect in von Willebrand’s factor (vWF) • Incidence - 1 in 1,000 individuals of either sex • Autosomal dominant inheritance

  18. vWF comprises the larger fraction of factor VIII-vWF complex which circulates in the blood • Two components of factor VIII-vWF complex circulate together as a unit • Function in clotting & facilitate platelet adhesion to subendothelial collagen

  19. vWF differs from factor VIII in the following respects: 1. Gene for vWF - chromosome 12; Factor VIII – X chromosome. vWD is inherited as an autosomal dominant trait & occur in either sex, factor VIII deficiency (haemophilia A) is a sex (X-)- linked recessive disorder 2. vWF is synthesised in the endothelial cells, megakaryocytes & platelets; factor VIII  liver 3. Function of vWF is to facilitate the adhesion of platelets to subendothelial collagen Factor VIII is involved in activation of factor X in the intrinsic coagulation pathway

  20. Clinical features • Spontaneous bleeding from mucous membranes • Excessive bleeding from wounds

  21. There are 3 major types of vWD: • Type I disease - most common - mild to moderate decrease in plasma vWF (50% activity) - synthesis of vWF is normal but the release of its multimers is inhibited • Type II disease - less common - normal or near normal levels of vWF which is functionally defective • Type III disease - extremely rare - most severe form of the disease - no detectable Vwf activity

  22. Laboratory findings 1. Prolonged bleeding time 2. Normal platelet count 3. Reduced plasma vWF concentration 4. Defective platelet aggregation with ristocetin, an antibiotic 5. Reduced factor VIII activity

  23. Treatment • Cryoprecipitates • Factor VIII concentrates

  24. Vitamin K Deficiency • Fat-soluble vitamin • Important role in haemostasis since it serves as a cofactor in the formation vitamin Kdependent coagulation factors: factor II, VII, IX, X, protein C and protein S • Source: green vegetables & endogenously synthesised by the bacteria in the colon

  25. Neonatal vitamin K deficiency • Causes haemorrhagic disease of the newborn • Liver cell immaturity, lack of gut bacterial synthesis of the vitamin and low quantities in breast milk, all contribute to vitamin K deficiency in the newborn • Cause haemorrhage on 2nd to 4th day of life • Routine administration of vitamin K to all newly born infants

  26. Vitamin K deficiency in children and adult - 3 major causes : 1. Inadequate dietary intake 2. Intestinal malabsorption 3. Loss of storage site due to hepatocellular disease

  27. With the onset of vitamin K deficiency, the plasma levels of all the 6 vitamin K-dependent factors (prothrombin complex proteins) fall. • Prolonged PT and PTTK • Parenteral administration of vitamin K rapidly restores vitamin K levels in the liver

  28. Coagulation Disorders in Liver Disease • Liver is the major site for synthesis and metabolism of coagulation factors • Liver disease  multiple haemostatic abnormalities • Liver also produces inhibitorsof coagulation such as antithrombin III and protein C and S and plays a role in the clearance of activated factors and fibrinolytic enzymes • Patients with liver disease may develop hypercoagulability and are predisposed to develop DIC and systemic fibrinolysis

  29. DISSEMINATED INTRAVASCULAR COAGULATION (DIC) • Also termed defibrination syndrome or consumption coagulopathy • It is a complex thrombo-haemorrhagic disorder (intravascular coagulation and haemorrhage) occurring as a secondary complication in some systemic diseases.

  30. Definition • DIC is an acute, subacute, or chronic thrombohemorrhagic disorder characterized by the excessive activation of coagulation, which leads to the formation of thrombi in the microvasculature of the body.

  31. Etiology 1.Massive tissue injury: in obstetrical syndromes (e.g. abruptioplacentae, amniotic fluid embolism, retained dead foetus), massive trauma, metastatic malignancies, surgery. 2. Infections: especially endotoxaemia, gram-negative andmeningococcal septicaemia, certain viral infections, malaria, aspergillosis. 3. Widespread endothelial damage: in aortic aneurysm, haemolytic-uraemic syndrome, severe burns, acute glomerulonephritis. 4. Miscellaneous: snake bite, shock, acute intravascularhaemolysis, heat stroke.

  32. Pathogenesis 1. Activation of coagulation. Etiologic factors initiate widespread activation of coagulation pathway by release of tissue factor. 2. Thrombotic phase. Endothelial damage from the various thrombogenic stimuli causes generalised platelet aggregation and adhesion with resultant deposition of small thrombi and emboli throughout the microvasculature. 3. Consumption phase. Early thrombotic phase is followed by a phase of consumption of coagulation factors and platelets. 4. Secondary fibrinolysis. As a protective mechanism, fibrinolytic system is secondarily activated at the site of intravascular coagulation. Secondary fibrinolysis causes breakdown of fibrin resulting in formation of FDPs in the circulation.

  33. Morphology • Thrombi are most often found in the brain, heart, lungs, kidneys, adrenals, spleen & liver • Kidneys: - small thrombi in the glomeruli - reactive swelling of endothelial cells or - microinfarcts or even bilateral renal cortical necrosis

  34. Lung: - Numerous fibrin thrombi in alveolar capillaries - pulmonary edema and fibrin exudation, creating “hyaline membranes” • Central nervous system: - fibrin thrombi can cause microinfarcts & simultaneous hemorrhage lead to variable neurologic signs and symptoms

  35. Endocrine glands: - In meningococcemia, fibrin thrombi within the microcirculation of the adrenal cortex cause massive adrenal hemorrhages, seen in Waterhouse-Friderichsen syndrome - Sheehan postpartum pituitary necrosis is a form of DIC complicating labor and delivery

  36. Clinical features • Bleeding - most common manifestation • Organ damage  kidney and brain - due to ischaemia caused by the effect of widespread intravascular thrombosis • Less common manifestations include: • microangiopathic haemolytic anaemia • thrombosis in larger arteries and veins

  37. Laboratory findings 1. Platelet count - low 2. Blood film - shows the features of microangiopathic haemolytic anaemia - schistocytes and fragmented red cells 3. Prothrombin time, thrombin time and activated partial thromboplastin time - prolonged 4. Plasma fibrinogen levels - reduced due to consumption in microvascular coagulation 5. Fibrin degradation products (FDPs) are raised due to secondary fibrinolysis

  38. THANK YOU

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