Haemostasis and bleeding disorders for students

Hemostasis and bleeding disorders

1. The coagulation factors

2. Hemostasis: Coagulation & Clot Stabilization Figure 16-13: The coagulation cascade Prothrombin Ca++ Fibrinogen Fibrin Polymerization

3. Contact activation FX12a FX11a AT Tissue factor FVIIa FV FIXa Protein S APC FXa TFPI AT Intrinsic system AT FIX FVIII Ca 2 + PL FVIII i Extrinsic system FX TFPI PAI-1 Plasmingoen Prothrombin Thrombin Fibriogen FIBRIN FDP Plasmin Plasmin inhibitor u-PA t-PA FX12a FV Ca 2 + PL FV 1 Protein C Thrombo-modulin Overview of coagulation showing procoagulant events ( ) and inhibition of coagulation ( ) by anti-thrombin (AT), tissue factor pathway inhibitor (TFPI) and activated protein C (APC). F denotes coagulation factors.

4. Coagulation factor inhibitors Tissue factor pathway inhibitors which is present in the plasma and platelet and accumulation at the site of injury caused by local platelet activation. It inhibits factors Xa and VIIa and tissue factor to limit the main in vivo pathway. Antithrombin III, most potent. It inactivate seriene proteases by combining with them. Heparin potentiates its action markedly.

5. Coagulation factor inhibitors (Cont) 3-Protein C and protein S Thrombin binds to an endothelial surface receptor thrombomodulin. The resulting complex activate the vitamin K dependent serine protease C with the help of PS they inactivate V and VIII preventing thrombin synthesis.

6. Dissolving the Clot and Anticoagulants Figure 16-14: Coagulation and fibrinolysis

7. FIBRILOLYSIS Fibrinolysis (like coagulation) is a normal haemostatic response to vascular injury. Plasminogen , a proenzyme in blood and tissue fluid, is converted to the serine protease plasmin by tissue plasminogen activator (TPA) released from endothelial cells. Plasmin generation at the site of injury limits the extent of the evolving thrombus α2 -antiplasmin inhibits any local free plasmin. Tissue plasminogen activator is inactivated by plasminogen activator inhibitor (PAI ).

8. Fibrinolytic agents are widely used in clinical practice. Recombinant TPA, the bacterial agent, streptokinase and urokinase, initially isolated from human urine, are available. Anti-fibrinolytic agents such as epsilon aminocaproic acid and tranexamic acid are used to prevent fibrinolysis, such as in trauma or post-partum haemorrhage

9. COAGULATION FACTOR DEFICIENCIES

10. Coagulation Factors Defficiencies I.Congenital Hereditary deficincies of each of the coagulation factor have been recorded, the most common of them are. Haemophilia A. Haemophilia B. fibrinogen abnormalities II.Acquired – due to: Vitamin K deficiency Liver disease Consumption coagulopathy

11. Genetics: Haemophilia A is inherited as X-linbed recessive disorder affecting males and transmitted by female. Deficiency of factor VIII results from an abnormality in factor VIII gene which lies at the tip of the long arm of the x-chromosome (xq2.6 region). The plasma level of factor VIII clotting activity (F VIII C) is low or absent, VWF and VWF Ag normal.

12. According to disease severity: <1% factor level severe disease with recurrent episodes of spontaneous bleeding in muscles and joints , leading to crippling arthropathy 2-Clinical features (cont)

13. 1-5% Moderate disease with attacks of bleeding usually following trauma with occasional spontaneous attacks >5 % Mild disease with bleeding only following trauma or surgery

14. Bleeding-Coagulation disorder Deep bleeding Haematoma Joint bleeds Haemophilia

15. Bachelor of Chinese Medicine, The University of Hong Kong Haemophilia A showing severe disability

16. Lab investigations Prolonged PTT Decreased factor level by factor assay

17. Complication Arthritis, secondary to repeated haemorrhages Peripheral nerve compression and pseudotumour . FVIII antibodies/inhibitors in 5-10% of patients. Chronic liver disease, related to previous exposure to hepatitis B or C.

18. Treatment It should be given prophylactically before any type of operation. It should be given at the earlist sign of spontaneous or post- traumtic bleeding.

19. Treatment consists of I.V injection of factor VIII in a the form of f VIIII concentrate or recombinant factor VIII to maintain plasma factor VIII activity between 5 and 100% according to the severity of injury or extent of surgical procedure. Desmopressin provides an alternative means of increasing the plasma factor VIII level in mild haemophilics . It induces a release of F VIII from endothelial cells. FFP and cryoppt may be used as alternatives when f VIII is not available

20. Haemophilia B (or Christmas disease) It results from a quantitative or qualitative defect in factor IX. It is similar in every aspect to haemophilic A, including the mode of inheritance. The gene coding for factor IX is located on the long arm of X-chromosome. It is much less than hemophilia A. Bleeding is treated by fresh frozen plasma or factor IX concentrate.

21. Vitamin K deficiency The prothrombin complex or group which consist of factors II, VII, IX, X which are produced in the liver. The fat soluble vitamin K is necessary for synthesis of these factor. Acquired coagulation diseases

22. The final stages in the synthesis of these factors, involve a vitamin K-dependent carboxylation , which adden carboxyl (-COOH) group to the proteins, these groups are necessary for the efficient function of the molecules. vit K is obtained form green vegetables and bacterial synthesis in the gut

23. Aetiology : 1-Impaired absorption due to: Biliary obstruction. Pancreatic disease. Steatorahea of other causes. 2- Secondary to oral anticoagulants 3- Prolonged treatment with broad spectrum antibiotics in association with low dietary intake in severly ill patients. 4- Haemorrhagic disease of the new born

24. . Lab investigations PT increased APTT increased Management Vitamin K Fresh frozen plasma.

25. II. Liver Disease Pathogenesis Deficiency of factor II, VII, IX and X Thrombocytopenia due to viral hepatitis or hypersplenism Defect in fibrinolytic pathway Acute liver failure may lead to DIC

26. Disseminated intravascular coagulation Widespread generation of fibrin within blood vessels , caused by overstimulation of the coagulation pathway DIC can be intiated by a variety of different mechanism Bacterial toxin e.g. gram negative septicemia, miningoccacal septicaemia . Other infection e.g. falciparm maleria . Hypovolemic shock. malignancy

27. 5. obstetric complications. E.g. amniotic fluid embolism, abruptio placentae, and intrauterine death. 6. Tissue factor release due to trauma, Burn, malignancy. 7. Acute promyelocytic leukemia (AML M3)

28. Clinical features Some patients are asymptomatic. Symptoms and sign related to associated diseases. Symptom and signs related to DIC. Haemorrhagic manifestation of variable severity:

29. The pathogenesis of DIC

30. DIAGNOSIS Thrombocytopenia. Blood: film-red cell fragments and schistocytes . Bleeding, prothombin time, APTT, and thrombin T prolonged. Fibrinogen level-decreased, fibrin degredation products (FDP) and D-dimers presents.

31. Treatment of DIC Treatment of the underlying disease e.g. antibiotics in septicemia. Treatment of haemorrhage with: Fresh plasma, fresh frozen plasma and cryoprecipitate to replace clotting Factors Platelet concentrates in case of major bleeding

32. Thrombophilia

33. Virchow’s Triade

34. For venous thrombosis, increased systemic coagulability and stasis are most important, with vessel wall damage being somewhat less important than in arterial thrombosis. The risk factors for arterial thrombosis are related to the development of atherosclerosis

35. Risk factors for arterial thrombosis (atherosclerosis).

36. Arterial thrombosis is also associated with collagen vascular disorders e.g. Behcet’s disease

37. risk factors for venous thrombosis oestrogen therapy pregnancy and puerperium prolonged recumbency surgery esp abdominal and hip surgery major trauma malignancy myeloproliferative neoplasms Dehydaration old age obesity .

38. Congenital thrombophilia Approximately one-third of patients who suffer DVT or PE have an identifiable heritable risk factor May be spontaneous or due to additional risk factors (surgery, immobility, oestrogen exposure)

39. Congenital thrombophilia ; causes

40. Antiphospholipid syndrome A rterial or venous thrombosis or recurrent pregnancy loss or placental dysfunction

41. 2 Diagnostic criteria in APS . Clinical criteria ∗ _ Thrombosis: arterial, venous or microvascular thrombosis in any tissue or organ Laboratory criteria ∗ _ IgG or IgM anticardiolipin antibodies at moderate or high concentration†; _IgG or IgM anti-β2-GPI > 99th percentile and/or _ Lupus anticoagulant ∗

42. Pregnancy complications _ Unexplained death of morphologically normal fetus at beyond 10 weeks of gestation OR _ Three or more unexplained consecutive miscarriages before 10 weeks _ One or more premature births of a morphologically normal fetus before 34th weeks of gestation due to pre-eclampsia, eclampsia or severe placental insufficiency

43. There must be at least one clinical and at least one laboratory criterion present. The laboratory test must be consistently positive on at least two occasions 12 weeks apart

44. Types Thrombotic Obstetric Microvascular Catastrophic antiphospholipid

45. Treatment is based on anticoagulation (warfarin) Immunosuppressive therapy is not indicated in primary APS. immunomodulatory therapies have been administered in microvascular APS. An exception may be catastrophic APS when combination treatment with antithrombotics , corticosteroids and other immunomodulatory therapies such as rituximab is administered as a life saving.