ACQUIRED HEMOSTATIC DISORDERS

1. ACQUIRED HEMOSTATIC DISORDERS LugyantiSukrisman Div. of Hematology & Medical Oncology Dept. of Internal Medicine University of Indonesia/ CiptoMangunkusumo Hospital

2. BLEEDING • Liver diseases • ITP • Acquired qualitative platelet defects • Def of vit K-dependent factors • Excessive fibrinolysis THROMBOSIS • Disseminated intravascular coagulation • Antiphospholipid syndrome • Pathologic anticoagulant • (immune coagulopathies) ACQUIRED HEMOSTASTIC DISORDERS

3. Classification of disorders of hemostasis

4. Classification of disorders of hemostasis

5. Liver’s central role in hemostasis: • The major site of synthesis of • all coagulation factors (except vWF), • regulatory proteins of coagulation system (antithrombin, protein C & S), • component of fibrinolytic system • Clearance of activated clotting factors from circulation A. Coagulation abnormalities of liver diseases (1) Colman RW. Hemostasis & thrombosis. Basic principles & clinical practice 2006

6. Thrombocytopenia • Platelet dysfunction • Coagulation abnormalities • Disseminated intravascular coagulation & hyperfibrinolysis A. Coagulation abnormalities of liver diseases (2) Colman RW. Hemostasis & thrombosis. Basic principles & clinical practice 2006

7. Pathogenesis: • Splenic sequestration due to portal hypertension • Impaired platelet production • Thrombin-mediated platelet consumption • HCV infection: • Viral infection of megakaryocytes • Platelet destruction due to autoimmune mechanisms 1. Thrombocytopenia

8. Reduced platelet adhesion • Impaired platelet aggregation 2. Platelet dysfunction Colman RW. Hemostasis & thrombosis. Basic principles & clinical practice 2006

9. Reduced of vit-K-dependent coagulation factors (II, VII, IX, X) & F. V • Fibrinogen: normal/increased  decreased: • Impaired synthesis • Increased catabolism • Loss into extra vascular space • Massive hemorrhage • Diminished antithrombin, protein C & S, heparin cofactor II, α-2 macroglobulin 3. Coagulation abnormalities Colman RW. Hemostasis & thrombosis. Basic principles & clinical practice 2006

10. History of jaundice/acute hepatitis, risk of infection (iv drug user, liver disease in family, etc) • (History of) bleeding: hematemesis &/melena • Clinical sign of liver disease & complication: • Jaundice • Other signs: pale, ascites, splenomegaly, palmarerythema, edema, etc • Bleeding signs: petechiae, hematoma, hematemesis/melena, etc Diagnosis (1)

11. Laboratory results: • CBC: thrombocytopenia ± anemia/leukopenia • Liver function tests: low albumin level, increased transaminase/bilirubin (variably) • Coagulation tests: PT, aPTT, fibrinogen, D-dimer • Hepatitis markers (hepatitis B/C) • Abdominal US: liver disease & others (bile stone, etc) • Others: endoscopy of upper GI Diagnosis (2)

12. Active bleeding/plan of invasive procedure: • Vit K, FFP/cryoprecipitate, platelet concentrate, packed red cells • Stop the bleeding: ligation/sclerosing therapy & pharmacology treatment • Treatment of liver disease & complication, non pharmacologic treatment & nutritional support Treatment

13. Consumptive coagulation • Defibrin(ogen)ation syndrome • Thrombohemorrhagic syndrome B. Disseminated intravascular coagulation

16. Marder VJ. Hemost and Thromb.. 2006.1571-1600 Activation of coagulation Events leading to bleeding Events leading to thrombosis Circulating thrombi Circulating fibrin degradation products Consumption of platelets and coagulation proteins Thrombotic occlusion of microcirculation of all organs Fibrinolysis in microcirculation + • Signs of microvascular thrombosis • Neurologic : multifocal, delirium, coma • Skin : focal ischemia, superficial gangrene • Renal : oliguria, azotemia, cortical necrosis • Pulmonary: acute respiratory distress • syndrome • GI: acute ulceration • Fragmentation hemolytic anemia • Signs of hemorrhagic diathesis • Neurologic : intracerebral • bleeding • Skin : petechiae, ecchymoses, • venipunctureoozing • Renal : hematuria • Mucous membranes: epistaxis, • gingival oozing • GI: massive bleeding Marder VJ. Hemost and Thromb. 5edt. 2006.1571-1600

17. Underlying disorder Systemic activation of coagulation Consumption of platelets and clotting factors Widespread intravascular fibrin deposition (severe) Bleeding Thrombosis and organ failure

18. Complexity and variability depends on: • Triggering event(s) • Host Response • Comorbid conditions Clinical manifestation

19. Clinical features Bleeding: mucosal oozing, ecchymoses, petechiae, massive GI blood loss Renal/cerebral/ hepatic dysfunction, ARDS • Laboratory • Increased D-Dimer level • Increased FDP level • Decreased AT level • Decreased platelet level • Bload smear:schistocytes • Decreased fibrinogen level • Prolonged thrombin time/aPTT/PT Diagnostic approach

20. Severe liver failure/liver disease • Vitamin K deficiency • HELLP syndrome • Thrombotic thrombocytopenic purpura • Congenital abnormalities of fibrinogen Differential Diagnosis

21. Treat the underlying disease • Restore the circulation • Replacement therapy • FFP/cryoprecipitate, platelet concentrate, packed red cells • Other pharmacologic therapy: • Heparin, antithrombin, activated Protein C, others TREATMENT OF DIC

22. vitamin K: essential for the final postribosomal carboxylation of coagulation factors II, VII, IX, X and protein C and protein S • laboratory features: prolonged PT &decreased factors II, VII, IX, X level • in severe, protracted vitamin K deficiency: prolonged aPTT C. Deficiency ofvitamin K-dependent factors

23. I. Inadequate supply: 1. Dietary deficiency 2. Destroying the gut flora by administration of broad-spectrum antibiotics II. Impaired absorption of vitamin K: 1. Biliary obstruction (gallstone, tumor) 2. Malabsorption of vitamin K 3. Drugs (cholestyramine) III. Pharmacologic antagonists of vitamin K (coumarins, warfarin) Vitamin K deficiency

24. D. Excessive fibrinolysis • Primary fibrinolysis (excessive release of tissue Plasminogen Activator): rare • Acquired: • Thrombolytic therapy • Secondary  disease-related: • surgical/ trauma • neoplasms (prostate, pancreas, leukemia) • systemic lupus erythemathosus • severe liver disease (defective clearance of activator) • Fibrinolysis secondary to intravascular coagulation Ratnoff OD, Forbes CD. Disorders of hemostasis 1996, 296-322

26. Diagnosis • Bleeding signs • Thrombolytic therapy/other condition related to acquired excessive fibrinolysis • Laboratory: • FDP: increased • Plasma fibrinogen level: reduced • Euglobulin clot lysis time: rapid • TT, PT, aPTT: prolonged Ratnoff OD, Forbes CD. Disorders of hemostasis 1996, 296-322

27. Treatment of excessive fibrinolysis • Fibrinolytic inhibitors: • Tranexamic acid • -Aminocaproic acid (EACA) • Fibrinolytic inhibitor: contraindicated for fibrinolysis secondary to/associated with intravascular clotting Ratnoff OD, Forbes CD. Disorders of hemostasis 1996, 296-322

29. E. Pathologic anticoagulants (immune coagulopathies) (1) • Appear spontaneously in subjects with previously normal hemostatic function. • Antibodies to factor VIII, “idiopathic” inhibitor • Autoimmune disorders (SLE, rheumatoid arthritis, multiple sclerosis, pemphigus, etc) • Hematologic malignancies: chronic lymphocytic leukemia, non-Hodgkin lymphoma, multiple myeloma, etc • Drug reactions: allergies to penicillin, sulfonamides, chloramphenicol, methyldopa, etc

30. E. Pathologic anticoagulants (immune coagulopathies) – (2) • Prolonged aPTT • Reduced F. VIII levels • Inhibitor F. VIII • Spontaneous, often severe/life-threatening bleeding Colman RW. Hemostasis & thrombosis. Basic principles & clinical practice 2006