ACQUIRED HEMOSTATIC DISORDERS Lugyanti Sukrisman Div. of Hematology & Medical Oncology Dept. of Internal Medicine University of Indonesia/ Cipto Mangunkusumo Hospital

ACQUIRED HEMOSTASTIC DISORDERS 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)

Classification of disorders of hemostasis Major types DisordersExamples AcquiredThrombocytopeniaAuto- and alloimune, drug-induced, hypersplenism, hypoplastic (primary, suppressive), DIC Liver diseaseCirrhosis, acute liver failure, liver transplantation Renal failure Vitamin K deficiencyMalabsorption syndrome, hemorrhagic disease of the newborn, prolonged antibiotic therapy, malnutrition, prolonged billiary obstruction Hematologic disorders Acute leukemias (particulary promyelocytic), myelodysplasias, monoclonal gammopathies, essential thrombocytemia

Classification of disorders of hemostasis Major types disordersExamples AcquiredAcquired antibodies against coagulation factors Neutralizing antibodies against F.V, VIII & XIII; accelerated clearance of antibody-factor complexes, e.g. acquired von Willebrand disease, hypoprothrombinemia associated with APS Disseminated intravascular coagulation Acute (sepsis, malignancies, trauma, obstetric complications) and chronic (malignancies, giant hemangiomas, missed abortion) DrugsAntiplatelet agents, anticoagulants, antithrombins, and thrombolytic, myelosuppressive, hepatotoxic, and nephrotoxic agents VascularNonpalpable purpura (“senile”, solar, factitious purpura), use of corticosteroids, vitamin C deficiency, purpura fulminans; palpable purpura (Henoch-Schönlein, vasculitis, dysproteinemias)

A. Coagulation abnormalities of liver diseases (1) 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 Colman RW. Hemostasis & thrombosis. Basic principles & clinical practice 2006

A. Coagulation abnormalities of liver diseases (2) 1. Thrombocytopenia 2. Platelet dysfunction 3. Coagulation abnormalities 4. Disseminated intravascular coagulation & hyperfibrinolysis Colman RW. Hemostasis & thrombosis. Basic principles & clinical practice 2006

1. Thrombocytopenia 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

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

3. Coagulation abnormalities 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 Colman RW. Hemostasis & thrombosis. Basic principles & clinical practice 2006

Diagnosis (1) 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, palmar erythema, edema, etc ◦Bleeding signs: petechiae, hematoma, hematemesis/melena, etc

Diagnosis (2) 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

Treatment 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

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

Activation of coagulation Circulating thrombi Thrombotic occlusion of microcirculation of all organs Fibrinolysis in microcirculation Circulating fibrin degradation products Consumption of platelets and coagulation proteins + Events leading to thrombosis 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 Events leading to bleeding Signs of hemorrhagic diathesis Neurologic : intracerebral bleeding Skin : petechiae, ecchymoses, venipuncture oozing Renal : hematuria Mucous membranes: epistaxis, gingival oozing GI: massive bleeding Marder VJ. Hemost and Thromb. 5edt Marder VJ. Hemost and Thromb

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

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

Diagnostic approach 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

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

TREATMENT OF DIC  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

C. Deficiency of vitamin K-dependent factors 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

Vitamin K deficiency 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)

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,

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,

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,

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

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