ACQUIRED HEMOSTATIC DISORDERS

Lugyanti SukrismanDiv. of Hematology & Medical Oncology

Dept. of Internal Medicine University of Indonesia/

Cipto Mangunkusumo Hospital

ACQUIRED HEMOSTASTIC DISORDERSBLEEDINGLiver diseasesITPAcquired qualitative

platelet defectsDef of vit K-

dependent factorsExcessive

fibrinolysis

THROMBOSISDisseminated

intravascular coagulation

Antiphospholipid syndrome

• Pathologic anticoagulant (immune coagulopathies)

Classification of disorders of hemostasisMajor types

Disorders Examples

Acquired Thrombocytopenia Auto- and alloimune, drug-induced, hypersplenism, hypoplastic (primary, suppressive), DIC

Liver disease Cirrhosis, acute liver failure, liver transplantation

Renal failureVitamin K deficiency Malabsorption 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 hemostasisMajor types

disorders Examples

Acquired Acquired 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)

Drugs Antiplatelet agents, anticoagulants, antithrombins, and thrombolytic, myelosuppressive, hepatotoxic, and nephrotoxic agents

Vascular Nonpalpable 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. Thrombocytopenia2. Platelet dysfunction3. Coagulation abnormalities4. Disseminated intravascular coagulation

& hyperfibrinolysis

Colman RW. Hemostasis & thrombosis. Basic principles & clinical practice 2006

1. ThrombocytopeniaPathogenesis: 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 &/melenaClinical 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

TreatmentActive 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 syndromeThrombohemorrhagic syndrome

Activation of coagulation

Circulating thrombi

Thrombotic occlusion of microcirculation of all organs

Fibrinolysis inmicrocirculation

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. 2006.1571-1600

Marder VJ. Hemost and Thromb.. 2006.1571-1600

Underlying disorder

Systemic activation of coagulation

Widespread intravascular fibrin deposition

Consumption of platelets and clotting factors

Thrombosis and organ failure

(severe) Bleeding

Clinical manifestationComplexity and variability depends on:Triggering event(s)Host ResponseComorbid conditions

Diagnostic approachClinical featuresBleeding: mucosal

oozing, ecchymoses, petechiae, massive GI blood loss

Renal/cerebral/ hepatic dysfunction, ARDS

LaboratoryIncreased D-Dimer level Increased FDP level Decreased AT levelDecreased platelet levelBload smear:

schistocytesDecreased fibrinogen

levelProlonged 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 deficiencyI. 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, 296-322

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

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

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