The Hematopoietic & Lymphoid System (3): Bleeding Disorders

Richard A. McPherson, M.D.

Hemostasis and Thrombosis

Dependent on three factors:
Vascular endothelium Platelets Coagulation system

Bleeding Disorders
Increased fragility of vessels
Aging Medications (steroids)

Platelet defect (deficiency)

Low platelet count Medication (aspirin, clopidogrel) Congenital platelet defect

Deranged clotting
Factor deficiency Medication (coumadin) Coagulation inhibitor

Definitions
Petechiae: minute hemorrhages into skin, mucous membranes, serosal surfaces (1 to 2 mm) Purpura: slightly larger hemorrhages into skin, etc. (3 to 5 mm) Ecchymosis: subcutaneous hematomas, bruises (1 to 2 cm)

Laboratory tests
Prothrombin Time (PT) Activated Partial Thromboplastin Time (APTT, PTT) Platelet Count Bleeding Time (limited use) Factors, fibrinogen, FSP, anticoagulants, platelet function tests (aggregation) Take a history of bleeding, medications

Disseminated Intravascular Coagulation (DIC)

Activation of coagulation sequence: thrombi throughout microcirculation Consumption of platelets and coagulation factors to sub-hemostatic levels Activation of fibrinolysis Tissue hypoxia; microinfarcts Hemorrhage from (minor) trauma due to consumption/depletion of clotting factors and fibrinolysis destroying clots

Disseminated Intravascular Coagulation (DIC)

Etiologies
Release of tissue factor or thromboplastins into circulation Widespread injury to endothelial cells

Clinical examples
Sepsis Obstetric complications Malignancy Major trauma

Treatment: anticoagulate

Thrombocytopenia (Platelets <100K/mm3)

Platelets 20-50K: post traumatic bleeding Platelets <20K: spontaneous bleeding Etiologies
Decreased production: bone marrow failure Increased destruction: immunologic (ITP) Increased destruction: nonimmunologic (DIC, TTP) Sequestration (hypersplenism) AIDS: immune complexes, low megakaryocytes

Idiopathic Thrombocytopenic Purpura (ITP)

Autoimmune: isolated; or part of SLE; or selflimited in children (postviral) Antiplatelet Ab against GPIIb/IIIa or Ib Petechiae, easy bruisability, epistaxis, gum bleeding, hemorrhages after minor trauma Intracerebral/subarachnoid hemorrhage Treatment: steroids; splenectomy: >2/3 of patients recover (spleen is source of Ab and site of destruction)

Thrombotic Thrombocytopenic Purpura (TTP)

Diagnostic criteria:
fever, thrombocytopenia, microangiopathic hemolytic anemia, neurologic deficit, renal failure

Hyaline thrombi in microcirculation: aggregates of platelets coated by fibrin Abnormally large von Willebrands antigen Hemolytic Uremic Syndrome
Toxin from E. coli 0157:H7 Bloody diarrhea

Treatment: total plasma exchange transfusion

Coagulation Factor Disorders

Acquired
Vitamin K deficiency Parenchymal disease of liver

Hereditary deficiencies
Factor VIII: hemophilia A Factor IX: hemophilia B VIII and IX sex-linked on X chromosome Factor XI: hemophilia C Other factors

Factor VIII/von Willebrand Factor

Complex of 2 proteins: non-covalent bonds
VIII procoagulant protein vWF, much larger protein (~99% of complex), series of high molecular weight multimers

vWF binds to collagen and to platelet glycoproteins Ib and IIb/IIIa vWF is the glue that adheres platelets to subendothelial collagen

Von Willebrands Disease

Bleeding disorder
Spontaneous bleeding from mucous membranes Excess bleeding from wounds; menorrhagia Autosomal dominant: spectrum of mild to severe

Most common inherited bleeding disorder Lab tests

Normal platelet count; increased bleeding time vWF Ag quantitation; platelet aggregation (ristocetin) vWF multimeric analysis (molecular sizes)

Von Willebrands Disease

vWF multimeric analysis (esoteric procedure)
Type I: decreased amount of vWF Type II: loss of high molecular weight multimers Type III: total lack of vWF

Treatment
DDAVP Fresh frozen plasma Cryoprecipitate

Factor VIII Deficiency

Hemophilia A
Most common hereditary disease of serious bleeding Sex-linked (males) ~30% of cases are due to new mutations in VIII gene Bleeding:
Severe Mild Moderate <1% VIII 1-5% VIII 5-75% VIII

Antibodies against VIII

After transfusion in hemophilia A De novo in normals

Factor VIII Deficiency Hemophilia A

Clinical features
Easy bruising/hemorrhage after trauma, surgery Spontaneous hemorrhages Hemarthroses Dentists watch for dissecting hematoma around airway

Factor VIII Deficiency Hemophilia A, cont.

Labs
Bleeding time normal APTT prolonged; PT normal; VIII low

Treatment:
VIII concentrates (HIV risk from pools in past) Recombinant VIII

Be aware of Hemophilia B: Factor IX deficiency

Summary of Bleeding Disorders

Integrity of vasculature, platelets, coagulation Tests: Plt ct, PT, PTT, special studies DIC: consumptive coagulopathy/fibrinolysis ITP: immune TTP: thrombotic HUS assoc with E. coli 0157:H7 toxin Coagulation factor disorders
Multifactor: nutrition, liver disease, medication Single factor: VIII, IX VWD: platelet function and VIII