Thrombocytopenia

Normal platelet count is 150,000-350,000/µL. Thrombocytopenia is defined as a platelet count <100,000/µL. Bleeding time, a measurement of platelet function, is abnormally increased if platelet count is <100,000/µL; injury or surgery may provoke excess bleeding. Spontaneous bleeding is unusual unless count <20,000/µL; platelet count <10,000/µL may be associated with serious hemorrhage. Bone marrow examination shows increased number of megakaryocytes in disorders associated with accelerated platelet destruction; decreased number in disorders of platelet production. Evaluation of thrombocytopenia is shown in Fig. 65-1. Algorithm for Evaluating the Thrombocytopenic Pt.

Causes

(1) Production defects such as marrow injury (e.g., drugs, irradiation), marrow failure (e.g., aplastic anemia), marrow invasion (e.g., carcinoma, leukemia, fibrosis);

(2) sequestration due to splenomegaly; (3) accelerated destruction-causes include:

• Drugs such as chemotherapeutic agents, thiazides, ethanol, estrogens, sulfonamides, quinidine, quinine, methyldopa.
• Heparin-induced thrombocytopenia (HIT) is seen in 5% of pts receiving >5 days of therapy and is due to in vivo platelet aggregation often from anti-platelet factor 4 antibodies. Arterial and occasionally venous thromboses may result. Despite the low platelets, HIT is a hypercoagulable state.
• Autoimmune destruction by an antibody mechanism; may be idiopathic or associated with systemic lupus erythematosus (SLE), lymphoma, HIV.
• Idiopathic thrombocytopenic purpura (ITP) has two forms: an acute, self-limited disorder of childhood requiring no specific therapy, and a chronic disorder of adults (esp. women 20-40 years). Chronic ITP may be due to autoantibodies to glycoprotein IIb/IIIa or glycoprotein Ib-IX complexes.
• Disseminated intravascular coagulation (DIC): platelet consumption with coagulation factor depletion (prolonged prothrombin time [PT], partial thromboplastin time [PTT]) and stimulation of fibrinolysis (generation of fibrin split products [FSPs]). Blood smear shows microangiopathic hemolysis (schistocytes). Causes include infection (esp. meningococcal, pneumococcal, gram-negative bacteremias), extensive burns, trauma, or thrombosis; giant hemangioma, retained dead fetus, heat stroke, mismatched blood transfusion, metastatic carcinoma, acute promyelocytic leukemia.
• Thrombotic thrombocytopenic purpura (TTP): rare disorder characterized by microangiopathic hemolytic anemia, fever, thrombocytopenia, renal dysfunction (and/or hematuria), and neurologic dysfunction most commonly caused by antibodies to ADAMTS13, a protease that normally cleaves von Willebrand factor (vWF); when vWF is not cleaved, it spontaneously binds and activates adherence of platelets.
• Hemorrhage with extensive transfusion.

Pseudothrombocytopenia

Platelet clumping usually secondary to collection of blood in EDTA (0.3% of pts). Examination of blood smear establishes diagnosis.

Thrombocytosis

Platelet count >350,000/µL. Either primary (essential thrombocytosis; Chap. 66 Myeloid Leukemias, Myelodysplasia, and Myeloproliferative Syndromes) or secondary (reactive); latter secondary to severe hemorrhage, iron deficiency, surgery, after splenectomy (transient), malignant neoplasms (esp. Hodgkin's lymphoma, polycythemia vera, ovarian cancer; possibly related to IL6 production by the tumor), chronic inflammatory diseases (e.g., inflammatory bowel disease), recovery from acute infection, vitamin B₁₂ deficiency, drugs (e.g., vincristine, epinephrine). Rebound thrombocytosis may occur after marrow recovery from cytotoxic agents, alcohol, vitamin B₁₂ replenishment. Primary thrombocytosis may be complicated by bleeding and/or thrombosis; generally problems not seen until the platelet count is >1.5 million/µL; secondary rarely causes hemostatic problems.

Disorders of Platelet Function

Suggested by the finding of prolonged bleeding time with normal platelet count. Defect is in platelet adhesion, aggregation, or granule release. Causes include (1) drugs-aspirin, other nonsteroidal anti-inflammatory drugs, dipyridamole, clopidogrel or prasugrel, heparin, penicillins, esp. carbenicillin, ticarcillin; (2) uremia; (3) cirrhosis; (4) dysproteinemias; (5) myeloproliferative and myelodysplastic disorders; (6) von Willebrand disease (vWD; see below); (7) cardiopulmonary bypass.

Congenital Disorders

1. Hemophilia A: incidence 1:5000; sex-linked recessive deficiency of factor VIII (low plasma factor VIII coagulant activity, but normal amount of factor VIII-related antigen-vWF). Laboratory features: elevated PTT, normal PT.
2. Hemophilia B (Christmas disease): incidence 1:30,000, sex-linked recessive, due to factor IX deficiency. Clinical and laboratory features similar to hemophilia A.
3. von Willebrand disease: most common inherited coagulation disorder (1:800-1000), usually autosomal dominant; primary defect is reduced synthesis or chemically abnormal factor VIII-related antigen produced by platelets and endothelium, resulting in abnormal platelet function.

Acquired Disorders

1. Vitamin K deficiency: impairs production of factors II (prothrombin), VII, IX, and X; vitamin K is a cofactor in the carboxylation of glutamate residues on prothrombin complex proteins; major source of vitamin K is dietary (esp. green vegetables), with minor production by gut bacteria. Laboratory features: elevated PT and PTT.
2. Liver disease: results in deficiencies of all clotting factors except VIII. Laboratory features: elevated PT, normal or elevated PTT.
3. Other disorders: DIC, fibrinogen deficiency (liver disease, L-asparaginase therapy, rattlesnake bites), other factor deficiencies, circulating anticoagulants (lymphoma, SLE, idiopathic), massive transfusion (dilutional coagulopathy).