60 BLEEDING AND THROMBOTIC DISORDERS
Harrison’s Manual of Medicine
BLEEDING AND THROMBOTIC DISORDERS
Hemostatic Disorders due to Blood Vessel Wall Defects
Disorders of Blood Coagulation
Bleeding may result from abnormalities of (1) platelets, (2) blood vessel walls, or (3) coagulation. Platelet disorders characteristically produce petechial and purpuric skin lesions and bleeding from mucosal surfaces. Defective coagulation results in ecchymoses, hematomas, and mucosal and, in some disorders, recurrent joint bleeding (hemarthroses).
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 <100,000/µL; injury or surgery may provoke excess bleeding. Spontaneous bleeding is unusual unless count is <20,000/µL; platelet count <10,000/ µL is often 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.
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 is seen in 5% of pts receiving >5 d of therapy and is due to in vivo platelet aggregation. Arterial and occasionally venous thromboses may result.
Autoimmune destruction by an antibody mechanism; may be idiopathic or associated with 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 PT, PTT) and stimulation of fibrinolysis (generation of fibrin split products, FSP). 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—rare disorder characterized by microangiopathic hemolytic anemia, fever, thrombocytopenia, renal dysfunction (and/or hematuria), and neurologic dysfunction.
Hemorrhage with extensive transfusion.
PSEUDOTHROMBOCYTOPENIA Platelet clumping 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 (thrombocythemia; Chap. 63) or secondary (reactive); latter secondary to severe hemorrhage, iron deficiency, surgery, after splenectomy (transient), malignant neoplasms (esp. Hodgkin’s disease), 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. Primary thrombocytosis may be complicated by bleeding and/or thrombosis; 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 NSAIDs, dipyridamole, heparin, penicillins, esp. carbenicillin, ticarcillin; (2) uremia; (3) cirrhosis; (4) dysproteinemias; (5) myeloproliferative and myelodysplastic disorders; (6) von Willebrand’s disease (see below); (7) cardiopulmonary bypass.
Hemostatic Disorders due to Blood Vessel Wall Defects
Causes include: (1) aging; (2) drugs—e.g., glucocorticoids (chronic therapy), penicillins, sulfonamides; (3) vitamin C deficiency; (4) thrombotic thrombocytopenic purpura (TTP); (5) hemolytic uremic syndrome; (6) Henoch-Schönlein purpura; (7) paraproteinemias; (8) hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease).
Disorders of Blood Coagulation
1. Hemophilia A—incidence 1:10,000; sex-linked recessive deficiency of factor VIII (low plasma factor VIII coagulant activity, but normal amount of factor VIII–related antigen—von Willebrand’s factor). Laboratory features: elevated PTT, normal PT.
2. Hemophilia B (Christmas disease)—incidence 1:100,000, sex-linked recessive, due to factor IX deficiency. Clinical and laboratory features similar to hemophilia A.
3. von Willebrand’s 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.
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).
Thrombocytopenia Caused by Drugs Includes discontinuation of possible offending agents; expect recovery in 7–10 d. Platelet transfusions may be needed if platelet count <10,000/µL.
Heparin-Induced Thrombocytopenia Includes prompt discontinuation of heparin. Warfarin and/or a fibrinolytic agent (see below) should be used for treatment of thromboses.
Chronic ITP Prednisone, initially 1–2 (mg/kg)/d, then slow taper, to keep the platelet count >60,000/µL. IV immunoglobulin to block phagocytic destruction may be useful. Splenectomy, danazol (androgen), or other agents (e.g., vincristine, cyclophosphamide, fludarabine) are indicated for pts requiring >5–10 mg prednisone daily.
DIC Control of underlying disease most important; platelets, fresh-frozen plasma (FFP) to correct clotting parameters. Heparin may be beneficial in pts with acute promyelocytic leukemia.
Thrombotic Thrombocytopenic Purpura Plasmapheresis and FFP infusions, possibly IV IgG; recovery in two-thirds of cases.
Disorders of Platelet Function Remove or reverse underlying cause. Dialysis and/or cryoprecipitate infusions (10 bags/24 h) may be helpful for platelet dysfunction associated with uremia.
Hemostatic Disorders Withdraw offending drugs, replace vitamin C, plasmapheresis and plasma infusion for TTP.
Hemophilia A Factor VIII replacement for bleeding or before surgical procedure; degree and duration of replacement depends on severity of bleeding. Give factor VIII to obtain a 15% (for mild bleeding) to 50% (for severe bleeding) factor VIII level. The duration should range from a single dose of factor VIII to therapy bid for up to 2 weeks.
Hemophilia B FFP or factor IX concentrates (Proplex, Konyne).
von Willebrand’s Disease Cryoprecipitate (plasma product rich in factor VIII) or factor VIII concentrate (Humate-P, Koate HS); up to 10 bags bid for 48–72 h, depending on the severity of bleeding. Desmopressin (vasopressin analogue) may benefit some pts.
Vitamin K Deficiency Vitamin K 10 mg SC or slow IV.
Liver Disease Fresh-frozen plasma.
Consider in pts with recurrent episodes of venous thrombosis (i.e., deep venous thrombosis, DVT; pulmonary embolism). Causes include: (1) Venous stasis (e.g., pregnancy, immobilization); (2) vasculitis; (3) myeloproliferative disorders; (4) oral contraceptives; (5) lupus anticoagulant—antibody to platelet phospholipid, stimulates coagulation; (6) heparin-induced thrombocytopenia; (7) deficiencies of endogenous anticoagulant factors—antithrombin III, protein C, protein S; (8) factor V Leiden—mutation in factor V (Arg ® Glu at position 506) confers resistance to inactivation by protein C, accounts for 25% of cases of recurrent thrombosis; (9) prothrombin gene mutation—Glu ® Arg at position 20210 results in increased prothrombin levels; accounts for about 6% of thromboses; (10) other—paroxysmal nocturnal hemoglobinuria, dysfibrinogenemias (abnormal fibrinogen).
Correct underlying disorder whenever possible; long-term warfarin therapy is otherwise indicated.
1. Heparin (Table 60-1)—enhances activity of antithrombin III; parenteral agent of choice. Low-molecular-weight heparin is the preparation of choice (enoxoparin or dalteparin). It can be administered SC, monitoring of the PTT is unnecessary, and it is less likely to induce antibodies and thrombocytopenia. The usual dose is 100 U/kg SC bid. Unfractionated heparin should be given only if low-molecular-weight heparin is unavailable. In adults, the dose of unfractionated heparin is 25,000–40,000 U continuous IV infusion over 24 h following initial IV bolus of 5000 U; monitor by following PTT; should be maintained between 1.5 and 2 times upper normal limit. Prophylactic anticoagulation to lower risk of venous thrombosis recommended in some pts (e.g., postoperative, immobilized) (Table 60-1). Major complication of unfractionated heparin therapy is hemorrhage—manage by discontinuing heparin; for severe bleeding, administer protamine (1 mg/100 U heparin); results in rapid neutralization.
Table 60-1 Anticoagulant Therapy with Low-Molecular-Weight and Unfractionated Heparin
2. Warfarin (Coumadin)—vitamin K antagonist, decreases levels of factors II, VII, IX, X, and anticoagulant proteins C and S. Administered over 2–3 d; initial load of 5–10 mg PO qd followed by titration of daily dose to keep PT 1.5–2 times control PT or 2–3 times if the International Normalized Ratio method is used. Complications include hemorrhage, warfarin-induced skin necrosis (rare, occurs in persons deficient in protein C), teratogenic effects. Warfarin effect reversed by administration of vitamin K; FFP infused if urgent reversal necessary. Numerous drugs potentiate or antagonize warfarin effect. Potentiating agents include chlorpromazine, chloral hydrate, sulfonamides, chloramphenicol, other broad-spectrum antibiotics, allopurinol, cimetidine, tricyclic antidepressants, disulfiram, laxatives, high-dose salicylates, thyroxine, clofibrate. Antagonizing agents include vitamin K, barbiturates, rifampin, cholestyramine, oral contraceptives, thiazides.
In-hospital anticoagulation usually initiated with heparin, with subsequent maintenance on warfarin after an overlap of 3 d.
Tissue plasminogen activator (tPA, alteplase), streptokinase, and urokinase; mediate clot lysis by activating plasmin, which degrades fibrin. Indications include treatment of DVT, with lower incidence of postphlebitic syndrome (chronic venous stasis, skin ulceration) than with heparin therapy; massive pulmonary embolism, arterial embolic occlusion of extremity, treatment of acute MI, unstable angina pectoris. Dosages for fibrinolytic agents: (1) tPA—for acute MI and massive PE (adult >65 kg), 10-mg IV bolus over 1–2 min, then 50 mg IV over 1 h and 40 mg IV over next 2 h (total dose = 100 mg). tPA is slightly more effective but more expensive than streptokinase for treatment of acute MI. (2) Streptokinase—for acute MI, 1.5 million IU IV over 60 min; or 20,000 IU as a bolus intracoronary (IC) infusion, followed by 2000 IU/min for 60 min IC. For pulmonary embolism or arterial or deep venous thrombosis, 250,000 IU over 30 min, then 100,000 IU/h for 24 h (pulmonary embolism) or 72 h (arterial or deep venous thrombosis). (3) Urokinase—for pulmonary embolism, 4400 IU/kg IV over 10 min, then 4400 (IU/kg)/h IV for 12 h.
Fibrinolytic therapy is usually followed by period of anticoagulant therapy with heparin. Fibrinolytic agents are contraindicated in pts with: (1) active internal bleeding; (2) recent (<2–3 months) cerebrovascular accident; (3) intracranial neoplasm, aneurysm, or recent head trauma.
Aspirin (160–325 mg/d) with or without dipyridamole (50–100 mg qid) may be beneficial in lowering incidence of arterial thrombotic events (stroke, MI) in high-risk pts.
For a more detailed discussion, see Handin RI: Bleeding and Thrombosis, Chap. 62, p. 354; Disorders of the Platelet and Vessel Wall, Chap. 116, p. 745; Disorders of Coagulation and Thrombosis, Chap. 117, p. 751; and Anticoagulant, Fibrinolytic, and Antiplatelet Therapy, Chap. 118, p. 758, in HPIM-15.