Harrisons Manual of Medicine, 18th Ed.

CHAPTER 70. Bleeding and Thrombotic Disorders


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).



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 <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. Evaluation of thrombocytopenia is shown in Fig. 70-1.


FIGURE 70-1 Algorithm for evaluating the thrombocytopenic pt.


(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 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 micro-angiopathic 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 caused by failure to cleave von Willebrand factor (vWF) normally.

• Hemorrhage with extensive transfusion.


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


Platelet count >350,000/μL. Either primary (essential thrombocytosis; Chap. 72) or secondary (reactive); latter secondary to severe hemorrhage, iron deficiency, surgery, after splenectomy (transient), malignant neoplasms (esp. Hodgkin’s disease, polycythemia vera), 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; 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.


Causes include (1) aging; (2) drugs—e.g., glucocorticoids (chronic therapy), penicillins, sulfonamides; (3) vitamin C deficiency; (4) TTP; (5) hemolytic uremic syndrome; (6) Henoch-Schönlein purpura; (7) paraproteinemias; (8) hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease).


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).

TREATMENT Bleeding Disorders

THROMBOCYTOPENIA CAUSED BY DRUGS Discontinue use of possible offending agents; expect recovery in 7–10 days. Platelet transfusions may be needed if platelet count <10,000/μL.

HEPARIN-INDUCED THROMBOCYTOPENIA Discontinue heparin promptly. A direct thrombin inhibitor such as lepirudin (0.4-mg/kg bolus, 0.15-mg/kg per hour infusion; PTT target 1.5–2.5 × baseline) or argatroban (2-μg/kg per min infusion; PTT target 1.5–3 × baseline) should be used for treatment of thromboses. Do not use low-molecular-weight heparin (LMWH), as antibodies often cross-react.

CHRONIC ITP Prednisone, initially 1–2 mg/kg per day, then slow taper to keep the platelet count >60,000/μL. IV immunoglobulin (2 g/kg in divided doses over 2–5 days) to block phagocytic destruction may be useful. Rituximab is effective in pts refractory to glucocorticoids. Eltrombopag (50 mg PO qd) boosts platelet production and allows delay or avoidance of splenectomy. Splenectomy, danazol (androgen), or other agents (e.g., vincristine, cyclophosphamide, fludarabine) are indicated for refractory pts or those 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.

TTP Plasmapheresis and FFP infusions (plasma exchange), possibly IV IgG; recovery in two-thirds of cases. Plasmapheresis removes inhibitors of the vWF cleavage enzyme (ADAMTS13), and FFP replaces the enzyme.

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 (e.g., Recombinate) 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. Dose is calculated as follows:

Factor VIII dose = (Target level – baseline level) × weight (kg) × 0.5 unit/kg

Up to 30% of pts may develop anti–factor VIII antibodies; activated factor VII or factor eight inhibitor bypass agent (FEIBA) may stop or prevent bleeding in these pts.

HEMOPHILIA B Recombinant factor IX (e.g., Benefix), FFP or factor IX concentrates (e.g., Proplex, Konyne). Because of the longer half-life, once-daily treatment is sufficient. Dose is calculated as follows:

Factor IX dose = (Target level – baseline level) × weight (kg) × 1 unit/kg

VON WILLEBRAND DISEASE Desmopressin (1-deamino-8-D-arginine vasopressin) increases release of vWF from endothelial stores in type 1 vWD. It is given IV (0.3 μg/kg) or by nasal spray (2 squirts of 1.5-mg/mL fluid in each nostril). For types 2A, 2M, and 3, cryoprecipitate (plasma product rich in factor VIII) or factor VIII concentrate (Humate-P, Koate HS) is used: up to 10 bags bid for 48–72 h, depending on the severity of bleeding.

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-vein thrombosis (DVT), pulmonary embolism (PE)]. Causes include (1) venous stasis (e.g., pregnancy, immobilization); (2) vasculitis; (3) cancer and 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).

The approach to the diagnosis of the pt with DVT and/or PE is discussed in Chap. 142.

TREATMENT Thrombotic Disorders

Correct underlying disorder whenever possible; long-term warfarin therapy is otherwise indicated.


1. Heparin (Table 70-1)—enhances activity of antithrombin III; parenteral agent of choice. LMWH is the preparation of choice (enoxaparin 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 LMWH 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 70-1). Prophylactic doses of unfractionated heparin are 5000 U SC bid or tid. 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.




2. Warfarin (Coumadin)—vitamin K antagonist, decreases levels of factors II, VII, IX, X, and anticoagulant proteins C and S. Administered over 2–3 days; 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 (INR) 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. Some pts who are sensitive to warfarin effects have genetic defects metabolizing the drug. Antagonizing agents include vitamin K, barbiturates, rifampin, cholestyramine, oral contraceptives, thiazides.

3. Fondaparinux—a pentapeptide that directly inhibits factor Xa. It is given at a dose of 2.5 mg SC daily for prophylaxis and 7.5 mg SC daily for treatment of thrombosis and does not require monitoring. Unlike the heparins, it does not bind to platelet factor 4 and does not elicit the antibodies that produce heparin-induced thrombocytopenia. Apixaban and rivaroxaban are oral factor Xa inhibitors. Apixaban (5 mg PO bid) as effective as warfarin in DVT and more effective in stroke prevention in atrial fibrillation (AF).

4. Argatroban and lepirudin—direct thrombin inhibitors. These agents are being compared to LMWH and are commonly used in pts with heparin-induced thrombocytopenia. Both are monitored with the activated PTT. Dabigatran(150 mg PO bid) is an oral thrombin inhibitor and is non-inferior to warfarin in both DVT and stroke prevention in AF.

In-hospital anticoagulation is usually initiated with heparin for 4–10 days, with subsequent maintenance on warfarin after an overlap of 3 days. Duration of therapy depends on underlying condition; calf DVT with clear precipitating cause, 3 months; proximal or idiopathic DVT or PE, 6–12 months; recurrent idiopathic DVT, 12 months minimum; embolic disease with ongoing risk factor, long-term, indefinite. The new oral Xa and thrombin inhibitors are easier to use than warfarin but much more expensive.

FIBRINOLYTIC AGENTS Tissue plasminogen activators mediate clot lysis by activating plasmin, which degrades fibrin. Currently available versions include streptokinase, urokinase, anistreplase (acylated plasminogen streptokinase activator complex), and three modestly distinct forms of recombinant tissue plasminogen activator (tPA): alteplase, tenecteplase, and reteplase. Indications include treatment of DVT, with lower incidence of postphlebitic syndrome (chronic venous stasis, skin ulceration) than with heparin therapy; massive PE, arterial embolic occlusion of an extremity, treatment of acute myocardial infarction (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 PE or arterial or deep-vein thrombosis, 250,000 IU over 30 min, then 100,000 IU/h for 24 h (PE) or 72 h (arterial or deep-vein thrombosis). (3) Urokinase—for PE, 4400 IU/kg IV over 10 min, then 4400 (IU/kg)/h IV for 12 h.

Fibrinolytic therapy is usually followed by a 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.

ANTIPLATELET AGENTS Aspirin inhibits platelet function by blocking the ability of cyclooxygenase (COX-1) to synthesize thromboxane A2. The thienopyridines (ticlopidine and clopidogrel) inhibit ADP-induced platelet aggregation by blocking its receptor (P2Y12). Dipyridamole acts by inhibiting phosphodiesterase, which permits cAMP levels to increase and block activation. Glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists block the integrin receptors on the platelet and prevent platelet aggregation. Three such agents are now in use: abciximab, an Fab antibody fragment that binds to the activated form of GPIIb/IIIa; eptifibatide, a cyclic heptapeptide that includes the KGD tripeptide motif that the GPIIb/IIIa receptor recognizes; and tirofiban, a tyrosine derivative that mimics the KGD motif.

Aspirin (160–325 mg/d) plus clopidogrel (400-mg loading dose then 75 mg/d) may be beneficial in lowering incidence of arterial thrombotic events (stroke, MI) in high-risk pts. Antiplatelet agents are useful in preventing strokes, complications from percutaneous coronary interventions, and progression of unstable angina.


For a more detailed discussion, see Konkle BA: Bleeding and Thrombosis, Chap. 58, p. 457; Konkle BA: Disorders of Platelets and Vessel Wall, Chap. 115, p. 965; Arruda VR, High KA: Coagulation Disorders, Chap. 116, p. 973; Freedman JE, Loscalzo J: Arterial and Venous Thrombosis, Chap. 117, p. 983; and Weitz JI: Antiplatelet, Anticoagulant, and Fibrinolytic Drugs, Chap. 118, p. 988, in HPIM-18.