References

Alving BM, Shulman NR, Bell WR, Evatt BL, Tack KM. In vitro studies of heparin associated thrombocytopenia. Thromb Res 11:827-834, 1977.

Amiral J, Bridey F, Dreyfus M, Vissac AM, Fressinaud E, Wolf M, Meyer D. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin induced thrombocytopenia [letter]. Thromb Haemost 68:95-96, 1992.

Babcock RB, Dumper CW, Scharfman WB. Heparin-induced thrombocytopenia. N Engl J Med 295:237-241,1976.

Barker CF, Rosato FE, Roberts B. Peripheral arterial embolism. Surg Gynecol Obstet 123:22-26, 1966.

Bell WR. Heparin-associated thrombocytopenia and thrombosis. J Lab Clin Med 111:600-605, 1988.

Bell WR, Royall RM. Heparin-associated thrombocytopenia: a comparison of three heparin preparations. N Engl J Med 303:902-907, 1980.

Bell WR, Tomasulo PA, Alving BM, Duffy TP. Thrombocytopenia occurring during the administration of heparin. A prospective study in 52 patients. Ann Intern Med 85:155-160, 1976.

Benhamou AC, Gruel Y, Barsotti J, Castellani L, Marchand M, Guerois C, Leclerc MH, Delahousse B, Griguer P, Leroy J. The white clot syndrome or heparin associated thrombocytopenia and thrombosis (WCS or HATT). Int Angiol 4:303-310, 1985.

Best CH. Preparation of heparin, and its use in the first clinical cases. Circulation 19:79-86, 1959.

Chamberlin JR, Lewis B, Wallis D, Messmore H, Hoppensteadt D, Walenga JM, Moran S, Fareed J, McKiernan T. Successful treatment of heparin-associated thrombocyto-penia and thrombosis using Hirulog. Can J Cardiol 11:511-514,1995.

Chong BH, Berndt MC. Heparin-induced thrombocytopenia. Blut 58:53-57, 1989.

Chong BH, Grace CS, Rozenberg MC. Heparin-induced thrombocytopenia: effect of heparin platelet antibody on platelets. Br J Haematol 49:531-540, 1981.

Chong BH, Pitney WR, Castaldi PA. Heparin-induced thrombocytopenia: association of thrombotic complications with heparin-dependent IgG antibody that induces thromboxane synthesis and platelet aggregation. Lancet 2:1246-1249, 1982.

Chong BH, Gallus AS, Cade JF, Magnani H, Manoharan A, Oldmeadow M, Arthur C, Rickard K, Gallo J, Lloyd J, Seshadri P, Chesterman CN. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopenia with thrombosis: a clinical outcome study. Thromb Haemost 86:1170-1175, 2001.

Cimo PL, Moake JL, Weinger RS, Ben-Menachem Y, Khalil KG. Heparin-induced thrombocytopenia: association with a platelet aggregating factor and arterial thromboses. Am J Hematol 6:125-133, 1979.

Cines DB, Kaywin P, Bina M, Tomaski A, Schreiber AD. Heparin-associated thrombocytopenia. N Engl J Med 303:788-795, 1980.

Crafoord C. Preliminary report on post-operative treatment with heparin as a preventive of thrombosis. Acta Chir Scand 79:407-426,1937.

Farner B, Eichler P, Kroll H, Greinacher A. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia. Thromb Haemost 85:950-957, 2001.

Francis JL, Drexler A, Gwyn G, Moroose R. Bivalirudin, a direct thrombin inhibitor, in the treatment of heparin-induced thrombocytopenia [abstr]. J Thromb Haemost 1(suppl 1):1909, 2003.

Fratantoni JC, Pollet R, Gralnick HR. Heparin-induced thrombocytopenia: confirmation of diagnosis with in vitro methods. Blood 45:395-401,1975.

Green D, Harris K, Reynolds N, Roberts M, Patterson R. Heparin immune thrombocy-topenia: evidence for a heparin-platelet complex as the antigenic determinant. J Lab Clin Med 91:167-175, 1978.

Greinacher A, Pötzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 71: 247-251, 1994.

Greinacher A, Völpel H, Janssens U, Hach-Wunderle V, Kemkes-Matthes B, Eichler P, Mueller-Velten HG, Potzsch B, for the HIT Investigators Group. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia. Circulation 99:73-80, 1999.

Greinacher A, Eichler P, Lubenow N, Kwasny H, Luz M. Heparin-induced thrombocy-topenia with thromboembolic complications: meta-analysis of two prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. Blood 96:846-851, 2000.

Haas G. Versuche der Blutauswaschung am Lebenden mit Hilfe der Dialyse. Klin Wochenschr 4:13-14, 1925.

Harenberg J, Zimmermann R, Schwarz F, Kubler W. Treatment of heparin-induced thrombocytopenia with thrombosis by new heparinoid [letter]. Lancet 1:986-987, 1983.

Harenberg J, Huhle G, Piazolo L, Wang LU, Heene DL. Anticoagulation in patients with heparin-induced thrombocytopenia type II. Semin Thromb Hemost 23:189-196, 1997.

Hirsh J. From bench to bedside: history of development of LMWHs. Orthop Rev 23(suppl l):40-46, 1994.

Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin JL, Raschke R, Granger C, Ohman EM, Dalen JE. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 119(suppl): 64S-94S, 2001.

Howell WH, Holt E. Two new factors in blood coagulation—heparin and pro-antith-rombin. Am J Physiol 47:328-341, 1918.

Hussey CV, Bernhard VM, McLean MR, Fobian JE. Heparin induced platelet aggregation: in vitro confirmation of thrombotic complications associated with heparin therapy. Ann Clin Lab Sci 9:487-493,1979.

Kaupp HA, Roberts B. Arterial embolization during subcutaneous heparin therapy. Case report. J Cardiovasc Surg 13:210-212,1972.

Kelton JG, Sheridan D, Brain H, Powers PJ, Turpie AG, Carter CJ. Clinical usefulness of testing for a heparin-dependent platelet-aggregating factor in patients with suspected heparin-associated thrombocytopenia. J Lab Clin Med 103:606-612, 1984.

Kelton JG, Sheridan D, Santos A, Smith J, Steeves K, Smith C, Brown C, Murphy WG. Heparin-induced thrombocytopenia: laboratory studies. Blood 72:925-930, 1988.

Kinlough-Rathbone RL, Packham MA, Mustard JF. Platelet aggregation. In: Harker LA, Zimmerman TS, eds. Methods in Hematology. Measurements of Platelet Function. Edinburgh: Churchill Livingstone, 64-91,1983.

Klein HG, Bell WR. Disseminated intravascular coagulation during heparin therapy. Ann Intern Med 80:477-481,1974.

Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG, for the ARG-911 Study Investigators. Circulation 103:1838-1843, 2001.

Li ZQ, Liu W, Park KS, Sachais BS, Arepally GM, Cines AB, Poncz M. Defining a second epitope for heparin-induced thrombocytopenia/thrombosis antibodies using KKO, a murine HIT-like monoclonal antibody. Blood 99:1230-1236, 2002.

Mason EC. Blood coagulation. The production and prevention of experimental thrombosis and pulmonary embolism. Surg Gynecol Obstet 39:421-428, 1924.

Matsuo T, Chikahira Y, Yamada T, Nakao K, Ueshima S, Matsuo O. Effect of synthetic thrombin inhibitor (MD805) as an alternative drug on heparin induced thrombocy-topenia during hemodialysis. Thromb Res 52:165-171, 1988.

McLean J. The thromboplastic action of cephalin. Am J Physiol 41:250-257, 1916.

Nand S. Hirudin therapy for heparin-associated thrombocytopenia and deep venous thrombosis. Am J Hematol 43:310-311,1993.

Natelson EA, Lynch EC, Alfrey CP Jr, Gross JB. Heparin-induced thrombocytopenia. An unexpected response to treatment of consumption coagulopathy. Ann Intern Med 71:1121-1125, 1969.

Nelson JC, Lerner RG, Goldstein R, Cagin NA. Heparin-induced thrombocytopenia. Arch Intern Med 138:548-552,1978.

Pouplard C, Couvret C, Regina S, Gruel Y. Development of antibodies specific to polyanion-modified platelet factor 4 during treatment with fondaparinux. J Thromb Haemost 3:2813-2815, 2005.

Powers PJ, Cuthbert D, Hirsh J. Thrombocytopenia found uncommonly during heparin therapy. JAMA 241:2396-2397,1979.

Reid T III, Alving BM. Hirulog® therapy for heparin-associated thrombocytopenia and deep venous thrombosis. Am J Hematol 43:352-353, 1994.

Rhodes GR, Dixon RH, Silver D. Heparin induced thrombocytopenia with thrombotic and hemorrhagic manifestations. Surg Gynecol Obstet 136:409-416,1973.

Rhodes GR, Dixon RH, Silver D. Heparin induced thrombocytopenia: eight cases with thrombotic-hemorrhagic complications. Ann Surg 186:752-758, 1977.

Roberts B, Rosato FE, Rosato EF. Heparin—a cause of arterial emboli? Surgery 55: 803-808, 1964.

Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 67:27-30,1986.

Shionoya T. Studies on experimental extracorporeal thrombosis. III. Effects of certain anticoagulants (heparin and hirudin) on extracorporeal thrombosis and on the mechanism of thrombus formation. J Exp Med 46:19-26, 1927.

Stanton PE Jr, Evans JR, Lefemine AA, Vo RN, Rannick GA, Morgan CV Jr, Hinton JP, Read M. White clot syndrome. South Med J 81:616-620, 1988.

Tanabe T. Clinical results of MD-805, antithrombin agent, on chronic arterial occlusion. J Clin Ther Med 2:1645,1986.

Tardy B, Tardy-Poncet B, Fournel P, Venet C, Jospe R, Dacosta A. Lower limb veins should be systematically explored in patients with isolated heparin-induced throm-bocytopenia [letter]. Thromb Haemost 82:1199-1200, 1999.

Towne JB, Bernhard VM, Hussey C, Garancis JC. White clot syndrome. Peripheral vascular complications of heparin therapy. Arch Surg 114:372-377, 1979.

Trowbridge AA, Caraveo J, Green JB III, Amaral B, Stone MJ. Heparin-related immune thrombocytopenia. Studies of antibody-heparin specificity. Am J Med 65:277-283, 1978.

Wahl TO, Lipschitz DA, Stechschulte DJ. Thrombocytopenia associated with anti-heparin antibody. JAMA 240:2560-2562, 1978.

Wallis DE, Workman DL, Lewis BE, Steen L, Pifarre R, Moran JF. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med; 106:629-635, 1999.

Warkentin TE. Heparin-induced thrombocytopenia: yet another treatment paradox? Thromb Haemost 85:947-949, 2001.

Warkentin TE, Kelton JG. Heparin and platelets. Hematol Oncol Clin North Am 4: 243-264, 1990.

Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 101:502-507,1996.

Warkentin TE, Kelton JG. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med 135:502-506, 2001.

Warkentin TE, Koster A. Bivalirudin: a review. Expert Opin Pharmacother 6: 1349-1371, 2005.

Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, Kelton JG. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 332:1330-1335, 1995.

Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MA, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocy-topenia. Ann Intern Med 127:804-812,1997.

Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 79:1-7, 1998.

Warkentin TE, Roberts RS, Hirsh J, Kelton JG. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients. Arch Intern Med 163:2518-2524, 2003.

Warkentin TE, Cook RJ, Marder VJ, Sheppard JI, Moore JC, Eriksson BI, Greinacher A, Kelton JG. Anti-platelet factor 4 antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 106:3791-3796, 2005.

Weismann RE, Tobin RW. Arterial embolism occurring during systemic heparin therapy. Arch Surg 76:219-227,1958.

Clinical Picture of Heparin-Induced Thrombocytopenia

Theodore E. Warkentin

Michael G. DeGroote School of Medicine, McMaster University, and Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada

I. INTRODUCTION

Heparin-induced thrombocytopenia (HIT) is a distinct clinicopathologic syndrome caused by platelet-activating antibodies that recognize complexes of platelet factor 4-heparin (PF4/H). Its strong association with venous and arterial thrombosis represents a striking paradox. However, thrombocytopenia itself is common in clinical medicine. Furthermore, heparin is usually given to patients who either have thrombosis, or who are judged to be at high risk for thrombosis. Thus, thrombocytopenia with or without thrombosis during heparin treatment does not necessarily indicate a diagnosis of HIT. Indeed, several disorders can closely resemble HIT (see Chapter 11).

On the other hand, HIT is associated with a wide spectrum of unusual thrombotic and other complications (Table 1). Unrecognized HIT may have been an important contributing factor in otherwise bizarre clinical events that have occurred in certain heparin-treated patients (Anderson et al., 1981; Solomon et al., 1988; Pfueller et al., 1990; Muntean et al., 1992). Laboratory documentation of HIT antibodies has been crucial in determining the clinical scope of the HIT syndrome. Accordingly, this chapter emphasizes clinical data obtained from large prospective and retrospective studies that have used diagnostic testing for HIT antibodies.

Estimated frequencies of the various complications of HIT are taken from reports with serological confirmation of the diagnosis (Warkentin et al., 1995, 1997; Warkentin and Kelton, 1996). "Rare" indicates an estimated frequency <3% of HIT patients.

II. THROMBOCYTOPENIA

Thrombocytopenia, using the standard definition of a platelet count of less than 150 X 10 /L, is the most common clinical effect of HIT, occurring in 85-90% of patients (Warkentin, 1998a). An even higher proportion develops "thrombo-cytopenia" if a definition appropriate for the clinical situation is used.

A. Timing

The characteristic delay of 5 or more days between initiation of heparin and onset of thrombocytopenia was the major clue that led early investigators to recognize the immune pathogenesis of HIT (Roberts et al., 1964; Rhodes et al., 1973). King and Kelton (1984) noted that thrombocytopenia occurred between days 6 and 15 for more than 90% of patients in whom HIT occurred during their first exposure to heparin. In contrast, for patients who developed HIT during a repeat course of heparin, the onset of thrombocytopenia was often more rapid, occurring within 2 days. These data have been interpreted as indicating an "anamnestic"

TABLE 1 Thrombotic and Other Sequelae of HIT

Venous thrombosis

Arterial thrombosis

Miscellaneous

DVT (50%): new, progressive, recurrent; lower limb (often bilateral); upper limb (at site of venous catheter); phlegmasia cerulea dolens Coumarin-induced venous limb gangrene (~5-10% of DVT treated with warfarin) Pulmonary embolism (25%): with or without right-sided cardiac intra-atrial or intraventricular thrombi Cerebral dural sinus thrombosis (rare) Adrenal hemorrhagic infarction (rare): bilateral (acute or chronic adrenal failure) or unilateral DIC, with hypofibrinogenemia deficiency, causing multiple

Aortic or iliofemoral thrombosis resulting in acute limb ischemia/infarction (5-10%) or spinal cord infarction (rare)

Acute thrombotic stroke (3-5%)

Myocardial infarction (3-5%) Cardiac intraventricular or intra-atrial thrombosis, in situ or via embolization of DVT (rare) Thrombosis involving miscellaneous arteries (rare): upper limb, renal, mesenteric, spinal, and other arteries Embolization of thrombus from heart or proximal aorta can also contribute to microvascular ischemic syndromes and acquired natural anticoagulant venous and arterial thromboses (rare)

Heparin-induced skin lesions at heparin injection sites (10-20%): Erythematous plaques Skin necrosis Coumarin-induced skin necrosis complicating HIT involving "central" sites (breast, abdomen, thigh, leg, etc.) (rare) Acute systemic reactions postintravenous heparin bolus (~25% of sensitized patients who receive an intravenous heparin bolus): Inflammatory: e.g., fever, chills, flushing Cardiorespiratory: e.g., tachycardia, hypertension, dyspnea; cardiopulmonary arrest (rare) Gastrointestinal: nausea, vomiting, diarrhea Neurological: transient global amnesia, headache

Abbreviations: DIC, disseminated intravascular coagulation; DVT, deep vein thrombosis.

(Gr., memory) or "secondary" immune response in HIT; i.e., the immune system produces HIT antibodies more quickly on reencountering an antigen "remembered" within its memory cell repertoire. Recent data, however, suggest another explanation for these two temporal profiles of HIT, typical and rapid (discussed subsequently).

Typical Onset of HIT

A prospective study of serologically confirmed HIT showed that the platelet count typically begins to fall between days 5 and 10 (inclusive) of postoperative subcutaneous heparin prophylaxis (Warkentin et al., 1995, 2003) (Fig. 1). Note that the data refer to the day the platelet count begins to fall, and not the later day on which an arbitrary threshold defining thrombocytopenia is crossed. This study also showed that most patients who developed thrombocytopenia beginning after day 5 had HIT rather than another explanation for the thrombocytopenia. The data suggest the following clinical rule:

Rule 1

A thrombocytopenic patient whose platelet count fall began between days 5 and 10 of heparin treatment (inclusive) should be considered to have HIT unless proved otherwise (first day of heparin use is considered "day 0").

HIT-IgG antibodies generally are not detectable before day 5 of heparin treatment, but are readily detectable using sensitive assays when the platelet count first begins to fall due to HIT.

A recent study (Warkentin and Kelton, 2001a) that analyzed temporal aspects of the platelet count fall in 243 patients with serological confirmed HIT in

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