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[학술영업부 / 날짜:05-03 / 조회: 9154 ]
The Diagnosis and Clinical Significance of Heparin-Induced Thrombocytopenia (HIT) Type II

Heparin is one of the most widely prescribed parenteral anticoagulant medications in the United States, with an estimated 12 million patients receiving the drug annually.1

Although the most common adverse event associated with heparin is dose-dependent bleeding, a significant number of patients develop a prothrombotic state known as Heparin-Induced Thrombocytopenia, the clinical course of which can be as mild as an asymptomatic decrease in platelet count (Type I) or as severe and potentially devastating as a thromboembolic complication (Type II).

Type I or Heparin-Associated Thrombocytopenia (HAT), is mild and transient, and is usually not associated with thrombosis.

HAT is characterized by a mild decrease in platelet count immediately after initiation of heparin therapy. Normally, HAT is not detected clinically, and there is no need to stop heparin therapy, since platelet counts will usually return to normal even if therapy is continued.2

Type II, commonly referred to as Heparin-Induced Thrombocytopenia (HIT), is an immune-mediated condition that occurs in approximately 1% to 5% of patients receiving heparin therapy.

Typically, HIT occurs between days 5 and 10 after initiation of heparin therapy, but patients may present with clinical symptoms within minutes or hours of a heparin re-challenge if the prior
exposure was within the previous 100 days.3 There have also been reports of delayed-onset HIT that begin several days to weeks after heparin has been discontinued.4,5 Clinical features of HIT include a drop in platelet count (below 100,000, or 50% of the pre-heparin platelet count), although severe thrombocytopenia (<20,000 per cubic millimeter) is uncommon. Approximately 20% of patients with HIT develop potentially life-threatening thrombosis, with a reported mortality rate of up to 25%.5 Patients receiving heparin therapy should be monitored for decreasing platelet counts and the development of new thrombotic events.

Heparin must be stopped immediately upon diagnosis of HIT. Alternatives to heparin must be considered if continuing anticoagulation is necessary.

The major determinant in the pathogenesis of HIT appears to be IgG antibodies to the heparin/Platelet Factor-4 (PF4) omplex.6,7,8 The antibodies bind to heparin/PF4 complexes on the platelet surface, leading to platelet aggregation and platelet thrombus formation. The resulting thrombus, which consists mainly of platelets,remains pale in color and is referred to as a white clot.

These antibodies are most frequently induced by the use
of unfractionated heparin (UFH) following cardiopulmonary bypass surgery (50%) and major orthopedic surgery (15%)9 although HIT has also occurred in patients receiving low molecular weight heparin preparations (LMWH).

HIT is more common in patients receiving large doses of heparin therapy intravenously, however HIT can occur following incidental exposure to heparin through heparin flushes, subcutaneous administration, or heparin-coated catheters and prostheses, such as those used in chronic dialysis patients.10 Two types of assays are most commonly used to help diagnose HIT: functional assays and antigenic assays.

Functional assays detect platelet activation following exposure of normal donor platelets to heparin/PF4 antibody in patient''s platelet-poor serum or plasma in the presence of heparin.
The Platelet Aggregation Method and the Serotonin Release Assay fall within this category. Antigenic assays measure the presence of antibodies capable of binding to PF4 complexed to heparin or a heparin-like molecule.6,7,11 These assays are often performed in an enzyme-linked immunosorbent assay (ELISA) format.

All of the aforementioned testing methods are CLIA-classified as high complexity, take hours to perform, require special instrumentation, and are technically demanding. They are not conducive to cost-effectively or efficiently processing single patient samples. Recently, a rapid, manual antigenic assay known as the PIFA�Heparin/PF4 Rapid Assay was introduced to the clinical laboratory marketplace. A rapid antigenic method for identifying heparin/PF4 antibodies in patient plasma could provide clinicians with time-sensitive information that can influence therapeutic decisions.

More information on the PIFA Heparin/PF4 Rapid Assay will be presented in a future issue of THE REAADER from Corgenix Inc.


1. Mahaffey KW. Anticoagulation for acute coronary syndromes and percutaneous coronary intervention in patients with heparin-induced thrombocytopenia. Curr Cardiol Rep. 2001;3:362-370.
2. Fahey VA. Heparin-induced thrombocytopenia. J Vasc Nurs 1995;13:112-116.
3. Lubenow N, Kempf R, Eichner A, Eichler P, Carllson LE, Greinacher A. Heparin-induced thrombocytopenia: temporal pattern of thrombocytopenia in relation to initial use and re-exposure to heparin. Chest 2002; 122:37-42.
4. Warkentin TE, Kelton JG. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med. 2001;135:502-50.
5. Rice L, Attisha WK, Drexler A, Francis JL. Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med. 2002;136:210-215.
6. Amiral, J., F. Bridey, M. Dreyfus, A. M. Vissoc, E. Fressinaud, M. Wolf, and D. Meyer. 1992. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992;68:95-96.
7. Amiral, J., F. Bridey, M. Wolf, C. Boyer-Neumann, E.Fressinaud, A. M. Vissac, E. Peynaud-Debayle, M. Dreyfus, and D. Meyer. 1995. Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: a study of 44 cases. Thromb Haemost.1995;673:21-28.
8. Greinacher, A., and T. E. Warkentin. 2001. Treatment of heparin-induced thrombocytopenia: an overview, p. 291-322. In T. E.
Warkentin and A. Greinacher (ed.), Heparin-induced thrombocytopenia., 2nd ed. Marcel Dekker, New York, N.Y.
9. Warkentin TE, Greinacher A, eds. Heparin-induced thrombocytopenia, 3rd ed. New York: Marcel Dekker, Inc. 2004, 53, 205, 271, 295.
10. Nand S, Wong W, Yuen B et al. Heparin-induced thrombocytopenia with thrombosis: incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution. Am J Hematol. 1997; 56:12-6.
11. Visentin GP, Ford SE, Scott JP, Aster RH. Antibodies from patients with -heparin-induced thrombocytopenia/ thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin Invest. 1994;93:81-88.
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