Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction to heparin products leading to a prothrombotic state. Devastating clinical sequelae may result, including venous or arterial thromboembolism, limb amputation, and death. Heparin cessation alone is insufficient to manage HIT. Pharmacotherapy with argatroban or lepirudin is essential. This article reviews the pathogenesis, diagnosis, and pharmacotherapy of HIT.
GreinacherA. Antigengeneratin in heparin-associated thrombocytopenia: the nonimmunologic type and the immunologic type are closely linked in their pathogenesis. Semin Thromb Hemost. 1995;21(1):106–116.
2.
AhmedIMajeedAPowellR. Heparin induced thrombocytopenia: diagnosis and management update. Postgrad Med J. 2007;83(983):575–582.
3.
WarkentinTELevineMNHirshJ. Heparin-induced thrombocytopenia in patients treated with low-molecular weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330–1335.
4.
LevineRL. Finding haystacks full of needles. From Opus to Osler [editorial]. Chest. 2005;127(5):1488–1490.
5.
RiceL. Heparin-induced thrombocytopenia. Myths and misconceptions (that will cause trouble for you and your patients). Arch Intern Med. 2004;164(18):1961–64.
6.
LevyJHHurstingMJ. Heparin-induced thrombocytopenia, a prothrombotic disease. Hematol Oncol Clin N Am. 2007;21(1):65–88.
7.
LeeDHWarkentinTE. Frequency of heparin-induced thrombocytopenia, inWarkentinTEGreinacherA (eds): Heparin-induced thrombocytopenia (ed 3). New York, NY: Marcel Dekker; 2004:107–148.
8.
WarkentinTESheppardJIHorsewoodPSimpsonPJMooreJCKeltonJG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood. 2000;96(5):1703–1708.
9.
WarkentinTEBarkinRL. Newer strategies for the treatment of heparin-induced thrombocytopenia. Pharmacotherapy. 1999;19(2):181–195.
10.
WarkentinTEGreinacherAKosterALincoffAM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):340–380.
11.
GruelYPouplardCNguyenP. Biological and clinical features of low–molecular-weight heparin-induced thrombocytopenia. Br J Haematol. 2003;121(5):786–792.
12.
WarkentinTE. Heparin-induced thrombocytopenia: part 1: the diagnostic clues. J Crit Illn. 2002;17(5):172–178.
13.
AmiralJBrideyFWolfM. Antibodies to macromolecular platelet factor 4-heaprin complexes in heparin induced thrombocytopenia: a study of 44 cases. Thromb Haemost. 1995;73(1):21–28.
14.
BartholomewJR. The incidence and clinical features of heparin-induced thrombocytopenia. Semin Hematol. 2005;42(3 suppl 3):S3–S8.
15.
AndreescuACPossidenteCHsiehM. Evaluation of a pharmacy based surveillance program for heparin-induced thrombocytopenia. Pharmacotherapy. 2000;20(8):974–980.
16.
ReilyRF. The pathophysiology of immune-mediated heparin-induced thrombocytopenia. Semin Dial. 2003;16(1):54–60.
17.
KeltonJGSmithJWWarkentinTE. Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4. Blood. 1994;83(11):3232–3239.
18.
HughesMHaywardCPWarkentinTE. Morphological analysis of microparticle generation in heparin-induced thrombocytopenia. Blood. 2000;96(1):188–194.
19.
WallisDEWorkmanDLLewisBE. Failure of early heparin cessation as treatment of heparin-induced thrombocytopenia. Am J Med. 1999;106(6):629–635.
20.
DagerWEDoughertyJANguyenPH. Heparin-induced thrombocytopenia: treatment options and special considerations. Pharmacotherapy. 2007;27(4):564–587.
21.
WarkentinTEKeltonJG. Temporal aspects of heparin induced thrombocytopenia. N Engl J Med. 2001;344(17):1286–1292.
22.
ArepallyGMMayerIM. Antibodies from patients with heparin-induced thrombocytopenia stimulate monocytic cells to express tissue factor and secrete interleukin-8. Blood. 2001;98(4):1252–1254.
23.
VisentinGPMoghaddamMBeerySE. Heparin is not required for detection of antibodies associated with heparin-induced thrombocytopenia/thrombosis. J Lab Clin Med. 2001; 138(1):22–31.
24.
ArepallyGMOrtelTL. Heparin-induced thrombocytopenia. N Engl J Med. 2006;355(8):809–817.
25.
PouplardCCouvertCReginaS. Development of antibodies specific to polyanion-modified platelet factor 4 during treatment with fondaparinux. J Thromb Haemost. 2005;3(12):2813–2815.
26.
YuAJacobsonSHBygdenA. The presence of heparin-platelet factor 4 antibodies as a marker of hypercoagulability during hemodialysis. Clin Chem Lab Med. 2002;40(1):21–26.
27.
Lindhoff-LastEEichlerPSteinM. A prospective study on the incidence and clinical relevance of heparin-induced antibodies in patients after vascular surgery. Thromb Res. 2000;97(6):387–393.
28.
SuvarnaSEspinasseBQiR. Determinants of PF4/heparin immunogenicity. Blood. 2007;110(13):4253–4260.
29.
WilliamsRTDamarajuLVMascelliMA. Anti-platelet factor 4/heparin antibodies: an independent predictor of 30-day myocardial infarction after acute coronary ischemic syndromes. Circulation. 2003;107(18):2307–2312.
30.
WarkentinTE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol. 2003;121(4):535–555.
WarkentinTE. Clinical picture of HIT. In WarkentinTEGreinacherAeds. Heparin-induced thrombocytopenia. 3 ed. New York, NY: Marcel Dekker; 2004:53–106.
34.
GruelYPouplardCNguyenP. Biological and clinical features of low-molecular-weight heparin-induced thrombocytopenia. Br J Haematol. 2003;121(5):786–792.
35.
WarkentinTE. Clinical presentation of heparin-induced thrombocytopenia. Semin Hematol. 1998;35(suppl 5):9–16.
36.
WarkentinTEKeltonJG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med. 2001;344(17):1286–1292.
37.
WarkentinTEKeltonJG. Delayed onset heparin induced thrombocytopenia and thrombosis. Ann Intern Med. 2001;135(7):502–506.
38.
RiceLAttishaWKDrexlerA. Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med. 2002; 136(3):210–215.
39.
WarkentinTEKeltonKG. A 14-year study of heparin-induced thrombocytopenia. Am J Med. 1996;101(5):502–507.
40.
HirshJHeddleNKeltonJG. Treatment of heparin-induced thrombocytopenia: a critical review. Arch Intern Med. 2004; 164(4):361–369.
41.
WarkentinTEGreinacherA. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg. 2003;76(6):2121–2131.
42.
JangIKHurstingMJ. When heparins promote thrombosis; review of heparin-induced thrombocytopenia. Circulation. 2005;111(20):2671–2683.
43.
KeelingDMRichardsEMBaglingTP. Platelet aggregation in response to four low molecular weight heparins and the heparinoid ORG 10172 in patients with heparin-induced thrombocytopenia. Br J Haematol. 1994;86:425–426.
44.
FrancisJL. Detection and significance of heparin-platelet factor 4 antibodies. Semin Hematol. 2005;42(3 suppl 3):S9–S14.
45.
KeelingDMRichardsEMBaglinTP. Platelet aggregation in response to four low molecular weight heparins and the heparinoid ORG 10172 in patients with heparin-induced thrombocytopenia. Br J Haematol. 1994;86(2):425–426.
46.
SrinivasanAFRiceLBartholomewJR. Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia. Arch Intern Med. 2004;164(1):66–70.
47.
ArepallyGMOrtelTL. Heparin-induced thrombocytopenia. N Engl J Med. 2006;355(8):809–817.
48.
Argatroban Injection. Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; May2008.
LubenowNEichlerPLietzT. Lepirudin in patients with heparin-induced thrombocytopenia-results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3. J Thromb Haemost. 2005;3(11):2428–2436.
57.
LubenowNEichlerPLietzT. Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin induced thrombocytopenia; an analysis of 3 prospective studies. Blood. 2004;104(10):3072–3077.
58.
GreinacherAJanssensUBergG. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Heparin-Associated Thrombocytopenia Study (HAT) investigators. Circulation. 1999; 100(6):587–593.
59.
EicherPFriesenHJLubenowN. Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood. 2000;96(7):2373–2378.
60.
GreinacherALubenowNEichlerP. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation. 2003;108(17):2062–2065.
61.
RobsonRWhiteHAylwardP. Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose, and gender. Clin Pharmacol Ther. 2002;71(6):433–439.
62.
BuftonMGRubinWDSpringhornME. Bivalirudin effects on the INR and experience with prolonged inpatient and outpatient anticoagulation with bivalirudin for treatment of leg ischemia and arterial thrombosis due to HIT-TS [abstract]. Blood. 2002;100:124b.
FrancisJLDrexlerAGwynG. Successful use of bivalirudin in the treatment of patients suspected, or at risk of, heparin-induced thrombocytopenia [abstract]. Blood. 2004; 104:abstract 4077.
65.
MahaffeyKWLewisBEWildermanNM. The anticoagulant therapy with bivalirudin to assist in the performance of PCI in patients with heparin-induced thrombocytopenia (ATBAT) study. J Invasive Cardiol. 2003;15(11):611–616.
66.
WarkentinTEGreinacherACravenS. Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation. Thromb Haemost. 2005;94(5):958–964.
67.
BrownPMHurstingMJ. Lack of pharmacokinetic interactions between argatroban and warfarin. Am J Health Syst Pharm. 2002;59(21):2078–2083.
68.
GosselinRCDagerWEKingJH. Effect of direct thrombin inhibitors, bivalirudin, lepirudin, and argatroban, on prothrombin time and INR values. Am J Clin Pathol. 2004;121(4):593–599.
69.
StephensJLKoerberJMMattsonJC. Effect of lepirudin on the international normalized ratio. Ann Pharmacother. 2005;39(1):28–31.
70.
MagnaniHNGallusA. Heparin-induced thrombocytopenia (HIT). A report of 1,478 clinical outcomes of patients from 1982 to mid-2004. Thromb Res. 2006;95(6):967–981.
71.
LubenowNWarkentinTEGreinacherA. Results of a systematic evaluation of treatment outcomes for heparin-induced thrombocytopenia in patients receiving danaparoid, ancrod, and/or coumarin explain the rapid shift in clinical practice during the 1990s. Thromb Res. 2006;117(5):507–515.
72.
FarnerBEichlerPKrollHGreinacherA. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia. Thromb Haemost. 2001;85(6):950–957.
73.
GreinacherAGopinadhanMGuentherJU. The molecular structure of the antigen in heparin-induced thrombocytopenia [abstract]. J Thromb Haemost. 2005;3: OR217.
74.
GreinacherAAlbanSOmer-AdamMA. Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux in different clinical settings. Thromb Res. 2008;122(2):211–220.
75.
BullerHRDavidsonBLDecousus. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis. Ann Intern Med. 2004;140(11):867–873.
76.
BullerHRDavidsonBLDecousus. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003; 349(18):1659–1702.
77.
GlaxoSmithKline. Data on file. Oasis 5 clinical trial (AR1103420) report (ZM2005/0083/00). Research Triangle Park, NC: GlaxoSmithKline; July7, 2005.
78.
LoboBfinchCHowardA. Fondaparinux for the treatment of patients with acute heparin-induced thrombocytopenia. Thromb Haemost. 2008;99(1):208–214.
79.
WarkentinTEMaurerBTAsterRH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med. 2007;356(25):2653–2654.
80.
SpinlerSA. New concepts in heparin-induced thrombocytopenia: diagnosis and management. J Thromb Thrombolysis. 2006;21(1):717–721.
81.
WarkentinTE. Fondaparinux versus direct thrombin inhibitor therapy for the management of heparin-induced thrombocytopenia (HIT)—bridging the river coumarin. Thromb Haemost. 2008;99(1):2–3.
82.
KearonCJohnstonMMoffatK. Effect of warfarin on activated partial thromboplastin time in patients receiving heparin. Arch Intern Med. 1998;158(10):1140–1143.
