Heparin-induced thrombocytopenia (HIT) is a clinically important drug-induced complication. The rates of HIT vary significantly based on the clinical context, but estimates have ranged from 0.2% to 3%.1 Rates are higher among general medical, surgical, orthopedic, and cardiac patients, but lower in chronic hemodialysis, obstetric, and pediatric patients.2,3 The formulation of heparin also influences incidence, with markedly lower rates associated with low-molecular-weight heparin (LMWH; 0.2%) than with unfractionated heparin (UFH; ∼3%). Other minor factors reported to impact HIT incidence include route of administration (e.g., intravenous, subcutaneous4), gender,5 and heparin source (e.g., bovine, porcine6).
Although a full discussion of the pathophysiology of HIT is beyond the scope of this review, several articles were recently published.7 Briefly, HIT is an immunemediated response to UFH or LMWH. The immunologic targets are macromolecular complexes between platelet factor 4 (PF4), which is an abundant platelet protein, and heparin products, resulting in heparin-PF4 antibodies. These antibodies bind to the macromolecular heparin-PF4 complexes and can then bind to Fc receptors on the surface of platelets. The size of the macromolecular complexes often allows binding to multiple Fc receptors, leading to platelet activation, release of procoagulant microparticles, and significant thrombin generation. The massive thrombin generation leads to thrombosis, both arterial and venous, and is the basis for treatment with direct thrombin inhibitors.7 The heparin-PF4 antibodies are detectable in the laboratory using immunologic or functional assays, and are often used to support the clinical suspicion of HIT.
Patients with cancer represent a population of interest with respect to HIT, both because of the potential diagnostic complexity, given the number of potential confounders, and the relatively high risk for heparin exposure, which is driven through multiple mechanisms. For example, venous thromboembolism (VTE) is common in cancer patients. Approximately 15% of all cancer patients have clinically detectable VTE, and VTE is identified in 2% to 8% of hospitalized cancer patients.8 Hospitalization also results in heparin exposure, in many cases for thromboprophylaxis. Active treatment with chemotherapy increases the risk for VTE, and certain agents such as thalidomide, bevacizumab, and irinotecan increase the risk further.8 Additionally, routine care for venous access devices, commonly found in cancer patients, often involves heparin flushes.
The authors have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors.
MartelNLeeJWellsPS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a metanalysis. Blood2005;106;2710-2715.
WarkentinTEGreinacherAKosterA. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians evidence-based clinical practice guidelines (eighth edition). Chest2008;133:340S-380S.
WarkentinTESheppardJASigouinCS. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood2006;108:2937-2941.
FrancisJLPalmer GJIIIMorooseR. Comparison of bovine and porcine heparin in heparin antibody formation after cardiac surgery. Ann Thorac Surg2003;75:17-22.
HitronASteinkeDSutphinS. Incidence and risk factors of clinically significant chemotherapy-induced thrombocytopenia in patients with solid tumors. J Oncol Pharm Pract; in press.
OliveraGBFCrespoEBeckerRC. Incidence and prognostic significance of thrombocytopenia in patients treated with prolonged heparin therapy. Arch Intern Med2008;168:94-102.
GreinacherAFarnerBKrollH. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis: a retrospective analysis of 408 patients. Thromb Haemost2005;94:132-135.
SmytheMAKoerberJMMattsonJC. The incidence of recognized heparin-induced thrombocytopenia in a large, tertiary care teaching hospital. Chest2007;131:1644-1649.
GirolamiBPrandoniPStefaniPM. The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. Blood2003;101:2955-2959.
PrandoniPSiragusaSGirolamiB. The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: a prospective cohort study. Blood2005;106:3049-3054.
OpatrnyLWarnerMN. Risk of thrombosis in patients with malignancy and heparin-induced thrombocytopenia. Am J Hematol2004;76:240-244.
LeeAYLevineMNBakerRI. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med2003;349:146-153.
LeeAYRicklesFRJulianJA. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol2005;23:2123-2129.
KakkarAKLevineMKadziolaZ. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the Fragmin Advanced Malignancy Outcomes Study (FAMOUS). J Clin Oncol2004;22:1944-1948.
PrandoniPLensingAWPiccioliA. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood2002;100:3484-3488.
ENOXACAN Study Group. Efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. Br J Surg1997;84:1099-1103.
KlerkCPSmorenburgSMOttenHM. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol2005;23:2130-2135.
HullRDPineoGFBrantRF. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med2006;119:1062-1072.
MayoDJCullinaneAMMerrymanPK. Serologic evidence of heparin sensitization in cancer patients receiving heparin flushes of venous access devices. Support Cancer Care1999;7:425-427.
GreinacherAEichlerPLubenowN. Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. Blood2000;96:846-851.
CukerAArepallyGCrowtherMA. The HIT Expert Probability (HEP) score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion. J Thromb Haemost2010;8:2642-2650.
LoGKJuhlDWarkentinTE. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost2006;4:759-765.
StreiffMBBockenstedtPLCatalandSR. NCCN Clinical Practice Guidelines in Oncology: Venous Thromboembolic Disease. Version 22011. Available at: http://www.nccn.org/professionals/physician_gls/pdf/vte.pdf Accessed December 11 2010.
PriceEAHaywardCPMoffatKA. Laboratory testing for heparin-induced thrombocytopenia is inconsistent in North America: a survey of North American specialized coagulation laboratories. Thromb Haemost2007;98:1357-1361.
WarkentinTECookRJMarderVJ. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood2005;106:3791-3796.
GreinacherAJuhlDStrobelU. Heparin-induced thrombocytopenia: a prospective study on the incidence, platelet-activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes. J Thromb Haemost2007;5:1666-1673.
PouplardCAmiralJBorgJY. Decision analysis for use of platelet aggregation test, carbon 14-serotonin release assay, and heparin-platelet factor 4 enzyme-linked immunosorbent assay for diagnosis of heparin-induced thrombocytopenia. Am J Clin Pathol1999;111:700-706.
WarkentinTESheppardJAMooreJC. Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class do we need?J Lab Clin Med2005;146:341-346.
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 Haemost2005;3:2428-2436.
GreinacherALubenowNEichlerP. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation2003;108:2062-2065.
LewisBEWallisDELeyaF. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med2003;163:1849-1856.
LewisBEWallisDEBerkowitzSD. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation2001;103:1838-1843.