Heparin-Induced Thrombocytopenia

Drug-induced thrombocytopenia due to heparin differs from that seen with other drugs in two major ways.

(1) The thrombocytopenia is not usually severe, with nadir counts rarely <20,000/L.

(2) Heparin-induced thrombocytopenia (HIT) is not associated with bleeding and, in fact, markedly increases the risk of thrombosis.

HIT results from antibody formation to a complex of the platelet-specific protein platelet factor 4 (PF4) and heparin. The antiheparin/PF4 antibody can activate platelets through the FcRIIa receptor and also likely activates endothelial cells. Many patients exposed to heparin develop antibodies to heparin/PF4, but do not appear to have adverse consequences. A fraction of those who develop antibodies will develop thrombocytopenia, and a portion of those (up to 50%) will develop HIT and thrombosis (HITT).

HIT can occur after exposure to low-molecular-weight heparin (LMWH), as well as unfractionated heparin (UFH), although it is about 10 times more common with the latter. Most patients develop HIT after exposure to heparin for 5–10 days (Fig. 109-3). It occurs before 5 days only in those who were exposed to heparin in the prior few weeks or months (< ~100 days) and have circulating antiheparin/PF4 antibodies. Rarely, thrombocytopenia and thrombosis begin several days after all heparin has been stopped (termed delayed onset HIT). The 4 "T"s have been recommended to be used in a diagnostic algorithm for HIT: thrombocytopenia, timing of platelet count drop, thrombosis and other sequelae such as localized skin reactions, and other cause of thrombocytopenia not evident.


Time course of heparin-induced thrombocytopenia (HIT) development after heparin exposure. The timing of development after heparin exposure is a critical factor in determining the likelihood of HIT in a patient. HIT occurs early in heparin exposure only in the presence of preexisting heparin/platelet factor 4 (PF4) antibodies, which disappear from circulation by ~100 days following a prior exposure. Rarely, HIT may occur later after heparin exposure (termed delayed-onset HIT). In this setting, heparin/PF4 antibody testing is markedly positive. HIT can occur after exposure to either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH).

Laboratory Testing for HIT


HIT (antiheparin/PF4) antibodies can be detected using two types of assays. The most widely available is an enzyme-linked immunoassay (ELISA) with PF4/polyanion complex as the antigen. Since many patients develop antibodies but do not develop clinical HIT, the test has a low specificity for the diagnosis of HIT. This is especially true in patients who have undergone cardiopulmonary bypass surgery, where approximately 50% of patients develop these antibodies postoperatively. The other assay is a platelet activation assay that measures the ability of the patients' serum to activate platelets in the presence of heparin in a concentration-dependent manner. This test has lower sensitivity but higher specificity than the ELISA. However, HIT remains a clinical diagnosis. The main value in testing is in excluding the diagnosis with negative tests, particularly ELISA.


Heparin-Induced Thrombocytopenia: Treatment


Early recognition is key in treatment of HIT, with prompt discontinuation of heparin and use of alternative anticoagulants. Thrombosis is a common complication of HIT, even after heparin discontinuation, and can occur in both the venous and arterial systems. In patients diagnosed with HIT, imaging studies to evaluate the presence of thrombosis (at least lower-extremity duplex dopplers) are recommended.

Patients requiring anticoagulation should be switched from heparin to an alternative anticoagulant. The direct thrombin inhibitors (DTIs) argatroban and lepirudin are effective in HITT. The DTI bivalirudin and the antithrombin-binding pentasaccharide fondaparinux appear to be effective but are not yet approved by the U.S. Food and Drug Administration (FDA) for this indication. Danaparoid, a mixture of glycosoaminoglycans with anti-Xa activity, has been used extensively for the treatment of HITT; it is no longer available in the United States but is in other countries. HIT antibodies cross-react with LMWH, and these preparations should not be used in the treatment of HIT.

Because of the high rate of thrombosis in patients with HIT, anticoagulation should be strongly considered, even in the absence of thrombosis. In patients with thrombosis, patients can be transitioned to warfarin, with treatment usually for 3–6 months. In patients without thrombosis, the duration of anticoagulation needed is undefined. An increased risk of thrombosis is present for at least 1 month after diagnosis; however, most thromboses occur early, and whether thrombosis occurs later if the patient is initially anticoagulated is unknown. Options include continuing anticoagulation until a few days after platelet recovery or for one month. Introduction of warfarin alone in the setting of HIT or HITT may precipitate thrombosis, particularly venous gangrene, presumably due to clotting activation and severely reduced levels of proteins C and S. Warfarin should only be started after alternative anticoagulation has been given for several days and the prothrombotic state has lessened.