Heparin-induced thrombocytopenia (HIT)

Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by plateletactivating IgG that recognizes multimolecular platelet factor 4 (PF4)/heparin complexes. The frequency of HIT is higher with unfractionated heparin (UFH) than with low-molecular-weight heparin (LMWH) based on two meta-analyses that analyzed randomized trials 848 and prospective observational studies of postoperative thromboprophylaxis. 

The PROTECT (The Prophylaxis for Thromboembolism in Critical Care Trial) randomized trial, which compared UFH with the LMWH, dalteparin, for thromboprophylaxis in mixed surgical-medical critically ill patients, used the serotonin-release assay (SRA) to classify patients as having HIT among those who underwent serologic investigations because of thrombocytopenia or thrombosis. 

Seventeen patients had HIT based on SRA-positive (SRA+) status: five in the dalteparin group and 12 in the UFH group, a nonsignificant difference in the intention-to-treat analysis (five of 1,873 [0.3%] vs 12 of 1,873 [0.6%]; hazard ratio, 0.47; 95% CI, 0.16-1.35; P = .16; Fisher exact test, P = .14). However, the difference in HIT was statistically significant in a prespecified per-protocol analysis that excluded two patients who had VTE at trial entry: dalteparin, three of 1,566 (0.2%) vs UFH, 12 of 1,561 (0.8%); hazard ratio, 0.27 (95% CI, 0.08-0.98); P = .046; Fisher exact test, P = .021. The current study had two objectives. 

First, we sought to characterize the clinical picture of HIT in critically ill patients enrolled in PROTECT (timing and severity of thrombocytopenia and frequency of HIT-associated thrombosis and other sequelae [eg, HIT-associated anaphylactoid reactions]). We were particularly interested in determining whether SRA+ patients in whom heparin was continued (because of low clinical suspicion of HIT) had subsequent platelet count recovery, a phenomenon reported in some patients with HIT who continue to receive heparin.  

Second, we sought to determine whether the reduced risk of HIT with dalteparin observed in PROTECT reflected decreased seroconversion (ie, lower immu-nogenicity) by the study drug (dalteparin vs UFH), or decreased breakthrough of HIT-related thrombocytopenia and/or thrombosis among SRA+ patients while receiving the study drug (dalteparin vs UFH), or both. We undertook this analysis to address the role of confounding open-label heparin in PROTECT and because there are two distinct heparin-dependent pathophysiologic events to explain a given episode of HIT: (1) formation of HIT antibodies (seroconversion to SRA+ status) and, subsequently, (2) platelet activation, resulting in thrombocytopenia and/or thrombosis among SRA+ patients (breakthrough).

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