Heparin-Induced Thrombocytopenia: Current Concepts and Emerging Roles of Fondaparinux

Heparin induced thrombocytopenia (HIT) is a highly prothrombotic disorder mediated by platelet activating immunogloubulin G antibodies that bind to conformational epitopes on platelet factor 4 (PF4) when it is complexed with heparin. HIT occurs in 0.2% to 5% of adults treated with heparin. The risk is higher with the use of unfractionated heparin, longer duration of therapy, older women and surgical patients. HIT can present with isolated thrombocytopenia, thrombosis or other unusual manifestations. Typically, platelet count drops by ≥50% from baseline, beginning 5 to 10 days after the initiation of heparin therapy. However "rapid-onset" HIT and "delayedonset" HIT can present diagnostic challenge. Approximately half of the untreated cases of isolated thrombocytopenia can develop thromboembolic events, predominantly venous thromboembolism. HIT is paradoxically under-recognized and over-diagnosed. As such, the current diagnostic algorithm utilizes both pre-test clinical probability and the results of laboratory assays. The widely utilized risk assessment system (4Ts score) provides an estimate of the pre-test probability of HIT by assigning scores based on the degree of thrombocytopenia, the timing of the drop in the platelet count, the presence of a thrombosis and the exclusion of other causes of thrombocytopenia. Laboratory diagnosis relies on the determination of the presence of circulating anti-PF4/heparin antibodies (immunologic assays) or the ability of such antibodies to cause platelet activation (functional assays). Enzyme linked immunosorbent assay has excellent sensitivity but suffers from poor specificity because of the detection of non-pathogenic anti-PF4/heparin antibodies. Functional assays such as serotonin release assay have significantly higher specificity but are not widely available. Treatment of HIT includes immediate withdrawal of all heparin products, initiation of a non-heparin anticoagulant (frequently argatroban) and transition to warfarin once the platelet count has normalized. Anticoagulation is maintained for at least 4 to 6 weeks in cases with isolated thrombocytopenia, and at least 3 months with thrombosis. Subcutaneous fondaparinux has emerged as an alternative agent for the management of HIT. Multiple small case series have demonstrated comparable efficacy to argatroban and lepirudin, and excellent safety profile. Additionally, its fixed weight-based dosing and subcutaneous route prevents the need for frequent monitoring and allows easier transition to warfarin. Consequently, in the absence of kidney dysfunction, some experts utilize it as the therapy of choice in HIT. Conversely, there are documented cases of fondaparinux-associated HIT as well as worsening of HIT with the use of therapeutic fondaparinux. Although fondaparinux offers several advantages over alternate therapeutic options, such instances require carefulness during its use for the management of HIT.