Clinical Presentation of HIT. Part 5
Of the alternative anticoagulant therapies that have been tried in patients requiring early management for the thromboembolic manifestations of HIT, LMW heparin, the LMW heparinoid Orgaran and the defibrinogenating agent ancrod have been used most extensively. In the setting of acute coronary disease, however, the most promising therapy is direct thrombin inhibition.
Direct thrombin inhibitors. After anecdotal reports of the successful use of the prototypic direct thrombin inhibitor hirudin in the management of patients with HIT, a prospective, open-label evaluation of this drug in achieving therapeutic levels of anticoagulation in patients with HIT is under way in Europe. In a recent preliminary report on the first 82 patients enrolled in this study, effective anticoagulation was achieved in the majority. Five patients (6%) had new thromboembolic complications, 7 (8%) had major bleeding events and 3 (4%) had to undergo limb amputation.
Six patients died, but all fatal events were due to aggravation of underlying medical problems; none were causally related to hirudin. In the United States, the cost of hirudin, together with a general perception that it performed less well than expected in two recent large-scale trials in patients with acute coronary syndromes, has discouraged manufacturers from pursuing its further development for management of patients with acute coronary disease. However, these studies did confirm the safety and antithrombotic efficacy of direct thrombin inhibition, features which, together with the lack of cross reactivity with the heparin-dependent antibody, render the direct thrombin inhibitors potentially ideal alternatives for HIT. The synthetic thrombin inhibitor argatroban has been successfully used in patients with HIT. One center recently reported a reduction in mortality from 32% in untreated historical control subjects to 18% in argatroban-treated patients with HIT (107). Open-label, prospective studies evaluating argatroban in patients with a history or current evidence of HIT undergoing percutaneous coronary intervention or peripheral vascular procedures are nearing completion in the United States, and it is hoped that the margin of benefit will be sufficient to encourage the further development and marketing of this agent for the management of this condition.
LMW heparins. Several retrospective reports have shown that LMW heparin administered to patients with HIT in the absence of cross reactivity, as detected by in vitro platelet ggregation assay, results in a favorable outcome, whereas if cross reactivity is demonstrated, there is a significant likelihood of further thrombotic events. However, when sera from patients with HIT are tested for reactivity with LMW heparin using the sensitive serotonin release or HIPA assays, cross reactivity with unfractionated heparin approaches 100%. For this reason, LMW heparin therapy should be avoided in patients with HIT. However, in the absence of readily available alternatives, if the in vitro platelet aggregation assay does not demonstrate cross reactivity with LMW heparin, it is currently common practice to administer LMW heparin to these patients and monitor them closely for further thrombotic events, persisting thrombocytopenia or the development of a LMW heparin-dependent antiplatelet antibody.