LMW heparinoid, Ancrod and Antiplatelet agents
LMW heparinoid. Although it belongs to the same family of drugs as heparin and LMW heparin, the LMW heparinoid Orgaran, which is presently available for compassionate use in the United States, differs from the LMW heparins in a number of ways. It is a mixture of sulfated glycosaminoglycans derived from porcine intestinal mucosa and consists of 84% heparan sulfate, 12% dermatan sulfate and 4% chondroitin sulfate. In contrast to LMW heparin, each component of Orgaran is structurally distinct from unfractionated heparin. As a consequence, it has relatively low cross reactivity (10% to 20%) with the heparin-dependent antibody, as determined by aggregation, serotonin release or HIPA assays. In an overview of 230 patients with HIT treated with Orgaran, 93% of patients were considered to have responded adequately to the drug during the treatment period. Approximately 26% of the patients died, but in only 7 patients (3%) was the death deemed directly attributable to Orgaran. The use of Orgaran in patients undergoing open heart surgery is potentially limited by the fact that its anticoagulant effect cannot be neutralized by protamine sulfate. Consistent with this, of 19 patients undergoing cardiopulmonary bypass surgery with Orgaran in place of heparin, 11 bled more than expected. Although Orgaran has been demonstrated to be effective in the prevention and treatment of venous thrombosis, experience in patients with acute coronary disease or in those requiring coronary or vascular surgery outside the contexts cited earlier is limited. Nevertheless, in Canada and Australia, where the drug has been licensed for clinical use for some years, most authorities currently regard Orgaran as the treatment of choice for patients with HIT (T. Warkentin, personal communication, 1997).
Ancrod. This is a rapidly acting defibrinogenating agent derived from the Malayan pit viper; it is immunologically distinct from heparin and does not cause thrombocytopenia. It acts by cleaving fibrinopeptide A from fibrinogen, producing an unstable product that is rapidly removed from the circulation. It may be administered intravenously or subcutaneously and is monitored by measuring the fibrinogen concentration. Although ancrod has been used successfully in a number of patients with thrombotic complications of HIT, it is not readily available in the United States. Furthermore, it does not suppress thrombosis in all cases (T. Warkentin, personal communication, 1997) and should therefore be considered a less favorable alternative in these patients.
Antiplatelet agents. In the absence of controlled, prospective data, antiplatelet agents such as aspirin, dipyridamole or dextran have been recommended empirically as adjunctive therapy after cessation of heparin in patients with HIT, both in the presence and absence of thrombosis. Antiplatelet agents have also been given with continued administration of heparin in patients in whom cessation of the anticoagulant agent was believed to be undesirable. In a series of 12 patients with HIT requiring urgent open heart surgery with intraoperative heparin, the preoperative administration of aspirin and dipyridamole resulted in no postoperative thromboembolic events and bleeding in only three patients. In another small study of 9 patients, however, it was found that although this strategy protected patients from thromboembolic complications, it did not prevent the thrombocytopenia associated with limited heparin reexposure. Aspirin is not consistently effective in inhibiting the heparin-dependent antibody in vitro, presumably reflecting the fact that it has an impact on only one of several pathways of platelet activation and aggregation. Furthermore, even when aspirin does prevent heparin-induced platelet activation in vitro, this does not necessarily predict its efficacy in viv.