SAN ANTONIO, TEX—Two emerging drug therapies are offering hope for patients with massive hemorrhage or heparin-induced thrombocytopenia (HIT): recombinant activated factor VIIa and direct thrombin inhibitors. These agents were discussed by Colonel John B. Holcomb, MD, and Maureen A. Smythe, MD, at the annual meeting of the Society of Critical Care Medicine.[1]

MASSIVE HEMORRHAGE

Factor VIIa has been used as a treatment for hemophilia for years; it has been shown to be effective in patients with other coagulopathies. Only recently, however, have researchers investigated its use for massive hemorrhage. Factor VIIa generates a thrombin burst at the site of endothelial damage and it promotes hemostasis even in the setting of hypothermia, an important consideration in trauma patients.

Bleeding is by far the largest cause of death in trauma patients. Following a traumatic injury, levels of factor VIIa decline rapidly. It has thus been proposed that administration of factor VIIa could reduce the amount of hemorrhage—as well as the need for transfusions. Not only is a hemostatic plug formed more rapidly when this agent is given, but the plug may also be stronger, thereby lowering the risk of rebleeding. “By increasing factor VIIa, this clot may, in fact, be a ‘super clot’ that is stronger than a regular clot,” explained Colonel Holcomb, Director of the US Army Institute of Surgical Research in San Antonio.

Animal models have been promising thus far. In a porcine model of induced liver injury, factor VIIa (in comparison with placebo) shortened prothrombin time considerably; this effect occurred within one minute of administration and remained for at least one hour. More important, blood loss was markedly lower in the treated animals. Furthermore, there were no differences between the treated and untreated animals in platelet adhesion, thrombin activation time, or thrombin time, which suggests that no adverse systemic effect resulted from therapy.

Few human studies of factor VIIa exist, and most of those that have been done included only patients with preexisting coagulopathies. Most evidence to support the use of factor VIIa in trauma patients is anecdotal, consisting of testimonials and case reports. However, a recent placebo-controlled clinical trial examined prostatectomy patients; it demonstrated a significant decrease in blood loss in patients treated with factor VIIa.[2] In this study, as in the animal models, the agent did not appear to trigger systemic clotting, Colonel Holcomb stressed.

HEPARIN-INDUCED THROMBOCYTOPENIA

“HIT is a thrombin storm, and the most effective agents to use in patients with HIT are anticoagulants that target the problem,” noted Dr. Smythe, Professor of Pharmacy Practice at Wayne State University in Detroit. Thus, it is reasonable to consider whether direct thrombin inhibitors could save both lives and limbs.

The first step in managing HIT is, of course, immediate cessation of all forms of heparin. However, an alternative form of anticoagulation must then be started.

Three direct thrombin inhibitors are available, she said. Lepirudin is usually considered an irreversible binder of thrombin; argatroban and bivalirudin are reversible. Currently, only lepirudin and argatroban are approved for use in HIT.

Warfarin is best for HIT patients who require long-term anticoagulation, but increasing evidence suggests that such patients should be treated first with a direct thrombin inhibitor to achieve platelet recovery. The transition to warfarin should be slow and cautious: “The platelet count can be used as a surrogate marker for ongoing thrombin generation,” Dr. Smythe suggested.

In two studies of HIT patients with thromboembolic complications, the direct thrombin inhibitor lepirudin was shown to reduce the relative risk of the composite end point of new thromboembolic events, amputation, and death by about half, reported Dr. Smythe. The fact that the incidence of those outcomes remained low during postmarketing surveillance offers reassurance that “what we are seeing in clinical trials can be reproduced in clinical practice,” she said. Studies have also shown that this drug is effective in preventing thromboembolic complications in HIT patients. Studies of the use of argatroban for the management of HIT have also yielded positive results. HIT patients in the argatroban clinical trials who received argatroban had a relative risk reduction of approximately one third in the composite end point of amputation, new thromboembolic complications, and death as compared to historic control patients. A recent study has also demonstrated that argatroban almost always produces satisfactory anticoagulation and acute procedural success in HIT patients undergoing percutaneous coronary intervention.

Both drugs must be used with caution in critically ill patients. Because lepirudin is excreted renally, dosage adjustments are necessary in patients with kidney dysfunction, such as those undergoing dialysis or renal replacement. The hepatic elimination of argatroban warrants dosage adjustments in patients with liver disease. Also, recent reports suggest that lepirudin may cause anaphylaxis in a small number of patients.

—Timothy Begany

References
1. Holcomb JB, Parker R, Smythe MA, et al. Hematology: coagulation and thrombosis. Presented at: Annual Meeting of Society of Critical Care Medicine; February 1, 2003; San Antonio, Tex.
2. Friederich PW, Henny CP, Messelink EJ, et al. Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial. Lancet. 2003;361:201-205.

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