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Staunching Hemorrhage

New England Journal of Medicine reviewers present information about aprotinin, tranexamic acid, EACA, desmopressin, and rFVIIa.

Uncontrollable bleeding is every physician’s and patient’s nightmare. Such bleeding can be due to disease, injury, surgery, or anticoagulant therapy and can arise from lesions in the brain, lung, liver, or gastrointestinal or genitourinary tract. Most clinicians’ initial responses are to transfuse blood, plasma, and platelets, but adjunctive pharmacologic therapy also is available. The efficacy and safety of some of these pharmaceutical agents were reviewed by two experts in blood coagulation. The agents considered were aprotinin, tranexamic acid, -aminocaproic acid (EACA), desmopressin, and recombinant factor VIIa (rFVIIa).

Aprotinin is a powerful protease inhibitor that is derived from bovine lung tissue; it limits clot dissolution or fibrinolysis and markedly diminishes blood loss and need for transfusion in patients undergoing coronary-artery bypass surgery. However, this activity comes at a price: In one study, aprotinin, compared with placebo, doubled the risk for severe renal failure and led to higher risk for myocardial infarction, heart failure, and stroke (N Engl J Med 2006; 354:353). Other studies have confirmed these results, so aprotinin is recommended mainly for patients who are undergoing complicated procedures with very high bleeding risk.

Tranexamic acid and EACA bind to lysine receptors on plasminogen, which inhibits its conversion to plasmin (the enzyme that lyses fibrin). Although both agents have exhibited clinical efficacy, tranexamic acid is more potent than EACA, and both are weaker than aprotinin. Nevertheless, they do appear to limit blood loss and the need for reoperation. Unfortunately, the safety of these drugs has not been established firmly; a large randomized trial of tranexamic acid in cardiac surgical patients is underway.

Desmopressin induces the release of large multimers of von Willebrand factor from storage organelles in endothelial cells; these multimers enhance platelet adhesion and aggregation. Although desmopressin is quite effective in most patients with von Willebrand disease and in some with mild hemophilia A, trials of desmopressin in cardiac surgery have shown only small decreases in perioperative blood loss. Adverse effects include hyponatremia due to water retention as well as occasional thrombotic events.

Recombinant FVIIa is a potent hemostatic agent that binds to activated platelets at the site of injury and enhances thrombin generation and clot formation. This agent curbs blood loss in a variety of clinical situations, ranging from radical prostatectomy to battlefield injuries. However, not all trials have produced positive results, and no randomized controlled clinical trials have been completed. Furthermore, the optimal dose of rFVIIa is unknown; doses from 20 µg/kg to 200 µg/kg have been used. Whether observed serious thrombotic events are dose-related has not been established. Guidelines for the use of rFVIIa, including indications for treatment and identification of patients in whom treatment should be avoided because of high risk for thrombosis, are needed urgently.

— David Green, MD, PhD

Published in Journal Watch Oncology and Hematology May 30, 2007

Citation(s):

Mannucci PM and Levi M. Prevention and treatment of major blood loss. N Engl J Med 2007 May 31; 356:2301-11.

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