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Semin Thromb Hemost 2012; 38(03): 235-236
DOI: 10.1055/s-0032-1309288
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Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Prohemostatic Interventions: What's New?

Marcel Levi
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Publikationsdatum:
17. April 2012 (online)

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Pharmacological agents may interfere in the balance between activation of coagulation and physiological anticoagulation or fibrinolysis. Agents that are capable of promoting hemostasis or fibrin formation or those which block fibrinolytic activity belong to the group of “prohemostatic agents.” These drugs are not only useful in the prevention and treatment of bleeding in patients with coagulation defects, but also in patients with an a priori normal coagulation system who experience severe (postoperative) bleeding or are to undergo procedures known to be associated with major blood loss.[1]

Most experience with prohemostatic therapy has been accumulated in the prevention and treatment of bleeding in patients with congenital and acquired coagulation defects. Indeed, specific correction of a hemostatic defect is highly effective in this situation, as for example has been shown in the management of hemophilia with coagulation factor concentrates. Also, prohemostatic interventions may be useful when the anticoagulant effect of antithrombotic agents need to be reversed, in case of bleeding or when an emergency intervention has to be performed.[2] [3] There is, however, increasing evidence that in patients with less specific abnormalities or even a normal coagulation status and who encounter severe bleeding or are at high risk for bleeding, promoting hemostatic function may be of benefit.[1] [4] Interestingly, there seems in general not to be a strong need to specifically target a factor or pathway in the coagulation or fibrinolytic system that is causally related to the hemostatic defect, as interference in one part of the system may be able to compensate for a defect in another part.

In this issue of Seminars in Thrombosis & Hemostasis the aims and potential risks of prohemostatic therapy, the various agents with a prohemostatic potential, and the efficacy of prohemostatic drugs to reduce perioperative blood loss or treat excessive (postoperative) bleeding are discussed. In the first four series of articles a disease-specific approach has been chosen.

Cardiac surgery may be one of the clinical settings in which prohemostatic interventions have most intensely been evaluated. Numerous randomized controlled trials have focused on the potential of various interventions to reduce perioperative blood loss and to reduce the requirement for blood transfusion. Levy and Sniecinski critically review the available clinical evidence in this clinical situation.[5] Another setting that is accompanied with major perioperative blood loss is liver surgery. Due to the fact that the liver plays a central role in hemostasis, the extent of the surgical procedure and technical issues, major liver surgery may cause excessive blood loss and this may warrant a role for prohemostatic drugs. In the review of Stellingwerf et al, the authors discuss the various options and determine the role of this intervention in major liver surgery.[6] Trauma surgeons remain one of the best customers of blood bank. Indeed, excessive hemorrhage is a very important issue in trauma patients and is the second most frequent cause of death in these patients. Howard et al discuss new insights in the pathobiology of coagulopathy in trauma patients. These new insights have been translated to novel therapeutic approaches in the bleeding trauma patients, including prohemostatic interventions. The authors discuss in their article the efficacy and safety of prohemostatic agents in patients with severe trauma.[7] Another clinical setting that may be relevant for application of prohemostatic interventions is obstetrics. Peripartum major blood loss is one of the main causes of maternal morbidity in the Western world but even more so in developing countries. Recently, a lot of attention has been focused on the potential role of prohemostatic interventions in this area and although sound clinical studies are missing, Bonnet and Basso sum up available information and provide some clinical guidance on the application of prohemostatic drugs in this situation.[8]

Subsequently, some specific interventions are highlighted. Activated prothrombin complex concentrates represent one of the oldest prohemostatic interventions, mainly used for the prevention and treatment of hemorrhage in patients with hemophilia and inhibiting antibodies toward factor VIII or IX. Cromwell and Aledort describe the clinical studies that have been performed with this agent.[9] Another intervention that has been around for a while but may enjoy considerable renewed interest is fibrinogen concentrate. Stimulated by promising effects on ex vivo coagulation measurements and initial clinical observations, the use of fibrinogen concentrate in the management of excessive blood loss has been advocated, however, solid clinical evidence for this approach is emerging but still sparse, as Sørensen et al discuss.[10] Based on the success of recombinant factor VIIa as a prohemostatic agent in patients with major blood loss, new compounds are being developed with even stronger prohemostatic properties.[11] In the contribution of Persson et al the proposed mechanism of an enhanced variant of factor VIIa is described and available data on efficacy and safety is reviewed.[12]

Routine coagulation tests are hardly capable of monitoring efficacy of prohemostatic interventions. This may be a limitation as the treating physician is “blind” for the effect of the intervention (apart from any clinical benefit). It also hampers proper dosing, prevention of overtreatment, and parameters that would facilitate clinical evaluation of the treatment. Newer diagnostic point of care methodology to monitor coagulation may be helpful.[13] Finally, the safety of prohemostatic therapy also deserves some consideration. Interfering in the balance between coagulant and anticoagulant mechanisms can indeed result in undesirable adverse effects. The best illustration may be the higher risk of bleeding in patients receiving anticoagulant therapy. Conversely, prohemostatic agents may, at least theoretically, predispose for thrombotic complications. Levi focuses on the safety of currently available prohemostatic agents.[14] From this article it seems that the risk of thrombotic complications after prohemostatic treatment is increased in some situations, however, these events are relatively rare. In fact, the expected benefit of the application of prohemostatic agents in distinct clinical situations should be balanced with the risk of thrombosis in that particular patient population. Ideally, the benefit–risk ratio should be evaluated in properly controlled clinical trials.

Taken together, this issue of Seminars in Thrombosis & Hemostasis highlights an interesting group of pharmaceutical agents. Indeed, prohemostatic agents represent a class of pharmaceutical agents that may have a prominent role in the adjunctive treatment of excessive blood loss and the prevention of transfusion or adverse outcome. In specific clinical situations it seems that a positive benefit–risk rate of these agents has been established whereas in other settings this approach is promising but deserves further evaluation in proper clinical trials.