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LETTERS TO THE EDITOR: Letters & Announcements

Caveat Against the Use of Activated Recombinant Factor VII for Intractable Bleeding in Cardiac Surgery

Dietrich, Wulf MD, PhD; Spannagl, Michael MD

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doi: 10.1097/00000539-200205000-00070
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To the Editor:

In a recent issue of Anesthesia & Analgesia, Hendriks et al. (1) described the effective treatment of severe bleeding after open-heart surgery by a single dose of activated recombinant factor VII (rhFVIIa). A 65-yr-old man underwent a tricuspid and mitral valve repair. Termination of cardiopulmonary bypass was obviously difficult, the patient needed high doses of inotropes in addition to mechanical circulatory assistance, and he experienced excessive blood loss postoperatively. Two rethoracotomies could not identify a surgical source of bleeding. Despite transfusion of large amounts of blood products, oozing persisted. Finally, bleeding stopped after a bolus injection of 90 μg/kg rhFVIIa. The authors conclude that this treatment was apparently successful. However, we have some concerns regarding this new therapeutic approach of intractable bleeding after cardiac surgery.

RhFVIIa is approved only for the treatment of hemophilic patients with inhibitors of factor VIII or factor IX (i.e., in cases where the patient suffers from a localized factor deficit). Bleeding after cardiac surgery is, in contrast, caused by the activation of almost all plasmatic and cellular components of the hemostatic system comparable to disseminated intravascular coagulation (DIC). The established treatment in this situation is the inhibition of the activated hemostatic system (2) and the activation of this system is regarded as contraindicated. The central goal is the attenuation of thrombin generation (3). Therapy with rhFVIIa is a new therapeutic approach, which does not reduce but enhances thrombin generation (4). Why and how should it work in comparison to our established therapeutic methods?

The authors only provide limited information about measurement of the coagulation system. The TEG tracing, given in Figure 2, is consistent with a picture of DIC but also with hyperfibrinolysis. Typically, this state should be treated with antifibrinolytics. The authors applied a mixed antifibrinolytic approach: intraoperatively, they used small-dose aprotinin, during rethoracotomy they gave 2 g tranexamic acid, and finally, they treated the patient with a single bolus of aprotinin. Very little is known about the combined treatment of aprotinin and tranexamic acid. The applied dosages were very low, and one may wonder if they were sufficient to lessen fibrinolytic activation effectively.

The basic principle of rhFVIIa treatment is that it acts locally by binding to tissue factor (TF) at the site of bleeding and then activates factor IX and factor X. Another possible mechanism of action is that rhFVIIa acts independently of TF on the platelet surface, thus promoting platelet function (5). It is known that during and after cardiopulmonary bypass, monocytes are activated and that these monocytes are the main source of TF expression (6,7). This results in a hypercoagulable state. Adding in this situation a strong clotting activator like rhFVIIa may increase the propensity of not only local but also universal TF activation and finally promote thrombotic complications.

Given a local mode of action of rhFVIIa therapy, it may be possible that patients, especially patients undergoing cardiac surgery, have areas of TF expression besides their bleeding source; they may have vulnerable plaques in their coronary arteries and the risk of intracoronary activation of hemostasis and intravascular platelet activation with the consequence of ischemic events does exist (8). Acute myocardial infarction has been described after the administration of rhFVIIa in a hemophilic inhibitor patient (9). Hemophilic patients successfully treated with rhFVIIa are normally younger and their profound coagulation defect may protect them from ischemic events. In contrast, cardiac patients are older and their underlying disease is often of arthrosclerotic nature. It has to be demonstrated that the coagulation defect that can be treated in hemophilic patients successfully and safety (10) is comparable to that causing intractable bleeding after cardiac surgery.

This case report (1) adds another encouraging report to already existing case descriptions (11). However, we should keep in mind that the mode of action of rhFVIIa is still subject to some controversy, that there may be harmful side effects of this new therapeutic approach and, finally, we add an extremely expensive tool to our toolbox for treating hemostatic disorders. This case report merits scrutiny and further studies. However, before we recommend rhFVIIa as an effective treatment of “massive intractable bleeding after cardiac surgery” as recommended by Hendriks et al. (1), we should wait for controlled studies to elucidate the mode of action and—even more important—the safety of this treatment.

Wulf Dietrich, MD, PhD

Michael Spannagl, MD

References

1. Hendriks HG, van der Maaten JM, de Wolf J, et al. An effective treatment of severe intractable bleeding after valve repair by one single dose of activated recombinant factor VII. Anesth Analg 2001; 93: 287–9.
2. Levy JH. Hemostatic agents and their safety. J Cardiothorac Vasc Anesth 1999; 13: 6–11.
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4. Friederich PW, Levi M, Bauer KA, et al. Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects. Circulation 2001; 103: 2555–9.
5. Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 1997; 99: 542–7.
6. Ernofsson M, Thelin S, Siegbahn A. Monocyte tissue factor expression, cell activation, and thrombin formation during cardiopulmonary bypass: a clinical study. J Thorac Cardiovasc Surg 1997; 113: 576–84.
7. Parratt R, Hunt BJ. Direct activation of factor X by monocytes occurs during cardiopulmonary bypass. Br J Haematol 1998; 101: 40–46.
8. Cohen M. Update on the management of acute coronary syndromes. Cardiology 2000; 93: 210–219.
9. Peerlinck K, Vermylen J. Acute myocardial infarction following administration of recombinant activated factor VII (Novo Seven) in a patient with haemophilia A and inhibitor [letter]. Thromb Haemost 1999; 82: 1775–6.
10. Roberts HR. Clinical experience with activated factor VII: focus on safety aspects. Blood Coagul Fibrinolysis 1998; 9: S115–8.
11. Kenet G, Walden R, Eldad A, Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa [letter]. Lancet 1999; 354.
© 2002 International Anesthesia Research Society