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LETTERS TO THE EDITOR

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

Department of Anesthesiology, German Heart Center Munich, Munich, Germany Department of Hematology, University Munich, Munich, Germany

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.

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.[Abstract/Free Full Text]
2. Levy JH. Hemostatic agents and their safety. J Cardiothorac Vasc Anesth 1999; 13: 6–11.[Web of Science][Medline]
3. Peters DC, Noble S. Aprotinin - An update of its pharmacology and therapeutic use in open heart surgery and coronary artery bypass surgery. Drugs 1999; 57: 233–260.[Web of Science][Medline]
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.[Abstract/Free Full Text]
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.[Web of Science][Medline]
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.[Abstract/Free Full Text]
7. Parratt R, Hunt BJ. Direct activation of factor X by monocytes occurs during cardiopulmonary bypass. Br J Haematol 1998; 101: 40–46.[Web of Science][Medline]
8. Cohen M. Update on the management of acute coronary syndromes. Cardiology 2000; 93: 210–219.[Medline]
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.[Web of Science][Medline]
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.

Response

Department of Anesthesiology, University Hospital Groningen, The Netherlands Department of Anesthesiology, University Hospital Groningen, The Netherlands Department of Hematology, University Hospital Groningen, The Netherlands Division of Hemostasis, Thrombosis and Rheology, University Hospital Groningen, The Netherlands

In Response:

We appreciate Drs. Dietrich and Spannagl’s interest in our case report (1) and thank them for their comments. First of all, activated recombinant factor VII (rFVIIa) is indeed mainly used in hemophilia patients with inhibitors of factor VIII or factor IX. The experience in cardiac surgery with rFVIIa is limited. We used this drug in a patient after cardiac surgery as a last attempt to stop the life-threatening bleeding.

Most open-heart surgery patients show multiple changes in hemostatic variables as a result of cardiopulmonary bypass and only a minority of these patients experience excessive blood loss. Hemostatic changes include effects of diclofenac (DIC) or hyperfibrinolysis, as well as other causative mechanisms. Indeed, inhibition of thrombin generation and hyperfibrinolysis are aimed in DIC and hyperfibronolysis, respectively. However, anticoagulants may deteriorate already excessive blood loss from DIC, whereas antifibrinolytic drugs may become detrimental if DIC, rather than hyperfibrinolysis, causes the bleeding. There are no specific tests available to distinguish these and other often complex hemostatic disorders. Moreover, interpretation of coagulation tests and thromboelastogram tracings can be difficult, as these are not always unequivocal. This is illustrated by the thromboelastogram tracing in our patient before the administration of rFVIIa. It was interpreted by us as a result of impaired platelet function, thrombocytopenia, and deficiencies of coagulation factors, although in the opinion of Drs. Dietrich and Spannagl it was consistent with DIC or hyperfibrinolysis. We agree that prolonged treatment with antifibrinolytic drugs in more appropriate dosages might have been effective. However, we were not convinced that bleeding was (mainly) because of hyperfibrinolysis, an assumption that was supported by the thromboelastogram tracing after rFVIIa was administered.

There is no doubt that rFVIIa, irrespective of its still-not-precisely-explained mode of action, potentially increases the risk of venous or arterial thrombosis. This should be weighted against the risks of massive bleeding and resurgery, including myocardial infarction and a fatal outcome. Thus far, an increasing number of case reports showed the benefits of rFVIIa as a hemostatic drug in various conditions, apart from hemophilia with factor VIII or IX inhibitors (2). The results of a pilot study suggested that rFVIIa might be effective even in adult liver transplant patients with complex hemostatic disorders similar to those observed in open-heart surgery patients, although it provided no evidence of an increased risk of thrombosis (3).

We emphasize the need for properly conducted clinical trials to assess the efficacy and safety of rFVIIa in massive bleedings resulting from hemostatic disorders. Nevertheless, our case report shows that the administration of rFVIIa should incidentally be considered in patients who experience a life-threatening bleeding that do not respond to established therapies.

References

1. Hendriks HGD 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. Hedner U. Recombinant activated factor VII as a universal haemostatic agent. Blood Coagul Fibrinolysis 1998; 9: S147–52.
3. Hendriks HGD, Meijer K, de Wolf JTHM, et al. Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation, a pilot study. Transplantation 2001; 71: 402–5.[Web of Science][Medline]

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (38) Citing Articles via Google Scholar Google Scholar Articles by Dietrich, W. Articles by van der Meer, J. Search for Related Content PubMed PubMed Citation Articles by Dietrich, W. Articles by van der Meer, J.