Recombinant factor VIIa fails to correct coagulopathy induced by haemodilution with colloid

* E-mail: ingerslev{at}ki.au.dk

Editor—In recent years, numerous single case reports and a few series of retrospective cohorts of patients have been published dealing with serious bleeding and massive transfusion demands in whom recombinant activated factor VII concentrate (rFVIIa) has been tried as salvage therapy. In the absence of controlled clinical studies, practice has arisen in many places where rFVIIa has been adopted as part of the haemostasis armamentarium for treatment of uncontrollable bleeding after trauma and surgery.

We presented data recently in the British Journal of Anaesthesia that illustrate a hypocoagulable state of blood after exposure to haemodilution with various colloid plasma expanders, and our experiments point to a relatively beneficial change in the dynamic whole blood clotting profile if such blood is substituted with fibrinogen concentrate.1 More recently, Brummel-Ziedins and colleagues have supplemented our findings by demonstrating that haemodilution with colloids causes diminished platelet activation, compromised fibrin polymerization and reduced whole blood thrombin generation capacity.2

We have undertaken additional experimental work in our laboratory to address the question of whether colloid-induced coagulopathy could possibly be reversed with the aid of rFVIIa by testing ex vivo two dose levels of rFVIIa and a buffer control for their possible influence on coagulopathy induced by various levels of haemodilution with HES 130/4. Without haemodilution, rFVIIa, at the two dose-levels tested, normalized the prolonged clotting time in experiments with saline and HES 130/0.4. However, following haemodilution with colloid to a level of 25% or more, rFVIIa does not appear to improve the diminished maximum coagulation velocity of whole blood clot formation (Fig. 1).



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Fig 1 Continuous clot formation velocity profiles of whole blood subjected to haemodilution with colloid HES 130/0.4, or isotonic saline and patterns of haemostatic response to ex vivo addition of rFVIIa. Panels (A) and (B) reflect the initiation phase of coagulation. Panels (C) and (D) illustrate the propagation phase of clot formation. CT [clotting time (s)]: time duration until the initial formation of a fibrin clot; MaxVel [maximum velocity (mm 100 s–1)] is the peak value of the velocity of clot generation.

 
Recently, a randomized clinical trial on 300 trauma patients demonstrated that rFVIIa administered to bluntly traumatized patients significantly reduced the transfusion requirements as compared with placebo.3 Trauma patients with shock often receive volume substitution initially with quite large amounts of plasma expanders to maintain sufficient blood pressure. In view of this, our new data contribute to understanding the limited effect on haemostasis if rFVIIa is administered after large volumes of colloid HES 130/0.4. The critical issue here is the lack of improvement of the velocity of clot formation. Our original paper1 shows that addition of fibrinogen increases the velocity of clot formation. In view of this, severe bleeding occurring shortly after volume substitution with HES may be managed better with fibrinogen before rFVIIa.

B. Sørensen, C. Fenger-Eriksen and J. Ingerslev*

Aarhus, Denmark

References

1 Fenger-Eriksen C, Heslop J, Anker-Møller E, Ingerslev J, Sørensen B. Thrombelastographic whole blood clot formation following ex vivo addition of plasma substitutes: improvements of the induced coagulopathy with fibrinogen concentrate. Br J Anaesth 2005; 94: 324–9[Abstract/Free Full Text]

2 Brummel-Ziedins K, Whelihan MF, Ziedins EG, Mann KG. Resuscitation fluid you choose may potentiate bleeding. Blood 2004; 11: 104

3 Rossaint R, Boffard KD, Warren BL, et al. Decreased transfusion utilization using recombinant factor VIIa as an adjunct in trauma. Intensive Care Med 2004; 30: S199





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