Recombinant Factor VIIa, how is it looking?

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Kerry Gunn
Dept of Anaesthesia, Auckland City Hospital, Auckland, NEW ZEALAND

It is the normal daily activity of an anaesthetist to deal with surgical blood loss. Most situations are easily managed with the maintenance of normovolaemia, surgical haemostasis by sutures and cautery, and reliance on the integrity of the coagulation system.

Occasionally, as shown by Hippala¹ blood loss becomes greater than 1.5 blood volumes, and the coagulation system becomes unable to compensate with the blood loss and non surgical bleeding becomes an issue. This may occur earlier in the presence of hypothermia, shock, sepsis, or DIC. Pre-existing congenital deficiencies, liver or renal disease, or special circumstances such as cardiac bypass may modify the response so non surgical bleeding occurs earlier.

The traditional response by the anaesthetist is to replace red cells, platelets, and plasma products in an attempt to restore the integrity of the coagulation system. While consensus documents² suggest when to give these products, massive haemorrhage often continues, often leading to the development of end organ dysfunction.

Occasionally damage control surgery is required, with the triad of hypothermia, acidosis and coagulopathy, where high mortality results from ongoing blood loss.

It is in these dramatic circumstances that recombinant factor VIIa was initially used as an attempt to abate seemingly unresuscitatable patients in Israel suffering from blast injuries³. The initial results were impressive, with a succession of case reports showing dramatic reductions in blood loss, and required transfusions. Further "compassionate" use series lead to confirmation as to the efficacy of the drug to reduce non surgical blood loss, but also confirming high mortality from unrelated pathologies when used in such near dead patients. There was obviously a need to undertake randomized controlled trials in patients before they had developed to such a degree of exsanguation.

Factor VIIa was initially developed to manage haemophiliacs with antibodies to factor VIII and IX, which has no effective treatment for spontaneous bleeds. It importance was recognized by Hedner³, who realized activated Factor VIIa upon activated platelets could generate thrombin without requiring factor VIII or IX. Because only 5% of circulating factor VII is in the active form, and its binding to tissue factor can initiate thrombosis, large doses of factor VIIa were used in an attempt to arrest bleeding these trauma victims.

The issue now is to define the place in modern anaesthetic practice. Studies with haemophiliacs have not suggested the drug has an increased systemic thrombotic risk in these patients⁴. Initial results of studies suggest the same in surgical patients, unless used with prothrombotic other agents. Initial studies used 90-100 mcg/kg doses, repeated up to three times to arrest non surgical bleeding. These doses were known to be safe in haemophiliacs, but the optimal doses are currently unknown in non surgical bleeding of non haemophiliacs. Acidosis and to a lesser extent hypothermia impair factor VIIa efficacy⁵

Small prospective randomized trials in radical prostatectomy⁶ liver transplantation⁷ and cardiac surgery⁸ have confirmed the blood loss reducing potential of the drug, and its safety profile (albeit in small numbers), but these are circumstances where conventional factor replacement is effective at a fraction of the cost.

We await further trials confirming the optimal dosing, timing and safety data of using it in more massive, and uncontrolled circumstances. Until the consensus documents are available^9,10 to use as best evidence for its use. In such circumstances it is likely to provide a valuable tool to improve patient survival, and reduce depleting supplies from blood banks, in an area that still remains one of the most challenging in anaesthetic practice. The Australian Guideline developed by Mike Parr and his group is shown below.

Time of Presentation
Sunday 8 May 2005 - 1030-1200

References

1. Hiippala ST et al. Hemostatic factors and replacement of major blood loss with plasma poor red cell concentrates. Anesth Analg 1995; 81: 360-365
2. Report by the American Society of Anesthesiologists Task force on Blood Component Therapy; practice guidelines for blood component therapy. Anesthesiology 1996; 84: 732-747
3. Hedner U Potential role for rFVIIa in transfusion medicine. Transfusion 2002 42 114-124
4. Clarke A et al. Last ditch use of recombinant Factor VIIa in patients with massive haemorrhage. Vox Sanguis (2004) 86, 120-124
5. Meng Z et al. The effect of temperature and pH on the activity of Factor VIIa. Implications for the efficacy of high dose Factor VIIa in hypothermic and acidotic patients. J Trauma 2003; 55,886-891
6. Friedrich PW et al. Effect of recombinant factor VIIa on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind, placebo-controlled randomised trial. Lancet 2003; 361:201-5
7. Hendriks HG et al. Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation, a pilot study. Transplantation 2001;71 402-5
8. Hebertson M et al Recombinant factor VIIa in cardiac surgery. Blood Coagul Fibrinolysis 2004;15(suppl 1) S31-S32
9. Goodnough LT Transfusion Medicine service policies for recombinant factor VIIa administration. Transfusion 2004;44:1325-1331
10. Parr M, Guidelines for the management of critical bleeding and coagulopathy, and the role of recombinant activated factor VII, Personal Communication