In this month's WMSHP Newsletter, Jeffery Tichenor Pharm.D. writes of the use of recombinant factor VII for massive hemorrhage due to traumatic injury.

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Exsanguination is a leading cause of mortality in severe trauma patients, accounting for approximately 40% of mortality.¹ This high incidence of mortality stems from the "lethal triad" of coagulopathy, hypothermia and acidosis associated with massive hemorrhage. Preventing transition to any aspect of the lethal triad is the goal of current treatment. The mainstays of massive hemorrhage management are: ligation, tamponading, or compression of the affected vessels. Other common interventions being: transfusion with fresh frozen plasma, cryoprecipitate, and/or platelet concentrates. The high mortality rate associated with massive hemorrhage bears witness to the fact that current therapeutic options often fall short of their goal in this patient population.

Recombinant activated factor VII (rFVIIa; Novoseven^®) currently has Food and Drug Administration approval for the treatment and prophylaxis of bleeding in patients with Factor VII deficiency, and those with hemophilia with inhibitors to Factors VIII and IX. Factor VII is a vitamin K dependent glycoprotein, structurally similar to human factor VII. Factor VII can exert activity via both the extrinsic and intrinsic pathways in the clotting cascade (see figure below). As predicted by these mechanisms of action, rFVIIa only induces clot formation where vascular injury is present. This ability to form clots only at sites of injury has lead to the investigation of rFVIIa for the management of massive hemorrhage secondary to traumatic injury. Other traits of rFVIIa which make it a potentially attractive agent for use in patients with massive hemorrhage are its short half life of approximately two hours, and its ability to be rapidly infused over 2-5 minutes. rFVIIa has been studied in both penetrating (gunshots and stabbings) and blunt (collisions and attacks) traumas.

The largest and best carried out of the trials using rFVIIa for the treatment of massive hemorrhage was performed by Boffard and colleagues in 8 countries and 32 hospitals.² This study included 301 patients with severe trauma. It was a parallel, randomized, placebo controlled, double-blind trial to evaluate the ability of rFVIIa to control bleeding in trauma patients experiencing extensive hemorrhage.² One arm evaluated the use of rFVIIa in patients with blunt trauma, while the other evaluated its use in patients with penetrating trauma. rFVIIa was administered in consecutive doses of 200, 100, and 100 mcg/kg as deemed necessary by the clinician. The first dose was given after transfusion of the eighth unit of red blood cells (RBCs); and subsequent doses were given after 1 and 3 hours respectively. The blunt trauma arm resulted in RBC transfusions being significantly reduced by 2.6 units (90% CI 0.7 - 4.6, p= 0.02) with rFVIIa compared to placebo.² The need for massive RBC transfusion, defined as > 20 units of RBC, was also significantly reduced from 33% in patients on placebo to 14% with rFVIIa (p= 0.03).² Similar trends were noted in the penetrating trauma group, though the results there were not statistically significant.²

Another well performed trial of rFVIIa for the management of massive hemorrhage was done by Dutton and colleagues. This was a compassionate use study performed on 81 coagulopathic patients.³ The decision to use rFVIIa went through 1 of 2 "gatekeepers" at the facility, dosing was done at 100 mcg/kg. Factor VII restored hemostasis in 75% of the patients (61 of 81), with an average of 1.23 doses.³ Despite this success, mortality at hospital discharge was still approximately 32%.³ This trial also showed that an acidic body pH tempers the effects of rFVIIa. Responders to rFVIIa (n=61) in this study had an average pH of 7.29 while non-responders (n=20) averaged 7.02 (p= 0.0016).³ The research also confirms that patients must have sufficient functional platelet counts at baseline in order for rFVIIa treatment to be effective (patients below 50,000/mcL did not form clots with rFVIIa).³ The researchers compiled a group comparable to their patients as a control (matched on: age, sex, mechanism of injury, abbreviated injury score, laboratory data, clinical outcome, and TRISS probability of survival) and were unable to associate rFVIIa with a long-term survival benefit in their patients.³

Both of these extensive studies concluded rFVIIa to be beneficial in restoring hemostasis to patients suffering traumatic massive hemorrhage, especially those due to blunt trauma. However, no overall mortality benefit was established with the use of rFVIIa in their patient populations. Though, use of rFVIIa may be beneficial in a select group of trauma patients with massive hemorrhage. Patients with the following characteristics appear to be the best served by rFVIIa therapy.

- Blunt trauma victim
- Current treatments exhausted
- Absence of negative prognosis (sepsis, major organ failure, penetrating head injury)
- pH >7.1
- Glasgow Coma Score >8
- Age >18 & <65 years
- No history of atherosclerosis or thrombosis

References

1. Sauaia A, Moore FA, Moore EE, et. al. Epidemiology of trauma deaths: a reassessment. J Trauma. 1995;38:185-193.
2. Boffard KD, Riou B, Warren B, et. al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double blind clinical trials. J Trauma 2005;59:8-18.
3. Dutton RP, McCunn M, Hyder M, et. al. Factor VIIa for correction of traumatic coagulopathy. J Trauma 2004;57:709-719.