From the Editor

Activated factor VII proves to be a lifesaver in postpartum hemorrhage

OBG Manag. 2007 February;19(2):8-15

A patient bleeding to death following delivery is every OB’s greatest fear

References

1. Dildy GA, Scott JR, Saffer CS, Belfort MA. An effective pressure pack for severe pelvic hemorrhage. Obstet Gynecol. 2006;108:1222-1226.

2. Deneux-Tharaux C, Carmona E, Bouvier-Colle MH, Breart G. Postpartum maternal mortality and cesarean delivery. Obstet Gynecol. 2006;108:541-548.

3. Kane G, Walden R, Eldad A, Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa. Lancet. 1999;354:1879.-

4. 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.

5. Bouwmeester FW, Jonkhoff AR, Verheijen RH, van Geijn HP. Successful treatment of life-threatening postpartum hemorrhage with recombinant activated factor VII. Obstet Gynecol. 2003;101:1174-1176.

6. Moscardo F, Perez F, de la Rubia J, et al. Successful treatment of severe intra-abdominal bleeding associated with disseminated intravascular coagulation using recombinant activated factor VII. Br J Haematol. 2001;114:174-176.

7. Hellman L, Wild C, Hojnacki B, Pollow K. Successful treatment of life-threatening bleeding after cesarean section with recombinant factor VII. Clin Appl Thromb Hemost. 2006;12:227-229.

8. Baudo F, Caimi TM, Mostarda G, de Cataldo F, Morra E. Critical bleeding in pregnancy: a novel therapeutic approach to bleeding. Minerva Anestesiol. 2006;72:389-393.

9. Branch DW, Rodgers GM. Recombinant activated factor VII: a new weapon in the fight against hemorrhage. Obstet Gynecol. 2003;101:1155-1156.

10. Danilos J, Goral A, Paluskiewicz P, Przesmycki K, Kotarski J. Successful treatment with recombinant factor VIIa for intractable bleeding at pelvic surgery. Obstet Gynecol. 2003;101:1172-1173.

11. Lim Y, Loo CC, Chia V, Fun W. Recombinant factor VIIa after amniotic fluid embolism and disseminated intravascular coagulopathy. Int J Gynaecol Obstet. 2004;87:178-179.

12. Tanchev S, Platikanov V, Karadimov D. Administration of recombinant factor VIIa for the management of massive bleeding due to uterine atonia in the post-placental period. Acta Obstet Gynecol Scand. 2005;4:402-403.

13. Ahonen J, Jokela R. Recombinant factor VIIa for life-threatening postpartum hemorrhage. Br J Anaesth. 2005;94:592-595.

14. Aledort LM. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity. J Thromb Haemost. 2004;2:1700-1708.

15. Reynders FC, Senten L, Tjaima W, Jacquemyn Y. Postpartum hemorrhage: practical approach to a life-threatening complication. Clin Exp Obstet Gynecol. 2006;33:81-84.

Fast Track

There’s strong evidence from dozens of cases: rF-VIIa works well in severe postpartum hemorrhage when other interventions fall short

Obstetricians train relentlessly to respond to severe postpartum hemorrhage in a systematic manner by sequentially intervening with tocolytics, massive transfusion of blood products, surgical procedures (including hysterectomy and pelvic packing¹), and consultation with interventional radiologists, if available (TABLE). Even with optimal therapy, however, postpartum hemorrhage remains a major cause of maternal death throughout the world.²

TABLE

At your disposal, a range of interventions for obstetric hemorrhage

PHARMACOTHERAPY
Carboprost	Oxytocin
Methergine	Vasopressin
Misoprostol	Recombinant human factor VIIa*
BLOOD BANKING
Cryoprecipitate	Platelets
Fresh-frozen plasma	Red blood cells
SURGERY
Repair of lacerations	Ligation of the hypogastric artery
B-Lynch suture	Other uterine compression sutures
Hysterectomy, supracervical	Pelvic packing
Hysterectomy, total	Pelvic tourniquet
NONSURGICAL PROCEDURES
Bakri balloon	Uterine packing
Uterine balloon tamponade
INTERVENTIONAL RADIOLOGY
Uterine artery balloons	Uterine embolization
CONSULTATION
Anesthesiologist–intensivist	Trauma surgeon
Gynecologic oncologist	Urologist
Interventional radiologist
*Not approved by the FDA for this indication.

Evidence is growing that recombinant activated clotting factor VII (or rF-VIIa) is a potentially life-saving treatment for women with severe postpartum hemorrhage who are not responding to standard interventions. How does this agent work in such cases?

The coagulation cascade is complex. An abbreviated version reveals the therapeutic role that exogenous rF-VIIa may play:

F-VII binds to tissue factor (TF) that has been exposed on damaged blood vessels and other cells, resulting in activation of the protease function of F-VII
The TF–F-VIIa complex directly activates F-IX and F-X
This activation accelerates the conversion of prothrombin to thrombin and, in turn, of fibrinogen to fibrin
The enzymatic process is markedly enhanced by the action of platelet membranes.

In massive trauma or severe postpartum hemorrhage, exogenous rF-VIIa may enhance complexing of TF and F-VIIa on damaged cells, thereby accelerating clotting locally and reducing the magnitude of blood loss.

Evidence of efficacy

rF-VIIa (NovoSeven [Novo Nordisk]) has been approved by the FDA for treating bleeding in (a) patients with hemophilia who have antibodies to F-VIII and F-IX and (b) patients with F-VII deficiency. rF-VIIa is not approved for treating bleeding associated with major trauma or postpartum hemorrhage. However:

There are dozens of case reports of patients bleeding to death from severe trauma who apparently have had their life saved by rF-VIIa³
One large clinical trial indicates that rF-VIIa is beneficial for hemorrhage caused by trauma.⁴

In that clinical trial, 301 patients with severe trauma who had received at least 8 units of red blood cells (RBCs) were randomized to standard surgical care plus intravenous injection of placebo or to standard surgical care plus injection of rF-VIIa. Three doses of rF-VIIa were administered: 200 μg/kg after the initial 8 units of RBCs were transfused, 100 μg/kg 1 hour later, and 100 μg/kg 3 hours later. Compared with subjects given placebo injection, those who received rF-VIIa had fewer transfusions and lower rates of massive transfusion (>12 units), acute respiratory distress syndrome, and multiorgan failure.

In patients with blunt trauma, the percentage of subjects who received more than 12 units of RBCs declined from 33% in the placebo group to 14% in the group treated with rF-VIIa. Overall mortality, however, was not significantly reduced by rF-VIIa. Of note, an equal number of thromboembolic events occurred in the group treated with rF-VIIa and the group treated with placebo. (The trial was supported by the manufacturer of rF-VIIa.⁴)

Strong case evidence in ObGyn but no rigorous trials

Dozens of cases have been reported of women with massive postpartum hemorrhage who apparently had their life saved by rF-VIIa.^5-9 rF-VIIa has also been used successfully in severe hemorrhage following gynecologic surgery¹⁰ and after amniotic fluid embolism with coagulopathy.¹¹

Regrettably, there are no randomized trials of rF-VIIa in obstetrics to guide your clinical action. In the series cited most often, rF-VIIa was administered after available standard surgical procedures for severe postpartum hemorrhage were used and transfusion had reached the 8- to 30-unit range. This indicates that, in most series, only the most severe cases of postpartum hemorrhage were treated with rF-VIIa. The dose of rF-VIIa in these reports was, typically, in the range of 40 to 120 μg/kg.

An option after others fail

Based on a review of the literature, I propose the following approach to severe postpartum hemorrhage with rF-VIIa when other modalities prove insufficient:

Start with a dosage of 40 μg of rF-VIIa/kg of body weight to balance the benefit of hemostasis against the risk of harmful thromboembolic events
Because rF-VIIa has a circulating half-life of approximately 2 hours, consider a second dose of rF-VIIa, as was given in many of the reported cases of postpartum hemorrhage.

Note that, before rF-VIIa was administered in most series, standard surgical intervention had included hysterectomy. In 1 report of 4 cases, however, rF-VIIa was used successfully for postpartum hemorrhage after uterine tamponade had failed but before hysterectomy was performed.¹²