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Editorial


Activated factor VII proves to be a lifesaver in postpartum hemorrhage

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

February 2007 · Vol. 19, No. 02

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:

  1. 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
  2. The TF–F-VIIa complex directly activates F-IX and F-X
  3. This activation accelerates the conversion of prothrombin to thrombin and, in turn, of fibrinogen to fibrin
  4. 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

In another series, 11 of 12 patients with massive postpartum hemorrhage responded to rF-VIIa treatment.13 This report, as well as others, indicates that, first, not all women respond to rF-VIIa treatment and, second, a multimodal approach, including surgery and interventional radiology, is critical to maximizing the success rate.

What about risks to women of child-bearing age?

  • Thromboembolic events. There is concern that treatment with rF-VIIa may be associated with intravascular clotting, leading to clinical syndromes of stroke and myocardial infarction. The FDA has issued a warning to clinicians of an increased risk of thromboembolic events with rF-VIIa—specifically, in elderly persons with intracerebral hemorrhage. In persons with atherosclerotic disease, damaged blood vessels may increase the amount of exposed TF; this raises the likelihood that rF-VIIa will bind to cells in the atherosclerotic plaque, triggering the coagulation cascade locally and causing a thrombotic event. It is estimated that the risk of these adverse outcomes is in the range of 25 events for every 100,000 infusions of rF-VIIa.14
  • Protection of age? In young women with massive postpartum hemorrhage, the risk of thrombosis in association with rF-VIIa is likely to be somewhat lower than it is in elderly patients who have preexisting atherosclerotic vascular disease.
  • Cost is a secondary concern. rF-VIIa is expensive—about $1,400/g—and so should be used judiciously.

Add rF-VIIa to your toolkit

In 2004, the Joint Commission on the Accreditation of Healthcare Organizations recommended that obstetric services practice their response to common obstetric emergencies such as postpartum hemorrhage. Many medical, surgical, and radiologic interventions are available to the ObGyn for postpartum hemorrhage (TABLE), and rF-VIIa is an important addition to our armamentarium. Use of this agent in obstetrics is likely to expand significantly; it’s to be hoped that, with a multimodal approach to obstetric hemorrhage,15 we can reduce the maternal death rate from this common problem.

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.

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