A 40yr old multiparous woman required an emergency Caesarean section, during which she had a 3.5L blood loss requiring a B-Lynch suture, a Rusch balloon and 4 units of packed red cells. She suffered a further 1.5L postpartum vaginal bleed, returned to theatre and underwent a subtotal hysterectomy during which she received a massive transfusion. Postoperatively, she had a further 1.5L bleed and had a Rusch balloon reinserted. She was given recombinant Factor VIIa and regular tranexamic acid. Haemostasis was achieved and she left hospital with her healthy baby boy 8 days later.
What is the evidence for using recombinant FVIIa and antifibrinolytics in major obstetric haemorrhage?
Helen Vollmer
Major obstetric haemorrhage is the leading cause of maternal mortality worldwide and the sixth commonest cause nationally(1). Moderate blood loss after delivery is usually physiologically tolerated and the transfusion management of MOH is similar to that of major bleeding in other situations such as trauma. Obstetric haemorrhage is difficult to visually assess and it remains challenging to identify significant blood loss. During pregnancy blood volume increases by 40% and blood loss may have to exceed 1000ml before any deterioration in vital signs occurs.
All clotting factors (except Factor XI) increase during pregnancy. Fibrinogen levels reach 4-6g/l; significant bleeding has occurred if non-pregnant fibrinogen levels of 2g/l are seen. Total platelet number increases during pregnancy but as plasma volume also increases the overall platelet count decreases. Physiological coagulation inhibitors decrease and the net effect is a hypercoagulable state protective against excessive blood loss. It is unclear whether women bleeding from PPH exhibit different changes in coagulation from other patients who bleed e.g. from trauma(1).
Tranexamic acid is a competitive inhibitor of plasminogen activation. It is widely used in trauma and surgery. In the CRASH-2 study it reduced mortality in bleeding trauma patients with no increase in thrombo-embolic events. The World Health Organisation recommends its use in post-partum haemorrhage when all other measures fail or if there is a traumatic component. This is not substantiated by robust evidence and is extrapolated from surgical and trauma studies(3). A Cochrane review (4) concluded that TXA reduced blood loss after vaginal and caesarean deliveries. This was based on two small RCTs, one (92 patients) compared TXA with aminomethylbenzoic acid and no treatment in vaginal births. A second of 180 women undergoing caesarean section were randomised to TXA or placebo. Blood loss of >400mls was less common following TXA in both the vaginal births and Caesarean section studies (Risk ratio 0.51). No side effects were reported (4) but because high dose TXA inhibits cerebral glycine receptors and it may induce seizures.
The WOMAN trial (5) aims to recruit 15,000 women with post-partum haemorrhage into a double-blind RCT of tranexamic acid versus placebo which reports in 2015. The primary outcome is death or hysterectomy. The secondary endpoints include surgical procedures, blood transfusion, and thrombo-embolic events. Eligibility includes ‘substantial clinical uncertainty’ as to whether TXA should be administered and excludes cases where the clinician feels that it should be given. The investigators think this is closest to everyday practice but it may make result interpretation difficult because of differing clinical thresholds for TXA usage.
Recombinant factor VIIa (rFVIIa) induces haemostasis by enhancing thrombin generation on activated platelet surfaces, and provides stable clot formation resistant to fibrinolysis. FVII activates factor X through both Tissue Factor-dependent and TF-independent pathways. Activated FX initiates the conversion of prothrombin to thrombin and the activation of platelets.
It is licensed for use in inherited bleeding disorders but has been widely used in massive haemorrhage after trauma and surgery.
In 2009, a series of 105 women in Australia saw a reduction in bleeding in 64% and a European series reported an 83% reduction in bleeding in 92 women (1). Another case series of 4 patients and a review of 44 cases demonstrated favourable outcomes from rFVIIa in MOH, but there was a lack of uniformity in the way rFVIIa was used. In some cases it was used early on, in others it was a last resort. The doses varied widely (15-120mcg/kg) which may impact on complication rates (6). There was one complication reported, a brachial artery thrombosis. A review of 65 cases in 2006 drew similar conclusions. 46.1% of these underwent a hysterectomy, often before rFVIIa administration, so it is not clear if rFVIIa reduces the need for hysterectomy (7). No comment was made on the timing of rFVIIa administration in relation to surgical intervention, blood product administration or on complications.
McMorrow case-matched 6 patients with MOH who received rFVIIa to 6 patients who had standard surgical and haematological management. In both groups the prothrombin time improved with management. There was no statistical difference between the two groups in terms of magnitude of improvement or absolute value of PT (p = 0.09). 5 out of the 6 women in the rFVIIa group had normal or low PT within 6 hours versus 1 woman in the control group (p=0.08). No other endpoints were evaluated. They concluded that this study did not support the use of rFVIIa in the management of obstetric haemorrhage (8). There is a need for a RCT of placebo v rFVII in MOH with specific timing and dosing schedules to assess the impact on mortality and hysterectomy rates.
An analysis of 35 randomised clinical trials on 4468 patients with various clinical conditions (not obstetrics) found that the age-adjusted odds ratio for a thromboembolic event in patients who received rFVIIa was 1.17 (10.2% v 8.7%) and there was a higher proportion of arterial thromboembolic events in the rFVIIa group (5.5% v 3.2%, P=0.003), 53.9% were coronary thromboembolic events. The risk of arterial thromboembolic events increased with age, patients 75 years or over had an OR of 3.02. The risk increased with increasing doses of rFVIIa. In a sub-group of healthy volunteers, the thromboembolic rate was 0.9%, none of which were arterial in origin (9).
References:
1) Allard S, Green L, Hunt BJ. How we manage the haematological aspects of major obstetric haemorrhage. British Journal of Haematology 2014; 164: 177-188
2) World Health Organisation. WHO guidelines for the management of post-partum haemorrhage and retained placenta. http://whqlibdoc.who.int/publications/2009/9789241598514_eng.pdf
3) CRASH-2 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised placebo-controlled trial. Lancet 2010; 376: 23-32
4) Novikova N,HofmeyrGJ. Tranexamic acid for preventing postpartum haemorrhage. Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No.: CD007872. DOI: 10.1002/14651858.CD007872.pub2.
5) Shakur H, Elbourne D, Gulmezoglu M et al. The WOMAN trial (World Maternal Antifibrinolytic trial): tranexamic acid for the treatment of post-partum haemorrhage: an international, randomised, double blind placebo controlled trial. Trials 2010; 11:40 http://www.trialsjournal.com/content/11/1/40
6) Haynes J, Laffan M, Plaat F. Use of recombinant activated factor VII in massive obstetric haemorrhage. International Journal of Obstetric Anaesthesia 2007; 16: 40-49
7) Franchini M, Lippi G, Franchi M. The use of recombinant activated factor VII in obstetric and gynaecological haemorrhage. British Journal of Obstetrics and Gyanecology 2007; 114: 8-15
8) McMorrow RC, Ryan SM, Blunnie WP et al. Use of recombinant factor VIIa in massive post-partum haemorrhage. European Journal of Anaesthesiology 2008; 25(4):293-8
9) Levi M, Levy J, Andersen HF et al. Safety of recombinant activated factor VII in randomised clinical trials. New England Journal of Medicine 2010; 363(19): 1791-1800
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