I. WISSA2, E. EBEID2, S. EL-SHAWARBY1, S. CHANDAKAS2, T. KAMAL2 & N. HILL2

Department of Obstetrics and Gynaecology, 1University Hospital Lewisham, Lewisham and 2Princess Royal University

A 30-year-old woman delivered her first baby in our unit by an elective caesarean section at term for the presence of grade III placenta praevia. This was complicated by a massive postpartum haemorrhage (PPH). Conservative surgical techniques including intrauterine Sengstaken–Blakemore tube inflation failed to control the bleeding. Subtotal hysterectomy was performed. Meanwhile, she received crystalloids, blood transfusion and carboprost. Diffuse bleeding continued following hysterectomy. In total, she was transfused 16 units of blood, 10 units of cryoprecipitate, 4 units of FFP, 2 l of Gelofusin and 2 l of Hartmann’s solution. Before the hysterectomy was performed, Hb was 6.5 g/dl; platelet count at 73610 9/l, D-dimers 3,210 ng/ml and fibrinogen 1.4 g/l and INR 2.3. An intravenous single dose of rFVIIa 4.8 mg was administered intraoperatively. A dramatic effect on the diffuse bleeding was noted; fibrinogen level became 2.0 g/l and INR level dropped to 0.8–30 min later. Recovery was uneventful.

Discussion

Following a case of major obstetric haemorrhage, it is not uncommon to face a problem of disturbed coagulation, i.e. consumptive coagulopathy. During the course of massive bleeding, uterine material with tissue factor activity (TFA) gains access to the maternal circulation leading to intravascular coagulation. The resulting thrombocytopaenia and depletion of plasma clotting factors creates a serious bleeding tendency. This is worsened by secondary fibrinolysis. The latter can cause depletion of the plasma a2-antiplasmin which then results in more bleeding tendency. The endpoint would be diffuse bleeding from a placental bed or a pelvic raw surface. Inappropriate fibrin deposition within the small blood vessels may lead to haemorrhagic tissue necrosis, particularly in the kidneys. This may result in acute ‘renaltubular’ or ‘renal cortical’ necrosis. The laboratory findings include thrombocytopaenia, markedly prolonged prothrombin time (PT) and, to a less extent, prolonged partial thromboplastin time (PTT), reduced fibrinogen, and very high level of plasma D-dimer and fibrin degradation products in serum. Recombinant Factor VIIa (eptacog alpha activated, Novoseven) was introduced to clinical medicine in the 1980s as a prohaemostatic agent (Hedner and Kisiel 1983). With the exposure of subendothelium following blood vessel injury, cell-bound tissue factor (TF) is also exposed. Under the usual circumstances, circulating Factor VII binds to TF and is activated to Factor VIIa. The bound Factor VIIa then activates both Factors IX and X. Factor Xa (activated Factor X) then complexes with Factor Va on TF-bearing cells to convert prothrombin to a small amount of thrombin – ‘thrombin burst’, which is sufficient to activate platelets as well as Factors V, VIII, and XI on platelet surface, and to act as a signalling event that triggers subsequent coagulation events (O’Neill et al. 2002). The activated platelet surface can then form a template on which Factor VIIa can directly or indirectly mediate further activation of coagulation, resulting in the generation of more thrombin and, ultimately, fibrinogen to fibrin conversion (Butenas et al. 2002; ten Cate et al. 1993). Clot formation is stabilised by inhibition of fibrinolysis, due to Factor VIIa-mediated activation of thrombin-activatable fibrinolysis inhibitor. Recombinant activated Factor VII (NovoSeven; Novo Nordisk A/S, Bagsvaerd, Denmark) has been approved by the US Food and Drug Administration (FDA) for nearly a decade for the prevention and treatment of bleeding episodes in haemophilic patients with inhibitors to coagulation Factor VIII or Factor IX (Martinowitz and Michaelson 2005). In recent years, the potential of recombinant Factor VIIa to act as a prohaemostatic agent in patients with a pre-existent normal coagulation system but who experience excessive bleeding, has been explored (Ingerslev 2000). With the use of rFVIIa, the resulting haemostasis generally occurs only at the site of injury for two reasons: (1) Factor VII is not biologically active unless it is bound to TF, and (2) thrombin generation occurs on the surface of activated platelets localised to the site of injury (Barletta et al. 2005). 22 I. Wissa et al. There is always a delicate balance between clot formation and maintaining the fluid status of the blood within the vessels. This balance could theoretically be disturbed when administering a clotting factor, a treatment that may lead to an acute thrombotic event particularly in clinical conditions associated with exposure of the circulation to tissue factor (Levi et al. 2005). RFVIIa is no exception, and there has been a continuing debate as to whether it would increase the risk of thromboembolism. However, as disruption to the subendothelium is a pre-requisite to the action of rFVIIa; therefore, it is unlikely that it will lead to a hypercoagulable state within the remnant normal blood vessels. An example of subendothelial disruption and tissue factor exposure is a semi-ruptured atherosclerotic plaque, which, most probably, is the mechanism for acute myocardial infarction observed in rare cases after administration of rFVIIa (Martinowitz et al. 2001). This is more likely to occur in elderly population; therefore, it may not be the case in obstetric patients. Aledort showed that the incidence of thrombotic events is 24.6 per 100,000 infusions for rFVIIa compared with 8.2 per 100,000 infusions of activated prothrombin complex concentrate (Aledort 2004). However, in many other studies, the risk of thrombosis has been consistently low. Boffard et al. (2005) have studied rFVIIa in two parallel, randomised trials. They established the safety of rFVIIa in trauma population, and found no increased risk of thromboembolism in the treatment group when compared with the placebo group. It is possible however, that rFVIIa may contribute to the inappropriate microvascular thrombosis known to occur within injured brain tissue (Stein et al. 2002). Other adverse reactions include skin reactions, raised blood pressure, mild fever and low-grade consumptive coagulopathy (Lusher et al. 1998). Strict clinical surveillance to allow early diagnosis of thromboembolism is recommended. In obstetrics, the experience with the use of rFVIIa to control haemorrhage has been limited to isolated case reports. To our knowledge, there has not been any randomised trial. The main indications for its use include diffuse bleeding as a sign of coagulopathy, or deranged haematological values. This is when rFVIIa could be of great benefit and may be life saving. It would be of no value in the event of the arterial bleeding, when surgical intervention or embolisation is required. Where diffuse bleeding is observed, particularly where there is evidence of coagulation defect that is most likely manifested as prolonged INR, rFVIIa may be an alternative to extreme surgical procedure such as hysterectomy. In a series of 12 cases of major obstetric haemorrhage rFVIIa was used with a dose range of 42–120 mg/kg. There has been a good or partial response in 11 cases with a resultant dramatic reduction in transfusion requirements (Ahonen and Jokela 2005). Tanchev et al. (2005) have reported four cases of PPH, which were successfully controlled with the administration of rFVIIa at a dose range between 61 and 82 mg/kg. The time elapsed until bleeding stopped ranged between 15 and 40 min. In another report, rFVIIa was effective in three cases of obstetric haemorrhage at a dose of 90–100 mg/kg. In two out of these three cases, bleeding continued in spite of hysterectomy and internal iliac artery ligation (Segal et al. 2003). It has also been used in two cases of uncontrollable haemorrhage secondary to extensive vaginal lacerations and amniotic fluid embolism where a favourable outcome was observed (Bouwmeester et al. 2003; Lim et al. 2004). As a prophylactic treatment, intravenous rFVIIa was used at a dose ranging between 35–50 mg/kg in a primigravida who was diagnosed at 20 weeks with Factor VII deficiency, which is a rare autosomal recessive hereditary condition. She then had a normal labour and uncomplicated postpartum period (Eskandari et al. 2002; Hunault and Bauer 2000). Glanzmann’s thrombasthenia is another rare hereditary autosomal recessive platelet function disorder, which can cause major haemorrhage at delivery. Prophylactic use of rFVIIa together with platelet transfusion could effectively prevent postpartum haemorrhage in those patients (Kale et al. 2004). The effective dosage of rFVIIa in obstetric haemorrhage is not determined, however it is likely that 90 mg/kg could be the optimum dose. Measuring the plasma level of FVIIa may prove to be a helpful guide in determining dose. In our unit, rFVIIa was given in cases of life-threatening obstetric haemorrhage, which persisted despite optimal blood products replacement, as well as surgical and medical interventions. In our protocol, a dose of 90 mg/kg is administered by slow i.v. bolus injection, to be repeated after 2 h if needed. The serum half-life of rFVIIa is 2.7 h (Mohr et al. 2005). It is recommended that FBC, APTT, INR, fibrinogen and D-dimers are checked before as well as 20–30 min after its use. It is not clear whether repeated injections or continuous infusion is better. Dramatic changes of the coagulation profile were reported. These have been confirmed by our own experience with the above-described cases. A decrease in prothrombin time (PT) values was manifested, while activated partial thromboplastin time (APTT) values were not equally affected. Administration of rFVIIa is indicated only when conventional measures fail to be effective. Choosing the optimal timing for its administration requires detailed assessment of the condition of the puerperal patient. The criteria should include haemoglobin, platelet count, and most importantly the prothrombin time. There are some important factors which could reduce the efficacy of rFVIIa in treatment of coagulopathy, such as acidosis (low pH), hypoxia, hypothermia, and a platelet count of less than 50610 9/l. A drop in pH from 7.4 to 7.0 could reduce rFVIIa activity by more than 90% (Meng et al. 2003). It is therefore of paramount importance to apply the rules of ITU care, in order to optimise the body homeostasis, and maximise the benefit of rFVIIa. Cost might be the main deterrent to its wider use, as a single 90 mg/kg dose to an 80 kg person in the UK costs at present rates GB£2,400 (US$4,500) for a 4.8 mg dose, and in some patients, repeated doses might be necessary. However, in order to make an objective assessment, the indirect cost of the use of other kinds of treatments, such as FFP, prolonged hospitalisation, admission to the ITU and additional nursing should be taken into consideration. Therefore the cost may not be much different for those patients who receive rFVIIa compared with those who stay longer in ITU. Previously, Food and Drug Administration (FDA) has limited its use to bleeding haemophilia A or B. This has limited its usefulness in other coagulopathies. We expect its cost to be reduced if it is used on a wider scale in the future. The Farnborough experience 23 Conclusion Massive obstetric bleeding is treated according to the primary cause, in addition to prompt transfusion of blood and coagulation factors as required. When those procedures are accomplished and bleeding continues, the options are limited. The results in those three patients raise the possibility that the drug may be administered in obstetric cases with life-threatening haemorrhage, particularly in the presence of coagulopathy. It may help in halting the coagulopathy process and lead to prompt control of the bleeding. However, it is necessary to simultaneously correct substrates deficiency – namely fibrinogen and platelets – for it to fulfil its role. Injection of rFVIIa should be also considered before hysterectomy in a young parturient with severe bleeding. In view of the cost, the product should be used when there is a realistic chance of patient’s survival. It may be difficult to set up a randomised controlled trial to assess rFVIIa role in major obstetric haemorrhage, as the obstacles will include an insufficient number of cases to produce statistically significant results, as well as the ethical issues related to withholding treatment in critically ill patients. Cohort studies may provide an alternative. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References

Correspondence: I. Wissa, 72 Valliers Wood Road, Sidcup, Kent DA 15 8BG, UK. E-mail: ihab@doctors.org.uk Journal of Obstetrics and Gynaecology, January 2009; 29(1): 21–24 ISSN 0144-3615 print/ISSN 1364-6893 online 2009 Informa Healthcare USA, Inc.DOI: 10.1080/01443610802628692