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Hemorrhage after childbirth, whether the delivery is vaginal or operative, is a clinical situation where knowledge, communication, and the availability and utilization of resources all play prominent roles. In this article we describe the thought processes and decisions that should occur, and the actions that should be taken by the anesthesiologist in the face of suspected, expected, or unexpected hemorrhage in the labor and delivery suite.

Recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) is well established as an effective hemostatic agent for the management and prophylaxis of hemorrhage in hemophilia patients with inhibitors. Treatment schedules usually involve multiple bolus doses of 90 to 120 microg/kg administered every 2 to 3 hours, but recent evidence suggests that the use of higher doses might be justified. Such high-dose regimens may overcome the rapid clearance rate observed in pediatric patients, and may be more convenient for patients with poor venous access. It has been suggested that individually tailored high-dose therapies might be beneficial in selected groups of patients, although careful monitoring of such patients is advised. Thrombelastography has demonstrated considerable success in this regard, allowing accurate assessment of both hemostatic efficacy and individual response to rFVIIa. To date, no safety issues associated with high-dose rFVIIa have been identified. However, it is hoped that further research will support these favorable observations and thus contribute towards more effective dose optimization of rFVIIa in hemophilic inhibitor patients.

Optimal dosing schedules of recombinant factor VIIa (rFVIIa) for the treatment of mild to moderate bleeding episodes in hemophilia patients with inhibitors are currently the subject of much debate. Standard doses of 90 to 110 microg/kg have provided hemostatic efficacy in many cases in the current literature. However, recent studies using doses greater than 200 microg/kg suggest that high-dose regimens may not only be more effective, but may also reduce the number of doses required. Work using in vitro models has indicated that the increased efficacy of high-dose rFVIIa may be attributed to accelerated clot formation and a stronger, more rapid thrombin burst on the surface of activated platelets. Before higher dosing schedules become more widely used, however, a number of unanswered questions remain to be resolved. It is expected that ongoing and future trials will help to clarify some of these issues. Until such information is available, it is recommended that children and adolescents may be treated with a single bolus dose of 300 microg/kg rFVIIa within 1 to 2 hours of bleed onset. Due to a current lack of information regarding high-dose rFVIIa therapy in adults, however, it would be prudent to use standard doses (90 microg/kg every 2 to 3 hours for two or three doses) in this patient population.

Recombinant factor VIIa (rFVIIa; NovoSeven(R), Novo Nordisk, Bagsvaerd, Denmark) induces hemostasis in patients with severe hemophilia and inhibitors, and has been found to control hemorrhage associated with severe trauma and surgery in patients with basically normal hemostatic mechanisms from the start. By enhancing the generation of thrombin on activated platelets, rFVIIa facilitates the formation of a tight, stable fibrin plug that is resistant to premature lysis. Clinical efficacy has been achieved with doses of rFVIIa much lower than originally proposed by in vitro models. Based on early clinical experiences, a dosing schedule of 90 to 120 microg/kg every 2 hours for the first 24 hours was recommended for serious bleeds and surgical cover. This schedule has been shown to induce and maintain hemostasis in 83% to 95% of serious bleeding episodes, and in 90% to 100% of major surgical cases. However, "mega" doses of rFVIIa may demonstrate greater efficacy in the treatment of joint bleeds, as they are more likely to evoke a full thrombin burst. Interpatient variation in recovery rates, clearance rates, and the ability to generate thrombin on the activated platelet surface may influence the efficacy of rFVIIa. Optimal doses may thus vary not only between hemophilia patients, but also between patients treated for other bleeding disorders.

The development of recombinant factor VIIa (rFVIIa) has greatly augmented the range of treatment options available for hemophilia patients with inhibitors. However, there still remains a lack of consensus regarding several aspects of treatment with bypassing agents such as rFVIIa, prothrombin complex concentrates (PCC), and activated PCC (aPCC). Such unresolved issues may be clarified by the identification of a suitable laboratory monitoring method with which to correlate clinical outcomes. This paper will review the need for an effective and informative monitoring strategy, and will discuss several candidate methods that have been employed for the measurement of hemostatic efficacy following therapy with bypassing agents. To date, however, no assay endpoint has been developed that can correlate accurately with clinical outcomes in a sufficiently large patient sample.

The treatment of hemophilic patients with inhibitors presents many challenges. Recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Copenhagen, Denmark) is a new therapeutic option for this patient population. Optimization of dosing regimens may be achieved by considering (1) individual pharmacokinetics (especially in the pediatric population); (2) high-dose bolus regimens; (3) continuous infusion (CI) including high-dose CI; (4) early treatment with NovoSeven in the course of a bleeding event; and (5) use of NovoSeven as a prophylactic therapy. The literature involving these issues is reviewed here. Institution of early therapy has been shown to decrease total NovoSeven requirement while increasing efficacy. Pediatric patients may require a higher dose of NovoSeven due to the higher clearance rate and shorter half-life demonstrated by this population. Therefore, the patient's age and/or individual pharmacokinetics and clearance rate should be considered when calculating doses and CI rates. High-dose NovoSeven has been shown to be effective in some patient populations without increased reported adverse events. Despite its short half-life, prophylactic use of NovoSeven has been reported in a small number of patients, with an apparent decrease in bleeding episodes experienced. There has been significant interest in administration of NovoSeven by CI, particularly in patients requiring prolonged treatment, and it has been shown to be successful, although the optimal target factor VII activity has yet to be established and some authors have recommended the use of concomitant antifibrinolytics., (Copyright 2001 by W.B. Saunders Company.)