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netherlands journal of critical care Copyright ©2006, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received March 2006; accepted in revised form August 2006 r e v i e w Intensive Care and Recombinant Factor VIIa Use: A Review R. Sherrington 1 , A. Tillyard 1 , A. Rhodes 2 and R.M. Grounds 2 1 Specialist Registrar in Intensive Care, St Georges Hospital, London, UK. 2 Consultant in Intensive Care, St Georges Hospital, London, UK. Abstract. Objective – Currently recombinant factor VIIa (rFVIIa) is licensed only for use in the management of haemorrhage in patients with congenital and acquired haemophilia, congenital factor VII deficiency and Glanzmann’s thrombasthenia that is refractory to platelet transfusion. However, there has recently been a profusion of case reports and a number of randomised controlled trials regarding the use of rFVIIa in the setting of life-threatening bleeding in patients without specific coagulopathies. The purpose of this review is to examine its mechanism of action, use and efficacy in these ‘non-licensed’ conditions that often require intensive care support. Search Strategy – A Pubmed and Medline search in November 2005 was used with the keywords ‘recombinant activated factor VIIa’ and ‘critical care’. Any appropriate referenced articles from this search were also retrieved. Summary of findings – In the majority of clinical settings there is a lack of prospective randomised controlled trials of rFVIIa. The few that have been performed have shown minimal mortality and morbidity benefit. Conclusion – Further, well-performed, randomised controlled trials are recommended. Until this time, rFVIIa should be reserved for clinical trials and patients with life-threatening surgical bleeding where all conventional treatments have at least been initiated, and shown to have failed. Introduction Factor VIIa is not a new agent. Following reports of the use of prothrombin complex concentrate on patients with haemophilia and antibodies to Factor VIII, Hedner and Kisiel first reported, in 1983, the successful use of plasma-derived activated Factor VIIa (FVIIa) in controlling haemorrhage in two patients with Factor VIII antibodies [1]. The development of recombinant human Factor VIIa - rFVIIa – (‘eptacog alpha’ - NovoSeven by Novo Nordisk A/S, Bagsvaerd, Denmark) using transfected baby hamster cells led to the widespread licence in many countries for the treatment of spontaneous and surgical bleeding in patients with inhibitors against FVIII or Factor IX. There have now been over 700,000 doses administered to patients with haemophilia [2]. In 1999 Kenet et al reported the first use of rFVIIa in a patient without a specific factor deficiency who had a high velocity gunshot wound to the inferior vena cava [3]. In 2002, O’Neill et al [4] achieved haemorrhagic control with a single dose of rFVIIa in a victim of multiple stab wounds who had inadequate haemostasis despite 100 units of blood products. Currently rFVIIa is licensed for use in the management of haemorrhage in patients with congenital and acquired haemophilia, congenital factor VII deficiency and Glanzmann’s thrombasthenia that is refractory to platelet transfusion. However, since the publication by Kenet et al, interest in the application of this treatment to other medical and surgical conditions has rapidly increased. The purpose of this paper is to review rFVIIa’s efficacy from the published results in conditions that are seen in the intensive care unit (ITU). To achieve this, we conducted a Pubmed and Medline search Correspondence: Andrew Tillyard E-mail: arjtillyard@hotmail.com in November 2005 using the keywords ‘recombinant activated factor VIIa’ and ‘critical care’, and retrieved any appropriate referenced articles. Coagulation and Factor VIIa Pharmacological doses of rFVIIa increase thrombin generation locally without systemic activation. In order to understand the mechanism by which this occurs we must first understand the process of coagulation in vivo. The traditional model of coagulation includes the intrinsic and extrinsic or tissue factor (TF) pathways. However, it is now believed that the TF pathway has the greatest importance to normal haemostasis [5]. In 2001, Hoffmann and colleagues [6] proposed a cellbased model of coagulation, which emphasises the cellular control of coagulation in vivo, based on the expression of tissue factor. They describe three overlapping phases, which occur on different cell surfaces. The phases are called initiation, amplification and propagation. Initiation TF is present in the sub-endothelium and other tissues that are not normally exposed to blood [7,8]. Damage to the vascular endothelium exposes this TF and is the primary physiological initiator of coagulation [5]. Both Factor VII and activated Factor VII (1% of the total circulating FVII) bind to TF. This FVIIa/TF complex inturn activates both factors X and IX [9]. This generation of a small amount of factor Xa initiates a cascade process leading to the further generation of factor Xa and thrombin [9,10]. The initiation of coagulation also leads to the inhibition of fibrinolytic activity. Amplification This starts with vascular disruption and exposure of tissue factor bearing cells to platelets, Von Willebrand factor and Factor VIII. The 542 neth j crit care • volume 10 • no 5 • october 2006
netherlands journal of critical care thrombin generated in the initiation phase activates the platelets forming a platelet plug and their surface is primed with factors Va, VIIIa and XIa. Factor IX is activated by both tissue-factors—factor VIIa complex and factor XIa, so the coagulation cascade has moved to the platelet surface where all the necessary factors are assembled ready for the propagation stage [10]. Propagation Factor IXa produced in both the initiation and amplification phases, binds to the platelet surface and combines with FVIIIa to form the tenase complex (FIXa/FVIIIa/calcium). This activates FX which combines with FVa to form prothrombinase complex leading to the large scale production of thrombin. Thrombin cleaves fibrinogen to fibrin monomers, which polymerise to consolidate the initial platelet plug and form a stable clot. This thrombin generation also exerts positive feedback into the coagulation process by activating factors V, VIII, XI and Thrombin Activatable Fibrinolysis Inhibitor (TAFI). This process is localised to the site of injury by localised exposure of TF causing localised binding and activation of FVII and platelets. Factor VIIa Mechanism of Action Normal circulating levels of FVII and FVIIa are in the ratio of 100:1 (10nmol/l and 0.10nmol/l respectively). Administration of rFVIIa increases the circulating concentration of activated factor 100 fold (to 3-20nmol/l) [11]. Although it is widely agreed that rFVIIa acts by local activation of thrombin production there is disagreement regarding the exact mechanism by which this is achieved. There are two principal pathways – TF-dependent and TF-independent [12]. However both require the initial interaction of rFVIIa with TF, which leads to the activation of FX and thrombin formation. In the TF-dependent pathway, higher concentrations of FVIIa/TF complex go on to enhance FXa production and subsequent thrombin formation [13]. In the TF-independent pathway, rFVIIa itself activates FX on the platelet surface. As platelets accumulate at the site of injury, FXa production is independent of TF [10,14]. Although this reaction is less efficient than activation by the FVIIa/TF complex, the pharmacological concentration of factor offsets this inefficiency. The continuation of both pathways requires the combination of FXa with FVa on the platelet surface to form the prothrombinase complex, which converts prothrombin to thrombin. This localised generation of large amounts of thrombin may carry the additional benefits of enhanced platelet adhesion and aggregation [15] as well as producing thinner, more tightly packed fibrin fibres and increased activation of thrombin activatable fibrinolysis inhibitor (TAFI) making the clots more resistant to fibrinolysis [16,17]. It is worth noting, that since the process of haemostasis involves both coagulation and anti-fibrinolysis (as stimulated in the propagation phase described above), rFVIIa will never replace the rational use of appropriately dosed antifibrinolytic drugs. The authors believe the use of tranexamic acid should be considered in conjunction with rFVIIa administration. Laboratory Monitoring of the Effects of Factor VIIa There is no definitive laboratory test that is satisfactory for monitoring the efficacy of rFVIIa treatment. The use of Prothrombin Time (PT) is recommended but a reduction in PT does not predict clinical haemostasis. The improved clotting time reflects only the enzymatic activity of FVIIa. It is not a marker of the therapeutic efficacy of FVIIa [18]. It can only be suggested that the correction of the PT to within a normal range is an indicator that the drug was administered and therefore may be beneficial [11]. The failure to reduce PT may also predict non-responders. Thromboelastography has been used to assess the effect of rFVIIa [19]. It was found that the speed of clot formation and the physical properties of the clot are improved, both of which cannot be detected by routine coagulation tests. This correlates with the mechanism of action being most probably dependant on the presence of activated platelets which are localised to the site of the injury [20]. This would also explain why there is little systemic activation of coagulation because the maximum effect of rFVIIa occurs at the site of injury. The best test of efficacy remains the observation of haemostasis. Blood Product Management. There are no universal guidelines or evidence for the efficacy of a particular regime for fresh frozen plasma (FFP), platelets, fibrinogen and cryoprecipitate replacement [21]. There is also very little information to guide the use of rFVIIa outside its licensed indications. Due to rFVIIa’s mechanism of action, severe thrombocytopaenia (
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