Bone Marrow Transplantation (2007) 39, 729–735 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00 www.nature.com/bmt REVIEW The potential role of recombinant activated FVII in the management of critical hemato-oncological bleeding: a systematic review M Franchini1, D Veneri2 and G Lippi3 1Servizio di Immunoematologia e Trasfusione – Centro Emofilia, Azienda Ospedaliera di Verona, Verona, Italy; 2Dipartimento di Medicina Clinica e Sperimentale, Sezione di Ematologia, Universita` di Verona, Verona, Italy and 3Dipartimento di Scienze Biomediche e Morfologiche, Istituto di Chimica e Microscopia Clinica, Universita` di Verona, Verona, Italy Recombinant activated factor VII (rFVIIa) is an hemo- situations unresponsive to conventional therapy to control static agent that was originally developed for the excessive bleeding and reduce exposure to allogeneic blood. treatment of hemorrhage in patients with hemophilia and These include intracerebral hemorrhage, oral anticoagu- inhibitors.However, in the last few years rFVIIa has been lant-induced hemorrhage, thrombocytopenia, bleeding employed with success in a broad spectrum of congenital associated with hepatic failure, major surgery, trauma and acquired bleeding conditions.In this systematic review and life-threatening obstetrical, and gynecologic hemor- we present the current knowledge on the use of this drug in rhagic complications.5–9 patients suffering from hemato-oncological disorders, In this systematic review we have collected the available which are quite commonly complicated by severe hemor- data from the literature on the use of rFVIIa in hemato- rhage.On the whole, data in the literature suggest a oncological patients with severe bleeding, unresponsive to potential role for rFVIIa in the management of bleeding standard therapy. unresponsive to standard therapy in patients with hematological malignancies, including those undergoing bone marrow transplant.However, the vast majority of Literature search the currently available data are derived from uncontrolled We firstly performed an electronic search on hemato- studies including single cases or small series of patients. oncology and rFVIIa on MEDLINE, EMBASE, SCOPUS, Thus, further trials with larger numbers of patients are OVID and the Cochrane Library without temporal limits needed to establish the most appropriate doses and timing using different combinations of the following keywords: of rFVIIa and to assess its efficacy and safety in this ‘hemato-oncology’, ‘oncology’, ‘hematology’, ‘leukemia’, setting. ‘myeloproliferative disorders’, ‘myelodysplastic syn- Bone Marrow Transplantation (2007) 39, 729–735; dromes’, ‘bleeding’, ‘hemorrhage’, ‘bone marrow trans- doi:10.1038/sj.bmt.1705670; published online 9 April 2007 plant’ and ‘rFVIIa’. Only articles with at least an abstract Keywords: rFVIIa; bleeding; leukemia; myeloprolifera- in English were considered. In addition, the bibliographic tive disorders references of all studies and reviews retrieved were assessed for additional reports of clinical trials. Unpublished works were identified by searching the abstract books of the most important conferences on hemato-oncological diseases. In total, we identified 74 references through electronic and Introduction hand searches. After reading the titles and abstracts, we excluded 36 irrelevant references and retrieved 38 references Recombinant activated factor VII (rFVIIa, NovoSeven, for further assessment. A further five studies were excluded Novo Nordisk, Denmark) is an effective hemostatic agent because they were reviews (three articles)10–12 or duplicates in 75–90% of hemophiliacs with inhibitors, and in other (two articles). Thus, a total of 33 articles/abstracts, coagulation disorders such as acquired hemophilia, con- including 162 hemato-oncological patients treated with genital factor VII deficiency and Glanzmann throm- rFVIIa, were retrieved from this literature search (31 boasthenia.1–5 Recently, unlicensed use of rFVIIa has articles and two abstracts).13–45 All the articles found, with provided benefit in many other non-hemophilic bleeding the exception of the randomized trial by Pihusch et al.,44 were uncontrolled studies. Figure 1 shows the flowchart of inclusion of studies. Correspondence: Dr M Franchini, Servizio di Immunoematologia e Trasfusione – Centro Emofilia, Ospedale Policlinico, Piazzale L. Scuro, Mechanisms of action of rFVIIa 10, 37134 Verona, Italy. E-mail: [email protected] According to current knowledge, activated factor VII Received 8 December 2006; revised 23 February 2007; accepted 27 functions primarily through two mechanisms. The first February 2007; published online 9 April 2007 pathway is tissue factor (TF)-dependent mechanism and rFVIIa in oncohematological bleeding M Franchini et al 730 involves the formation, following a vessel injury, of a TF- premature fibrinolysis and thus provides reliable and FVIIa complex, which in turn activates FX leading to the sustained hemostasis. However, the hemostatic process is conversion of prothrombin to thrombin. The initial limited not systemic but confined to the surface of the thrombin- amount of thrombin formed subsequently activates FVIII, activated platelets and the TF-bearing cells. FV and platelets so that the tenase complex (FVIIIa/FIXa) The second pathway involves a TF-independent mechan- and the prothrombinase complex (FXa/FVa) assembled on ism. In fact, recent data suggest that rFVIIa at high the activated platelet surface lead to full thrombin pharmacologic doses can directly activate FX leading to generation. This ‘thrombin burst’ is essential for the an additional burst of thrombin. Figure 2 illustrates the formation of a stable fibrin clot which is resistant to mechanisms of action of activated FVII.46–48 The use of rFVIIa in non-transplanted hemato-oncological patients Electronic and hand search (n=74) Hemato-oncological diseases are quite commonly compli- cated by severe hemorrhagic episodes, which may be due to factors related to the primary disorder or to chemotherapy- Excluded (n=36): irrelevant induced toxicity. For example, thrombocytopenia, the commonest risk factor for bleeding in hemato-oncological patients, may be a feature of the hematological malignancy Potentially relevant studies identified (i.e., acute leukemias or myelodysplastic syndromes) or the (n=38) consequence of myeloablative therapy. On the other hand, other conditions (i.e., myeloproliferative disorders) may be Excluded (n=3): characterized by a normal or even increased platelet count reviews but defective platelet function, predisposing to a bleeding tendency. There is increasing evidence of the usefulness of rFVIIa Potentially relevant observational and for the treatment of severe bleeding refractory to standard randomized clinical trials retrieved for more detailed evaluation identified and transfusional therapy in patients with hemato-oncological screened for diseases.10 (n=35) The first description was made in 1999 by White et al.,13 who described the successful use of rFVIIa in the treatment of pulmonary hemorrhage secondary to Aspergillus in a Excluded (n=2): duplicate publications patients with acquired FVII deficiency undergoing treat- ment for acute myeloid leukemia (AML). The largest case series was that recently reported by Brenner et al.27 The Studies with usable information included in the analysis authors, using an Internet-based registry (www.haemostasis. (n=33) com), collected 24 cases in which rFVIIa was used in the management of hemorrhage in patients with thrombocyto- Figure 1 Flowchart of study inclusion. penia associated with hematologic malignancies. Patients TF-dependent mechanism TF-independent mechanism Fibrin FVIIa TF rFVIIa Xa X Fibrinogen Prothrombin Va Thrombin burst Thrombin Xa Va IXa VIIIa ActivatedActivated plateletplatelet Prothrombin Platelet Figure 2 Mechanisms of action of rFVIIa. Bone Marrow Transplantation rFVIIa in oncohematological bleeding M Franchini et al 731 received a median dose of rFVIIa of 85 mg/kg (range 18– Several pathologic changes in the hemostatic system are 1040 mg/kg) and a median number of 1.6 doses (range 1–8). observed in patients undergoing BMT. First of all, graft- Bleeding stopped in 11 of 24 patients (46%), markedly versus-host disease is strongly associated with severe decreasedin8of24patients(33%)anddecreasedin4of24 gastrointestinal bleeding due to the presence of chronic patients (17%). In most patients, the response was achieved inflammatory bowel disease with extensive mucosal lesions within 2.5 h of administration of rFVIIa. On the basis of these worsened by the reduction of coagulation factor XIII, results, the authors suggested the beneficial effect of rFVIIa in which is important for wound healing. Moreover, trans- this clinical setting. However, a case of ischemic stroke, plant-related thrombocytopenia and liver toxicity (with possibly related to the use of rFVIIa, was documented. the consequent reduction in plasma levels of vitamin Another severe rFVIIa-related adverse reaction was described K-dependent coagulation factors) also occur and increase by Mantzios et al.,34 who reported massive pulmonary the bleeding risk. Several organ systems appear to be at embolism after treatment with rFVIIa in a thrombocytopenic increased risk of bleeding in BMT patients. Pihusch et al.49 patient with AML and refractory bleeding. We recently recently conducted a retrospective evaluation of 447 described a 66-year-old female Jehovah’s witness suffering hemopoietic stem cell transplantation (HSCT) patients