The use of rituximab therapy in patients with acquired factor v inhibitors (2012)

Acquired factor V inhibitor is a rare cause of factor V deficiency [1] with a clinical spectrum ranging from the absence of symptoms to life-threatening bleeding manifestations [2, 3]. Inhibitors may develop as spontaneous autoantibodies or as alloantibodies after exposure to bovine thrombin preparations. There is no defined standard care. Immunosuppressive agents are the most commonly proposed management, or alternately supportive care with recombinant activated factor VII [1, 4]. Extrapolating the management recommendations of factor VIII inhibitors, the use of rituximab has been recently suggested [5, 6]. However, there is scarce information about the safety and long-term efficacy of this therapy. In addition, the rarity of the disorder limits the source of information to extensively studied individual cases or small series. Here, we report the results obtained during long-term follow-up of two cases of spontaneous factor V inhibitors managed with rituximab. In April 2004, a 72-year-old woman was admitted to Alvarez General Hospital for an extensive hematoma in the oral cavity. Prothrombin time (PT) activity was < 2%, activated partial thromboplastin time (aPTT) was noncoagulable, and thrombin time was normal. Factor V activity was undetectable (<2%), but factors II, VII, X, and fibrinogen were normal. The presence of an acquired factor V inhibitor was confirmed by the inhibitory effect of patient plasma on factor V activity of normal plasma [7]. The patient was first treated with intravenous methylprednisolone (1 g/d for 3 days). After 3 days, the clinical manifestations were worsened, and a new spontaneous hematoma was developed on her left forearm. The patient received a single infusion of cyclophosphamide (400 mg/m2) with a clinical response and partial improvement of factor V activity up to 29% without remission of antifactor V. This initial response lasted for 8 weeks, however, during maintenance therapy with prednisone (1 mg/kg/d) and cyclophosphamide (100 mg/d), she developed new spontaneous hematomas on the right leg and a drop in factor V activity below 2%. Repeated intravenous infusions of methylprednisolone and cyclophosphamide showed no response. She was then treated with rituximab (375 mg/m2/week for 4 weeks). Rituximab was well tolerated, and clinical manifestations were improved while the factor V level started a sustained rise reaching 50% 2 weeks after the first infusion of rituximab. Prednisone dose was then tapered and stopped. After 2 weeks the initial rituximab infusion, when being in partial laboratory response (factor V activity of 50% with persistence of antifactor V), the patient complained of a painful left leg. Doppler ultrasound confirmed thrombosis of the popliteal vein. Heparin and subsequently acenocoumarol were administered without bleeding. The response duration to rituximab therapy was 2 years and a subsequent drop in factor levels, this time without bleeding, was successfully treated with a single dose infusion of rituximab and oral prednisone. After 1 year, a third single dose rituximab infusion seems to have helped to keep factor V activity levels above 50% (Fig. 1). After 5 years of follow-up, the patient remains free of clinical manifestations. However, factor V inhibitor activity is still present in her plasma. Extensive further evaluations and follow-up excluded underlying infection, malignancies, hematological disorders, autoimmunity, and thrombophilia. Time course of factor V (FV) activity in 2 patients with antifactor V autoantibodies. Black arrows represent the time of each rituximab infusion: 375mg/m2. Filled boxes indicate immunosuppressive treatment (see text for details). Gray arrow depicts the moment of thrombotic event. Gray lines indicate the periods of complete laboratory remission (undetectable antifactor V). A 51-year-old man was referred to Leiden University Medical Center with hematuria, gum bleeds, epistaxis, and hematomas in upper and lower limbs. The patient had no history of exposure to bovine thrombin or recent surgery. Laboratory at admission: PT >100 sec, aPTT >100 sec, factor V activity <3%, Antifactor V 17 Bethesda Units. To control the ongoing hematuria the patient was first treated with platelet concentrates (1 Unit/day during 4 days), hypothesizing that the intraplatelet factor V might contribute to local hemostasis. The patient showed a dramatic clinical improvement and hemorrhagic manifestations disappeared within few days. Simultaneously, oral prednisolone and cyclophosphamide was initiated to eradicate the factor V inhibitor. Complete laboratory response (undetectable antifactor V) was observed 9 weeks after start of treatment. A subsequent decrease in factor V activity with reappearance of antifactor V activity responded to azathioprine. Prednisolone was tapered and stopped 3 months after start; cyclophosphamide was stopped 1 year later and azathioprine 30 months later. After 3 years, the initial manifestation the patient had a laboratory relapse without bleeding and he was treated with rituximab (375 mg/m2/week for 4 weeks) achieving a remission that lasted for 2 years. A subsequent relapse, again without bleeding manifestations was managed successfully with initial prednisolone and cyclophosphamide followed by cyclophosphamide maintenance. The patient remains in clinical and laboratory remission. Our cases illustrate common clinical approaches of the disease, mostly extrapolated from the management recommendations of factor VIII inhibitors. Although steroids, intravenous immunoglobulin, and immunosuppressive therapy have been reported in the literature to be successful [1, 2, 4, 8], the presented data highlight that some patients may be refractory to or relapse after this therapy. It has been previously suggested that platelet factor V may support hemostasis in acquired factor V inhibitor [9]. Our second patient received platelet concentrates in the context of persistent hematuria. After the platelet infusion, our patient showed a dramatic improvement in bleeding manifestations, therefore, we speculate that this intervention may have contributed to local hemostasis in this particular case. Apart from our two cases, there have been three cases reported in the literature on the use of rituximab for the treatment of factor V inhibitors, and the most commonly used dosing regimen for rituximab was 375 mg/m2 weekly for 4 weeks, with the cycle repeated if the patient relapsed. Our data extend these reports on the efficacy of rituximab in the management of factor V inhibitors, particularly in patients who relapsed or are refractory to standard immunosuppressive therapy. However, our data also identify potential complications as well as time to response and duration of remission as important issues. In the first publication reporting the rituximab efficacy, PT and factor V activity returned to normal after 10-weekly infusions of rituximab [6]. In another case, factor V activity and PT normalized within 24 days after the first infusion of rituximab [5] and in the most recent report, levels normalized after 15 days [10]. We observed, in both cases, a rapid increase in factor V activity after the first rituximab infusion rising from undetectable levels to >15% within the first weeks (15 days and 21 days in our first and second case respectively). The maximal response and factor V activity normalization, however, required longer periods. In our second patient, the complete response required 21 weeks and the response lasted 2 years. In the first case, factor V activity normalized in 7 weeks. Antifactor V, however, has not remitted and inhibitory activity is still present after 5 years of follow-up. To the best of our knowledge, our first patient is the second published case of bleeding associated with a factor V inhibitor followed by thrombosis. However, in the previously reported case, the thrombosis appeared after disappearance of the inhibitor [11], while in our case the thrombosis developed at low normal factor V levels and laboratory evidence of the inhibitor still being present. Whether the thrombotic event can be attributed to rituximab therapy remains unanswered. In addition, we present for the first time long-term follow-up (> 5 years) of factor V inhibitors managed with rituximab therapy. The patients showed long lasting responses, however both cases tend to relapse without maintenance therapy. In conclusion, rituximab seems to be effective in treating factor V inhibitors even in patients with relapse or resistance to standard immunosuppression. Therefore, rituximab can be considered in factor V inhibitor affected patients who do not respond to standard therapy or in those in whom cytotoxic therapy bears a high risk of morbidity. Although long lasting responses tend to be transient. Because recurrences appear after several months or years, patients need to be carefully monitored over time. Our data also alert for the potential appearance of thrombotic manifestations; events which call for additional caution in a patient with active hemorrhagic diathesis. The efficacy of the use of rituximab for the treatment of factor V inhibitors would ideally be addressed in a clinical trial, but the rarity of this disease makes such clinical trial unlikely and therefore clinicians will have to rely on reported cases. M.A. Navarrete* , F.J.M. van der Meer , G. Damiani*, A. Diaz*, J. Eikenboom , * Department of Hematology, Alvarez General Hospital, Buenos Aires, Argentina, Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands, Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.