Successful treatment with thalidomide of a patient with congenital factor V deficiency and factor V inhibitor with recurrent gastrointestinal bleeding from small bowel arteriovenous malformations

Factor V (FV) deficiency is a rare bleeding disorder with variable bleeding manifestations that do not necessarily correlate with the level of FV activity 1. Treatment of bleeding episodes is generally based on factor replacement through fresh frozen plasma (FFP) transfusions, as necessary, with adjunctive pharmacological therapy. The presence of FV inhibitor requires alternative treatment modalities that include bypassing agents and immunotolerance induction to decrease antibody titres 2. We describe the case of a patient with FV deficiency and FV inhibitor with recurrent gastrointestinal tract (GI) bleeding from small bowel arteriovenous malformations (AVMs) successfully treated with thalidomide after endoscopic, haemostatic and hormonal treatment failed. A 67-year-old man with congenital FV deficiency was seen at our institution in 2005 with recurrent GI bleeding. His lifelong history of mild bleeding had worsened over the preceding 10 years, and the bleeding did not respond to treatment with FFP. His laboratory data are summarized in Table 1. His FV inhibitor value was initially 17 Bethesda units. This was a new finding corresponding to an acquired inhibitor. Additional testing revealed normal von Willebrand antigen. Extended oesophagogastroduodenoscopy revealed several AVMs in the duodenum that were successfully treated with argon plasma cauterization. Small non-bleeding AVMs were seen in the jejunum and were also treated with argon plasma cauterization. He received recombinant activated factor VII and aminocaproic acid for management of haemostasis. Pulse intravenous glucocorticoids (two doses of 1 g methylprednisolone) followed by high-dose oral prednisone (1 mg kg−1) were given to treat the FV inhibitor. In the following year, the patient had three episodes of major bleeding requiring hospitalization and was maintained on prophylactic and on-demand activated prothrombin complex concentrate (FEIBA), but still required 26 units of packed red blood cells (pRBCs). Corticosteroids were tapered and stopped after 4 months when his FV inhibitor titre decreased to 4 Bethesda units. In 2006, in an effort to decrease pRBC transfusion and FEIBA requirements, danazol was started at a dosage of 100 mg day−1 with progressive titration to 500 mg day−1. An 8-month period free of major bleeding without FEIBA prophylaxis was achieved with this therapy (Table 2). During that time, symptomatic severe mitral regurgitation and angina developed, for which valve replacement and coronary artery bypass grafting were recommended. The patient received 4 weekly doses of rituximab (375 mg m−2 per dose) with resolution of the inhibitor (Table 2), but he declined cardiac surgery. Two years later, he discontinued use of danazol because of mood swings and FEIBA was restarted. Approximately 6 months later, he experienced recurrent GI bleeding from jejunal AVMs and recurrence of angina. Persistent GI bleeding despite FEIBA prophylaxis and a negative FV inhibitor prompted an attempt at antiangiogenic therapy (thalidomide, 50 mg orally daily). For 4 months he experienced no major bleeding. However, constipation prompted transient discontinuation of thalidomide, with recurrence of GI bleeding that led to anaemia and a non–ST-segment elevation myocardial infarction. Thalidomide was restarted after the myocardial infarction in early 2010. For 6 months he had two bleeds that required FEIBA and intensive transfusion of pRBCs, in addition to endoscopic argon plasma cauterization treatment achieving coagulation of the single visible jejunal vascular lesion. Thereafter, no bleeding occurred, despite tapering and completely discontinuing FEIBA, with no pRBC transfusion or FEIBA in the ensuing 1.5 years. The most recent jejunal bleeding in December 2011 was treated endoscopically, along with pRBCs and two units of FFP but no FEIBA. He is currently receiving thalidomide 50 mg day−1 and is under medical management and lifestyle modification given his severe coronary artery disease. Treatment of FV deficiency and inhibitors has two objectives: controlling acute haemorrhagic events while the inhibitor is present and attempting to eliminate the antibody. For GI bleeding, after initial stabilization, source control is more likely to resolve the bleeding than is exclusive haemostatic management 3. This is illustrated in our case, in which endoscopic treatment and haemostatic management with bypassing agents and antifibrinolytics failed to decrease the frequency and severity of haemorrhagic episodes. For patients without coagulopathy and multiple vascular intestinal malformations who present with recurrent, intractable GI bleeding, varying degrees of success have been achieved with hormonal treatment, somatostatin and antiangiogenic treatment 1, 4, 5. In our patient's case, hormonal treatment with danazol was transiently successful at decreasing the frequency of bleeding, but medication compliance was poor. Coinciding with the results from the open-label trial by Ge et al. 6, who showed a 1-year response rate of 71.4% with thalidomide vs. 3.7% with placebo, antiangiogenic treatment with thalidomide has been most successful at combining adequate efficacy and tolerability of adverse effects in this case. Given the large volume of transfused FFP required to attempt immunotolerance induction with high-dose factor, this was not a viable option for inhibitor treatment in our patient 2. Instead, alternative treatment with high-dose corticosteroids decreased the inhibitor titre, and remission was later achieved with four doses of rituximab therapy. Treatment directed at the underlying lesions leading to the recurrent GI bleeding has been the most effective modality for the management of this complex condition. Other antiangiogenic agents such as lenalidomide and vascular endothelial growth factor inhibitors are options that may be required in the future if thalidomide therapy fails or if untenable adverse effects develop. Dr Perez Botero analysed the data and wrote the paper; Dr Burns provided clinical care, data and contributed to writing the paper; Dr Thompson collected the data, provided clinical care and contributed to writing the paper; Dr Pruthi collated the data, provided clinical care and contributed to writing the paper. The authors stated that they had no interests which might be perceived as posing a conflict or bias.