Acquired hemophilia: We now see it with myeloproliferative neoplasms
Authors: Marina Kremyanskaya, Louis Aledort
Journal: American Journal of Hematology (2010)

Acquired hemophilia is an autoimmune disorder with acquired inhibitors to clotting factors resulting in a severe bleeding diathesis. Factor VIII is the most common factor involved and results from development of monoclonal autoantibodies against the A2 or C2 domain of factor VIII. Pathogenesis of inhibitor production is not well characterized, but it is associated with other autoimmune disorders and older age suggesting a generalized immune dysregulation. About half of the cases have no associated disorders, with other half being associated with other autoimmune disorders, malignancies, pregnancies, infections, or medications. Here, we report a case of a 74-year-old woman with Jak2+ essential thrombocythemia (ET), who developed an acquired factor VIII inhibitor. To our knowledge, this is the first case of known Jak2+ myeloproliferative neoplasm (MPN) complicated by acquired hemophilia. In this report, we also summarize other cases of acquired factor VIII inhibitors associated with hematologic malignancies, with specific focus on MPN. Majority of acquired hemophilia cases in patients with hematologic malignancies are associated with lymphoproliferative disorders, which is not surprising given the propensity of lymphoproliferative disorders for autoimmunity. This observation of acquired hemophilia in a patient with MPN suggests immune dysregulation also associated with myeloid cell dysfunction. A 74-year-old Caucasian woman presented to the Emergency Department with a 2-week history of left arm swelling and tenderness. She denied any trauma to the area. One week prior, she was evaluated by her primary care physician and treated for presumptive cellulitis with oral levofloxacin. The day prior to presentation, she also developed ecchymosis, edema, and tenderness in her right arm. She was referred to a hematologist, when she was noted to have a prolonged partial thromboplastin time (PTT) and an increased platelet count. Her CBC showed WBC of 13.9, Hemoglobin of 10.2, and platelet count of 1,000,000. Of note, she was recently diagnosed with Jak2+ essential thrombocythemia, which had not required treatment. Her past medical history was significant for hypothyroidism, macular degeneration, hypertension, and transient ischemic attack, 5 years ago. Her medications were synthroid, aggrenox, and hyzaar. On examination, the patient appeared to be in moderate distress from pain and anxiety. Her L arm showed diffuse echymoses, edema, and full range of motion of elbow, wrist, and fingers. Her R arm showed swelling of forearm with associated erythema, pain with passive extension of wrist and fingers, and limited range of motion due to pain of fingers and wrist. She was evaluated by plastic surgery and was thought to have evolving compartment syndrome of right forearm. On admission, her coagulation labs revealed a PTT 66.5 and a normal INR, and a mixing study demonstrated a circulating inhibitor. Her factor VIII level was found to be 4%, and Factor VIII inhibitor titer was 5.8 Bethesda units. The bleeding episode was treated with DDAVP to reverse the effect of aspirin in aggrenox, and activated prothrombin complex concentrate (aPCC), factor eight inhibitor bypassing agent (FEIBA), at 75 u/kg every 8 hr. A surgical intervention was successfully performed with a fasciotomy to relieve the impending compartment syndrome, while she was maintained on the above regimen. For antibody eradication, the patient was started on 60 mg prednisone per day. Within 3 days, her Factor VIII level was elevated to 12%. The patient was continued on FEIBA for a total of 5 days. She was discharged home on a steroid regimen. Within 5 weeks, her Factor VIII level had risen to 158%, and the prednisone was slowly tapered. In this report, we discuss a rare case of an acquired factor VIII inhibitor associated with a MPN. The patient was treated successfully with FEIBA and prednisone, with rapid rise in her factor VIII levels [1, 2]. Pathogenesis of inhibitor development is not well understood, but 50% of patients have associated co-morbidities. Approximately, 10% of patients with a factor inhibitor have an underlying malignancy [3]. The autoantibodies to factor VIII have been reported in various solid tumors, including prostate, colon, lung, breast, hepatobilliary, and glioblastoma [4]. Factor VIII inhibitor has also been associated with hematologic malignancies. Franchini et al. published a systemic review in 2008 of acquired factor VIII inhibitors associated with hematologic malignancies, which included a total of 30 cases [5]. Lymphoproliferative disorders appear to be most frequent hematologic malignancies in which inhibitors have been reported, with CLL being the most frequent diagnosis. This finding is not surprising as lymphoproliferative neoplasms are well known to be associated with a variety of autoimmune disorders. A number of cases were associated with therapeutic agents used to treat these malignancies, such as fludarabine and interferon. Treatment with fludarabine itself is known to be associated with autoimmune phenomena such as autoimmune hemolytic anemia and immune thrombocytopenic purpura [6]. Interferon is a known modulator of the immune system and is also associated with the development of autoimmune disorders [7]. What is interesting about this case is that this is one of the few cases of an autoimmune process associated with a myeloid neoplasm. While there is anecdotal evidence of increased prevalence of autoimmune disorders in MPN, there is not much literature published on this topic. A population-based study from Swedish Cancer Registry looking at 11,039 patients with MPN, showed a modest, but statistically significant risk of myeloproliferative neoplasms associated with prior autoimmune disease [8]. On the other hand, another population based case-control study using SEER-Medicare data in 13,486 patients with myeloid malignancies showed no statistically significant association between autoimmune conditions and chronic myeloproliferative disorders [9]. Further studies are needed to elucidate the complex relationship between myeloid neoplasm and autoimmunity. There are only a few reports of acquired factor VIII inhibitor associated with myeloproliferative neoplasms. In a case series of acquired hemophilia in eight patients with hematologic malignancies, Sallah et al. report one patient with myelofibrosis and one patient with myelodysplastic syndrome (MDS) as well as a case of lymphoma, multiple myeloma, and erythroleukemia [10]. There are two additional case reports of factor VIII inhibitor in MDS patients [11, 12]. There is also a single case report of an acquired factor VIII inhibitor in association with an overlap myeloproliferative/myelodysplastic disorder [13]. To our knowledge, this is a first report of Jak2+ MPN associated with an acquired factor VIII inhibitor and severe bleeding. While an association between ET and acquired von Willebrand syndrome (AVWS) has been established previously, the mechanism is thought to be completely different and does not involve an inhibitor. AVWS in ET is related to high number of platelets in circulating blood, causing loss of large vWF-multimers and resulting in bleeding [14]. Interestingly, while preparing this report, another patient followed in our institution for a MPN (primary myelofibrosis), developed spontaneous bleeding and was diagnosed with an acquired factor VIII inhibitor. These cases demonstrate that acquired factor VIII inhibitor must be considered in a patient with a myeloproliferative neoplasm and inappropriate bleeding, and proper laboratory evaluation should be carried out to rule out AVWS and acquired inhibitors.