Factor VIII Inhibitor: A Case Presentation Alice Hsu, MD

1. Factor VIII Inhibitor: A Case PresentationAlice Hsu, MD • DISCUSSION • HISTORY • Patients with Factor VIII inhibitor often present with • spontaneous intramuscular, mucosal, or post-operative • bleeding. • PHYSICAL EXAM • Clinical presentation is variable and includes large • hematomas or ecchymoses, epistaxis, hematuria, or GI • bleeding. Bleeding is often severe and patients can • become hemodynamically unstable. • DIAGNOSTIC TESTS • Check INR, PTT, CBC, fibrinogen, peripheral smear. • Rule out other causes of coagulopathy, including DIC, thrombocytopenia, or use of heparin products. • Image the site of suspected bleeding. • Perform a 1:1 mixing study for PTT, which will reveal the characteristic time dependent correction of PTT. Confirmatory tests include Factor VIII activity assay and Factor VIII inhibitor titer. • TREATMENT • Control active bleeding: • 1. Factor VIII infusion • 2. Factor VII infusion • 3. Factor eight inhibitor bypassing activity (FEIBA) infusion • 4. Desmopression • Eliminate Factor VIII inhibitor: • 1. Plasmapheresis • 2. Immunosuppressive agents • First line – prednisone, cyclophosphamide • Second line – rituximab, vincristine, cyclosporine, azathioprine • 3. Spontaneous recovery in 36% patients • 4. Identify and treat underlying cause DIAGNOSIS This patient was diagnosed with Factor VIII inhibitor. His elevated PTT prompted a 1:1 mixing study of PTT. The 1:1 mixing study of PTT showed a characteristic pattern of initial PTT correction at 0 seconds followed by prolongation of PTT at 60 seconds. This time dependent inhibition of Factor VIII is pathognomonic for the presence of a Factor VIII inhibitor. The patient also had markedly decreased Factor VIII activity and an elevated Factor VIII inhibitor titer. • OBJECTIVE • To present a case of spontaneous bleeding due to a rare • acquired coagulopathy. • INTRODUCTION • Factor VIII inhibitor, or acquired hemophilia A, is a rare disease that presents as spontaneous bleeding. IgG • autoantibodies against Factor VIII result in decreased Factor VIII activity, often leading to intramuscular, subcutaneous, or mucosal bleeds. Diagnosis is made with a 1:1 mixing study of PTT showing a characteristic time dependent inhibition of Factor VIII. Identifiable causes include age, pregnancy or postpartum states, rheumatologic disease, malignancy, and drug-induced effects. Greater than 50% of cases are idiopathic. Treatment includes control of active bleeding and • elimination of the Factor VIII inhibitor. • CASE PRESENTATION • A previously healthy 72 year-old male presented with a two week history of left leg weakness. On exam, he had distension and induration extending from the left flank down to the left thigh. Labs revealed a hemoglobin of 8.5mg/dL (unknown baseline hemoglobin) and an elevated PTT 47.8. A left leg doppler ultrasound was negative for deep vein thrombosis. A computed tomography of the abdomen and pelvis showed a retroperitoneal bleed and an intramuscular bleed of the left iliopsoas and iliacus muscles. A 1:1 mixing study of PTT revealed the presence of a Factor VIII inhibitor. Factor VIII inhibitor titer was elevated and Factor VIII activity was markedly decreased. Treatment with Prednisone, Factor VIII infusions, and Factor VII infusions plus rituximab did not improve his coagulopathy. Factor eight inhibitor bypassing activity (FEIBA -- inactive factors II, IX, X and active factor VII) infusions plus cyclophosphamide improved his coagulopathy. A positron emission tomography (PET) scan to evaluate for an underlying malignancy revealed a right thyroid nodule with increased metabolic activity. A biopsy of the nodule was not attempted due to high bleeding risk. The patient’s active bleeding eventually ceased and he was discharged home. He received multiple doses of chemotherapy with rituximab and cyclophosphamide as an outpatient. His most recent labs revealed resolution of the Factor VIII inhibitor. A biospy of his thyroid has not been obtained. TREATMENT There are two main treatment objectives: control of active bleeding and elimination of the Factor VIII inhibitor. The patient must first be stabilized with adequate IV access and blood products readily available for transfusion. Control of active bleeding can be achieved with Factor VIII, Factor VII, or factor eight inhibitor bypassing activity (FEIBA) infusions. Desmopressin can also be used to stimulate release of von Willebrand factor, which is a Factor VIII stablizer. Elimination of the Factor VIII inhibitor can be achieved by plasmapharesis or immunosuppressive agents such as prednisone, cyclophosphamide, or rituximab. Spontaneous recovery occurs in approximately 36% of patients. An underlying cause should be identified and treated, if possible. Figure 1. Clotting Cascade. Factor VIII and Factor IX join together to form Factor X-ase complex. Figure 2. Factor X-ase complex. Factor VIII IgG antibodies form against the A2 or C2 domain. REFERENCES Lollar P, Parker ET, Curtis JE, et al. Inhibition of Human Factor VIIIa by Anti-A2 Subunit Antibodies. J. Clin. Invest. 1994; 93: 2497. Coutre S. Acquired inhibitors of coagulation. UpToDate. Buczma A, Windyga J. Acquired haemophilia. Pol Arch Med. Wewn. 2007; 117: 1-5. Giangrande P. Acquired Hemophilia. Treatment of Hemophilia. 2005, 38: 1-5. Collins P, Hirsch S, Baglin TP, et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors’ Organisation. 2007; 109: 1870-1877 Figure 3. CT abdomen with intramuscular psoas bleed.