Acquired Hemophilia A (AHA) associated with monoclonal gammopathy: A single institution case series Free

Case 1:

A 68-year-old woman with IgA lambda monoclonal gammopathy of undetermined significance (MGUS) and beta thalassemia minor presented with persistent bleeding from a CT-guided bone marrow biopsy. Imaging showed a right gluteal hematoma with active bleeding. Initial Hb was 7 g/dL, dropping to a nadir of 3.9 g/dL. As a Jehovah's Witness, she declined transfusions and was managed with IV iron. aPTT was prolonged at 91.8 secs with no heparin exposure. Mixing study showed incomplete correction and further prolongation with incubation. Factor VIII activity was <1%, with Factor VIII inhibitor detected at level of 83.2 BU/mL. She was treated with NovoSeven, corticosteroids, and Rituximab. Bleeding resolved, and she was discharged on Hemlibra. She completed 4 weeks of Rituximab, tapered off steroids. No further bleeding occurred, and the factor inhibitor resolved.

Case 2:

An 83-year-old man with IgG kappa MGUS presented with gross hematuria and a right antecubital fossa hematoma detected on ultrasound. Labs showed Hb 7.1 g/dL (baseline 9) and a prolonged aPTT of 91.9 secs with incomplete correction on mixing study. Further work up revealed Factor VIII activity <1% with an inhibitor level of 62 BU/mL. Bleeding resolved with Novoseven, corticosteroids, and weekly Rituximab. He was transitioned to Hemlibra, completed 4 doses of Rituximab and tapered off with complete resolution of the inhibitor.

Case 3:

An 80-year-old female with IgG lambda MGUS presented with a spontaneous and enlarging left upper thigh hematoma with active extravasation, requiring IR guided embolization and multiple units of blood transfusions. Work up was significant for prolonged aPTT with incomplete correction on mixing study and factor VIII levels <1%. Factor VIII inhibitor level was detected at 31 BU/mL and she was started on corticosteroids, Rituximab and Novoseven with resolution of bleeding. She was subsequently transitioned to Hemlibra.

Discussion: Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder caused by inhibitors against clotting factor VIII, leading to potentially severe bleeding. About 50% of cases are idiopathic, with around approximately 10% linked to malignancies. While infrequently seen in plasma cell dyscrasias, Decaux et al demonstrated ex vivo that monoclonal proteins produced by myeloma cells can act as factor VIII inhibitors, leading to associated bleeding complications in a patient with smoldering multiple myeloma.

MGUS, a premalignant plasma cell disorder, is classically associated with thrombotic complications and acquired von Willebrand disease but is rarely implicated in bleeding diatheses. Although AHA has been reported in multiple myeloma and smoldering myeloma, its association with MGUS is exceedingly rare, with only two prior cases reported in literature.

We present the first single-institution case series of AHA in association with MGUS, highlighting the importance of maintaining heightened clinical suspicion in patients with unexplained bleeding, prolonged aPTT, and a known or new monoclonal gammopathy.

An interesting and significant observation in these cases is that despite the typically low monoclonal protein levels in MGUS, it is linked with the production of factor VIII inhibitors at titers high enough to cause clinically significant bleeding. This suggests that even minimal clonal plasma cell activity, characteristic of MGUS, can cause significant immune dysregulation leading to severe autoimmune complications like AHA.

Although MGUS typically requires no treatment, persistent or refractory bleeding with sustained inhibitor levels may warrant myeloma directed therapy targeting the plasma cell clone. Hence further awareness about of this novel association could also inform the treatment strategies in patients not responding to initial measures.