Acquired Hemophilia Associated with Smoldering Myeloma: Demonstration That the Monoclonal Gammopathy Acts as the Factor VIII Inhibitor.
Authors: Decaux Olivier , Guillet Benoit , Millet Arnaud , Harding Stephen , Bradwell Arthur R. , Grosbois Bernard , Jego Patrick 
Published: October 2019

Abstract
Abstract 1307
Poster Board I-329
A 44 years old woman presented with metrorrhagia. Coagulation tests revealed a prolongation of activated partial thromboplastin time up to 77 seconds (control 33 seconds) which could not be corrected by mixing with normal plasma. The factor VIII activity level was reduced to 0.06 IU/mL. The Bethesda assay demonstrated the presence of a factor VIII inhibitor at 29 Bethesda units per ml (BU/mL). Other coagulations studies were within the normal ranges. Serum protein electrophoresis revealed a monoclonal band in the gamma region. IgA kappa monoclonal gammopathy was confirmed by immunofixation. The concentration of IgA kappa was 2.1 g/L. The haemoglobin level was 13.1 g/dL, creatininemia 80 μmol/L and calcemia 2.38 mmol/L. Standard bone X Rays and MRI of spine showed no lytic bone lesions. Bone marrow aspiration showed 11% plasma cell infiltration. A diagnosis of IgA kappa smoldering multiple myeloma associated with acquired hemophilia was made. The patient initially received four Rituximab infusions without significant effect. Several episodes of moderate uterine bleedings were treated with recombinant activated Factor VII infusions. It is noteworthy that she never had any other bleeding. Finally, electrocoagulation of endometrium definitively stopped metrorrhagia despite persistence of factor VIII inhibitor activity. Given that the acquired haemophilia was no longer symptomatic and that there were no other complications associated with multiple myeloma no specific treatment of multiple myeloma was proposed. To investigate the link between the IgA kappa smoldering myeloma and the factor VIII inhibitor activity, polyclonal antibodies that are specific for IgA kappa or IgA lambda were used ex vivo. These antibodies target unique conformational epitopes located at the junctions of heavy chains and light chains of immunoglobulins (Binding Site Group Ltd). Bethesda assay was performed on patient's plasma diluted at 1/30 (patient's monoclonal IgA kappa final concentration: 0.07 g/L) mixed with either anti IgA kappa or anti IgA lambda antibodies (final concentration: 2.5 g/L). The anti factor VIII activity was decreased with addition of anti IgA kappa antibody (7.2 UB/ml) but not with anti IgA lambda antibodies (24 UB/ml). We confirmed these results by using a Polyethyleneglycol (PEG) precipitation step. Patient's plasma was mixed with anti IgA Kappa antibodies (final concentration 9.2 g/L) and PEG (3%). After centrifugation, the anti factor VIII inhibitor activity in supernatant was totally suppressed (< 0.4 UB/mL). As a control, the titre was unchanged (24 BU/mL) when anti IgA Lambda were used following the same protocol. These results suggest that the IgA monoclonal protein is responsible of factor VIII inhibitor activity.
Acquired hemophilia is a rare autoimmune disorder in which the patients develop an autoantibody directed against coagulation factor VIII leading to a clinically significant bleeding diathesis. In 50% of the cases there is no detectable underlying disease; however in 10% of cases there is an association with an underlying malignancy, either solid or haematological. Concurrent acquired hemophilia and monoclonal gammopathy is rare and few reports have associated monoclonal proteins to factor VIII inhibition but without any in vitro confirmation. In this report, we described a case of an IgA kappa smoldering myeloma patient who presented with an acquired haemophilia and demonstrated that the IgA monoclonal protein was acting as the factor VIII inhibitor. A broad range of autoimmune phenomena frequently complicate hematologic malignancies and acquired hemophilia is considered to be the consequence of immune deregulation with usually oligoclonal anti-Factor VIII profile. Understanding of the underlying pathogenic mechanisms responsible for the acquired haemophilia could help to optimize treatment management. To the best of our knowledge, this is the first report of multiple myeloma associated acquired hemophilia with demonstration that monoclonal gammopathy could be responsible of factor VIII inhibitor activity.

Disclosures
Harding: The Binding Site Group Ltd: Employment. Bradwell:The Binding Site Group Ltd: Chairman.