Direct thrombin inhibition by paraprotein in multiple myeloma: A rare mechanism of paraprotein-mediated coagulopathy, corrected with myeloma therapy

Abstract Background Paraproteins, in monoclonal gammopathies, may lead to a range of coagulopathies. Direct thrombin inhibition from a paraprotein is rare, previously only reported in one case. We present a case of IgG kappa multiple myeloma (MM) in which the monoclonal protein led to coagulopathy, characterized as a direct inhibitor of fibrinogen cleavage by thrombin. The coagulopathy resolved with treatment of the myeloma. Case Presentation A 54-year-old woman whose only past medical history was an unexplained peripheral neuropathy presented with an elevated aPTT (48.9 seconds) and a normal PT/INR on pre-operative evaluation for elective surgery. The patient had no bleeding history. Over the subsequent year, the patient was diagnosed with smoldering myeloma. An IgG kappa M spike was 1.40 g/dL, free kappa light chain was 519.9 mg/dL, and κ/λ ratio was 114 (normal ratio 0.26 to 1.65). Bone marrow biopsy was hypercellular (70%) with 30% plasma cells. This met the SLiMCRAB criteria for MM. Her coagulopathy progressed with time, with peak aPTT of 65.6”. The PT/INR remained normal or minimally elevated (peak PT was 15.8” and INR was 1.3). The initial aPTT mixing studies failed to normalize; non-incubated 1:1 mix was 37.2” (normal 23.4 -36.0”) and 40.3” after incubation at 370C, consistent with an inhibitor. The fibrinogen functional level was 375 mg/dL, and the fibrinogen antigen was 314 mg/dL. Factor VIII, IX, XI, and XII levels were within normal limits and anticardiolipin antibodies were negative. The thrombin time was markedly elevated (68.6”, normal 14.2-19.2”). The aPTT and thrombin time were not improved with heparin neutralization. She had a normal reptilase time (13.5”, normal 11.2-18.6”) on multiple measurements. These studies, collectively, indicated an effect on thrombin cleavage of fibrinogen, presumably as the result of the paraprotein. Despite lack of clinical bleeding, her progressively abnormal coagulation parameters were judged to pose a risk. Myeloma-directed therapy was started with daratumumab, carfilzomib, lenalidomide, dexamethasone (Dara-KRd). After one cycle, the M-protein declined to undetectable, κ/λ ratio normalized (1.19), and she achieved a stringent complete response (sCR) by International Myeloma Working Group criteria. All coagulation parameters normalized as well. She remains in remission on maintenance lenalidomide with no return of coagulopathy at 12 months. Her peripheral neuropathy has not improved. Conclusion This case illustrates a rare mechanism of paraprotein-related coagulopathy, beginning during the smoldering myeloma phase. The normal fibrinogen functional and antigen levels, which are closely aligned, and the normal reptilase time are consistent with a normal fibrinogen protein. The markedly elevated thrombin time, aPTT, and positive mixing studies led us to conclude that the monoclonal IgG kappa paraprotein directly inhibited thrombin cleavage of fibrinogen. This paraprotein-related coagulopathy has only been reported once and without description of response to treatment (Chapman G.S, et al, AJCP, 1985). The progressive coagulopathy prompted the decision to initiate myeloma directed treatment, which led to stringent complete response and normalization of the coagulation parameters. This report helps guide the evaluation and therapeutic decision making in rare paraprotein induced coagulopathies.