Monoclonal gammopathy-related coagulopathies: A systematic analysis

Abstract Background: Monoclonal Gammopathy (MG)-related coagulopathies have been described in several case reports and small series involving multiple myeloma and other lymphoplasmacytic/plasma cell dyscrasia disorders and occur from a variety of mechanisms. To our knowledge, there are no systematic evaluations of the frequency, clinical associations, and underlying mechanisms of paraprotein induced coagulopathy in a cohort of patients with such disorders. Methods: We reviewed the 3,657 patients diagnosed with a MG over a ten-year period (5/2015-5/2025) at a single academic cancer center. Cases included MG of undetermined significance (MGUS), smoldering (SMM) and multiple myeloma (MM), AL amyloidosis, lymphoplasmacytic lymphoma (LPL), and marginal zone/splenic B-cell lymphoma. Cases were screened for elevated PT/INR (INR>1.3) and/or aPTT (>38.0) at presentation, and/or had a coagulation factor assay performed. This resulted in a total of 599 cases for detailed review. Results: Fifteen cases (0.41% of total cohort) had a coagulopathy that was attributable to the MG. Of these cases, coagulopathies were found in 6 patients with MM, 4 with MGUS, 2 with AL amyloidosis, 1 with LPL, 1 with splenic B-cell lymphoma, and 1 with marginal zone lymphoma. Four of the 15 cases presented with overt bleeding, which included muscle hematoma (n=2), hematochezia (n=1), and oral bleeding (n=1). The remaining 11 cases were diagnosed through abnormal coagulation laboratory analysis without overt bleeding. Nine of the cases had factor deficiency (von Willebrand Disease: n=4, factor X: n=4, factor VIII: n=1). Four had antiphospholipid antibody syndrome (APS), one had a direct thrombin inhibitor, and one had a mixed pattern (factor VIII deficiency and APS). Three of the factor X deficiency cases were in the context of known, or clinically suspected AL amyloidosis, while one patient with MM had a strong factor X inhibitor and no evidence of AL amyloidosis. Two-thirds of the cases had a kappa light-chain MG (n=10), consistent with the typical proportion in MG patients. Among the 11 cases with a heavy chain immunoglobulin component, IgM elevation occurred in 6 cases, and IgG in 5. Interestingly, all 4 of the APS cases were IgM (2 kappa and 2 lambda). The mean monoclonal protein level among cases with quantifiable spikes (n=11) was 1.48 g/dL. The majority of cases (n=10) underwent treatment for the underlying hematologic disorder. Half of the treated patients experienced a complete resolution of the coagulopathy (n=5), 2 cases demonstrated a partial improvement, and 3 cases had persistent coagulopathy despite treatment. No deaths were attributed to coagulopathy in these patients. Conclusions: To our knowledge, this is the first systematic evaluation of MG-related coagulopathies across a large population of lymphoid/plasmocytic neoplasms. Also unique to our study is the description of coagulopathy outcomes following treatment. Our findings reveal a spectrum of coagulation targets with implications for diagnosis and therapeutic decision-making.Treatment of the underlying disorder resulted in complete or partial improvement of the coagulopathy in most but not all cases. There was no specific pattern of IgG verus IGM, or kappa versus lambda light chain. Early recognition and consideration of treatment may prevent bleeding complications and improve coagulopathy in similar cases.