Monoclonal gammopathies of thrombotic and hemorrhagic significance: mapping into a classification schema

Monoclonal gammopathies of clinical significance represent a heterogeneous spectrum of nonmalignant disorders that may involve multiple organ systems or remain organ restricted. These conditions are driven by circulating monoclonal proteins (monoclonal immunoglobulin [MIg]) secreted by small, often indolent, B cell or plasma cell clones. Accumulating evidence has demonstrated that MIg may possess both thrombogenic and hemorrhagic potential, mediated through complex and multifactorial interactions with coagulation pathways, platelets, and the vascular endothelium. In this review, we critically appraise the spectrum of hemostatic complications associated with monoclonal gammopathies, encompassing entities such as amyloidosis, cold agglutinin disease, M protein-associated antiphospholipid antibody syndrome, antiplatelet factor 4 antibody-mediated disorders, and thrombotic microangiopathies, among others. Given their substantial clinical burden and frequent under recognition, we propose that these MIg-driven hemostatic disorders be classified separately as monoclonal gammopathies of thrombotic/hemorrhagic significance, encompassing both thrombotic and hemorrhagic subtypes. We additionally outline a proposed diagnostic approach emphasizing systematic evaluation for alternative etiologies, characterization of the monoclonal protein, and assessment for clinical, laboratory, and treatment-response features supporting pathogenic attribution. Establishing such a nosological framework highlights the clinical importance of these conditions and underscores the need for systematic recognition, diagnostic evaluation, and multidisciplinary management of these often overlooked but clinically consequential entities.