Diagnostic and therapeutic challenges in rare hematologic entities: monoclonal gammopathy of thrombotic and bleeding significance.

Monoclonal gammopathies encompass a spectrum of clonal B-cell or plasma cell disorders characterized by the production of a monoclonal immunoglobulin. While most cases remain asymptomatic, certain clones can elicit organ or tissue injury through distinct pathogenic mechanisms, leading to the concept of monoclonal gammopathy of clinical significance (MGCS). Among the least recognized but clinically important MGCS entities are monoclonal gammopathy of thrombotic significance (MGTS) and monoclonal gammopathy of bleeding significance (MGBS), in which the M-protein directly interferes with hemostatic pathways, resulting in thrombosis or bleeding. These conditions remain underdiagnosed due to their heterogeneous clinical presentations and challenges in establishing causal relationships between the paraprotein and hemostatic abnormalities. MGTS and MGBS encompass diverse mechanisms, including cryoprotein formation, complement activation, coagulation factor inhibition, and von Willebrand factor or platelet dysfunction. Currently, there are no standardized diagnostic criteria or evidence-based treatment recommendations, and the role of anti-clonal therapy remains undefined. This perspective outlines an ongoing multinational initiative under the auspices of the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee (ISTH SSC) Subcommittee on Cancer-Associated Thrombosis and Hemostasis, aiming to define diagnostic pathways, propose classification and treatment criteria, and identify patients who may benefit from targeted therapies. A unified framework will improve recognition, diagnosis, and management of these rare yet clinically significant entities.