Thrombin generation profiling in multiple myeloma: a comprehensive evaluation of prothrombotic state

Objective: Venous thromboembolism is a major complication in patients with multiple myeloma (MM), with treatment strategies further increasing thrombotic risk. Conventional coagulation tests (CCT) fail to reflect the in vivo hemostatic balance, whereas thrombin generation assay (TGA) provides a global assessment of thrombin dynamics and may better identify hypercoagulable states in MM. Methods: To this aim, to evaluated thrombin generation, we enrolled 20 MM patients during follow-up while receiving active MM-treatment: sixteen had immunoglobulin G (IgG) MM, one immunoglobulin A (IgA) MM, one light-chain MM, and two biclonal MM (IgG and IgA). Citrated blood samples were collected under standardized conditions for CCT and TGA. Thrombin generation was measured in platelet poor plasma, both in the absence and presence of thrombomodulin (TM) using the ST Genesia system. Results: TGA revealed increased peak height (139.75%; r.v. 40-69%), endogenous thrombin potential (107.80%; r.v. 58-78%), and velocity index (153.10%; r.v. 31-62%), along with shortened time to peak (ratio 1.04; r.v. 1.2-1.5). Notably, TM-mediated inhibition of thrombin generation was reduced (16.20%; r.v. 60-76%), indicating protein C pathway dysfunction despite preserved natural anticoagulant levels. This procoagulant state was further supported by elevated fibrinogen and D-dimer, together with increased factor VIII and von Willebrand levels. Conclusion: Our findings confirm a hypercoagulable state in MM patients, likely related to endothelial injury and systemic inflammation. Impairment of the protein C pathway, as highlighted by TGA, further contributes to this imbalance. In light of the limitations of prothrombin time and activated partial thromboplastin time, TGA provides a more sensitive and informative evaluation of coagulation dynamics in MM patients.