Patients with multiple myeloma and monoclonal gammopathy of undetermined significance have variably increased thrombin generation and different sensitivity to the anticoagulant effect of activated protein C

Abstract

Background: Patients with multiple myeloma (MM) are at high risk of thrombosis especially when receiving immunomodulatory therapy. Thrombotic risk in patients with monoclonal gammopathy of undetermined significance (MGUS) may also be increased. Although activated protein C (APC) resistance has been linked to an increased risk of thrombosis in MM, little is known about how APC influences thrombotic risk in MGUS. We compared thrombin generation (TG) in MM and MGUS patients to that of healthy controls (HCs) and investigated the exogenous effect of APC on TG in these groups.

Methods: Hemostasis tests including factor VIII (FVIII) and von Willebrand factor (vWF) levels were measured in platelet-poor plasma in 14 untreated MM patients, 34 MGUS patients, and 30 age and sex-matched HCs. TG assay was performed with or without the addition of APC.

Results: Peak thrombin and velocity index were significantly higher in MM and MGUS patients compared to HCs, while MM patients also had elevated endogenous thrombin potential (ETP). In MGUS cases, ETP and peak thrombin values significantly correlated with FVIII and vWF levels. In the presence of APC, peak thrombin and ETP were reduced in MGUS and control plasmas whereas lagtime and time to peak were significantly prolonged. In contrast, adding APC to MM plasma had no effect on any TG parameters.

Conclusions: Hypercoagulability was observed in MM and even in MGUS cases with very low monoclonal protein concentration. In MM patients, APC had no effect on TG, but it attenuated TG in MGUS patients.

Keywords: Activated protein C; Monoclonal gammopathy of undetermined significance; Multiple myeloma; Thrombin generation; Thrombosis.