Plasma Thrombin Generation and Sensitivity to Activated Protein C Among Patients With Myeloma and Monoclonal Gammopathy of Undetermined Significance

Abstract

The etiology of the prothrombotic state in myeloma has yet to be definitively characterized. Similarly, while recent evidence suggests that patients with monoclonal gammopathy of undetermined significance (MGUS) may also be at increased risk of thrombosis, the magnitude and the etiology of this risk have also yet to be defined. The present study aims to characterize patterns of plasma thrombin generation and sensitivity to the anticoagulant activity of activated protein C (APC) at the time of initial diagnosis of myeloma and in response to therapy in comparison to that observed among patients with MGUS and matched, healthy volunteers. Patients presenting with newly diagnosed/newly relapsed myeloma (n = 8), MGUS (n = 8), and matched healthy volunteers (n = 8) were recruited. Plasma thrombin generation was determined by calibrated automated thrombography. Peak thrombin generation was significantly higher in patients with myeloma (383.4 ± 33.4 nmol/L) and MGUS (353.4 ± 16.5 nmol/L) compared to healthy volunteers (276.7 ± 20.8 nmol/L; P< .05). In the presence of APC, endogenous thrombin potential was significantly lower in control plasma (228.6 ± 44.5 nmol/L × min) than in either myeloma (866.2 ± 241.3 nmol/L × min, P = .01) or MGUS plasma (627 ± 91.5 nmol/L × min, P = .003). Within the myeloma cohort, peak thrombin generation was significantly higher at diagnosis (353.2 ± 15.9 nmol/L) than following completion of the third cycle of therapy (282.1 ± 15.2 nmol/L; P < .005). Moreover, sensitivity to APC increased progressively with each cycle of chemotherapy. Further study of the etiology and evolving patterns of hypercoagulability among patients with these conditions is warranted and may have future implications for thromboprophylaxis strategies.

The hypercoagulable state in multiple myeloma: The contribution of thrombin generation test

“…With 1 PM TF, no significant difference was found between patients with and controls, which was in agreement with Leiba et al study comparing 13 patients to 14 controls . However, Crowley et al demonstrated an increase in TG in patients with MM, attested by a significantly higher peak thrombin in 8 patients compared with 8 controls …”

“…In addition, Tiong et al observed a significant acceleration of TG in 15 patients during treatment, attested by a significant increase in velocity index at 2 months of MM therapy compared with baseline . In contrast, in Crowley et al study including 10 patients before and during myeloma treatment (at 1, 2, and 3 months), thrombin generation was significantly decreased during treatment, as evidenced by a significant decrease in peak thrombin at 3 months of treatment compared with baseline . Similarly, Undas et al also demonstrated a significant decrease in peak thrombin at 3 months of treatment in 48 patients …”

Thrombin generation in newly diagnosed multiple myeloma during the first three cycles of treatment: An observational cohort study

“…16 In addition, we did not consistently find higher baseline values of either ETP or peak thrombin in patients with nMM compared to those reported in patients with monoclonal gammopathy of undetermined significance and healthy controls. 15,[17][18][19] The coagulability associated with nMM therefore remains an enigma.…”

“…The third limitation concerns the way in which we evaluated TG. In particular, TG assessment under conditions sensitive to the protein C inhibitor system (with addition of exogenously activated protein or thrombomodulin) and/or with the use of different concentrations of TF, might have given different results. Notably, we did not find any differences in TG determined in the presence of platelets (PRP) as opposed to their absence (PPP).…”

Multiple Myeloma and Thrombosis: Prophylaxis and Risk Prediction Tools

“…Thrombin generation (TG) is being increasingly studied by many groups who perform measurements at baseline and during treatment as well as explore the association with VTE occurrence. Most groups have reported abnormal TG in multiple parameters of the assay compared to healthy controls [56,57]. Data is variable and difficult to compare across studies as different TG assays have been used as well as different TG trigger concentrations and phospholipid reagents.…”