Abstract
Thalidomide has emerged as a promising treatment for multiple myeloma (MM). Thrombosis is the most serious complication of thalidomide therapy, essentially when it is combined with dexamethasone. The pathogenesis of thrombosis in MM patients (pts) treated with thalidomide is not clear and probably of multi factorial origin. We used the Thrombin Generation test (TGT) and measured the plasma levels of soluble thrombomodulin (sTM) to better clarify the MM-related and thalidomide-related thrombogenicity. TGT was performed in citrated frozen platelet poor plasma (PPP). Blood was obtained from 26 MM pts, Salmon and Durie stage II and III, 62.5 years old (42–77), 9 males and 17 females, 10 treated with thalidomide (100–200mg/d orally) and dexamethasone (40mg/d for 4 days) (TD group) and 16 receiving no treatment (MM group). 13 healthy volunteers formed the control group. Thrombin Generation (TG) was initiated by adding the PPP reagent (Thrombogram-Thrombinoscope®) and the triggering solution (CaCl2 and fluorogenic substrate). We analyzed the endogenous thrombin potential (ETP), the Cmax and the velocity index of TG. The plasma levels of sTM in PPP were measured by a specific ELISA (Diagnostica Stago, France). In the MM group we observed an increase of the ETP, though not significant compared to the controls. The Cmax was almost equal to the control group value, while the velocity index of TG was statistically lower in the MM group compared to controls. In the TD group, a statistically significant increase of ETP was observed as compared to the control group. The Cmax was higher, compared to controls, though not significantly, whereas the velocity index of TG was almost equal to the control group value. There was no significant difference in the TG parameters between MM and TD groups. sTM in the control group was 45±14ng/ml. Both groups of pts had significantly increased sTM plasma levels as compared to the control but the difference between the two groups did not reach significance. Results are shown in Table 1. In patients with MM coexists an increase of sTM, a marker of endothelial cell damage, together with an increased TG capacity. The addition of thalidomide treatment is associated with a slight but not significant increase of ETP and Cmax. The co-existence of endothelial cell damage with increased TG capacity could be associated to the increased thrombotic risk in MM patients treated with thalidomide. This hypothesis will be controlled in a prospective study.
Table 1: Thrombogram parameters and sTM plasma levels of studied pts. Control MM group TD group * Results significantly different between the MM and TD groups and the control group (p<0.05 vs the control group) ETP (nM×min) 1399±297 1651±478 1747±448* Cmax (nM) 366±54 342±52 402±99 Velocity Index (nM/min) 198±45 160±19* 184±65 STM (ng/ml) 45±14 84±42* 73±30*
Soluble Thrombomodulin Attenuates Endothelial Cell Damage in Hepatic Sinusoidal Obstruction Syndrome
