The challenge of myeloma-related thromboembolic disease: can thrombin generation assay help physicians to better predict the thromboembolic risk and personalize anti-thrombotic prophylaxis?

Venous thromboembolism (VTE) is a major complication of multiple myeloma (MM), occurring in 10% of patients. The VTE risk is increased when lenalidomide is used in combination with high-dose dexamethasone [1]. While the guidelines recommend thromboprophylaxis for high-risk medical patients, there is no validated risk stratification tool, along with serious uncertainty concerning optimal thromboprophylaxis. Hence, it proves to be a real challenge to both identify the individual VTE risk of each MM patient and personalize their thromboprophylaxis strategy. Thrombin, a key coagulation enzyme, is the ultimate product of the coagulation cascade that has the power to amplify and regulate hemostasis while transforming fibrinogen into fibrin. The overall real-time coagulation kinetics of thrombin formation in platelet-rich plasma (PRP) or platelet-poor plasma (PPP) samples is assessed by means of the thrombin generation assay (TGA) [2]. While this test has so far been primarily applied in specialized research laboratories, it has recently undergone significant improvement, rendering it likewise accessible to clinical laboratories. When using TGA, testing results correlated with the clinical risk of bleeding or thrombosis in patients with hereditary coagulation disorders. Hence, high TGA levels were shown to predict recurrent thrombosis, and in all congenital or acquired conditions associated with enhanced thrombosis risk, these levels were proven increased [3,4]. In addition, with antithrombotic treatment, TG was revealed to diminish proportionally to the treatment’s intensity. The TGA is likely able to identify MM patients at highest risk of VTE and can be used to individually tailor patient thromboprophylaxis within effective and safe limits. This pilot study sought to assess the calibrated automated TGA’s ability to detect MM-related hypercoagulability, comparing TG capacity of patients receiving lenalidomide in association with three different antithrombotic agents. Overall, 106MM patients and 89 healthy adult controls were included in the study, after having given their informed consent. The mean patient age was 67.8 ± 8.9 years, with 67 males and 39 females, of whom 53 patients had newly diagnosed Durie Salmon stage 1MM and 53 had Durie Salmon stage 2 or 3MM. Among them, 12 were receiving lenalidomide-dexamethasonebased therapy, 15 lenalidomide-dexamethasone and warfarin (INR between 2 and 3), six lenalidomide-dexamethasone and prophylaxis with low molecular weight heparin (LMWH), while the remaining 20 were given lenalidomide-dexamethasone and aspirin 100mg per day. Patients on warfarin had a personal history of recurrent VTE, those receiving LMWH prophylaxis exhibited the personal history of single VTE or known thrombophilia, while those on aspirin prophylaxis had no personal history of thrombosis and no thrombophilia. Blood was taken using a 21-G needle with a light tourniquet into S-Monovette tubes (Sarstedt, Orsay, France) containing 0.106mol/L trisodium citrate (1:9,v:v) with corn trypsin inhibitor (CTI; Haematologic Technologies Inc., Essex Junction, VT) at a concentration of 1.45 mmol/L in whole blood. Following double centrifugation at 2500 g for 15min at room temperature, PPP was collected from the upper half of the plasma supernatant; PRP was obtained by centrifugation at 150 g for 10min at room temperature, with collection from the upper half of the PRP fraction. The platelet count was systematically adjusted to 150 10/L with autologous PPP. PRP was prepared within 30min after venipuncture, and TG was immediately measured in fresh PRP. TG was assessed using the calibrated automated TGA, as previously described, with a low concentration of tissue factor at 1 pM in both PPP and PRP [2]. Some plasma samples were discarded because of unsuitable pre-analytical conditions. In patients on LMWH prophylaxis, samples were collected 4–6 h after the administration.