Induction therapy alters plasma fibrin clot properties in multiple myeloma patients

Abstract

Induction therapy in patients with multiple myeloma increases the risk of thromboembolism. We have recently shown that multiple myeloma patients tend to form denser fibrin clots displaying poor lysability. We investigated the effect of induction therapy on fibrin clot properties in multiple myeloma patients. Ex-vivo plasma fibrin clot permeability, turbidity, susceptibility to lysis, thrombin generation, factor VIII and fibrinolytic proteins were compared in 48 multiple myeloma patients prior to and following 3 months of induction therapy, mainly with cyclophosphamide-thalidomide-dexamethasone regimen. Patients on thromboprophylaxis with aspirin or heparins were eligible. A 3-month induction therapy resulted in improved clot properties, that is higher clot permeability, compaction, shorter lag phase and higher final turbidity, along with shorter clot lysis time and higher rate of D-dimer release from fibrin clots than the baseline values. The therapy also resulted in lower thrombin generation, antiplasmin and thrombin-activatable fibrinolysis inhibitor (TAFI), but elevated factor VIII. Progressive disease was associated with lower posttreatment clot permeability and lysability. Despite thromboprophylaxis, two patients developed ischemic stroke and 10 had venous thromboembolism. They were characterized by pretreatment lower clot permeability, prolonged clot lysis time, longer lag phase, higher peak thrombin generation, TAFI and plasminogen activator inhibitor -1. Formation of denser plasma fibrin clots with reduced lysability and increased thrombin generation at baseline could predispose to thrombotic complications during induction treatment in multiple myeloma patients. We observed improved fibrin clot properties and thrombin generation in multiple myeloma patients except those with progressive disease.

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

“…Current consensus guidelines recommend pharmacological thromboprophylaxis for subgroups of ambulatory patients with myeloma receiving treatment (provided the bleeding risk is favorable), although little evidence exists to guide duration of this therapy. 5,6 While the interpretation of our results is limited by the lack of a correlation with clinical outcomes, the suggestion that the thrombotic risk associated with active myeloma might diminish at an early stage of antimyeloma therapy reflects other recently published studies of evolving hypercoagulability in myeloma 47 and may have future implications for thromboprophylaxis strategies and patient risk stratification in this disease.…”

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

“…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 …”

“…It must be emphasized that during follow‐up, no thromboembolic events have been reported, except a symptomatic pulmonary embolism in one patient which occurred at diagnosis. However, the overall rate of thrombotic events during MM treatment varied between 10% and 25% depending on the series despite the thromboprophylaxis …”

“…So, TG has no role in the outcome of patients with MM and cannot be considered as a prognostic factor. Only one study has been documented on the evaluation of TG in patients with MM according to therapy response, demonstrating a significantly higher peak thrombin in 7 patients with progressive disease compared with 29 patients with a partial or complete response after 3 months of treatment …”

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

“…A low concentration of TF was used to maximize the possibility of evidencing hypercoagulability while taking into account factor VIII levels, which are known to be high and even very high in patients with MM 27,28. The predisposition of patients with MM to thrombosis could be due to changes in endothelium, leukocytes, fibrin structure and lysis,29,30 which are not captured by TG studies. Incidence of thromboembolic events, acute cardiovascular events and bleeding…”