Potential mechanisms of resistance to current anti-thrombotic strategies in Multiple Myeloma

Abstract

Multiple Myeloma (MM) is a common haematological malignancy that is associated with a high rate of venous thromboembolism (VTE) with almost 10% of patients suffering thrombosis during their disease course. Recent studies have shown that, despite current thromboprophylaxis strategies, VTE rates in MM remain disappointingly high. The pathophysiology behind this consistently high rate of VTE is likely multifactorial. A number of factors such as anti-thrombin deficiency or raised coagulation Factor VIII levels may confer resistance to heparin in these patients, however, the optimal method of clinically evaluating this is unclear at present, though some groups have attempted its characterisation with thrombin generation testing (TGT). In addition to testing for heparin resistance, TGT in patients with MM has shown markedly varied abnormalities in both endogenous thrombin potential and serum thrombomodulin levels. Apart from these thrombin-mediated processes, other mechanisms potentially contributing to thromboprophylaxis failure include activated protein C resistance, endothelial toxicity secondary to chemotherapy agents, tissue factor abnormalities and the effect of immunoglobulins/“M-proteins” on both the endothelium and on fibrin fibre polymerisation. It thus appears clear that there are a multitude of factors contributing to the prothrombotic milieu seen in MM and further work is necessitated to elucidate which factors may directly affect and inhibit response to anticoagulation and which factors are contributing in a broader fashion to the hypercoagulability phenotype observed in these patients so that effective thromboprophylaxis strategies can be employed.

The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies

“…Bradbury et al reported on the thrombosis rates observed in the Myeloma IX and Myeloma XI phase 3 trials and disappointingly, thrombosis incidence rates at 6 months remained >10% in the later trial despite much higher rates of thromboprophylaxis (80.5% vs. 22.3%) 25 . The reasons behind this failure are not fully understood but are likely multifactorial 27 . Some studies have proposed the possibility of “heparin resistance” in MM and have sought to evaluate the role of thrombin generation testing, a test of global hemostasis, to evaluate heparin efficacy in MM disease but results have been conflicting thus far 28,29 …”

“…25 The reasons behind this failure are not fully understood but are likely multifactorial. 27 Some studies have proposed the possibility of "heparin resistance" in MM and have sought to evaluate the role of thrombin generation testing, a test of global hemostasis, to evaluate heparin efficacy in MM disease but results have been conflicting thus far. 28,29 A number of internationally validated and clinically utilized risk scores have been developed to stratify VTE risk in patients with solid tumors who may benefit from thromboprophylaxis with anticoagulant agents.…”