Pathogenesis and management of bleeding and thrombosis in plasma cell dyscrasias

Abstract

Summary Unexpectedly high rates of venous thromboembolic events (VTE) concurrent with the introduction of highly effective immune modulating drugs thalidomide and lenolidomide for treatment of multiple myeloma have focused attention on the incidence and underlying pathophysiology of VTE in patients with plasma cell dyscrasias, and on thromboprophylaxis approaches. While bleeding complications are relatively uncommon in patients with lymphoproliferative disorders, acquired von Willebrand syndrome, typically occurring in patients with monoclonal gammopathy of unknown significance, and acquired coagulopathies associated with primary amyloidosis can present with haemorrhagic complications and both are challenging to manage. This review highlights these important haemostasis‐related complications of plasma cell dyscrasias and provides an overview of other uncommon bleeding and thrombotic events that can affect diagnostic and therapeutic management of clonal plasma cell disorders. Due to the infrequency of most of these haemostasis complications, available information is typically based on retrospective cases or series.

The Incidence of Major Hemorrhagic Complications After Renal Biopsies in Patients with Monoclonal Gammopathies

“…Potentially, however, this could also relate to the higher serum concentrations of monoclonal free light chains likely to have been present in these patients (22). Coating of platelets with free light chains is one recognized mechanism by which patients with monoclonal gammopathies have an increased bleeding risk (10). Other more common mechanisms, in this context, include thrombocytopenia caused by bone marrow infiltration and clotting defects caused by sepsis and uremia.…”

“…Indeed, there are a number of mechanisms by which paraproteins might confer this increased risk (10,11). Therefore, renal histology has not been used as an inclusion criterion for some studies that have investigated the optimal treatment strategies for paraprotein-related renal disease (9).…”

Thrombosis in Multiple Myeloma

“…High levels of inflammatory cytokines have also been suggested to play a role in the pathogenetic mechanism of VTE in MM, with interleukin-6, C-reactive protein, and tumor necrosis factor being the most important. 16 The observed excess risk for both arterial and venous thrombosis in MM patients suggests that there might be some shared biological features, most probably involving platelet activation. [8][9] Arterial thrombi consist mainly of platelets and fibrin, whereas venous thrombi consist mainly of fibrin and red blood cells.…”

“…There is evidence that the IMiDs enhance expression of tissue factor and vascular endothelial growth factor, down-regulate thrombospondin, and cause cytokine-mediated, activated protein C resistance. 12,16 Thalidomide has been shown to increase the levels of von Willebrand factor and factor VIII. 20 In addition, thalidomide regulates the level of the prothrombotic factor COX-2.…”

“…When bortezomib is given in combination with thalidomide or lenalidomide, the VTE incidence is low. The possibility of a protective role of bortezomib on VTE 16 has to be validated in a prospective randomized study.…”