Elevated von Willebrand factor levels in multiple myeloma: dysregulated mechanisms of both secretion and clearance

We read with great interest the recent publication by Ghansah et al whose work demonstrating increased thrombin generation and differential sensitivity to activated protein C (APC) in samples from patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is an important addition to our growing understanding of the critical factors behind the high rate of thrombosis in MM.1 In particular, we noted that these authors also found raised von Willebrand Factor (VWF) antigen and Factor VIII (FVIII) levels in patients with newly diagnosed MM and, to a lesser extent in patients with MGUS. However, they concluded that the biological mechanisms underpinning raised VWF:Ag levels in MM and MGUS remain unresolved with the authors suggesting endothelial damage may be a key contributing factor. In fact, following on from the work of Ghansah et al, here, we show for the first time that not only is VWF synthesis increased in MM but that VWF circulatory clearance is also reduced in this disease. Furthermore, we also report the novel finding of raised VWF propeptide in precursor MM disease, incorporating both MGUS and smouldering MM (SM), which strengthens the evidence of a hypercoagulable profile in these premalignant conditions.</div

Elevated von Willebrand factor levels in multiple myeloma: dysregulated mechanisms of both secretion and clearance

We read with great interest the recent publication by Ghansah et al whose work demonstrating increased thrombin generation and differential sensitivity to activated protein C (APC) in samples from patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is an important addition to our growing understanding of the critical factors behind the high rate of thrombosis in MM.1 In particular, we noted that these authors also found raised von Willebrand Factor (VWF) antigen and Factor VIII (FVIII) levels in patients with newly diagnosed MM and, to a lesser extent in patients with MGUS. However, they concluded that the biological mechanisms underpinning raised VWF:Ag levels in MM and MGUS remain unresolved with the authors suggesting endothelial damage may be a key contributing factor. In fact, following on from the work of Ghansah et al, here, we show for the first time that not only is VWF synthesis increased in MM but that VWF circulatory clearance is also reduced in this disease. Furthermore, we also report the novel finding of raised VWF propeptide in precursor MM disease, incorporating both MGUS and smouldering MM (SM), which strengthens the evidence of a hypercoagulable profile in these premalignant conditions.</div

Enhanced α2-3 linked sialylation determines the extended half-life of CHO-rVWF

The half-life of recombinant human von Willebrand factor (rVWF) expressed in CHO cells (CHO-rVWF; Vonicog alfa; and Vonvendi/Veyvondi) is significantly longer than that of plasma-derived VWF (pdVWF). This finding is intriguing because CHO cells do not generate α2-6 sialylation, which constitutes the majority of human pdVWF sialylation. We hypothesized that glycan differences might regulate the longer half-life of CHO-rVWF. In lectin plate-binding assays and liquid chromatography–mass spectrometry analysis, we confirmed that CHO-rVWF lacked α2-6 linked sialylation. Conversely, however, α2-3 linked sialylation was significantly increased on CHO-rVWF, which also had reduced exposed β-Galactose (β-Gal) compared to pdVWF. Consistent with human data, CHO-rVWF clearance was significantly (P </p