Hidden behind thromboinflammation: revealing the roles of von Willebrand factor in sickle cell disease pathophysiology

Abstract

Purpose of reviewThis review provides an update on the pathophysiology of sickle cell disease (SCD) with a particular focus on the dysregulation of the von Willebrand factor (VWF) - ADAMTS13 axis that contributes to its pathogenesis. In discussing recent developments, we hope to encourage new and ongoing discussions surrounding therapeutic targets for SCD.Recent findingsWithin the last 5 years, the role of VWF in the pathophysiology of SCD has been further elucidated and is now a target of study in ongoing clinical trials.SummaryThe pathophysiology of SCD is multifaceted, as it involves systemwide vascular activation, altered blood rheology, and the activation of immune responses and coagulative pathways. The presence of VWF in excess in SCD, particularly in its largest multimeric form, greatly contributes to its pathogenesis. Understanding the molecular mechanisms that underly the presence of large VWF multimers in SCD will provide further insight into the pathogenesis of SCD and provide specific targets for therapy.

Sickle cell anemia: hepatic macrophages to the rescue

“…Removal of VWF by these macrophages is preceded by ADAMTS13 proteolytic cleavage of VWF; the importance of this process is highlighted by the fact that administering recombinant ADAMTS13 alleviates VOEs, 7 and dysregulation of the VWF-ADAMTS13 axis promotes SCA pathogenesis. 8 Further, cleavage requires desialylation of VWF in the liver, thereby supporting the role of sialyation by hepatic macrophages in this process.…”

The invisible string of coagulation, complement, iron, and inflammation in sickle cell disease

“…Activation of the endothelium, resulting in expression of adhesion molecules and release of VWF and P-selectin, is a critical step in the pathophysiology of VOE [48]. Dysregulation of the VWF-ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, number 13) axis [49,50] has emerged as a major theme. In endothelial cells, VWF is stored as a multimerized polymer in Weibel-Palade bodies as ultra-large VWF (ULVWF); after activation, ULVWF is released and forms long strings.…”

“…One potential mechanism is that circulating free hemoglobin and thrombospondin-1, which are both elevated in the plasma of individuals with SCD, can bind VWF and inhibit its cleavage by ADAMTS-13. There is also a subset of SCD patients with reduced ADAMTS-13 proteolytic activity [49,50]. Increased ULVWF strands on the endothelium in SCD may provide an adhesive surface for sickle RBCs and contribute to VOE.…”

Early‐onset indicators of a hypercoagulable state and clinical complications in a cohort of children with sickle cell trait

“…4,7 The potential mechanisms underlying the augmented risk of VTE in SCT individuals are rooted in vessel occlusion, blood stasis, and chronic coagulation system activation, as evidenced by findings from adult cohorts. [8][9][10] Recent investigations have illuminated the role of plasminogen activator inhibitor type I (PAI-1) and the von Willebrand factor (VWF)-ADAMTS13 axis in this context, 11,12 further reinforcing the intricate nature of these associations. Notably, SCT is a genetically inherited condition present from birth, but reports on thromboembolic events in pediatric SCT cohorts and coagulation profiles in children remain confined to isolated clinical cases.…”