Dynamics of von Willebrand factor reactivity in sickle cell disease during vaso‐occlusive crisis and steady state

Abstract

The role of von Willebrand Factor (VWF) in the pathophysiology of sickle cell disease is unclear. We assessed markers of VWF during admission for vaso‐occlusive crisis (VOC) and steady state. VWF reactivity was higher during VOC and was associated with inflammation and neutrophil activation. Hyper‐adhesive VWF may promote VOC in sickle cell disease. Summary BackgroundEndothelial activation plays a central role in the pathophysiology of vaso‐occlusion in sickle cell disease (SCD), facilitating adhesive interactions with circulating blood cells. Upon activation, various adhesive molecules are expressed, including von Willebrand factor (VWF). Increased VWF levels have been observed in patients with SCD during steady state. However, the role of VWF in the pathogenesis of SCD vaso‐occlusion is unclear. ObjectivesTo longitudinally assess the quantity and reactivity of VWF and its regulating protease ADAMTS‐13 during vaso‐occlusive crisis (VOC). MethodsIn this observational study, we obtained sequential blood samples in adult SCD patients during VOC. ResultsVWF reactivity was significantly higher during VOC (active VWF, VWF glycoprotein Ib‐binding activity, and high molecular weight multimers), whereas platelet count and levels of ADAMTS‐13 antigen and ADAMTS‐13 activity were concomitantly lower than during steady state. Levels of VWF antigen, VWF propeptide (VWF:pp) and ADAMTS‐13 specific activity did not change during VOC. VWF reactivity correlated strongly with markers of inflammation and neutrophil activation, and was inversely correlated with the platelet count. In patients who developed acute chest syndrome, levels of VWF, VWF:pp and active, hyperadhesive VWF were significantly higher, whereas ADAMTS‐13 activity was lower, than in patients without this complication. ConclusionsWe provide the first evidence that VOC in SCD is associated with increased reactivity of VWF, without a pronounced ADAMTS‐13 deficiency. This hyper‐reactivity may be explained by resistance of VWF to proteolysis, secondary to processes such as inflammation and oxidative stress. Hyperadhesive VWF, scavenging blood cells in the microcirculation, may thereby amplify and sustain VOC in SCD.

Case series supporting heme detoxification via therapeutic plasma exchange in acute multiorgan failure syndrome resistant to red blood cell exchange in sickle cell disease

“…Thus TPE probably also decreases VWF resistance to proteolysis and generation of ul VWF, although this is difficult to study since ul VWF is also removed by TPE . The presence of ul VWF is consistent with the occasional schistocytes, thrombocytopenia, altered mental status, and renal dysfunction observed in our patients despite ADAMTS13 activity of more than 10%. Functional protein C and free protein S are also reduced in SCD patients, with increases in D‐dimer and thrombin‐antithrombin complexes in crisis, consistent with the 80% marrow necrosis and diffuse centrilobular coagulative necrosis of the liver observed in some patients.…”

“…Other mechanisms may also contribute to the beneficial effect of TPE, some of which are also heme related . For example, free Hb binds to von Willebrand factor (VWF) and prevents ADAMTS13 cleavage, thus increasing ultralarge (ul) VWF multimers and VWF reactivity, which correlate with hemolysis rate . Thus TPE probably also decreases VWF resistance to proteolysis and generation of ul VWF, although this is difficult to study since ul VWF is also removed by TPE .…”

“…78,79 For example, free Hb binds to von Willebrand factor (VWF) and prevents ADAMTS13 cleavage, 79 thus increasing ultralarge (ul) VWF multimers and VWF reactivity, which correlate with hemolysis rate. 12,13,80,81 Thus TPE probably also decreases VWF resistance to proteolysis and generation of ul VWF, although this is difficult to study since ul VWF is also removed by TPE. 79 The presence of ul VWF is consistent with the occasional schistocytes, thrombocytopenia, 81 altered mental status, and renal dysfunction observed in our patients despite ADAMTS13 activity of more than 10%.…”

Role of the coagulation system in the pathogenesis of sickle cell disease

“…104 VWF activity was reported to be augmented in SCD patients during VOC and was associated with the increased markers of inflammation without a pronounced ADAMTS-13 deficiency. 105 VWF also increases in SCD patients with sleep hypoxemia. 106 HbS present in the blood binds to VWF, which prevents its degradation by ADAMTS-13 resulting in accumulation of VWF in the circulation and endothelium.…”

The aptamer BT200 effectively inhibits von Willebrand factor (VWF) dependent platelet function after stimulated VWF release by desmopressin or endotoxin

“…As stated in a recent review 36 , improvement in the half-life is seen with higher PEG moieties, which has led to a considerable half-life extension to ~ 66 h for ARC15105 37 , which contains a 40 kDa PEG residue similar to BT200. Inhibiting VWF improves the outcome in patients with thrombotic thrombocytopenic purpura 32,33 , but it could also offer potential benefits for patients suffering from stroke 38 , myocardial infarction 3 , or other thrombotic diseases such as sickle cell disease 43 .…”