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.
Organ damage in sickle cell disease (SCD) is a crucial determinant for disease severity and prognosis. In a previous study, we analyzed the prevalence of SCD-related organ damage and complications in adult sickle cell patients. We now describe a seven-year follow-up of this cohort.All patients from the primary analysis in 2006 (n = 104), were included for follow-up. Patients were screened for SCD-related organ damage and complications (microalbuminuria, renal failure, elevated tricuspid regurgitation flow velocity (TRV) (≥2.5 m/seconds), retinopathy, iron overload, cholelithiasis, avascular osteonecrosis, leg ulcers, acute chest syndrome (ACS), stroke, priapism and admissions for vaso-occlusive crises (VOC) biannually. Upon 7 years of follow-up, progression in the prevalence of avascular osteonecrosis (from 12.5% to 20.4%), renal failure (from 6.7% to 23.4%), retinopathy (from 39.7% to 53.8%) was observed in the whole group. In HbSS/HbSβ -thal patients also progression in microalbuminuria (from 34% to 45%) and elevated TRV (from 40% to 48%) was observed while hardly any progression in the prevalence of cholelithiasis, priapism, stroke or chronic ulcers was seen. The proportion of patients with at least one episode of ACS increased in the group of HbSS/HbSβ -thal patients from 32% to 49.1%. In conclusion, 62% of the sickle cell patients in this prospective cohort study developed a new SCD-related complication in a comprehensive care setting within 7 years of follow-up. Although the hospital admission rate for VOC remained stable, multiple forms of organ damage increased substantially. These observations underline the need for continued screening for organ damage in all adult patients with SCD.
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