ADAMTS13 Activity in Sickle Cell Disease: A Role in the Development of Clinical Vaso-Occlusion?.

Endothelial cell activation occurs continuously in sickle cell disease (SCD). As VWF and especially the ultra large VWF multimers, released from activated endothelial cells, can serve as bridging proteins between the vessel wall and sickle red blood cells, we determined ADAMTS13 (the vWF-cleaving protease) activity as well as VWF:Rcof and VWF:Ag levels in SCD. Fourteen sickle cell patients (13 HbSS, 1 HbSC; 39 samples collected) and 9 HbAA controls were included. VWF:Rcof and VWF:Ag were assessed by commercially available assays, ADAMTS13 activity was determined by quantitative immunoblotting of proteolysed VWF-substrate. VWF:Rcof and VWF:Ag levels were higher in patients, as compared to controls. ADAMTS13 activity ranged from 45–128% in asymptomatic patients, from 38–205 in patients during acute vaso-occlusive events (VOE) and from 43-75% in controls. The ratios of ADAMTS13 to vWF:Ag levels and activity were lower in patients (SCD asymptomatic: 0.44 [interquartile range 0.34–0.55], SCD acute VOE: 0.29 [0.21–0.43], HbAA: median 0.61 [0.33–1.23], Kruskar Wallis test p=0.003). The ADAMTS13 - VWF:Rcof and the ADATS13 - VWF:Ag ratios dropped during acute vaso-occlusive events in 3 of 6 patients. In patients from whom multiple samples were collected (n=4), ADAMTS13 activity and VWF:Ag levels (and to a lesser extent VWF:Rcof) were inversely related. One patient showed no change in ADAMTS13 activity despite strong increments in VWF:Ag and VWF:Rcof during vaso-occlusive pain crises prior to his death (pulmonary embolism). VWF:Ag levels at initial presentation of acute VOE were related to the duration of pain (r_s=0.53, p=0.02), whereas the ratios of ADAMTS13 to VWF:Ag levels and ADAMTS13 to VWF:Rcof were inversely related hereto (r_s=−0.67, p=0.002, r_s=−0.53, p=0.02 respectively). These data demonstrate that ADAMTS13 activity is related to VWF:Ag levels and VWF:Rcof in SCD and that the role of ADAMTS13 and VWF in the pathophysiology of SCD deserves further evaluation.