Adhesion to VCAM1 and P-selectin Predict Time-to-Resolution (TTR) of Vaso-Occlusive Crisis

Abstract

AbstractSickle cell disease (SCD) is characterized by frequent and unpredictable vaso-occlusive crises (VOCs) resulting in increased morbidity and mortality. Reliable biomarkers that predict the onset and progression of VOCs in SCD are unavailable, thus the existing standard of care is more focused on VOC intervention as opposed to VOC prevention. Sickle blood cells contribute to VOCs by adhering to the endothelium and aggregating to other blood cells in the circulation through pathologic adhesive interactions. In our previously described ELIPSIS study, blood samples were collected from 35 study subjects with SCD every 3 weeks during self-reported baseline and during self-reported VOCs (at home or in a healthcare setting). An electronic, patient-reported outcomes (ePRO) tool captured daily pain, VOC, and VOC resolution. Flow adhesion of whole blood to VCAM-1 (FA-WB-VCAM) and P-selectin (FA-WB-Psel) were assessed during each visit. Time-To-Resolution was established as the duration between the onset and subject self-reported resolution of VOC resolution and varied between 2 and 48 days. For the subset of TTR limited to ≤ 7 day, TTR was negatively correlated with FA-WB-PSel measured at the onset of VOC (R2=0.45; r=-0.67;p<0.05). Coefficient of determination increased to 0.62 when baseline FA-WB-VCAM levels were used as a second predictor in the multi-parametric model. In such a model, baseline FA-WB-VCAM was positively correlated with TTR at ≤ 7 day, with the difference in the sign of P-selectin and VCAM-1 effect on the reduction of pain (TTR duration) likely reflecting different mechanisms driving VOCs. Supplementation of FA-WB-VCAM and FA-WB-Psel multiparametric model with select blood chemistry biomarkers including several inflammatory mediators, further enhanced models ability to predict TTR. This study indicates that functional biomarkers obtained both at baseline and at the time of VOC can give insight into the time it may take for that specific VOC to resolve. These could assist providers in predicting which VOCs may require more intensive intervention. These data may also identify specific VOC phenotypes, allowing providers to intervene with a more patient-specific approach. Future studies are required to determine if FA-WB-VCAM and FA-WB-Psel can be used clinically to enable a more precision medicine-based approach to manage VOCs and if such an approach could result in improved outcomes and reduced healthcare costs by predicting VOCs for early intervention.