Sickle cell anemia (SCA) is an autosomal recessive disease caused by the 
HBB:c.20A>T mutation that leads to hemoglobin S synthesis. The disease presents 
with high clinical heterogeneity characterized by chronic hemolysis, recurrent 
episodes of vaso-oclusion and infection. This work aimed to characterize by in 
silico studies some genetic modulators of severe hemolysis and stroke risk in 
children with SCA, and understand their consequences at the hemorheological 
level.Association studies were performed between hemolysis biomarkers as well as 
the degree of cerebral vasculopathy and the inheritance of several polymorphic 
regions in genes related with vascular cell adhesion and vascular tonus in 
pediatric SCA patients. In silico tools (e.g. MatInspector) were applied to 
investigate the main variant consequences.Variants in vascular adhesion 
molecule-1 (VCAM1) gene promoter and endothelial nitric oxide synthase (NOS3) 
gene were significantly associated with higher degree of hemolysis and stroke 
events. They potentially modify transcription factor binding sites (e.g. VCAM1 
rs1409419_T allele may lead to an EVI1 gain) or disturb the corresponding 
protein structure/function. Our findings emphasize the relevance of genetic 
variation in modulating the disease severity due to their effect on gene 
expression or modification of protein biological activities related with sickled 
erythrocyte/endothelial interactions and consequent hemorheological 
abnormalities.