The most important predictor of stroke in sickle cell disease is the ultrasound cerebral transcranial doppler flow rate. patients with a flow rate 200 cm/second or greater are at much higher risk (~10%/year) of stroke compared to those with a flow rate less than 170.

Apart from TCDs are there any genetic variants that predispose people to come down with a raised TCD? What makes one sickle cell patient to have a raised TCD and another a normal velocity on TCD?

Patients who have common genotypes of sickle cell disease, Cerebrovascular accidents are seen most frequently in those with sickle cell anemia (SS).

Not sure of genetic markers but markers of high levels of hemolysis (eg high LDH levels and lower resting Hb levels) have been used to stratify patients with sickle cell disease and assess the risk of certain specific complications. Patients with higher rates of hemolysis and lower resting Hb levels are at increased risk of pulmonary hypertension, leg ulceration and possibly CVA. Those with higher resting Hb levels may have higher risk of bony painful crises and acute chest syndrome. http://www.ncbi.nlm.nih.gov/pubmed/19074078 This is a link to an article tat I think outlines the concept quite well.

Many mechanisms contribute to the complex pathophysiology of sickle cell disease (SCD), with dysfunction of the vascular endothelium as a unifying theme. Specifically, hemolysis-associated low arginine and nitric oxide (NO) bioavailability, amplified by NO synthase uncoupling, elevated arginase activity, superoxide production, oxidative stress, accumulation of arginine analogs such as asymmetric dimethylarginine, ischemia-reperfusion injury, inflammation, apolipoprotein A-1 depletion, and a hypercoagulable state are significant mechanisms contributing to endothelial dysfunction. Genetic polymorphisms also influence disease severity. Clearly the variable spectrum of disease is the consequence of multiple events and genetic susceptibility that go beyond the occurrence of a single amino acid substitution in the beta globin chain of hemoglobin. Recent studies begin to demonstrate overlap among these seemingly unrelated processes. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a common denominator in the pathogenesis of vasculopathy in SCD. The consequences of decreased NO bioavailability include endothelial cell activation, upregulation of the potent vasoconstrictor endothelin-1, vasoconstriction, platelet activation, increased tissue factor, and activation of coagulation, all of which ultimately translate into the clinical manifestations of SCD. Evidence supporting vasculopathy subphenotypes in SCD, including pulmonary hypertension, priapism, cutaneous leg ulceration, and stroke, will be reviewed and relevance to other hemolytic disorders including the thalassemia syndromes will be considered.