BETA-S GENE-CLUSTER HAPLOTYPES MODULATE HEMATOLOGIC AND HEMORHEOLOGICEXPRESSION IN SICKLE-CELL-ANEMIA - USE IN PREDICTING CLINICAL SEVERITY

Purpose: The rate of progression of major organ failure in sickle cell anemia is genetically controlled. It is the direct consequence of the sickle cell-evoked vasculopathy. Patients and Methods: Presence of th e beta(S) gene cluster haplotypes and alpha gene deletions as genetic markers indicate the expected frequency of illness and the risk of end -stage major organ failure. The risk of irreversible soft tissue organ failure is greatest in patients with a Central African Republic (CAR) chromosome, whereas morbidity is consistently lowest in patients with a Senegalese chromosome. Presence of alpha-thalassemia-2 decreases th e risk of soft tissue organ failure in all haplotype combinations. Res ults: Other laboratory abnormalities, when combined with haplotype and oc gene status, also predict the risk of clinical morbidity. The mean hemoglobin level (or red blood cell count) is lowest in patients with the most severe clinical manifestations. On the other hand, the plate let count and leukocyte count as well as the plasma fibrinogen level a re elevated in the sickest patients. A threshold level of hemoglobin F at 1.2 g/dl (similar to 20% hemoglobin F) decreases the risk of major organ failure and is attained most frequently in those with a Senegal ese chromosome. Hemorheologic findings observed during the most stable state of patients with sickle cell, anemia indicate two trends: (a) t he mean percentage of dense red cells is nearly twice as high in the m aximal severity patients as compared with the minimal severity patient s; and (b) mean red cell rigidity is greatest in the maximal severity group and least in the minimal severity group. These findings suggest that a greater percentage of dense, poorly deformable red cells are pr esent in sickle cell patients in the genotypic category of maximal sev erity. Conclusions: The combination of the beta(S) gene cluster haplot ype and alpha-gene status correlates with both phenotypic laboratory f indings (hematologic profile) and morbidity. These associations increa se our ability to predict clinical severity and the future risk of maj or organ failure.