ACTIVATION OF THE ALTERNATIVE COMPLEMENT PATHWAY BY EXPOSURE OF PHOSPHATIDYLETHANOLAMINE AND PHOSPHATIDYLSERINE ON ERYTHROCYTES FROM SICKLE-CELL DISEASE PATIENTS

Deoxygenation of erythrocytes from sickle cell anemia (SCA) patients a lters membrane phospholipid distribution with increased exposure of ph osphatidylethanolamine (PE) and phosphatidylserine (PS) on the outer l eaflet. This study investigated whether altered membrane phospholipid exposure on sickle erythrocytes results in complement activation. In v itro deoxygenation of sickle but not normal erythrocytes resulted in c omplement activation measured by C3 binding. Additional evidence indic ated that this activation was the result of the alterations in membran e phospholipids. First, complement was activated by normal erythrocyte s after incubation with sodium tetrathionate, which produces similar p hospholipid changes. Second, antibody was not required for complement activation by sickle or tetrathionate-treated erythrocytes. Third, the membrane regulatory proteins, decay-accelerating factor (CD55) and th e C3b/C4b receptor (CD35), were normal on sickle and tetrathionate-tre ated erythrocytes. Finally, insertion of PE or PS into normal erythroc ytes induced alternative pathway activation. SCA patients in crisis ex hibited increased plasma factor Bb levels compared with baseline, and erythrocytes isolated from hospitalized SCA patients had increased lev els of bound C3, indicating that alternative pathway activation occurs in vivo. Activation of complement may be a contributing factor in sic kle crisis episodes, shortening the life span of erythrocytes, and dec reasing host defense against infections.