The fibrin D-dimer degradation fragment is produced by plasmin degradation of cross-linked fibrin. Elevated plasma D-dimer levels indicate increased plasmin degradation of cross-linked fibrin, and are therefore an indirect indication of increased thrombin activity and fibrin formation. With an ELISA assay sensitive to plasma D-dimer levels of less than 50 ng/ml, elevated levels of D-dimer were found in 23 of 25 subjects with sickle cell disease tested during the steady state, and in all 21 subjects tested serially while hospitalized for painful crisis (total of 40 samples). Mean D-dimer was 79 +/- (SD) 25 ng/ml in 35 normal subjects, 566 +/- 739 ng/ml in sickle cell disease subjects in the steady state, and 1,038 +/- 1,010 ng/ml in sickle cell subjects during painful crisis; these differences were highly significant (p less than 0.001). No correlation was observed between levels of D-dimer in the steady state and the time since the last painful crisis; D-dimer was elevated in all 7 patients tested more than 6 months after their last painful crisis. Most steady-state patients did not have other microvascular occlusive manifestations, such as active leg ulcers or aseptic necrosis of bone, which could explain the increased D-dimer levels observed. It is concluded that increased thrombin activity and fibrin formation are features of steady-state sickle cell disease, and that they further increase during painful crisis. Possible causes and implications of increased thrombin activity and fibrin formation in subjects with sickle cell disease are discussed.