Thrombospondin (TSP), a large protein found In platelet a-granules (as TSP-l), mediates adhesion of sickle reticulacytes to cultured vascular endothelium. To further explore the physiologic relevance of this observation, we have measured plasma TSP levels and platelet TSP-1 content In subjects with sickle cell disease. Plasma TSP levels were similar for normal controls (mean 491 nglml, range 331-723) and steady-state HbSS patients (mean 536, range 333-1107) and were slgnlflcantly (P = 0.012) but variably elevated for HbSS patients presenting with acute painful crisis (mean 868, range 442-2780). Some of these elevated plasma TSP levels reached those previously observed to support maximal red cell adhesion to endothelium In vltro. Compared to normals, both steady-state and ln-crisis HbSS patients had significantly (P < 0.001) depressed platelet TSP-1 content (82.6 f 11.9,47.1 f 16.0 and 45.9 f 20.7 ngllw platelets, respectively, mean =SD). HbSC disease patients, all examined during steady state, had low-normal plasma levels of TSP and either normal or depressed platelet TSP-1 content. Serial observations on three sickle cell anemia subjects indicated a probable relationship between platelet TSP-1 release, elevated plasma TSP levels, and acute vasoocclusive episodes. These results suggest a state of ongoing release and depletion of TSP-1 from activated platelets In patients with sickle cell disease.