In sickle cell disease (SCD), the expression of mutated hemoglobin allows the formation of rigid, sickle-shaped and dense red blood cell (RBC). In patients, hypoxia, exercise or cold lead to vaso-occlusive crisis (VOC), with hypoperfusion in microcirculatory beds occluded by sickled, dense erythrocytes, causing ischemic tissue injury with intense pain. The renal medulla has substantial metabolic activity, with high oxygen demand, hyperosmolarity and low pH. Kidneys are thus particularly vulnerable to hypoxia and acute VOC. Platelet TSP1 released during thrombosis, and its RBC surface receptor CD47 have previously been involved in increased adhesion of RBC to endothelium in SCD. Here, we investigated other effects of TSP1 and CD47 on RBC in connection with VOC. We used SAD transgenic mice expressing mutated human hemoglobin (⍺2β2SAD). We found that circulating TSP1 levels increased 4 fold in SAD mice under hypoxia (8 % O2) for 16hours, whereas TSP1 levels were strongly depressed in wild type mice (−70 %). Electron microscopy and ektacytometry revealed that TSP1-derived CD47 agonist peptides in synergy with hypoxia triggered RBC echinocytosis in healthy RBC (+600 %). Wild type echinocytes however conserved constant numbers of short round spicules. SAD RBC also responded with increased echinocytosis (+100 %), coupled to a doubling in the aberrantly rigid, fine and elongated spicules they carried, compared to normoxia. No true sickling was observed. Intravenous injection of CD47 agonist to anesthetized wild type mice significantly reduced renal blood flow by 17 %, as assessed by echo-Doppler, indicating increased renal microvascular resistance. Renal blood flow returned to normal values within 5minutes. In contrast, administration of CD47 agonist peptides to SAD mice reduced renal blood flow by 48 %, for more than 20minutes. Mutated control peptides had no effects, and we observed no significant modulation of heart beat rates, or cardiac output. We concluded that the release of TSP1 may synergize with hypoxia to mediate echinocytosis and contribute to lasting vasoocclusive crises.