Prevention of inflammatory bleeding by platelets can occur independent of G protein–coupled receptors and GPIIbIIIa. (A) Representative images of cutaneous rpa spots showing that, unlike thrombocytopenic mice (<3% platelets), mice treated with a blocking F(ab')2 fragment antibody to GPIIb/IIIa did not develop bleeding in the inflamed skin. Adapted from Deppermann et al.³³  (B) Representative images of mouse mammary tumor showing that, unlike thrombocytopenic mice (<3% platelets), mice with a genetic deficiency in β 3 integrins (β3^−/−) did not develop tumor bleeding. Adapted from Ho-Tin-Noé et al⁴⁹  with permission. (C) Transgenic hIL-4Rα/GPIbα mice were immunodepleted for platelets and transfused or not with control wild-type platelets or with platelets isolated from clopidogrel and aspirin-treated PAR4^−/− mice. Those mice were then challenged in the skin with the rpA or in the lungs with LPS, as indicated. Representative images of the rpa site (dashed outlines and arrows) and of the bronchoalveolar lavage fluid are shown. Remarkably, just like control wild-type platelets, clopidogrel- and aspirin-treated PAR4^−/− platelets protected against inflammatory bleeding in the inflamed skin and lungs. Adapted from Boulaftali et al³²  with permission. (D) Representative images showing brain sections from mice that were subjected to tMCAO. The photographs were taken 24 hours after reperfusion. Hemorrhagic transformation under the form of petechial bleeding developed in the ischemic hemisphere of thrombocytopenic mice (<3% platelets) and of mice treated with a blocking F(ab')2 fragment antibody to GPIIb/IIIa. (Upper) Adapted from Goerge et al.³²  (Lower) Adapted from Kleinschnitz et al.⁴⁸  (E) Intravital imaging of cortical microvessels during MCAO. (Left) Rhodamine 6G labeling revealed that proximal occlusion caused a rapid and marked margination of leukocytes in venules downstream of the MCA (upper), which persisted and continued developing after recanalization (lower). Scale bar, 100 µm. (Right) tMCAO eventually led to secondary occlusion of postcapillary venules characterized by accumulation of platelets and fibrin(ogen). Scale bar, 50 µm. A, arteriole; V, venule. Adapted from Desilles et al⁴⁹  with permission.