Platelet receptors and signaling cascades the protect from inflammatory hemorrhage. Increase in inflammatory bleeding by inhibition of the main receptors GPIIBIIIA, GPIb, GPVI and CLEC-2 expressed on the surface of platelets. Although single inhibition of GPIIBIIIA in models of acute lung injury, LCMV infection, cerebral ischemia–reperfusion injury (IRI) and cremaster inflammation using direct receptor antibody or whole-body knockout were sufficient, combined blockage of GPIIBIIIA and GPVI aggravated the bleeding phenotype in the models of acute lung injury and peritonitis. GPIIBIIIA outside-in signaling is targeted through the Gα13/c-Src/14-3-3ζ complex or Arpc2, relevant in actin nucleation and lamellipodium formation. GPIIBIIIA and GPVI downstream pathways increase intracellular Ca²⁺ concentrations in a Syk- and PLCγ2-dependent manner, resulting in PS expression on the outer platelet membrane. Inhibition of CypD, as part of the mitochondrial permeability transition pore (mPTP) formation, or transmembrane protein 16F, a calcium-dependent scramblase, decreases PA and aggravates inflammatory bleeding. Local recruitment of coagulations factors to PS-positive platelets can be directly inhibited by anti-FIIa/-FXa, interfering with inflammatory hemostasis. GPIb can be inhibited by a whole-body knockout or blocking antibody of its ligand von Willebrand factor (vWF) in acute lung injury and dermal rpA. Inhibition of CLEC-2 or its downstream effector Src-homology leucocyte protein 76 are sufficient to enhance inflammatory bleeding in acute lung injury, while in dermal rpA simultaneously blockage of CLEC-2 or its ligand podoplanin and GPVI is necessary. Ablation of both alpha and dense platelet granules is required to affect inflammatory hemostasis, eg, in cerebral ischemia-reperfusion injury.