Relevant receptors and signaling cascades
| Receptor/ signaling hub . | Models with aggravated bleeding upon inhibition . | No bleeding observed upon inhibition . | Reference . |
|---|---|---|---|
| GPIIBIIIA | Acute lung injury (full knockout, irreversible inhibition through eptifibatide, combined with GPVI), viral infection with LCMV, cerebral IRI (tMCAO), LPS-induced peritonitis (in synergy with GPVI), LPS-induced cremaster inflammation | Dermal rpA (incl. downstream Gα13), acute lung injury (reversible, single inhibition through tirofiban), immunization (ovalbumin) | 31,32,35,45,50,53,55-57,68,70,71 |
| GPIb/vWF interaction | Acute lung injury (vWF−/−), dermal rpA (vWF-blocking antibody) | Dermal rpA, cerebral IRI (tMCAO), solid tumors, LCMV infection, glomerulonephritis | 32,49,50,56,59 |
| GPVI | Acute lung injury (more severe in synergy with GPIIBIIIA blockade), tumor bleeding, dermal rpA (in synergy with CLEC-2/podoplanin), LPS-induced peritonitis (in synergy with GPIIBIIIA) | Dermal rpA (GPVI−/−), cerebral IRI (tMCAO), pulmonary rpA | 32,42,50,65,67,68 |
| CLEC-2 | Immunization (ovalbumin), dermal rpA (only in synergy with GPVI), acute lung injury | Dermal rpA (single inhibition, podoplanin blockade) | 45,50,55,60,64,65 |
| SLP-76 | Dermal rpA, acute lung injury | — | 65 |
| PAR4 | — | Dermal rpA, acute lung injury | 52,65,72 |
| Podoplanin (as counter receptor for platelet CLEC-2) | Immunization, dermal rpA (only in synergy with GPVI deletion) | Dermal rpA (single inhibition through antibody or endothelial deletion) | 50,55,60 |
| P-selectin (CD62P) | Acid-induced acute lung injury (enhanced neutrophil recruitment, no data on bleeding) | Dermal rpA, LCMV | 32,45,56,73 |
| CalDAG-GEFI | — | Dermal rpA | 32 |
| P2Y12 | — | Dermal rpA, acute lung injury | 65 |
| P2X1 | Inflammatory colitis | Acute lung injury | 48 |
| TXA2 | — | Dermal rpA, acute lung injury | 65 |
| S1P (platelet-derived) | — | Dermal rpA, immunization (ovalbumin) | 55,74 |
| BTK | — | Dermal rpA, acute lung injury | 66 |
| Arpc2 | Acute lung injury (high-dose and low-dose LPS), CCL2-induced cremaster inflammation | — | 53 |
| c-Src | Acute lung injury | — | 75 |
| CypD | Acute lung injury | — | 68 |
| TMEM16F | Acute lung injury | — | 68 |
| Receptor/ signaling hub . | Models with aggravated bleeding upon inhibition . | No bleeding observed upon inhibition . | Reference . |
|---|---|---|---|
| GPIIBIIIA | Acute lung injury (full knockout, irreversible inhibition through eptifibatide, combined with GPVI), viral infection with LCMV, cerebral IRI (tMCAO), LPS-induced peritonitis (in synergy with GPVI), LPS-induced cremaster inflammation | Dermal rpA (incl. downstream Gα13), acute lung injury (reversible, single inhibition through tirofiban), immunization (ovalbumin) | 31,32,35,45,50,53,55-57,68,70,71 |
| GPIb/vWF interaction | Acute lung injury (vWF−/−), dermal rpA (vWF-blocking antibody) | Dermal rpA, cerebral IRI (tMCAO), solid tumors, LCMV infection, glomerulonephritis | 32,49,50,56,59 |
| GPVI | Acute lung injury (more severe in synergy with GPIIBIIIA blockade), tumor bleeding, dermal rpA (in synergy with CLEC-2/podoplanin), LPS-induced peritonitis (in synergy with GPIIBIIIA) | Dermal rpA (GPVI−/−), cerebral IRI (tMCAO), pulmonary rpA | 32,42,50,65,67,68 |
| CLEC-2 | Immunization (ovalbumin), dermal rpA (only in synergy with GPVI), acute lung injury | Dermal rpA (single inhibition, podoplanin blockade) | 45,50,55,60,64,65 |
| SLP-76 | Dermal rpA, acute lung injury | — | 65 |
| PAR4 | — | Dermal rpA, acute lung injury | 52,65,72 |
| Podoplanin (as counter receptor for platelet CLEC-2) | Immunization, dermal rpA (only in synergy with GPVI deletion) | Dermal rpA (single inhibition through antibody or endothelial deletion) | 50,55,60 |
| P-selectin (CD62P) | Acid-induced acute lung injury (enhanced neutrophil recruitment, no data on bleeding) | Dermal rpA, LCMV | 32,45,56,73 |
| CalDAG-GEFI | — | Dermal rpA | 32 |
| P2Y12 | — | Dermal rpA, acute lung injury | 65 |
| P2X1 | Inflammatory colitis | Acute lung injury | 48 |
| TXA2 | — | Dermal rpA, acute lung injury | 65 |
| S1P (platelet-derived) | — | Dermal rpA, immunization (ovalbumin) | 55,74 |
| BTK | — | Dermal rpA, acute lung injury | 66 |
| Arpc2 | Acute lung injury (high-dose and low-dose LPS), CCL2-induced cremaster inflammation | — | 53 |
| c-Src | Acute lung injury | — | 75 |
| CypD | Acute lung injury | — | 68 |
| TMEM16F | Acute lung injury | — | 68 |
Unless otherwise stated, acute lung injury was induced using LPS.
BTK, Bruton tyrosine kinase; CypD, cyclophilin D; CalDAG-GEFI, Ca2+ and DAG-regulated guanine nucleotide exchange factor I; P2X1, P2X receptor 1; P2Y12, P2Y receptor 12; PAR4, protease-activated receptor 4; S1P, sphingosine-1-phosphate; SLP-76, Src-homology leucocyte protein 76 (also known as Lymphocyte cytosolic protein 2); TMEM16F, transmembrane protein 16F; TXA2, thromboxane.