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C-type lectin-like receptor 2 (CLEC-2) has been identified as a receptor for the platelet-activating snake venom, rhodocytin. It has a membrane protein, podoplanin (PDPN), as its endogenous ligand, expressed in lymphatic endothelial cells (LECs) and certain types of tumor cells. CLEC-2 clustering induces platelet-activating signals depending on protein tyrosine kinases. The interaction between platelet CLEC-2 and LEC PDPN during embryonic development contributes to blood/lymphatic vessel separation and lung development. Platelet CLEC-2 also interacts with PDPN in fibroblastic reticular cells surrounding high endothelial venules (HEVs) in lymph nodes and protects HEV integrity. CLEC-2-deficientt mice showed blood-filled lymphatics, lung malformation, and hemolymph. Platelet CLEC-2 interaction with PDPN in tumor cells and in cancer-associated fibroblasts facilitates hematogenous metastasis and cancer-associated thrombosis (CAT). Tumor-bearing CLEC-2-depleted mice showed inhibited CAT activity and survived longer compared with tumor-bearing control mice. CLEC-2 binds to heme and ferric ions inducing platelet aggregation, which regulates rhabdomyolysis-induced acute renal failure and ferroptosis. CLEC-2 is released upon platelet activation in shed and microparticle-bound forms. The soluble CLEC-2 level (sCLEC-2) in plasma increases in various arterial and venous thrombotic scenarios. Several sCLEC-2-containing formulas have been proposed, including sCLEC-2/D-dimer, C2PAC index (sCLEC-2/platelet count [PLT]), and a super formula (sCLEC-2 × D-dimer/PLT). The sCLEC-2/D-dimer ratio can be used to differentiate between atherosclerotic cerebral/lacunar brain and cardioembolic cerebral infarctions. The C2PAC index can be used for cancer-associated venous thromboembolism and septic disseminated intravascular coagulation (DIC). The super formula demonstrates high diagnostic performance and can be used for diagnosing DIC. The clinical performance study of sCLEC-2 (CLECSTRO) in stroke is currently ongoing. Thus, CLEC-2 has revealed unexpected roles of platelets, and can be both a potential therapeutic target and an in vivo platelet activation marker.

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Platelet CLEC-2

  • 章节

  • 发表日期：

    2025年

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  • Katsue Suzuki-Inoue,
  • Toshiaki Shirai,
  • Nagaharu Tsukiji

摘要

C-type lectin-like receptor 2 (CLEC-2) has been identified as a receptor for the platelet-activating snake venom, rhodocytin. It has a membrane protein, podoplanin (PDPN), as its endogenous ligand, expressed in lymphatic endothelial cells (LECs) and certain types of tumor cells. CLEC-2 clustering induces platelet-activating signals depending on protein tyrosine kinases. The interaction between platelet CLEC-2 and LEC PDPN during embryonic development contributes to blood/lymphatic vessel separation and lung development. Platelet CLEC-2 also interacts with PDPN in fibroblastic reticular cells surrounding high endothelial venules (HEVs) in lymph nodes and protects HEV integrity. CLEC-2-deficientt mice showed blood-filled lymphatics, lung malformation, and hemolymph. Platelet CLEC-2 interaction with PDPN in tumor cells and in cancer-associated fibroblasts facilitates hematogenous metastasis and cancer-associated thrombosis (CAT). Tumor-bearing CLEC-2-depleted mice showed inhibited CAT activity and survived longer compared with tumor-bearing control mice. CLEC-2 binds to heme and ferric ions inducing platelet aggregation, which regulates rhabdomyolysis-induced acute renal failure and ferroptosis. CLEC-2 is released upon platelet activation in shed and microparticle-bound forms. The soluble CLEC-2 level (sCLEC-2) in plasma increases in various arterial and venous thrombotic scenarios. Several sCLEC-2-containing formulas have been proposed, including sCLEC-2/D-dimer, C2PAC index (sCLEC-2/platelet count [PLT]), and a super formula (sCLEC-2 × D-dimer/PLT). The sCLEC-2/D-dimer ratio can be used to differentiate between atherosclerotic cerebral/lacunar brain and cardioembolic cerebral infarctions. The C2PAC index can be used for cancer-associated venous thromboembolism and septic disseminated intravascular coagulation (DIC). The super formula demonstrates high diagnostic performance and can be used for diagnosing DIC. The clinical performance study of sCLEC-2 (CLECSTRO) in stroke is currently ongoing. Thus, CLEC-2 has revealed unexpected roles of platelets, and can be both a potential therapeutic target and an in vivo platelet activation marker.