P-Selectin and Blood Coagulation
http://www.100md.com
动脉硬化血栓血管生物学 2005年第5期
From the Harvard Medical School, Boston, Mass.
Correspondence to Bruce Furie, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215. E-mail bfurie@bidmc.harvard.edu
Although P-selectin had already been established as a vascular adhesion molecule critical in the inflammatory response, in 1992 Palabrica et al were the first to demonstrate that P-selectin also played a significant role in blood coagulation and thrombosis.1 In these experiments using an arteriovenous shunt model of thrombosis in a baboon, anti–P-selectin antibodies were shown to block fibrin formation in the developing thrombus forming in a thrombogenic Dacron shunt. Shortly thereafter, P-selectin was not only shown to upregulate tissue factor generation in monocytes,2 but also to initiate signaling pathways in leukocytes and activate the elaboration of cytokines in a mechanism that involved P-selectin interaction with its receptor, PSGL-1.3,4 A number of more recent reports have secured a role for P-selectin in hemostasis and thrombosis, including the demonstration that overexpression of P-selectin can induce a procoagulant state,5 that circulating microparticles bearing PSGL-1, the counterreceptor for P-selectin, deliver tissue factor to the growing platelet thrombus via a mechanism dependent on P-selectin and PSGL-1,6 and that procoagulant microparticles can partially correct the hemostatic defect in hemophilic mice.7 The role of P-selectin and PSGL-1 along with microparticles has recently been reviewed.8,9 The current report by del Conde et al in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology10 adds yet another page to the growing list of mechanisms by which P-selectin can contribute to procoagulant activity.
See page 1065
The current study demonstrates that the interaction of P-selectin with PSGL-1 on monocytes or monocyte-like cells is associated with the exposure of phosphatidylserine on the plasma membrane. This anionic phospholipid, normally oriented within the cell membrane to face internally, flips during cell activation to expose its head group externally. Because this phospholipid is essential for the formation of the Factor IXa/Factor VIIIa complex and the Factor Xa/Factor Va complex on cell membranes, it is widely accepted that the exposure of phosphatidylserine on the activated cell surface localizes the blood coagulation complexes to membranes in the region of vascular injury to the surfaces of cells that have been activated. The Gla domain of the vitamin K–dependent proteins requires phosphatidylserine for membrane recognition. Indeed, on binding of calcium ions to these proteins, the vitamin K–dependent proteins undergo a major conformation change with the exposure of a hydrophobic patch in the T loop of the N terminus of the Gla domain (which seats itself into the membrane)11,12 and the development of a binding site for the phosphatidylserine head group within the Gla domain of the protein.13
As the authors indicate, the P-selectin–dependent exposure of phosphatidylserine on the monocyte surface takes place on a time scale of hours.10 This is parallel to the kinetics of P-selectin–dependent tissue factor expression on monocytes.2 These results again emphasize that that these mechanisms do not support physiological hemostasis because this host defense mechanism requires a response time of seconds or minutes. Rather, these processes are more likely contributors to the thrombotic tendencies associated with inflammation.
As is often the case in this line of work, the current results raise as many questions as they answer. Does this modest increase in phosphatidylserine significantly increase in vivo thrombin generation? Do activated monocytes provide a pathologically important surface for thrombin generation in vivo? These issues provide food for thought and possible directions of further investigation.
References
Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM, Sajer SA, Furie B. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature. 1992; 359: 848–851.
Celi A, Pellegrini G, Lorenzet R, De Blasi A, Ready N, Furie BC, Furie B. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci U S A. 1994; 91: 8767–8771.
Weyrich AS, Elstad MR, McEver RP, McIntyre TM, Moore KL, Morrissey JH, Prescott SM, Zimmerman GA. Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest. 1996; 97: 1525–1534.
Weyrich AS, McIntyre TM, McEver RP, Prescott SM, Zimmerman GA. Monocyte tethering by P-selectin regulates monocyte chemotactic protein- 1 and tumor necrosis factor- secretion. Signal integration and NF- B translocation. J Clin Invest. 1995; 95: 2297–2303.
Andre P, Hartwell D, Hrachovinova I, Saffaripour S, Wagner DD. Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc Natl Acad Sci U S A. 2000; 97: 13835–13840.
Falati S, Liu Q, Gross P, Merrill-Skoloff G, Chou J, Vandendries E, Celi A, Croce K, Furie BC, Furie B. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med. 2003; 197: 1585–1598.
Hrachovinova II, Cambien B, Hafezi-Moghadam A, Kappelmayer J, Camphausen RT, Widom A, Xia L, Kazazian HH, Schaub RG, McEver RP, Wagner DD. Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med. 2003; 9: 1020–1025.
Furie B, Furie BC. Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends Mol Med. 2004; 10: 171–178.
Cambien B, Wagner DD. A new role in hemostasis for the adhesion receptor P-selectin. Trends Mol Med. 2004; 10: 179–186.
del Conde I, Nabi F, Tonda R, Thiagarajan P, Lopez JA, Kleiman NS. Effect of P-selectin on phosphatidylserine exposure and surface-dependent thrombin generation on monocytes. Arterioscler Thromb Vasc Biol. 2005; 25: 1065–1070.
Soriano-Garcia M, Padmanabhan K, de Vos AM, Tulinsky A. The Ca2+ ion and membrane binding structure of the Gla domain of Ca-prothrombin fragment 1. Biochemistry. 1992; 31: 2554–2566.
Freedman SJ, Blostein MD, Baleja JD, Jacobs M, Furie BC, Furie B. Identification of the phospholipid binding site in the vitamin K–dependent blood coagulation protein Factor IX. J Biol Chem. 1996; 271: 16227–16236.
Huang M, Rigby AC, Morelli X, Grant MA, Huang G, Furie B, Seaton B, Furie BC. Structural basis of membrane binding by Gla domains of vitamin K–dependent proteins. Nat Struct Biol. 2003; 10: 751–756.(Bruce Furie)
Correspondence to Bruce Furie, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215. E-mail bfurie@bidmc.harvard.edu
Although P-selectin had already been established as a vascular adhesion molecule critical in the inflammatory response, in 1992 Palabrica et al were the first to demonstrate that P-selectin also played a significant role in blood coagulation and thrombosis.1 In these experiments using an arteriovenous shunt model of thrombosis in a baboon, anti–P-selectin antibodies were shown to block fibrin formation in the developing thrombus forming in a thrombogenic Dacron shunt. Shortly thereafter, P-selectin was not only shown to upregulate tissue factor generation in monocytes,2 but also to initiate signaling pathways in leukocytes and activate the elaboration of cytokines in a mechanism that involved P-selectin interaction with its receptor, PSGL-1.3,4 A number of more recent reports have secured a role for P-selectin in hemostasis and thrombosis, including the demonstration that overexpression of P-selectin can induce a procoagulant state,5 that circulating microparticles bearing PSGL-1, the counterreceptor for P-selectin, deliver tissue factor to the growing platelet thrombus via a mechanism dependent on P-selectin and PSGL-1,6 and that procoagulant microparticles can partially correct the hemostatic defect in hemophilic mice.7 The role of P-selectin and PSGL-1 along with microparticles has recently been reviewed.8,9 The current report by del Conde et al in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology10 adds yet another page to the growing list of mechanisms by which P-selectin can contribute to procoagulant activity.
See page 1065
The current study demonstrates that the interaction of P-selectin with PSGL-1 on monocytes or monocyte-like cells is associated with the exposure of phosphatidylserine on the plasma membrane. This anionic phospholipid, normally oriented within the cell membrane to face internally, flips during cell activation to expose its head group externally. Because this phospholipid is essential for the formation of the Factor IXa/Factor VIIIa complex and the Factor Xa/Factor Va complex on cell membranes, it is widely accepted that the exposure of phosphatidylserine on the activated cell surface localizes the blood coagulation complexes to membranes in the region of vascular injury to the surfaces of cells that have been activated. The Gla domain of the vitamin K–dependent proteins requires phosphatidylserine for membrane recognition. Indeed, on binding of calcium ions to these proteins, the vitamin K–dependent proteins undergo a major conformation change with the exposure of a hydrophobic patch in the T loop of the N terminus of the Gla domain (which seats itself into the membrane)11,12 and the development of a binding site for the phosphatidylserine head group within the Gla domain of the protein.13
As the authors indicate, the P-selectin–dependent exposure of phosphatidylserine on the monocyte surface takes place on a time scale of hours.10 This is parallel to the kinetics of P-selectin–dependent tissue factor expression on monocytes.2 These results again emphasize that that these mechanisms do not support physiological hemostasis because this host defense mechanism requires a response time of seconds or minutes. Rather, these processes are more likely contributors to the thrombotic tendencies associated with inflammation.
As is often the case in this line of work, the current results raise as many questions as they answer. Does this modest increase in phosphatidylserine significantly increase in vivo thrombin generation? Do activated monocytes provide a pathologically important surface for thrombin generation in vivo? These issues provide food for thought and possible directions of further investigation.
References
Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM, Sajer SA, Furie B. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature. 1992; 359: 848–851.
Celi A, Pellegrini G, Lorenzet R, De Blasi A, Ready N, Furie BC, Furie B. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci U S A. 1994; 91: 8767–8771.
Weyrich AS, Elstad MR, McEver RP, McIntyre TM, Moore KL, Morrissey JH, Prescott SM, Zimmerman GA. Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest. 1996; 97: 1525–1534.
Weyrich AS, McIntyre TM, McEver RP, Prescott SM, Zimmerman GA. Monocyte tethering by P-selectin regulates monocyte chemotactic protein- 1 and tumor necrosis factor- secretion. Signal integration and NF- B translocation. J Clin Invest. 1995; 95: 2297–2303.
Andre P, Hartwell D, Hrachovinova I, Saffaripour S, Wagner DD. Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc Natl Acad Sci U S A. 2000; 97: 13835–13840.
Falati S, Liu Q, Gross P, Merrill-Skoloff G, Chou J, Vandendries E, Celi A, Croce K, Furie BC, Furie B. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med. 2003; 197: 1585–1598.
Hrachovinova II, Cambien B, Hafezi-Moghadam A, Kappelmayer J, Camphausen RT, Widom A, Xia L, Kazazian HH, Schaub RG, McEver RP, Wagner DD. Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med. 2003; 9: 1020–1025.
Furie B, Furie BC. Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends Mol Med. 2004; 10: 171–178.
Cambien B, Wagner DD. A new role in hemostasis for the adhesion receptor P-selectin. Trends Mol Med. 2004; 10: 179–186.
del Conde I, Nabi F, Tonda R, Thiagarajan P, Lopez JA, Kleiman NS. Effect of P-selectin on phosphatidylserine exposure and surface-dependent thrombin generation on monocytes. Arterioscler Thromb Vasc Biol. 2005; 25: 1065–1070.
Soriano-Garcia M, Padmanabhan K, de Vos AM, Tulinsky A. The Ca2+ ion and membrane binding structure of the Gla domain of Ca-prothrombin fragment 1. Biochemistry. 1992; 31: 2554–2566.
Freedman SJ, Blostein MD, Baleja JD, Jacobs M, Furie BC, Furie B. Identification of the phospholipid binding site in the vitamin K–dependent blood coagulation protein Factor IX. J Biol Chem. 1996; 271: 16227–16236.
Huang M, Rigby AC, Morelli X, Grant MA, Huang G, Furie B, Seaton B, Furie BC. Structural basis of membrane binding by Gla domains of vitamin K–dependent proteins. Nat Struct Biol. 2003; 10: 751–756.(Bruce Furie)