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Overview of hemostasis

Lawrence LK Leung, MD
Section Editor
Pier Mannuccio Mannucci, MD
Deputy Editor
Jennifer S Tirnauer, MD


Hemostasis is the process of blood clot formation at the site of vessel injury. When a blood vessel wall is disrupted, the hemostatic response must be quick, localized, and carefully regulated. Abnormal bleeding or thrombosis (ie, nonphysiologic blood clotting not required for hemostatic regulation) may occur when specific elements of these processes are missing or dysfunctional.

The pathways of thrombin-stimulated fibrin clot formation and plasmin-induced clot lysis are linked and carefully regulated (figure 1 and figure 2 and figure 3) [1]. When they work in coordinated harmony, a clot is laid down initially to stop bleeding, followed by eventual clot lysis and tissue remodeling.

Abnormal bleeding can result from diminished thrombin generation (eg, due to factor VIII deficiency) or enhanced clot lysis (eg, due to alpha-2-antiplasmin deficiency). Conversely, excessive production of thrombin (eg, due to an inherited thrombophilia) can lead to thrombosis.

The elements responsible for normal hemostasis will be reviewed here. Approaches to the patient with abnormal bleeding or abnormal thrombosis are discussed separately. (See "Approach to the adult patient with a bleeding diathesis".)

The uses of platelet function testing and coagulation assays to diagnose hemostatic abnormalities are discussed separately. (See "Platelet function testing" and "Clinical use of coagulation tests".)


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  1. Lane DA, Philippou H, Huntington JA. Directing thrombin. Blood 2005; 106:2605.
  2. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359:938.
  3. Watson SP. Collagen receptor signaling in platelets and megakaryocytes. Thromb Haemost 1999; 82:365.
  4. Coughlin SR. Protease-activated receptors and platelet function. Thromb Haemost 1999; 82:353.
  5. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407:258.
  6. Brass LF. Thrombin and platelet activation. Chest 2003; 124:18S.
  7. Leger AJ, Covic L, Kuliopulos A. Protease-activated receptors in cardiovascular diseases. Circulation 2006; 114:1070.
  8. Kahn ML, Zheng YW, Huang W, et al. A dual thrombin receptor system for platelet activation. Nature 1998; 394:690.
  9. Dubois C, Panicot-Dubois L, Gainor JF, et al. Thrombin-initiated platelet activation in vivo is vWF independent during thrombus formation in a laser injury model. J Clin Invest 2007; 117:953.
  10. Hollopeter G, Jantzen HM, Vincent D, et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409:202.
  11. Clemetson KJ. Platelet GPIb-V-IX complex. Thromb Haemost 1997; 78:266.
  12. López JA, Andrews RK, Afshar-Kharghan V, Berndt MC. Bernard-Soulier syndrome. Blood 1998; 91:4397.
  13. Sixma JJ, van Zanten GH, Huizinga EG, et al. Platelet adhesion to collagen: an update. Thromb Haemost 1997; 78:434.
  14. Savage B, Saldívar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 1996; 84:289.
  15. Bennett JS, Vilaire G. Exposure of platelet fibrinogen receptors by ADP and epinephrine. J Clin Invest 1979; 64:1393.
  16. Savage B, Shattil SJ, Ruggeri ZM. Modulation of platelet function through adhesion receptors. A dual role for glycoprotein IIb-IIIa (integrin alpha IIb beta 3) mediated by fibrinogen and glycoprotein Ib-von Willebrand factor. J Biol Chem 1992; 267:11300.
  17. Shattil SJ, Kashiwagi H, Pampori N. Integrin signaling: the platelet paradigm. Blood 1998; 91:2645.
  18. Coller BS, Shattil SJ. The GPIIb/IIIa (integrin alphaIIbbeta3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend. Blood 2008; 112:3011.
  19. Hodivala-Dilke KM, McHugh KP, Tsakiris DA, et al. Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 1999; 103:229.
  20. Kroll MH, Schafer AI. Biochemical mechanisms of platelet activation. Blood 1989; 74:1181.
  21. Gawaz M, Neumann FJ, Dickfeld T, et al. Activated platelets induce monocyte chemotactic protein-1 secretion and surface expression of intercellular adhesion molecule-1 on endothelial cells. Circulation 1998; 98:1164.
  22. Harrison P, Savidge GF, Cramer EM. The origin and physiological relevance of alpha-granule adhesive proteins. Br J Haematol 1990; 74:125.
  23. Reinhardt C, von Brühl ML, Manukyan D, et al. Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation. J Clin Invest 2008; 118:1110.
  24. Cho J, Furie BC, Coughlin SR, Furie B. A critical role for extracellular protein disulfide isomerase during thrombus formation in mice. J Clin Invest 2008; 118:1123.
  25. Kojima H, Newton-Nash D, Weiss HJ, et al. Production and characterization of transformed B-lymphocytes expressing the membrane defect of Scott syndrome. J Clin Invest 1994; 94:2237.
  26. Hansson K, Stenflo J. Post-translational modifications in proteins involved in blood coagulation. J Thromb Haemost 2005; 3:2633.
  27. Furie B, Bouchard BA, Furie BC. Vitamin K-dependent biosynthesis of gamma-carboxyglutamic acid. Blood 1999; 93:1798.
  28. Rapaport SI, Rao LV. The tissue factor pathway: how it has become a "prima ballerina". Thromb Haemost 1995; 74:7.
  29. Mann KG, Brummel-Ziedins K, Orfeo T, Butenas S. Models of blood coagulation. Blood Cells Mol Dis 2006; 36:108.
  30. Camire RM, Bos MH. The molecular basis of factor V and VIII procofactor activation. J Thromb Haemost 2009; 7:1951.
  31. Ivanciu L, Krishnaswamy S, Camire RM. New insights into the spatiotemporal localization of prothrombinase in vivo. Blood 2014; 124:1705.
  32. Butenas S, van 't Veer C, Mann KG. Evaluation of the initiation phase of blood coagulation using ultrasensitive assays for serine proteases. J Biol Chem 1997; 272:21527.
  33. Jesty J, Spencer AK, Nemerson Y. The mechanism of activation of factor X. Kinetic control of alternative pathways leading to the formation of activated factor X. J Biol Chem 1974; 249:5614.
  34. Baugh RJ, Krishnaswamy S. Role of the activation peptide domain in human factor X activation by the extrinsic Xase complex. J Biol Chem 1996; 271:16126.
  35. Osterud B, Rapaport SI. Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation. Proc Natl Acad Sci U S A 1977; 74:5260.
  36. Morrison SA, Jesty J. Tissue factor-dependent activation of tritium-labeled factor IX and factor X in human plasma. Blood 1984; 63:1338.
  37. Rosing J, van Rijn JL, Bevers EM, et al. The role of activated human platelets in prothrombin and factor X activation. Blood 1985; 65:319.
  38. Esmon CT. The endothelial protein C receptor. Curr Opin Hematol 2006; 13:382.
  39. Krishnaswamy S. The transition of prothrombin to thrombin. J Thromb Haemost 2013; 11 Suppl 1:265.
  40. Sims PJ, Wiedmer T, Esmon CT, et al. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity. J Biol Chem 1989; 264:17049.
  41. Toti F, Satta N, Fressinaud E, et al. Scott syndrome, characterized by impaired transmembrane migration of procoagulant phosphatidylserine and hemorrhagic complications, is an inherited disorder. Blood 1996; 87:1409.
  42. Zhou Q, Sims PJ, Wiedmer T. Expression of proteins controlling transbilayer movement of plasma membrane phospholipids in the B lymphocytes from a patient with Scott syndrome. Blood 1998; 92:1707.
  43. Suzuki J, Umeda M, Sims PJ, Nagata S. Calcium-dependent phospholipid scrambling by TMEM16F. Nature 2010; 468:834.
  44. Yang H, Kim A, David T, et al. TMEM16F forms a Ca2+-activated cation channel required for lipid scrambling in platelets during blood coagulation. Cell 2012; 151:111.
  45. Bächli E. History of tissue factor. Br J Haematol 2000; 110:248.
  46. Mandal SK, Pendurthi UR, Rao LV. Cellular localization and trafficking of tissue factor. Blood 2006; 107:4746.
  47. Chen VM, Ahamed J, Versteeg HH, et al. Evidence for activation of tissue factor by an allosteric disulfide bond. Biochemistry 2006; 45:12020.
  48. Wong JW, Hogg PJ. Analysis of disulfide bonds in protein structures. J Thromb Haemost 2010.
  49. Butenas S, Orfeo T, Mann KG. Tissue factor in coagulation: Which? Where? When? Arterioscler Thromb Vasc Biol 2009; 29:1989.
  50. Bach RR, Monroe D. What is wrong with the allosteric disulfide bond hypothesis? Arterioscler Thromb Vasc Biol 2009; 29:1997.
  51. Kothari H, Nayak RC, Rao LV, Pendurthi UR. Cystine 186-cystine 209 disulfide bond is not essential for the procoagulant activity of tissue factor or for its de-encryption. Blood 2010; 115:4273.
  52. Giesen PL, Rauch U, Bohrmann B, et al. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci U S A 1999; 96:2311.
  53. Bogdanov VY, Balasubramanian V, Hathcock J, et al. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med 2003; 9:458.
  54. Del Conde I, Shrimpton CN, Thiagarajan P, López JA. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 2005; 106:1604.
  55. Panes O, Matus V, Sáez CG, et al. Human platelets synthesize and express functional tissue factor. Blood 2007; 109:5242.
  56. Bouchard BA, Mann KG, Butenas S. No evidence for tissue factor on platelets. Blood 2010; 116:854.
  57. Morrissey JH. Tissue factor: an enzyme cofactor and a true receptor. Thromb Haemost 2001; 86:66.
  58. Konigsberg W, Kirchhofer D, Riederer MA, Nemerson Y. The TF:VIIa complex: clinical significance, structure-function relationships and its role in signaling and metastasis. Thromb Haemost 2001; 86:757.
  59. Broze GJ Jr. Tissue factor pathway inhibitor and the revised theory of coagulation. Annu Rev Med 1995; 46:103.
  60. Pittman DD, Kaufman RJ. Proteolytic requirements for thrombin activation of anti-hemophilic factor (factor VIII). Proc Natl Acad Sci U S A 1988; 85:2429.
  61. Naito K, Fujikawa K. Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces. J Biol Chem 1991; 266:7353.
  62. von dem Borne PA, Meijers JC, Bouma BN. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995; 86:3035.
  63. Gailani D, Broze GJ Jr. Factor XI activation in a revised model of blood coagulation. Science 1991; 253:909.
  64. Di Scipio RG, Kurachi K, Davie EW. Activation of human factor IX (Christmas factor). J Clin Invest 1978; 61:1528.
  65. Sun Y, Gailani D. Identification of a factor IX binding site on the third apple domain of activated factor XI. J Biol Chem 1996; 271:29023.
  66. Kornberg A, Rao NN, Ault-Riché D. Inorganic polyphosphate: a molecule of many functions. Annu Rev Biochem 1999; 68:89.
  67. Ruiz FA, Lea CR, Oldfield E, Docampo R. Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J Biol Chem 2004; 279:44250.
  68. Morrissey JH, Choi SH, Smith SA. Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation. Blood 2012; 119:5972.
  69. Lämmle B, Wuillemin WA, Huber I, et al. Thromboembolism and bleeding tendency in congenital factor XII deficiency--a study on 74 subjects from 14 Swiss families. Thromb Haemost 1991; 65:117.
  70. Colman RW, Bagdasarian A, Talamo RC, et al. Williams trait. Human kininogen deficiency with diminished levels of plasminogen proactivator and prekallikrein associated with abnormalities of the Hageman factor-dependent pathways. J Clin Invest 1975; 56:1650.
  71. Asakai R, Chung DW, Davie EW, Seligsohn U. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med 1991; 325:153.
  72. Choi SH, Smith SA, Morrissey JH. Polyphosphate is a cofactor for the activation of factor XI by thrombin. Blood 2011; 118:6963.
  73. Renné T, Pozgajová M, Grüner S, et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005; 202:271.
  74. Rosen ED, Gailani D, Castellino FJ. FXI is essential for thrombus formation following FeCl3-induced injury of the carotid artery in the mouse. Thromb Haemost 2002; 87:774.
  75. Salomon O, Steinberg DM, Koren-Morag N, et al. Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood 2008; 111:4113.
  76. Büller HR, Bethune C, Bhanot S, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372:232.
  77. Cochery-Nouvellon E, Mercier E, Lissalde-Lavigne G, et al. Homozygosity for the C46T polymorphism of the F12 gene is a risk factor for venous thrombosis during the first pregnancy. J Thromb Haemost 2007; 5:700.
  78. Reuner KH, Jenetzky E, Aleu A, et al. Factor XII C46T gene polymorphism and the risk of cerebral venous thrombosis. Neurology 2008; 70:129.
  79. Tirado I, Soria JM, Mateo J, et al. Association after linkage analysis indicates that homozygosity for the 46C-->T polymorphism in the F12 gene is a genetic risk factor for venous thrombosis. Thromb Haemost 2004; 91:899.
  80. Von dem Borne PA, Bajzar L, Meijers JC, et al. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis. J Clin Invest 1997; 99:2323.
  81. Minnema MC, Friederich PW, Levi M, et al. Enhancement of rabbit jugular vein thrombolysis by neutralization of factor XI. In vivo evidence for a role of factor XI as an anti-fibrinolytic factor. J Clin Invest 1998; 101:10.
  82. Mann KG, Krishnaswamy S, Lawson JH. Surface-dependent hemostasis. Semin Hematol 1992; 29:213.
  83. Suzuki K, Dahlbäck B, Stenflo J. Thrombin-catalyzed activation of human coagulation factor V. J Biol Chem 1982; 257:6556.
  84. Tracy PB, Eide LL, Bowie EJ, Mann KG. Radioimmunoassay of factor V in human plasma and platelets. Blood 1982; 60:59.
  85. Mann KG, Nesheim ME, Hibbard LS, Tracy PB. The role of factor V in the assembly of the prothrombinase complex. Ann N Y Acad Sci 1981; 370:378.
  86. Tracy PB, Giles AR, Mann KG, et al. Factor V (Quebec): a bleeding diathesis associated with a qualitative platelet Factor V deficiency. J Clin Invest 1984; 74:1221.
  87. Kane WH, Lindhout MJ, Jackson CM, Majerus PW. Factor Va-dependent binding of factor Xa to human platelets. J Biol Chem 1980; 255:1170.
  88. Tracy PB, Eide LL, Mann KG. Human prothrombinase complex assembly and function on isolated peripheral blood cell populations. J Biol Chem 1985; 260:2119.
  89. Mosesson MW. The roles of fibrinogen and fibrin in hemostasis and thrombosis. Semin Hematol 1992; 29:177.
  90. Pisano JJ, Finlayson JS, Peyton MP. [Cross-link in fibrin polymerized by factor 13: epsilon-(gamma-glutamyl)lysine]. Science 1968; 160:892.
  91. Aleman MM, Byrnes JR, Wang JG, et al. Factor XIII activity mediates red blood cell retention in venous thrombi. J Clin Invest 2014; 124:3590.
  92. Greenberg CS, Achyuthan KE, Fenton JW 2nd. Factor XIIIa formation promoted by complexing of alpha-thrombin, fibrin, and plasma factor XIII. Blood 1987; 69:867.
  93. Rak J. New checkpoint of the coagulant phenotype. Blood 2014; 124:3511.
  94. Iqbal MB, Johns M, Cao J, et al. PARP-14 combines with tristetraprolin in the selective posttranscriptional control of macrophage tissue factor expression. Blood 2014; 124:3646.
  95. Perry DJ. Antithrombin and its inherited deficiencies. Blood Rev 1994; 8:37.
  96. Marcum JA, McKenney JB, Rosenberg RD. Acceleration of thrombin-antithrombin complex formation in rat hindquarters via heparinlike molecules bound to the endothelium. J Clin Invest 1984; 74:341.
  97. Mammen EF. Antithrombin: its physiological importance and role in DIC. Semin Thromb Hemost 1998; 24:19.
  98. Weitz JI. Heparan sulfate: antithrombotic or not? J Clin Invest 2003; 111:952.
  99. Esmon CT, Esmon NL, Harris KW. Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation. J Biol Chem 1982; 257:7944.
  100. Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264:4743.
  101. Esmon CT. The protein C pathway. Chest 2003; 124:26S.
  102. Dutt T, Toh CH. The Yin-Yang of thrombin and activated protein C. Br J Haematol 2008; 140:505.
  103. Esmon CT, Xu J, Gu JM, et al. Endothelial protein C receptor. Thromb Haemost 1999; 82:251.
  104. Taylor FB Jr, Peer GT, Lockhart MS, et al. Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood 2001; 97:1685.
  105. Saposnik B, Reny JL, Gaussem P, et al. A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis. Blood 2004; 103:1311.
  106. Isermann B, Hendrickson SB, Zogg M, et al. Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis. J Clin Invest 2001; 108:537.
  107. Walker FJ. Regulation of activated protein C by protein S. The role of phospholipid in factor Va inactivation. J Biol Chem 1981; 256:11128.
  108. Kalafatis M, Bertina RM, Rand MD, Mann KG. Characterization of the molecular defect in factor VR506Q. J Biol Chem 1995; 270:4053.
  109. Fulcher CA, Gardiner JE, Griffin JH, Zimmerman TS. Proteolytic inactivation of human factor VIII procoagulant protein by activated human protein C and its analogy with factor V. Blood 1984; 63:486.
  110. O'Brien LM, Mastri M, Fay PJ. Regulation of factor VIIIa by human activated protein C and protein S: inactivation of cofactor in the intrinsic factor Xase. Blood 2000; 95:1714.
  111. Thorelli E, Kaufman RJ, Dahlbäck B. Cleavage of factor V at Arg 506 by activated protein C and the expression of anticoagulant activity of factor V. Blood 1999; 93:2552.
  112. Castoldi E, Brugge JM, Nicolaes GA, et al. Impaired APC cofactor activity of factor V plays a major role in the APC resistance associated with the factor V Leiden (R506Q) and R2 (H1299R) mutations. Blood 2004; 103:4173.
  113. Bajaj MS, Birktoft JJ, Steer SA, Bajaj SP. Structure and biology of tissue factor pathway inhibitor. Thromb Haemost 2001; 86:959.
  114. Broze GJ Jr, Warren LA, Novotny WF, et al. The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action. Blood 1988; 71:335.
  115. Baugh RJ, Broze GJ Jr, Krishnaswamy S. Regulation of extrinsic pathway factor Xa formation by tissue factor pathway inhibitor. J Biol Chem 1998; 273:4378.
  116. Jesty J, Wun TC, Lorenz A. Kinetics of the inhibition of factor Xa and the tissue factor-factor VIIa complex by the tissue factor pathway inhibitor in the presence and absence of heparin. Biochemistry 1994; 33:12686.
  117. Caplice NM, Panetta C, Peterson TE, et al. Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: a novel link between lipoproteins and thrombosis. Blood 2001; 98:2980.
  118. Bajaj MS, Bajaj SP. Tissue factor pathway inhibitor: potential therapeutic applications. Thromb Haemost 1997; 78:471.
  119. Topper JN, Cai J, Falb D, Gimbrone MA Jr. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci U S A 1996; 93:10417.
  120. Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 2006; 116:4.
  121. Smith WL. The eicosanoids and their biochemical mechanisms of action. Biochem J 1989; 259:315.
  122. Phillips DR, Conley PB, Sinha U, Andre P. Therapeutic approaches in arterial thrombosis. J Thromb Haemost 2005; 3:1577.
  123. Clarke RJ, Mayo G, Price P, FitzGerald GA. Suppression of thromboxane A2 but not of systemic prostacyclin by controlled-release aspirin. N Engl J Med 1991; 325:1137.
  124. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329:2002.
  125. Cozzi MR, Guglielmini G, Battiston M, et al. Visualization of nitric oxide production by individual platelets during adhesion in flowing blood. Blood 2015; 125:697.
  126. Qiu C, Muchant D, Beierwaltes WH, et al. Evolution of chronic nitric oxide inhibition hypertension: relationship to renal function. Hypertension 1998; 31:21.
  127. Liang Y, Fu Y, Qi R, et al. Cartilage oligomeric matrix protein is a natural inhibitor of thrombin. Blood 2015; 126:905.
  128. Collen D. On the regulation and control of fibrinolysis. Edward Kowalski Memorial Lecture. Thromb Haemost 1980; 43:77.
  129. Hoylaerts M, Rijken DC, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem 1982; 257:2912.
  130. Samis JA, Ramsey GD, Walker JB, et al. Proteolytic processing of human coagulation factor IX by plasmin. Blood 2000; 95:943.
  131. Hur WS, Mazinani N, Lu XJ, et al. Coagulation factor XIIIa is inactivated by plasmin. Blood 2015; 126:2329.
  132. Kolev K, Machovich R. Molecular and cellular modulation of fibrinolysis. Thromb Haemost 2003; 89:610.
  133. Stein CM, Brown N, Vaughan DE, et al. Regulation of local tissue-type plasminogen activator release by endothelium-dependent and endothelium-independent agonists in human vasculature. J Am Coll Cardiol 1998; 32:117.
  134. Yamamoto C, Kaji T, Sakamoto M, et al. Calcium regulation of tissue plasminogen activator and plasminogen activator inhibitor-1 release from cultured human vascular endothelial cells. Thromb Res 1994; 74:163.
  135. van Zonneveld AJ, Veerman H, Pannekoek H. Autonomous functions of structural domains on human tissue-type plasminogen activator. Proc Natl Acad Sci U S A 1986; 83:4670.
  136. Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69:381.
  137. Van Meijer M, Pannekoek H. Structure of plasminogen activator inhibitor 1 (PAI-1) and its function in fibrinolysis: An update. Fibrinolysis 1995; 9:263.
  138. Edelberg JM, Pizzo SV. Lipoprotein (a) promotes plasmin inhibition by alpha 2-antiplasmin. Biochem J 1992; 286 ( Pt 1):79.
  139. Fay WP, Shapiro AD, Shih JL, et al. Brief report: complete deficiency of plasminogen-activator inhibitor type 1 due to a frame-shift mutation. N Engl J Med 1992; 327:1729.
  140. Fay WP, Parker AC, Condrey LR, Shapiro AD. Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene. Blood 1997; 90:204.
  141. Schwartz BS. Differential inhibition of soluble and cell surface receptor-bound single-chain urokinase by plasminogen activator inhibitor type 2. A potential regulatory mechanism. J Biol Chem 1994; 269:8319.
  142. Favier R, Aoki N, de Moerloose P. Congenital alpha(2)-plasmin inhibitor deficiencies: a review. Br J Haematol 2001; 114:4.
  143. Nesheim M. Fibrinolysis and the plasma carboxypeptidase. Curr Opin Hematol 1998; 5:309.
  144. Redlitz A, Tan AK, Eaton DL, Plow EF. Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest 1995; 96:2534.
  145. Booth NA. TAFI meets the sticky ends. Thromb Haemost 2001; 85:1.
  146. Binette TM, Taylor FB Jr, Peer G, Bajzar L. Thrombin-thrombomodulin connects coagulation and fibrinolysis: more than an in vitro phenomenon. Blood 2007; 110:3168.
  147. Bajzar L, Morser J, Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem 1996; 271:16603.
  148. Mosnier LO, Meijers JC, Bouma BN. Regulation of fibrinolysis in plasma by TAFI and protein C is dependent on the concentration of thrombomodulin. Thromb Haemost 2001; 85:5.
  149. Valnickova Z, Enghild JJ. Human procarboxypeptidase U, or thrombin-activable fibrinolysis inhibitor, is a substrate for transglutaminases. Evidence for transglutaminase-catalyzed cross-linking to fibrin. J Biol Chem 1998; 273:27220.
  150. Mosnier LO, Lisman T, van den Berg HM, et al. The defective down regulation of fibrinolysis in haemophilia A can be restored by increasing the TAFI plasma concentration. Thromb Haemost 2001; 86:1035.
  151. Broze GJ Jr, Higuchi DA. Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma. Blood 1996; 88:3815.
  152. Lisman T, Mosnier LO, Lambert T, et al. Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A. Blood 2002; 99:175.
  153. Foley JH, Nesheim ME. Soluble thrombomodulin partially corrects the premature lysis defect in FVIII-deficient plasma by stimulating the activation of thrombin activatable fibrinolysis inhibitor. J Thromb Haemost 2009; 7:453.
  154. Van Thiel DH, George M, Fareed J. Low levels of thrombin activatable fibrinolysis inhibitor (TAFI) in patients with chronic liver disease. Thromb Haemost 2001; 85:667.
  155. Colucci M, Binetti BM, Tripodi A, et al. Hyperprothrombinemia associated with prothrombin G20210A mutation inhibits plasma fibrinolysis through a TAFI-mediated mechanism. Blood 2004; 103:2157.
  156. Degen JL, Bugge TH, Goguen JD. Fibrin and fibrinolysis in infection and host defense. J Thromb Haemost 2007; 5 Suppl 1:24.
  157. Leung L, Morser J. Hemostasis and Vascular Inflammation. In: Inflammatory Diseases of Blood Vessels, Second Edition, Hoffman GS, Weyand CM, Langford CA, et al. (Eds), Wiley-Blackwell, Oxford, UK 2012. p.105.