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(Chest. 2003;124:1S-3S.)
© 2003 American College of Chest Physicians

Thrombin*

Can’t Live Without It; Probably Die From It

Kenneth G. Mann, PhD

* From the Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT.

Correspondence to: Kenneth G. Mann, PhD, Department of Biochemistry, 89 Beaumont Ave, Given Building, Room C401, University of Vermont College of Medicine, Burlington, VT 05405; e-mail: Kenneth.Mann{at}uvm.edu

Thrombin is a multifaceted protein with a wide range of functions. Walter Seegers, a pioneer in thrombin work, referred to it as "the living enzyme of my blood."1 The central importance of thrombin in biology, physiology, and pathology is clearly shown by studies conducted with genetically homogenous mice made deficient in components of coagulant pathways essential to thrombin generation and its regulation. Transgenic mice deficient in tissue factor,2 factor VII,3 tissue factor pathway inhibitor,4 factor X,5 factor V,6 prothrombin,7 and protein C8 die in utero or shortly after birth. In contrast, in the outbred human population, deficiencies of coagulation components, essential in mice, yield consequences ranging from mild-to-severe pathology. These observations underscore the complexity of managing the outbred human population with respect to interventions for both thrombosis and hemostasis.

This monograph begins with my article discussing the formation of thrombin and its contributions to activation of factor VII, factor V, factor VIII, factor XI, and factor XIII. Next, Dr. DiCera discusses the regulation and functions of thrombin, including its central role in blood coagulation and its contribution to reactions that ensure the overall maintenance of vascular integrity. Dr. Brass then follows with a discussion of the contribution of thrombin to platelet activation. The role of thrombin in anticoagulation when combined with thrombomodulin in the protein C activation process is clarified by Dr. Esmon. As explained by Dr. Nesheim, thrombin also serves as the activator of the thrombin-activatable fibrinolysis inhibitor. Dr. Tracy summarizes current thoughts on the involvement of thrombin in arterial disease, followed by a discussion by Dr. Heit on its significance in the pathology and management of venous thromboembolism. Dr. Rickles concludes the issue with a discussion of the potential contribution of thrombin to the pathogenesis of cancer.

The role of the "living enzyme" is not limited to procoagulant and anticoagulant processes (Fig 1 ). Thrombin also acts as a potent mitogen, influencing smooth-muscle cells,9 macrophages,10 and endothelial cells.11 These growth factor effects are consequences of both direct activation of mitogenic pathways and {alpha}-thrombin–mediated secretion of growth factors. Thrombin is also responsible for the release of cytokines,12 vasoactive active compounds,13 and chemoattractants.14 In addition, {alpha}-thrombin itself is a chemoattractant.10 The enzyme also increases the permeability of the vascular endothelium,15 promotes adhesion to endothelial cells,16 and induces contraction to smooth-muscle cells.17 Thrombin has also been implicated in angiogenesis,18 the growth and metastasis of tumors,19 the initiation of bone absorption,20 and regulation of neurite outgrowth,21 and it plays a key role in muscle development.22



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  		Figure 1. A schematic representation of the multiple functions of thrombin as a biological mediator. Note that many functions are antagonistic to one another, eg, both a procoagulant and anticoagulant.

 
In all of these processes, thrombin is tightly regulated in terms of its formation and destruction. Congenital diseases associated with the absence or reduced production of thrombin (hemophilias) represent important clinical problems that fortunately are rarely encountered. However, the unregulated production of thrombin in an inappropriate location leading to a thrombotic occlusion is a frequently encountered problem. For the past century, thrombosis in the venous circulation and the embolization of venous clots have been recognized to be important contributors to pathology (see the article by Dr. Heit in this supplement). More recently, the significance of clot formation in the arterial circulation has led to the development of both biochemical and mechanical interventions to disrupt clots that cause myocardial infarction and stroke (see the article by Dr. Tracy in this supplement).

Unfortunately, the pace of development of methods used in the diagnosis of risk and prophylaxis for thrombosis has been relatively deficient. The methods for assessment of hemorrhagic or thrombotic risk are primarily the "prothrombin time" invented by Quick in 193523 and the "activated partial thromboplastin time" invented by Langdell and colleagues in 1953.24 While these tests have proved useful in identifying bleeding risk, they have limited utility when applied to the evaluation of thrombotic risk. Epidemiologic studies have identified a wide variety of risk factors for clinical thrombosis, but no study provides sufficiently strong incentives to invoke anticoagulant prophylaxis in the absence of a clinically defined thrombotic syndrome (see the articles by Dr. Tracy and Dr. Heit).

Methods for clinical intervention following the display of clinical thrombosis have been largely unchanged since the development of heparin in the 1920s and Warfarin in the 1940s. The development of low-molecular-weight heparins have represented a major advance in therapy for venous thrombosis (see the article by Dr. Heit in this supplement); however, these agents are still only available by subcutaneous injection. Warfarin is a powerful anticoagulant that acts to block the posttranslational modification of the vitamin K-dependent zymogens. It is the only orally available anticoagulant in routine use and must be regularly monitored by the prothrombin time standardized with the use of the international normalized ratio. Despite advances in monitoring, warfarin administration is a complex process that frequently occasions hemorrhagic risk.

This supplement will provide the reader with a current summary of progress in the field of thrombosis and hemostasis.


   Footnotes
 
Supported by grants HL 46703, HL 34575, and HL 07594 from the National Institutes of Health-National Heart, Lung and Blood Institute.


   References
TOP
 References
 

  1. Seegers, WH, Thomas, WR, Landaburu, RH, et al (1960) Prothrombin: living enzyme of my blood. Rec Chem Prog 21,1-18
  2. Toomey, JR, Kratzer, KE, Lasky, NM, et al Targeted disruption of the murine tissue factor gene results in embryonic lethality. Blood 1996;88,1583-1587[Abstract/Free Full Text]
  3. Rosen, ED, Chan, JC, Idusogie, E, et al Mice lacking factor VII develop normally but suffer fatal perinatal bleeding. Nature 1997;390,290-294[CrossRef][Medline]
  4. Huang, ZF, Higuchi, D, Lasky, N, et al Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice. Blood 1997;90,944-951[Abstract/Free Full Text]
  5. Dewerchin, M, Liang, Z, Moons, L, et al Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice. Thromb Haemost 2000;83,185-190[ISI][Medline]
  6. Cui, J, O’Shea, KS, Purkayastha, A, et al Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V. Nature 1996;384,66-68[CrossRef][Medline]
  7. Sun, WY, Witte, DP, Degen, JL, et al Prothrombin deficiency results in embryonic and neonatal lethality in mice. Proc Natl Acad Sci U S A 1998;95,7597-7602[Abstract/Free Full Text]
  8. Jalbert, LR, Rosen, ED, Moons, L, et al Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice. J Clin Invest 1998;102,1481-1488[ISI][Medline]
  9. McNamara, CA, Sarembock, IJ, Gimple, LW, et al Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytically activated receptor. J Clin Invest 1993;91,94-98[ISI][Medline]
  10. Bar-Shavit, R, Kahn, AJ, Mann, KG, et al Identification of a thrombin sequence with growth factor activity on macrophages. Proc Natl Acad Sci U S A 1986;83,976-980[Abstract/Free Full Text]
  11. Sago, H, Iinuma, K Cell shape change and cytosolic Ca2+ in human umbilical-vein endothelial cells stimulated with thrombin. Thromb Haemost 1992;67,331-334[ISI][Medline]
  12. Harlan, JM, Thompson, PJ, Ross, RR, et al Alpha-thrombin induces release of platelet-derived growth factor-like molecule(s) by cultured human endothelial cells. J Cell Biol 1986;103,1129-1133[Abstract/Free Full Text]
  13. Douglas, SA, Louden, C, Vickery-Clark, LM, et al A role for endogenous endothelin-1 in neointimal formation after rat carotid artery balloon angioplasty: protective effects of the novel nonpeptide endothelin receptor antagonist SB 209670. Circ Res 1994;75,190-197[Abstract]
  14. Seino, Y, Ikeda, U, Ikeda, M, et al Interleukin 6 gene transcripts are expressed in human atherosclerotic lesions. Cytokine 1994;6,87-91[CrossRef][ISI][Medline]
  15. Malik, AB, Fenton, JW Thrombin-mediated increase in vascular endothelial permeability. Semin Thromb Haemost 1992;18,193-199[ISI][Medline]
  16. Sugama, Y, Malik, AB Thrombin receptor 14-amino acid peptide mediates endothelial hyperadhesivity and neutrophil adhesion by P-selectin-dependent mechanism. Circ Res 1992;71,1015-1019[Abstract]
  17. Hollenberg, MD, Yang, SG, Laniyonu, AA, et al Action of thrombin receptor polypeptide in gastric smooth muscle: identification of a core pentapeptide retaining full thrombin-mimetic intrinsic activity. Mol Pharmacol 1992;42,186-191[Abstract]
  18. Tsopanoglou, NE, Maragoudakis, ME On the mechanism of thrombin-induced angiogenesis: potentiation of vascular endothelial growth factor activity on endothelial cells by up-regulation of its receptors. J Biol Chem 1999;274,23969-23976[Abstract/Free Full Text]
  19. Folkman, J Tumor angiogenesis. Adv Cancer Res 1985;43,175-203[ISI][Medline]
  20. Gustafson, GT, Lerner, U Thrombin, a stimulator of bone resorption. Biosci Rep 1983;3,255-261[CrossRef][ISI][Medline]
  21. Gurwitz, D, Cunningham, DD Thrombin modulates and reverses neuroblastoma neurite outgrowth. Proc Natl Acad Sci U S A 1988;85,3440-3444[Abstract/Free Full Text]
  22. Chinni, C, de Niese, MR, Tew, DJ, et al Thrombin, a survival factor for cultured myoblasts. J Biol Chem 1999;274,9169-9174[Abstract/Free Full Text]
  23. Quick, AJ The prothrombin time in haemophilia and in obstructive jaundice. J Biol Chem 1935;109,73-74
  24. Langdell, RD, Wagner, RH, Brinkhous, KM Effect of antihemophilic factor on one-stage clotting tests: a presumptive test of hemophilia and a single one-stage anti-hemophilic factor assay procedure. J Lab Clin Med 1953;41,7637-7647




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