SEARCH:   Advanced

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Santoro, S. A. Search for Related Content PubMed PubMed Citation Articles by Santoro, S. A. Social Bookmarking                   What's this? Next Article  Blood, Vol. 93 No. 11 (June 1), 1999: pp. 3575-3577 INTRODUCTION: FOCUS ON HEMATOLOGY Platelet Surface Collagen Receptor Polymorphisms: Variable Receptor Expression and Thrombotic/Hemorrhagic Risk By Samuel A. Santoro From the Division of Laboratory Medicine, Washington University School of Medicine, St Louis, MO.     ARTICLE TOP ARTICLE REFERENCES TWO ARTICLES in this issue focus attention on the 21 integrin, a platelet surface collagen receptor. The articles address the potential contributions of varying 21 integrin expression to the manifestation of hemorrhagic or thrombotic disease. For some years, fibrillar collagens have been recognized as the most thrombogenic macromolecular constituents of the vessel wall.1 Unlike many other components of the extracellular matrix, the collagens not only support platelet adhesion, but also promote platelet activation and subsequent aggregation. Remarkable progress has been made over the last 10 to 12 years in placing the platelet-collagen interaction on a firm mechanistic foundation.2-5 Of course, there are still important questions to be answered and details to be filled in, but a reasonable vision of the overall process now seems in hand. Formation of a stable platelet aggregate on collagenous substrates is the end result of a complex series of distinct, but integrated and inter-related, receptor-ligand adhesive interactions. The critical role of von Willebrand factor (vWF) in mediating platelet deposition onto injured vessel walls in the presence of the shear forces encountered at the interface between flowing blood and the vessel wall has been long appreciated.6 The platelet adhesion promoting activity of the multimeric vWF is largely mediated by the bridging of vessel wall constituents, such as collagens to which vWF binds, and the glycoprotein Ib-IX-V complex on the platelet surface by vWF. Collagen VI seems to play an especially important role as a vessel wall ligand for vWF.7 Quantitative deficiencies or qualitative defects in vWF that compromise the platelet adhesion promoting activity give rise to the bleeding disorder, von Willebrand disease.8 Recent studies have shed additional insight into the mechanism by which vWF confers shear resistance on adherent platelets and facilitates subsequent downstream hemostatic events.9 vWF mediates an initial tethering of platelets to the adhesive substrate. Under the influence of shear, platelets translocate along the surface in the direction of flow tethered by vWF until movement is arrested by firm engagement of a second receptor. In the case of collagen-rich substrates, it is the platelet surface 21 integrin that engages collagens and halts translocation.9 This paradigm mechanistically resembles the previously established mechanism of leukocyte adhesion to vessel walls in which tethering and rolling occur via selectin-mediated adhesive interactions with firm attachment and stable adhesion resulting from the subsequent engagement of leukocyte surface 2 integrins.10 The 21 integrin (glycoprotein Ia-IIa, VLA-2, CD49b/CD29) is the most intensively studied and best understood of the collagen receptors. The 21 integrin functions as a collagen receptor not only on platelets, but also on a wide variety of other cell types where it mediates adhesion to collagen and as a consequence makes important contributions to the control and maintenance of cell phenotype.3,11 The first real clue to the receptor function of the 21 integrin came from platelet pathobiology. Nieuwenhuis et al12,13 described a patient with a bleeding disorder that showed selective nonresponsiveness to collagen used as a stimulus for platelet aggregation, markedly impaired adhesion to collagenous substrates, and a selective deficiency of the 2 integrin subunit (glycoprotein Ia) resulting in the absence of platelet surface 21 integrin. Subsequently, additional patients have been described with bleeding disorders arising from the development of inhibitory antibodies against the 21 integrin14 or acquired deficiency of the integrin associated with myeloproliferative disorders or other etiologies.15,16 After the development of stable 21 integrin-mediated adhesion, glycoprotein VI engages collagen as a lower affinity, signal transducing coreceptor.14,17-19 Although glycoprotein VI has yet to be been purified, characterized, or cloned, its role in collagen-induced platelet activation seems relatively clear. In the absence of 21 integrin expression or in the presence of effective 21 integrin blockade, glycoprotein VI is unable to support effective platelet adhesion to collagen. On the other hand, in the absence of glycoprotein VI expression20,21 or in the presence of an inhibitory glycoprotein VI antibody,22 adhesion occurs (although it is reduced) but subsequent platelet activation is markedly impaired. Most recent studies point to roles for signals emanating from both the 21 integrin and glycoprotein VI as essential for the attainment of maximal collagen-induced aggregation/activation.18-23 In glycoprotein VI-deficient platelets, collagen-induced activation of syk is severely compromised; activation of c-src is not.24 A putative glycoprotein VI ligand stimulates tyrosine phosphorylation of syk and phospholipase C2.25 These events appear to represent important steps along the pathway to collagen-induced platelet activation. It is not yet clear where the 65-kD protein recently described by Chiang et al26 fits into the process. As a consequence of platelet activation and inside-out signaling, glycoprotein IIb-IIIa (IIb3 integrin) acquires the ability to bind fluid phase fibrinogen and thereby produce platelet aggregation.27 Only when the entire series of ligand-receptor interactions takes place in a concerted and coordinated manner does normal formation of the platelet hemostatic plug occur. The two articles in this issue draw our attention to previously unrecognized (potential) contributions of platelet surface 21 integrin expression to hemorrhagic and thrombotic disorders. One, by Di Paola et al,28 focuses on the exacerbation of bleeding manifestations in von Willebrand disease associated with lower levels of platelet surface 21 integrin. A second by Carlsson et al29 raises the possibility that higher levels of platelet 21 integrin expression constitute a genetic risk factor for the development of stroke in younger patients. The 21 integrin is expressed at relatively low level (only 1,000 to 3,000 copies per platelet) relative to other major platelet adhesive receptors. Although relatively low, the level of platelet 21 expression varies widely (up to 10-fold) and correlates with platelet adhesivity to collagens.30 Recent analyses indicate that DNA sequence polymorphisms within the 2 integrin gene are linked to the level of platelet surface 21 integrin expression.31,32 The sequence variants include two silent (ie, the amino acid sequence is unchanged) polymorphisms at nucleotide 807 (T or C) and nucleotide 873 (A or G). The two polymorphisms are linked. The 807C/873G pair is associated with lower levels of 21 integrin expression than is the 807T/873A pair. The molecular mechanism(s) underlying the differing levels of expression remain to be elucidated. Although the varying levels of 21 expression appear to be of little significance in individuals that are otherwise hemostatically normal, Di Paola et al28 reasoned that the varying collagen reactivity associated with varying 21 expression might become clinically significant/apparent in a setting where the overall platelet-collagen interaction was already partially compromised. Thus, they chose to study patients with von Willebrand disease. In the setting of mild type I von Willebrand disease they found that for a given level of ristocetin cofactor activity, the time to closure of a model wound was more prolonged in individuals with the 807C polymorphism (low 21 expressors) than in individuals with the 807T polymorphism (high 21 expressors). Not unexpectedly, in the setting of more severe von Willebrand disease which itself produced a profound defect in closure time, the level of 21 integrin expression was of no additional consequence. Thus, varying density of collagen receptor expression on the platelet surface might contribute to the recognized variability of bleeding manifestations observed among von Willebrand disease patients (even within a family) with similar von Willebrand factor antigen and ristocetin cofactor activity levels. Carlsson et al29 took a complementary approach. The intriguing results of their small case-control study revealed that the 807T/873G polymorphism (high expressors) was the only over-represented variable (odds ratio, 3.02; 95% confidence interval, 1.20 to 7.61) in a group of young (<50 years) stroke patients. The prevalence of traditional risk factors such as hypertension, diabetes mellitus, smoking, elevated cholesterol, and family history did not significantly differ between the case and control populations. Unfortunately, neither the presence of atherosclerosis nor of other hematologic risk factors was ascertained. In older patients (>50 years) the more traditional risk factors dominated and the 807T/873G polymorphism was not a significant risk factor. Although the finding of this intriguing investigation is intuitively pleasing, because the study is small and the risk relatively modest, it would be premature to trumpet the 807T/873G polymorphism as a newly established risk factor for stroke in the young. However, the early work is tantalizing and certainly merits more study, not only in the setting of stroke, but in the setting of other thromboembolic diseases where platelet reactivity with collagens might be implicated. These two studies nicely demonstrate the potential relevance of 2 integrin gene polymorphisms and the associated variation in platelet surface 21 integrin expression in complex hemorrhagic or thrombotic disorders where the degree of platelet reactivity with collagenous substrates might contribute to the clinical phenotype. The contributions and/or associations of platelet adhesive receptor polymorphisms with complex, multifactorial diseases is a growing and potentially important avenue of investigation.     FOOTNOTES Address reprint requests to Samuel A. Santoro, MD, PhD, Division of Laboratory Medicine, Box 8118, Washington University School of Medicine, St Louis, MO 63110.     REFERENCES TOP ARTICLE REFERENCES 1. Baumgartner HR: Platelet interaction with collagen fibrils in flowing blood. I. Reaction of human platelets with -chymotrypsin-digested subendothelium. Thromb Haemost 37:1, 1977[Medline] [Order article via Infotrieve] 2. Kehrel B: Platelet receptors for collagens. Platelets 6:11, 1995 3. Santoro SA, Zutter MM: The 21 integrin: A collagen receptor on platelets and other cells. Thromb Haemost 74:813, 1995[Medline] [Order article via Infotrieve] 4. Moroi M, Jung SM: Platelet receptors for collagen. Thromb Haemost 78:439, 1997[Medline] [Order article via Infotrieve] 5. Sixma JJ, van Zanten GH, Huizinga EG, vander Plas RM, Verkley M, Wu Y-P, Gros P, de Groot PG: Platelet adhesion to collagen: an update. Thromb Haemost 78:434, 1997[Medline] [Order article via Infotrieve] 6. Tschopp TB, Weiss HJ, Baumgartner HR: Decreased adhesion of platelets to subendothelium in von Willebrand's disease. J Lab Clin Med 83:296, 1974[Medline] [Order article via Infotrieve] 7. Rand JH, Patel ND, Schwartz E, Zhou S-L, Potter BJ: 150-kD von Willebrand factor binding protein extracted from human vascular subendothelium is type VI collagen. J Clin Invest 88:253, 1991 8. Sadler JE: A revised classification of von Willebrand disease. Thromb Haemost 71:520, 1944 9. Savage B, Almus-Jacobs F, Ruggeri ZM: Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 94:657, 1998[Medline] [Order article via Infotrieve] 10. Springer TA: Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm. Cell 76:301, 1994[Medline] [Order article via Infotrieve] 11. Zutter MM, Santoro SA: The ups and downs of 21 integrin expression: Contributions to epithelial cell differentiation and the malignant phenotype. Curr Topics Microbiol Immunol 231:167, 1998[Medline] [Order article via Infotrieve] 12. Nieuwenhuis HK, Akkerman JWN, Houdijk WPM, Sixma JJ: Human blood platelets showing no response to collagen fail to express surface glycoprotein Ia. Nature 318:470, 1985[Medline] [Order article via Infotrieve] 13. Nieuwenhuis HK, Sakariassen KS, Houdijk WPM, Nievelstein PFM, Sixma JJ: Deficiency of platelet membrane glycoprotein Ia associated with a decreased platelet adhesion to subendothelium: A defect in platelet spreading. Blood 68:692, 1986[Abstract/Free Full Text] 14. Deckmyn H, Chew SL, Vermylen J: Lack of platelet response to collagen associated with an autoantibody against glycoprotein Ia: A novel cause of acquired platelet dysfunction. Thromb Haemost 64:74, 1990[Medline] [Order article via Infotrieve] 15. Handa M, Watanabe K, Kawai Y, Kamata T, Koyama T, Nagai H, Ikeda Y: Platelet unresponsiveness to collagen: Involvement of glycoprotein Ia-IIa (21 integrin) deficiency associated with a myeloproliferative disorder. Thromb Haemost 73:521, 1995[Medline] [Order article via Infotrieve] 16. Kehrel B, Balleisen L, Kokott R, Mesters R, Stenzinger W, Clemetson KJ, Van de Loo J: Deficiency of intact thrombospondin and membrane glycoprotein Ia in platelets with defective collagen-induced aggregation and spontaneous loss of disorder. Blood 71:1074, 1988[Abstract/Free Full Text] 17. Santoro SA, Walsh JJ, Staatz WD, Baranski KJ: Distinct determinants on collagen support 21 integrin-mediated platelet adhesion and platelet activation. Cell Regul 2:905, 1991[Medline] [Order article via Infotrieve] 18. Watson SP, Gibbons J: Collagen receptor signaling in platelets: extending the role of the ITAM. Immunol Today 19:260, 1998[Medline] [Order article via Infotrieve] 19. Kehrel B, Wierwille S, Clemetson KJ, Anders O, Steiner M, Knight CG, Farndale R, Okuma M, Barnes MJ: Glycoprotein VI is a major collagen receptor for platelet activation: It recognizes the platelet activating quaternary structure of collagen, whereas CD36, glycoprotein IIb/IIIa, and von Willebrand factor do not. Blood 91:491, 1998[Abstract/Free Full Text] 20. Moroi M, Jung SM, Okuma M, Shinmyozu K: A patient with platelets deficient in glycoprotein VI that lack both collagen-induced aggregation and adhesion. J Clin Invest 84:1440, 1989 21. Arai M, Yamamoto N, Moroi M, Akamatsu N, Fukutake K, Tanoue K: Platelets with 10% of the normal amount of glycoprotein VI have an impaired response to collagen that results in a mild bleeding tendency. Br J Haematol 89:124, 1995[Medline] [Order article via Infotrieve] 22. Sugiyama T, Okuma M, Ushikubi F, Sensaki S, Kanaji K, Uchino H: A novel platelet aggregating factor found in a patient with defective collagen-induced platelet aggregation and autoimmune thrombocytopenia. Blood 69:1712, 1987[Abstract/Free Full Text] 23. Keely PJ, Parise LV: The 21 integrin is a necessary co-receptor for collagen-induced activation of syk and the subsequent phosphorylation of phospholipase C2 in platelets. J Biol Chem 271:26668, 1996[Abstract/Free Full Text] 24. Ichinoke T, Takayama H, Ezumi Y, Arai M, Yamamoto N, Takahashi H, Okuma M: Collagen stimulated activation of syk but not c-src is severely compromised in human platelets lacking membrane glycoprotein VI. J Biol Chem 272:63, 1997[Abstract/Free Full Text] 25. Asselin J, Gibbins JM, Ackison M, Lee YH, Morton LF, Farndale RW, Barnes MJ, Watson SP: A collagen-like peptide stimulates tyrosine phosphorylation of syk and phospholipase C2 in platelets independent of the integrin 21. Blood 89:1235, 1997[Abstract/Free Full Text] 26. Chiang TM, Rinaldy A, Kang AH: Cloning, characterization and functional studies of a non integrin platelet receptor for type I collagen. J Clin Invest 100:514, 1997[Medline] [Order article via Infotrieve] 27. Shattil SJ, Kashiwagi H, Pampori N: Integrin signaling: The platelet paradigm. Blood 91:2645, 1998[Free Full Text] 28. Di Paola J, Federici AB, Mannucci PM, Canciani MT, Kritzik M, Kunicki TJ, Nugent D: Low platelet 21 levels in type I von Willebrand disease correlate with impaired platelet function in a high shear stress system. Blood 93:3578, 1999[Abstract/Free Full Text] 29. Carlsson LE, Santoso S, Spitzer C, Kessler C, Greinacher A: The 2 gene coding sequence T807/A873 of the platelet collagen receptor integrin 21 might be a genetic risk factor for the development of stroke in younger patients. Blood 93:3583, 1999[Abstract/Free Full Text] 30. Kunicki TJ, Orchekowski R, Annis D, Honda Y: Variability of integrin 21 density on human platelets. Blood 82:2693, 1993[Abstract/Free Full Text] 31. Kunicki TJ, Kritzik M, Annis DS, Nugent DJ: Hereditary variation in platelet integrin 21 density is associated with two silent polymorphisms in the 2 gene coding sequence. Blood 89:1939, 1997[Abstract/Free Full Text] 32. Kritzik M, Savage B, Nugent DJ, Santoso S, Ruggeri ZM, Kunicki TJ: Nucleotide polymorphisms in the 2 gene define multiple alleles that are associated with differences in platelet 21 density. Blood 92:2382, 1998[Abstract/Free Full Text] © 1999 by The American Society of Hematology.   0006-4971/99/9311-0065$3.00/0 CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Lapecorella, R. Santacroce, M. Napolitano, V. Bafunno, G. Favuzzi, V. Longo, E. Grandone, G. Mariani, and M. Margaglione A Platelet Defect Modulates Bleeding in Mild Hemophilia: The Tale of 2 Brothers Clinical and Applied Thrombosis/Hemostasis, December 1, 2009; 15(6): 715 - 716. [PDF] N. Ajzenberg, C. Berroeta, I. Philip, B. Grandchamp, P. Ducellier, V. Huart, P. Verpillat, M.-C. Guillin, and J. Benessiano Association of the -92C/G and 807C/T Polymorphisms of the {alpha}2 Subunit Gene With Human Platelets {alpha}2{beta}1 Receptor Density Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1756 - 1760. [Abstract] [Full Text] [PDF] S. Gruner, M. Prostredna, B. Aktas, A. Moers, V. Schulte, T. Krieg, S. Offermanns, B. Eckes, and B. Nieswandt Anti-Glycoprotein VI Treatment Severely Compromises Hemostasis in Mice With Reduced {alpha}2{beta}1 Levels or Concomitant Aspirin Therapy Circulation, November 2, 2004; 110(18): 2946 - 2951. [Abstract] [Full Text] [PDF] S. Gruner, M. Prostredna, V. Schulte, T. Krieg, B. Eckes, C. Brakebusch, and B. Nieswandt Multiple integrin-ligand interactions synergize in shear-resistant platelet adhesion at sites of arterial injury in vivo Blood, December 1, 2003; 102(12): 4021 - 4027. [Abstract] [Full Text] [PDF] L. Pontiggia, R. Lassila, S. Pederiva, H.-R. Schmid, M. Burger, and J. H. Beer Increased Platelet-Collagen Interaction Associated With Double Homozygosity for Receptor Polymorphisms of Platelet GPIa and GPIIIa Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 2093 - 2098. [Abstract] [Full Text] [PDF] A. M. Mercurio Lessons from the {alpha}2 Integrin Knockout Mouse Am. J. Pathol., July 1, 2002; 161(1): 3 - 6. [Full Text] [PDF] O. Holtkotter, B. Nieswandt, N. Smyth, W. Muller, M. Hafner, V. Schulte, T. Krieg, and B. Eckes Integrin alpha 2-Deficient Mice Develop Normally, Are Fertile, but Display Partially Defective Platelet Interaction with Collagen J. Biol. Chem., March 22, 2002; 277(13): 10789 - 10794. [Abstract] [Full Text] [PDF] D. Bouvard, C. Brakebusch, E. Gustafsson, A. Aszodi, T. Bengtsson, A. Berna, and R. Fassler Functional Consequences of Integrin Gene Mutations in Mice Circ. Res., July 30, 2001; 89(3): 211 - 223. [Abstract] [Full Text] [PDF] S. Ilveskero, P. Siljander, and R. Lassila Procoagulant Activity on Platelets Adhered to Collagen or Plasma Clot Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 628 - 635. [Abstract] [Full Text] [PDF] N. von Beckerath, W. Koch, J. Mehilli, C. Bottiger, A. Schomig, and A. Kastrati Glycoprotein Ia gene C807T polymorphism and risk for major adverse cardiac events within the first 30 days after coronary artery stenting Blood, June 1, 2000; 95(11): 3297 - 3301. [Abstract] [Full Text] [PDF] A. Oda, Y. Ikeda, H. D. Ochs, B. J. Druker, K. Ozaki, M. Handa, T. Ariga, Y. Sakiyama, O. N. Witte, and M. I. Wahl Rapid tyrosine phosphorylation and activation of Bruton's tyrosine/Tec kinases in platelets induced by collagen binding or CD32 cross-linking Blood, March 1, 2000; 95(5): 1663 - 1670. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Santoro, S. A. Search for Related Content PubMed PubMed Citation Articles by Santoro, S. A. Social Bookmarking                   What's this?

	Copyright © 1999 by American Society of Hematology         Online ISSN: 1528-0020