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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Libby, P. Articles by Simon, D. I. Search for Related Content PubMed PubMed Citation Articles by Libby, P. Articles by Simon, D. I. Related Collections Growth factors/cytokines Arterial thrombosis Platelets Mechanism of atherosclerosis/growth factors

(Circulation. 2001;103:1718.)
© 2001 American Heart Association, Inc.

Editorial

Inflammation and Thrombosis

The Clot Thickens

Peter Libby, MD; Daniel I. Simon, MD

From the Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Peter Libby, MD, Brigham and Women’s Hospital, 221 Longwood Ave, LMRC 307, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu

Key Words: Editorials • growth substances • thrombosis • platelets • atherosclerosis • inflammation

Textbooks often portray thrombosis as a bland protective mechanism critical for stanching blood loss after injury: the prick of a lancet, the wound of a scalpel, or the predator’s fangs neatly trigger a proteolytic cascade culminating in fibrin formation and cross-linking. However, in diseases such as atherosclerosis, the picture differs substantially from this simplistic model. In the natural history of atherosclerosis, thrombosis involves an inciting injury more subtle than a wound. In such pathological states, the importance of an intricate interface between inflammation and thrombosis becomes apparent.

Septic Shock: An Extreme Example of Inflammatory Activation of the Endothelium

Consider the case of septic shock, a dramatic example of the link between inflammation and thrombosis. When Gram-negative bacteria release their endotoxin into the bloodstream, the lipopolysaccharide can change endothelial lining of blood vessels from an anticoagulant, profibrinolytic surface into one that promotes thrombosis. Bacterial endotoxin potently stimulates expression of the gene encoding tissue factor, a procoagulant molecule that multiplies manyfold the activity of coagulation factors VIIa and Xa. Endotoxin also can augment endothelial cell production of fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1). These alterations in endothelial function lead to the frequent clinical scenario of disseminated intravascular coagulation, a common concomitant of Gram-negative sepsis.

Less-global endothelial activation may contribute to thrombosis in situ in more-chronic diseases such as atherosclerosis. Many inflammatory mediators found in human atherosclerotic plaques can augment tissue factor gene expression by endothelial cells. For example, interleukin-1 (IL-1) or tumor necrosis factor not only augment tissue factor gene expression but also PAI-1 production by human endothelial cells. Bacterial endotoxins within atheroma conceivably could derive from local Chlamydia pneumonia or other microbial infection. Endotoxin-induced expression of tissue factor and PAI-1 by endothelium thus may provide a stimulus that promotes thrombotic complication of "active" atherosclerotic plaques. In this manner, endogenous or bacterial inflammatory mediators can critically mediate functions of endothelial cells that promote systemic or local thrombosis in disease.

Inflammatory Leukocytes as a Source of Thrombogenic Stimuli

In the atheromatous plaque, macrophages often localize under the endothelial layer. A subpopulation of foamy macrophages in human atheroma express tissue factor.¹ When plaques rupture, allowing contact of the blood with these tissue factor–bearing macrophages, thrombosis can ensue. Blood monocytes and resting tissue macrophages do not express tissue factor. However, when stimulated by certain inflammatory mediators, these mononuclear phagocytes transcribe the tissue factor gene. Bacterial endotoxin potently stimulates tissue factor gene expression in human mononuclear phagocytes.² But what nonmicrobial stimuli might elicit tissue factor gene expression in atherosclerotic plaques? Unlike human endothelial cells, human mononuclear phagocytes do not augment tissue factor gene expression appreciably in response to soluble mediators such as IL-1 or tumor necrosis factor. Recent work has identified a cell surface–based signaling system, CD154 (CD40 ligand), binding to its receptor CD40 on the leukocyte, that can induce tissue factor expression.³ Because several cell types in atheroma bear CD154, this novel pathway probably contributes to macrophage tissue factor expression in the human atheroma.⁴

Smooth Muscle Cells: Source of Procoagulants and Amplifier of Inflammatory Responses During Thrombosis

The smooth muscle cell is not commonly implicated in clotting. However, smooth muscle cells, like endothelial cells and macrophages, can express tissue factor procoagulant.⁵ Indeed, in superficial arterial erosion accounting for some fatal coronary thrombi, tissue factor expressed by smooth muscle cells uncovered by the endothelial erosion may contribute to thrombogenesis. Like the macrophage, for smooth muscle cells, CD154 may represent an important pathway of procoagulant activation of relevance to atherosclerosis.⁶

The smooth muscle cell not only produces procoagulant but also can undergo inflammatory activation when exposed to thrombin and products of thrombosis. For example, thrombin stimulation causes smooth muscle cells to produce IL-6 abundantly.⁷ Platelet-derived growth factor, released from platelet alpha granules during thrombosis, can also markedly augment IL-6 production by smooth muscle cells.⁸ IL-6, in turn, can induce the acute phase response. Altering the pattern of hepatic protein synthesis from everyday "housekeeping" to the proteins in acute-phase response, IL-6 can increase plasma concentrations of fibrinogen, PAI-1, and the inflammatory marker C-reactive protein. Thus, local thrombotic stimulation of smooth muscle cells in the artery wall can amplify inflammatory response and promote a systemic procoagulant effect due to increased fibrinogen and PAI-1 levels in the circulation.

New Roles for the Platelet in Inflammation

Although physicians readily acknowledge the key function of platelets in arterial thrombosis, most relegate platelets to a limited role as a responder to thrombotic stimuli. Platelets are nonnucleated and incapable of protein synthesis, and few researchers have accorded a regulatory role to these cell fragments. We now increasingly appreciate that the lowly platelet can take its rightful place beside its nucleated brethren as a source of inflammatory mediators (Table). For example, platelet factor 4, long recognized to be a platelet product, belongs to the CXC chemokine family of inflammatory mediators. Curiously, one particular chemokine (stromal cell–derived factor-1) can potently stimulate platelet aggregation; thus, platelets can both produce and respond to chemoattractant cytokines.⁹ Recent work has established that platelets can express CD154, the very molecule that regulates tissue factor gene expression in the macrophage and smooth muscle cell.¹⁰ von Hundelshausen et al,¹¹ in this issue of Circulation, indicate that the T-cell cytokine "regulated on activation, normal T expressed and secreted" (RANTES), can participate in macrophage adhesion to endothelial cell by functioning as a bridge. Precedent for this kind of function for chemokines bound to the surface of endothelial cells and leukocyte adhesion exists in the cases of other chemokines, including macrophage chemoattractant protein-1 and IL-8.¹² The new observations of von Hundelshausen and colleagues extend our appreciation of the links between thrombosis and inflammatory mediators.

View this table: [in this window] [in a new window]   Table 1. Examples of Inflammatory Modulators Produced by Platelets

In injured arteries, recruitment of inflammatory leukocytes also can involve thrombosis. Platelets colocalize with leukocytes at sites of hemorrhage, within atherosclerotic and postangioplasty restenotic lesions, and in areas of ischemia-reperfusion injury. This heterotypic interaction between platelets and leukocytes links hemostatic/thrombotic and inflammatory responses. Just as adhesion of leukocytes to the inflamed endothelium involves rolling (mediated by selectins) followed by a tighter integrin-mediated adhesion, leukocyte attachment to and transmigration across a carpet of platelets adherent to the injured intima may occur in similar sequential steps.¹³ Initial tethering and rolling of leukocytes on platelet P-selectin precedes their firm adhesion and transplatelet migration, processes that depend on the leukocyte integrin Mac-1 and platelet glycoprotein Ib.¹⁴ In addition to promoting accumulation of leukocytes at sites of platelet coverage within the vasculature, binding of platelets to neutrophils influences key cellular effector responses by inducing leukocyte activation; augmenting cell-adhesion molecule expression; and generating signals that promote integrin activation, chemokine synthesis, and the respiratory burst. Interestingly, both neutrophil-platelet and monocyte-platelet aggregates circulate in the peripheral blood of patients with coronary artery disease and may correlate with disease activity.^{15 16}

Inflammation and Thrombosis: Intertwined in Vascular Pathology

The examples above illustrate how major cell types involved in vascular diseases express multiple functions at the interface of thrombosis and inflammation. Inflammation can beget local thrombosis, and thrombosis can amplify inflammation. Thus, we can regard anti-inflammatory therapies as potentially antithrombotic, obvious in the case of aspirin but a useful framework for rethinking mechanisms of benefit of other strategies (Figure 1). In addition, antithrombotic treatment may suppress inflammation and help break the vicious cycle of the acute coronary syndromes by limiting the local and systemic amplification loops described above. The biology of the diseases that preoccupy us in the clinic guide us in adjustment of our classic textbook categorizations of cells and their functions.

View larger version (30K): [in this window] [in a new window]   Figure 1. Accumulating data linking inflammation and thrombosis support the hypothesis illustrated here that anti-inflammatory therapies may limit thrombosis and that antithrombotic therapies may reduce vascular inflammation.

Acknowledgments

This work was supported in part by grants from the National Institutes of Health (HL-57506 and DK-55656 to D.I.S. and HL-34636 to P.L.).

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

1. Wilcox JN, Smith KM, Schwartz S, et al. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A. 1989;86:2839–2843.[Abstract/Free Full Text]
   
2. Brand K, Fowler BJ, Edgington T, et al. Tissue factor mRNA in THP-1 monocytic cells is regulated at both transcriptional and posttranscriptional levels in response to lipopolysaccharide. Mol Cell Biol. 1991;11:4732–4738.[Abstract/Free Full Text]
   
3. Mach F, Schoenbeck U, Bonnefoy J-Y, et al. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor. Circulation. 1997;96:396–399.[Abstract/Free Full Text]
   
4. Mach F, Schönbeck U, Sukhova GK, et al. Functional CD 40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci U S A. 1997;94:1931–1936.[Abstract/Free Full Text]
   
5. Schecter AD, Giesen PL, Taby O, et al. Tissue factor expression in human arterial smooth muscle cells: TF is present in three cellular pools after growth factor stimulation. J Clin Invest. 1997;100:2276–2285.[Medline] [Order article via Infotrieve]
   
6. Schonbeck U, Mach F, Sukhova GK, et al. CD40 ligation induces tissue factor expression in human vascular smooth muscle cells. Am J Pathol. 2000;156:7–14.[Abstract/Free Full Text]
   
7. Kranzhöfer R, Clinton SK, Ishii K, et al. Thrombin potently induces cytokine production by human vascular smooth muscle cells but not in mononuclear phagocytes. Circ Res. 1996;79:286–294.[Abstract/Free Full Text]
   
8. Loppnow H, Libby P. Proliferating or interleukin 1-activated human vascular smooth muscle cells secrete copious interleukin 6. J Clin Invest. 1990;85:731-738.
   
9. Abi-Younes S, Sauty A, Mach F, et al. The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques. Circ Res. 2000;86:131–138.[Abstract/Free Full Text]
   
10. Henn V, Slupsky JR, Grafe M, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998:391:591–594.
    
11. von Hundelshausen P, Weber KSC, Huo Y, et al. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation. 2001;103:1772–1777.[Abstract/Free Full Text]
    
12. Gerszten RE, Garcia-Zepeda EA, Lim YC, et al. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature. 1999;398:718–723.[Medline] [Order article via Infotrieve]
    
13. Ostrovsky L, King AJ, Bond S, et al. A juxtacrine mechanism for neutrophil adhesion on platelets involves platelet-activating factor and a selectin-dependent activation process. Blood. 1998;91:3028–3036.[Abstract/Free Full Text]
    
14. Simon DI, Chen Z, Xu H, et al. Platelet glycoprotein Ib alpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med. 2000;192:193–204.[Abstract/Free Full Text]
    
15. Ott I, Neumann FJ, Gawaz M, et al. Increased neutrophil-platelet adhesion in patients with unstable angina [see Comments]. Circulation. 1996;94:1239–1246.[Abstract/Free Full Text]
    
16. Furman MI, Benoit SE, Barnard MR, et al. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol. 1998;31:352–358.[Abstract/Free Full Text]
    

This article has been cited by other articles:

				D. A. Morrow, M. S. Sabatine, M.-L. Brennan, J. A. de Lemos, S. A. Murphy, C. T. Ruff, N. Rifai, C. P. Cannon, and S. L. Hazen Concurrent evaluation of novel cardiac biomarkers in acute coronary syndrome: myeloperoxidase and soluble CD40 ligand and the risk of recurrent ischaemic events in TACTICS-TIMI 18 Eur. Heart J., May 1, 2008; 29(9): 1096 - 1102. [Abstract] [Full Text] [PDF]

				G. A. Zimmerman and A. S. Weyrich Signal-Dependent Protein Synthesis by Activated Platelets: New Pathways to Altered Phenotype and Function Arterioscler. Thromb. Vasc. Biol., March 1, 2008; 28(3): s17 - s24. [Abstract] [Full Text] [PDF]

				R. R. S. Packard and P. Libby Inflammation in Atherosclerosis: From Vascular Biology to Biomarker Discovery and Risk Prediction Clin. Chem., January 1, 2008; 54(1): 24 - 38. [Abstract] [Full Text] [PDF]

				A. Chaudhuri, M. Miller, R. Nesto, N. Rosenberg, and P. Dandona Targeting Glucose in Acute Myocardial Infarction: Has glucose, insulin, and potassium infusion missed the target? Diabetes Care, December 1, 2007; 30(12): 3026 - 3028. [Full Text] [PDF]

				G. P. Joshi, R. Gertler, and R. Fricker Cardiovascular Thromboembolic Adverse Effects Associated with Cyclooxygenase-2 Selective Inhibitors and Nonselective Antiinflammatory Drugs Anesth. Analg., December 1, 2007; 105(6): 1793 - 1804. [Abstract] [Full Text] [PDF]

				S. R. Steinhubl, J. J. Badimon, D. L. Bhatt, J.-M. Herbert, and T. F. Luscher Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease Vascular Medicine, May 1, 2007; 12(2): 113 - 122. [Abstract] [PDF]

				R. Khan, A. Agrotis, and A. Bobik Understanding the role of transforming growth factor-{beta}1 in intimal thickening after vascular injury Cardiovasc Res, May 1, 2007; 74(2): 223 - 234. [Abstract] [Full Text] [PDF]

				M. Mayr, J. Zhang, A. S. Greene, D. Gutterman, J. Perloff, and P. Ping Proteomics-based Development of Biomarkers in Cardiovascular Disease: Mechanistic, Clinical, and Therapeutic Insights Mol. Cell. Proteomics, October 1, 2006; 5(10): 1853 - 1864. [Full Text] [PDF]

				T Kilic, D Ural, E Ural, Z Yumuk, A Agacdiken, T Sahin, G Kahraman, G Kozdag, A Vural, and B Komsuoglu Relation between proinflammatory to anti-inflammatory cytokine ratios and long-term prognosis in patients with non-ST elevation acute coronary syndrome Heart, August 1, 2006; 92(8): 1041 - 1046. [Abstract] [Full Text] [PDF]

				R. von Kanel, U. Hepp, C. Buddeberg, M. Keel, L. Mica, K. Aschbacher, and U. Schnyder Altered Blood Coagulation in Patients With Posttraumatic Stress Disorder Psychosom Med, July 1, 2006; 68(4): 598 - 604. [Abstract] [Full Text] [PDF]

				E. Paffen and M. P.M. deMaat C-reactive protein in atherosclerosis: A causal factor? Cardiovasc Res, July 1, 2006; 71(1): 30 - 39. [Abstract] [Full Text] [PDF]

				A. M. Healy, M. D. Pickard, A. D. Pradhan, Y. Wang, Z. Chen, K. Croce, M. Sakuma, C. Shi, A. C. Zago, J. Garasic, et al. Platelet Expression Profiling and Clinical Validation of Myeloid-Related Protein-14 as a Novel Determinant of Cardiovascular Events Circulation, May 16, 2006; 113(19): 2278 - 2284. [Abstract] [Full Text] [PDF]

				S. L Augustin, S. Horton, C. Thuys, M. Bennett, C. Claessen, and C. Brizard The use of extracorporeal life support in the treatment of influenza-associated myositis/rhabdomyolysis Perfusion, March 1, 2006; 21(2): 121 - 125. [Abstract] [PDF]

				A K Mitra and D K Agrawal In stent restenosis: bane of the stent era. J. Clin. Pathol., March 1, 2006; 59(3): 232 - 239. [Abstract] [Full Text] [PDF]

				V. R. Vaidyula, A. K. Rao, M. Mozzoli, C. Homko, P. Cheung, and G. Boden Effects of Hyperglycemia and Hyperinsulinemia on Circulating Tissue Factor Procoagulant Activity and Platelet CD40 Ligand Diabetes, January 1, 2006; 55(1): 202 - 208. [Abstract] [Full Text] [PDF]

				S. Eligini, F. Violi, C. Banfi, S. S. Barbieri, M. Brambilla, M. Saliola, E. Tremoli, and S. Colli Indobufen inhibits tissue factor in human monocytes through a thromboxane-mediated mechanism Cardiovasc Res, January 1, 2006; 69(1): 218 - 226. [Abstract] [Full Text] [PDF]

				Y. Wang, M. Sakuma, Z. Chen, V. Ustinov, C. Shi, K. Croce, A. C. Zago, J. Lopez, P. Andre, E. Plow, et al. Leukocyte Engagement of Platelet Glycoprotein Ib{alpha} via the Integrin Mac-1 Is Critical for the Biological Response to Vascular Injury Circulation, November 8, 2005; 112(19): 2993 - 3000. [Abstract] [Full Text] [PDF]

				E. Fung, R. R. Fiscus, A. P. C. Yim, G. D. Angelini, and A. A. Arifi The Potential Use of Type-5 Phosphodiesterase Inhibitors in Coronary Artery Bypass Graft Surgery Chest, October 1, 2005; 128(4): 3065 - 3073. [Abstract] [Full Text] [PDF]

				P. K. MacCallum Markers of Hemostasis and Systemic Inflammation in Heart Disease and Atherosclerosis in Smokers Proceedings of the ATS, April 1, 2005; 2(1): 34 - 43. [Abstract] [Full Text] [PDF]

				J. A. Ambrose and D. J. D'Agate Plaque rupture and intracoronary thrombus in nonculprit vessels: An eyewitness account J. Am. Coll. Cardiol., March 1, 2005; 45(5): 659 - 660. [Full Text] [PDF]

				A. S. Weyrich, M. M. Denis, J. R. Kuhlmann-Eyre, E. D. Spencer, D. A. Dixon, G. K. Marathe, T. M. McIntyre, G. A. Zimmerman, and S. M. Prescott Dipyridamole Selectively Inhibits Inflammatory Gene Expression in Platelet-Monocyte Aggregates Circulation, February 8, 2005; 111(5): 633 - 642. [Abstract] [Full Text] [PDF]

				L. Ma, R. Perini, W. McKnight, M. Dicay, A. Klein, M. D. Hollenberg, and J. L. Wallace Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets PNAS, January 4, 2005; 102(1): 216 - 220. [Abstract] [Full Text] [PDF]

				M-H Gaugler A unifying system: does the vascular endothelium have a role to play in multi-organ failure following radiation exposure? Br. J. Radiol., January 1, 2005; Supplement_27(1): 100 - 105. [Abstract] [Full Text] [PDF]

				M. Gyongyosi, C. Strehblow, M. Haumer, P. Wexberg, W. Sperker, S. Lehr, D. Glogar, G. Pasterkamp, and E. Minar Vascular Remodeling in Atherosclerotic Femoral Arteries: Three-dimensional US Analysis Radiology, November 1, 2004; 233(2): 366 - 375. [Abstract] [Full Text] [PDF]

				T. Khreiss, L. Jozsef, L. A. Potempa, and J. G. Filep Opposing Effects of C-Reactive Protein Isoforms on Shear-Induced Neutrophil-Platelet Adhesion and Neutrophil Aggregation in Whole Blood Circulation, October 26, 2004; 110(17): 2713 - 2720. [Abstract] [Full Text] [PDF]

				L. G. Spagnoli, A. Mauriello, G. Sangiorgi, S. Fratoni, E. Bonanno, R. S. Schwartz, D. G. Piepgras, R. Pistolese, A. Ippoliti, and D. R. Holmes Jr Extracranial Thrombotically Active Carotid Plaque as a Risk Factor for Ischemic Stroke JAMA, October 20, 2004; 292(15): 1845 - 1852. [Abstract] [Full Text] [PDF]

				A. D Blann Angiogenesis and platelets: the clot thickens further Cardiovasc Res, August 1, 2004; 63(2): 192 - 193. [Full Text] [PDF]

				C. Chrysohoou, D. B. Panagiotakos, C. Pitsavos, U. N. Das, and C. Stefanadis Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: The Attica study J. Am. Coll. Cardiol., July 7, 2004; 44(1): 152 - 158. [Abstract] [Full Text] [PDF]

				J.-F. Legare and D. B. Ross Suggestion for functional model to test effects of decellularization of rat aortic valve allografts on leaflet destruction and extracellular matrix remodeling. J. Thorac. Cardiovasc. Surg., July 1, 2004; 128(1): 155 - 156. [Full Text] [PDF]

				J. T. Willerson and P. M. Ridker Inflammation as a Cardiovascular Risk Factor Circulation, June 1, 2004; 109(21_suppl_1): II-2 - II-10. [Abstract] [Full Text] [PDF]

				M. Miceli, R. Atoui, R. Walker, T. Mahfouz, N. Mirza, J. Diaz, G. Tricot, B. Barlogie, and E. Anaissie Diagnosis of Deep Septic Thrombophlebitis in Cancer Patients by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography Scanning: A Preliminary Report J. Clin. Oncol., May 15, 2004; 22(10): 1949 - 1956. [Abstract] [Full Text] [PDF]

				E. Paffen, H. L. Vos, and R. M. Bertina C-Reactive Protein Does Not Directly Induce Tissue Factor in Human Monocytes Arterioscler. Thromb. Vasc. Biol., May 1, 2004; 24(5): 975 - 981. [Abstract] [Full Text]

				N. Bassilios, M. Tassart, A. Restoux, J.-M. Bigot, E. Rondeau, and J.-D. Sraer Inferior vena cava thrombosis due to acute pyelonephritis Nephrol. Dial. Transplant., April 1, 2004; 19(4): 981 - 983. [Full Text] [PDF]

				F. O'Rourke, N. Dean, N. Akhtar, and A. Shuaib Current and future concepts in stroke prevention Can. Med. Assoc. J., March 30, 2004; 170(7): 1123 - 1133. [Abstract] [Full Text] [PDF]

				M. Roffi and E. J. Topol Percutaneous coronary intervention in diabetic patients with non-ST-segment elevation acute coronary syndromes Eur. Heart J., February 1, 2004; 25(3): 190 - 198. [Abstract] [Full Text] [PDF]

				A. D. Blann, S. K. Nadar, and G. Y.H. Lip The adhesion molecule P-selectin and cardiovascular disease Eur. Heart J., December 2, 2003; 24(24): 2166 - 2179. [Abstract] [Full Text] [PDF]

				S Kennon, A D Timmis, R Whitbourn, and C Knight C reactive protein for risk stratification in acute coronary syndromes? Verdict: unproven Heart, November 1, 2003; 89(11): 1288 - 1290. [Abstract] [Full Text] [PDF]

				K. Schafer, K. Muller, A. Hecke, E. Mounier, J. Goebel, D. J. Loskutoff, and S. Konstantinides Enhanced Thrombosis in Atherosclerosis-Prone Mice Is Associated With Increased Arterial Expression of Plasminogen Activator Inhibitor-1 Arterioscler. Thromb. Vasc. Biol., November 1, 2003; 23(11): 2097 - 2103. [Abstract] [Full Text] [PDF]

				M. Naghavi, P. Libby, E. Falk, S. W. Casscells, S. Litovsky, J. Rumberger, J. J. Badimon, C. Stefanadis, P. Moreno, G. Pasterkamp, et al. From Vulnerable Plaque to Vulnerable Patient: A Call for New Definitions and Risk Assessment Strategies: Part II Circulation, October 14, 2003; 108(15): 1772 - 1778. [Abstract] [Full Text] [PDF]

				A. D Timmis Plaque stabilisation in acute coronary syndromes: clinical considerations Heart, October 1, 2003; 89(10): 1268 - 1272. [Full Text] [PDF]

				E. G. Butchart, A. Ionescu, N. Payne, J. Giddings, G. L. Grunkemeier, and A. G. Fraser A New Scoring System to Determine Thromboembolic Risk After Heart Valve Replacement Circulation, September 9, 2003; 108(90101): II-68 - 74. [Abstract] [Full Text] [PDF]

				T. Takahashi and R. T. Lee Dendritic cells in neointima formation: from where did you come, and what are you doing here? J. Am. Coll. Cardiol., September 3, 2003; 42(5): 939 - 941. [Full Text] [PDF]

				H. D. Danenberg, A. J. Szalai, R. V. Swaminathan, L. Peng, Z. Chen, P. Seifert, W. P. Fay, D. I. Simon, and E. R. Edelman Increased Thrombosis After Arterial Injury in Human C-Reactive Protein-Transgenic Mice Circulation, August 5, 2003; 108(5): 512 - 515. [Abstract] [Full Text] [PDF]

				P. Lagadec, O. Dejoux, M. Ticchioni, F. Cottrez, M. Johansen, E. J. Brown, and A. Bernard Involvement of a CD47-dependent pathway in platelet adhesion on inflamed vascular endothelium under flow Blood, June 15, 2003; 101(12): 4836 - 4843. [Abstract] [Full Text] [PDF]

				C.D. Garlichs, S. Kozina, S. Fateh-Moghadam, B. Tomandl, C. Stumpf, S. Eskafi, D. Raaz, A. Schmeisser, A. Yilmaz, J. Ludwig, et al. Upregulation of CD40-CD40 Ligand (CD154) in Patients With Acute Cerebral Ischemia Stroke, June 1, 2003; 34(6): 1412 - 1418. [Abstract] [Full Text] [PDF]

				M. C. Berndt Induction of Platelet-Endothelial Interactions in Postcapillary Venules in Hypercholesterolemia: Critical Role of P-Selectin Arterioscler. Thromb. Vasc. Biol., April 1, 2003; 23(4): 525 - 527. [Full Text] [PDF]

E. J. Topol A guide to therapeutic decision-making in patients with non-ST-segment elevation acute coronary syndromes J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 123S - 129S. [Abstract] [Full Text] [PDF]