(Circulation. 2001;103:1718.)
© 2001 American Heart Association, Inc.
Editorial |
Inflammation and Thrombosis
The Clot Thickens
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.
|
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.
|
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.
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 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]
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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]
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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]
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M. Naghavi, P. Wyde, S. Litovsky, M. Madjid, A. Akhtar, S. Naguib, M. S. Siadaty, S. Sanati, and W. Casscells Influenza Infection Exerts Prominent Inflammatory and Thrombotic Effects on the Atherosclerotic Plaques of Apolipoprotein E-Deficient Mice Circulation, February 11, 2003; 107(5): 762 - 768. [Abstract] [Full Text] [PDF]
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 C. R. Isasi, R. J. Deckelbaum, R. P. Tracy, T. J. Starc, L. Berglund, and S. Shea Physical Fitness and C-Reactive Protein Level in Children and Young Adults: The Columbia University BioMarkers Study Pediatrics, February 1, 2003; 111(2): 332 - 338. [Abstract] [Full Text] [PDF]
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G. Engstrom, P. Lind, B. Hedblad, L. Stavenow, L. Janzon, and F. Lindgarde Long-Term Effects of Inflammation-Sensitive Plasma Proteins and Systolic Blood Pressure on Incidence of Stroke Stroke, December 1, 2002; 33(12): 2744 - 2749. [Abstract] [Full Text] [PDF]
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M. S. Sabatine, D. A. Morrow, C. P. Cannon, S. A. Murphy, L. A. Demopoulos, P. M. DiBattiste, C. H. McCabe, E. Braunwald, and C. M. Gibson Relationship between baseline white blood cell count and degree of coronary artery disease and mortality in patients with acute coronary syndromes: A TACTICS-TIMI 18 substudy J. Am. Coll. Cardiol., November 20, 2002; 40(10): 1761 - 1768. [Abstract] [Full Text] [PDF]
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F. G.P. Welt and C. Rogers Inflammation and Restenosis in the Stent Era Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1769 - 1776. [Abstract] [Full Text] [PDF]
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 E. J. Topol Aspirin with Bypass Surgery -- From Taboo to New Standard of Care N. Engl. J. Med., October 24, 2002; 347(17): 1359 - 1360. [Full Text] [PDF]
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A. D. Blann, P. M. Ridker, and G. Y.H. Lip Inflammation, Cell Adhesion Molecules, and Stroke: Tools in Pathophysiology and Epidemiology? Stroke, September 1, 2002; 33(9): 2141 - 2143. [Full Text] [PDF]
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D. Tanne, M. Haim, V. Boyko, U. Goldbourt, T. Reshef, S. Matetzky, Y. Adler, Y. A. Mekori, and S. Behar Soluble Intercellular Adhesion Molecule-1 and Risk of Future Ischemic Stroke: A Nested Case-Control Study From the Bezafibrate Infarction Prevention (BIP) Study Cohort Stroke, September 1, 2002; 33(9): 2182 - 2186. [Abstract] [Full Text] [PDF]
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G. Engstrom, P. Lind, B. Hedblad, L. Stavenow, L. Janzon, and F. Lindgarde Effects of Cholesterol and Inflammation-Sensitive Plasma Proteins on Incidence of Myocardial Infarction and Stroke in Men Circulation, June 4, 2002; 105(22): 2632 - 2637. [Abstract] [Full Text] [PDF]
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J. L. Hunt, R. Fairman, M. E. Mitchell, J. P. Carpenter, M. Golden, T. Khalapyan, M. Wolfe, D. Neschis, R. Milner, B. Scoll, et al. Bone Formation in Carotid Plaques: A Clinicopathological Study Stroke, May 1, 2002; 33(5): 1214 - 1219. [Abstract] [Full Text] [PDF]
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J. A. Ambrose and E. E. Martinez A New Paradigm for Plaque Stabilization Circulation, April 23, 2002; 105(16): 2000 - 2004. [Abstract] [Full Text] [PDF]
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M. Haim, D. Tanne, V. Boyko, T. Reshef, U. Goldbourt, J. Leor, Y. A. Mekori, and S. Behar Soluble intercellular adhesion molecule-1 and long-term risk of acute coronary events in patients with chronic coronary heart disease: Data from the Bezafibrate Infarction Prevention (BIP) Study J. Am. Coll. Cardiol., April 3, 2002; 39(7): 1133 - 1138. [Abstract] [Full Text] [PDF]
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P. Libby, P. M. Ridker, and A. Maseri Inflammation and Atherosclerosis Circulation, March 5, 2002; 105(9): 1135 - 1143. [Abstract] [Full Text] [PDF]
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 G.M. Andreozzi and R. Martini The fate of the claudicant limb Eur. Heart J. Suppl., March 1, 2002; 4(suppl_B): B41 - B45. [Abstract] [PDF]
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J. Vermylen, M. Hoylaerts, J. Arnout, D. P. Chew, D. L. Bhatt, E. J. Topol, and S. Sapp Increased Mortality With Long-Term Platelet Glycoprotein IIb/IIIa Antagonists: An Explanation? Response Circulation, November 13, 2001; 104 (20): e109 - e109. [Full Text] [PDF]
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G. J. Blake and P. M. Ridker Novel Clinical Markers of Vascular Wall Inflammation Circ. Res., October 26, 2001; 89(9): 763 - 771. [Abstract] [Full Text] [PDF]
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D. Mukherjee, S. E. Nissen, and E. J. Topol Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors JAMA, August 22, 2001; 286(8): 954 - 959. [Abstract] [Full Text] [PDF]
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M. Eto, T. Kozai, F. Cosentino, H. Joch, and T. F. Luscher Statin Prevents Tissue Factor Expression in Human Endothelial Cells: Role of Rho/Rho-Kinase and Akt Pathways Circulation, April 16, 2002; 105(15): 1756 - 1759. [Abstract] [Full Text] [PDF]
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