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Introduction
Hemostasis is the host defense system aimed at preserv Notably, arterial and venous thrombi differ in their com
ing the integrity of the circulatory system in mammals. position. Arterial thrombi are typically composed mainly
By necessity, hemostasis is a highly complex and tightly of platelet aggregates, giving the appearance of white clots.
regulated process that involves blood cells (erythrocytes, Venous thrombi largely consist of fibrin and red blood cells
platelets, and leukocytes), soluble plasma proteins, and and are thereby identified as red clots. Although platelets
the vessel wall. The endothelium is an inert surface that accumulate at the head of the venous thrombus, their
separates blood cells and soluble plasma proteins involved incorporation gradually decreases and the clots become
in blood coagulation and fibrinolysis from subendothelial more red, because they are predominantly composed of
vessel components. Physiologically, hemostasis is activated fibrin and erythrocytes.2,3
after injury of the vessel wall. Pathological thrombosis occurs when the hemostatic
Exposure of the subendothelial matrix and activation pathway is so strongly activated that it exceeds the normal
of endothelial cells are the two most important events regulatory counterbalance by anticoagulant factors, which
following vessel injury. Two consequences of endothelial are supposed to limit and localize thrombus formation
activation are the expression of adhesion receptors, to the injured area (Figure1).47 Such strong activation
Clinical Chemistry
including intercellular adhesion molecule (ICAM)1, of the hemostatic pathway in arteries can result from
Laboratory (G. Lippi), ICAM2, ICAM3, vascular adhesion molecule, and plate atherosclerotic plaque disruption. This Review details
Immunohematology let endothelial cell adhesion molecule on the endothelial our current knowledge of the mechanisms of pathological
and Transfusional
Medicine Service cell membrane, and the release of WeibelPalade bodies arterial thrombus formation, and we also discuss genetic
(M.Franchini), via exocytosis.1 Alterations of the plasma membrane lipid and acquired risk factors of atherothrombosis.
Department of Clinical
Pathology and
bilayer result in the exposure of an endothelial surface to
Laboratory Medicine, the blood flow that is rich in negatively charged phospho Pathological arterial thrombosis
Academic Hospital,
lipids, which can bind coagulation factors and other Pathological arterial thrombosis is preceded by a complex
University of Parma,
Via Gramsci 14, hemostatic molecules (such as tissue factor), thereby pro interplay between environmental and genetic factors, and
43126Parma, Italy. moting prothrombotic signaling. After release of tissue represents the most-frequent cause of death worldwide.8
Section of
Endocrinology and factor from injured endothelial cells, inactive blood coagu Our understanding of the molecular and cellular basis of
Metabolism, lation proteins (zymogens) are sequentially converted into arterial thrombus formation has advanced greatly through
Department of
Medicine, University
the corresponding active enzymes through a cascade of the use of novel mouse models of thrombosis.
of Verona, Piazzale sequential, calcium-dependent enzymatic reactions. The
Aristide Stefani 1, rapid production of thrombin marks the initiation of Atherosclerotic plaque disruption
37126Verona, Italy
(G.Targher). thrombus formation. Atherosclerosis is widely recognized as a chronic disease
that is characterized by lipid retention and chronic inflam
Correspondence to:
G. Lippi Competing interests mation in the arterial intima.4,5 The prevailing hypothesis
glippi@ao.pr.it The authors declare no competing interests. is that rupture of the fibrous cap of atherosclerotic plaques
Thrombus formation
Figure 1 | An imbalance between prothrombotic and antithrombotic forces in the blood promotes the development
of arterial thrombi.
Table1 | Genes and chromosomal loci associated with CAD or myocardial infarction
Study n Chromosome/SNP Genes Odds ratio
(95% CI)
Cases Controls
Helgadottir etal.118 7,790 624 13q1213/HapA* ALOX5AP 1.80
Zwicker etal. 119
1,425 1,425 N700S
TSP1 1.40 (1.11.8)
Helgadottir etal.120 1,553 863 12q22/HapK* LTA4H 1.45||
Helgadottir etal. 84
4,587 12,767 9p21.3/rs2383207 ALOX5AP 1.25 (1.181.31)
9p21.3/rs10757278 CDKN2A, CDKN2B 1.28 (1.221.35)
McPherson etal.86 3,989 18,808 9p21.3/rs10757274 CDKN2A, CDKN2B 1.38 (1.191.60)
9p21.3/rs1333049 CDKN2A, CDKN2B 1.37 (1.261.48)
Samani etal.87 875 1,644 9p21.3/rs4977574 CDKN2A, CDKN2B 1.36 (1.201.53)
9p21.3/rs1333049 CDKN2A, CDKN 2B 1.33 (1.181.51)
1p13.3/rs599839 CELSR2, PSRC1, SORT1 1.20 (1.101.31)
2q36.3/rs2943634 Pseudogene 1.21 (1.131.30)
10q11.2/rs501120 Unknown 1.33 (1.201.48)
6q25.1/rs6922269 MTHFD1L 1.23 (1.151.33)
WTCCC88 1,926 3,000 9p21.3/rs4977574 CDKN2A, CDKN2B 1.35 (1.241.46)
9p21.3/rs1333049 CDKN2A, CDKN2B 1.37 (1.261.48)
1p13.3/rs599839 CELSR2, PSRC1, SORT1 1.29 (1.181.40)
1q41/rs17465637 MIA3 1.20 (1.121.30)
6q25.1/rs6922269 MTHFD1L 1.23 (1.011.50)
MIGen92 12,713 12,821 21q22/rs9982601 SLC5A3, MRPS6, KCNE2 1.20 (1.141.27)
6p24/rs12526453 PHACTR1 1.12 (1.081.17)
2q33/rs6725887 WDR12 1.17 (1.111.23)
10q11/rs1746048 CXCL12 1.17 (1.111.24)
1q41/rs17465637 MIA3 1.14 (1.101.19)
19p13/rs1122608 LDLR 1.15 (1.101.20)
1p13.3/rs646776 CELSR2, PSRC1, SORT1 1.19 (1.131.26)
9p21.3/rs4977574 CDKN2A, CDKN2B 1.29 (1.251.34)
1p32/rs11206510 PCSK9 1.15 (1.101.21)
Erdmann etal.93 19,407 21,366 3q22.3/rs9818870 MRAS 1.15 (1.101.19)
12q24/rs2259816 HNF1A 1.08 (1.051.11)
Gudbjartsson etal. 121 6,650 40,621 12q24/rs3184504 SH2B3 1.13 (1.081.18)
Tregouet etal.122 8,999 10,263 6q2627/CTTG* SLC22A3-LPAL2-LPA 1.20 (1.131.28)
6q2627/CTTC* SLC22A3-LPAL2-LPA 1.82 (1.572.12)
He etal.123 1,003 1,003 +190CC HSPA1A 1.56 (1.102.20)
110C/+190C* HSPA1A 1.17 (1.011.34)
Clarke etal.124 3,145 3,352 6q2627/rs10455872 LPA 1.70 (1.491.95)
6q2627/rs3798220 LPA 1.92 (1.482.49)
*Haplotype; genotype; polymorphism; ||relative risk. Abbreviations: CAD, coronary artery disease; SNP, single-nucleotide polymorphisms.
Findings from several studies have convincingly the association between plasma homocysteine levels and
demonstrated an influence of fibrinogen polymorphisms CAD were assessed.109 The investigators concluded that
on fibrinogen plasma concentration. The most striking hyperhomocysteinemia is a weak predictor of CAD in
association has been demonstrated for the 455A allele, low-risk, healthy people.109 Conversely, clinical and experi
which can increase the mean concentration of plasma mental evidence attests that increased levels of homo
fibrinogen by ~0.15g/l (the normal plasma concentration cysteine might play a synergic role in the pathogenesis of
of fibrinogen is 1.54.0g/l).97 CAD in combination with other risk factors, such as raised
Significant associations between the genetic variants of concentrations of LDL, lipoprotein(a), orboth.110
fibrinolytic markers, such as the 4G/5G PAI1 gene poly Using data from the Atherosclerosis Risk in Com
morphism, or the 325Thr/Ile TAFI gene polymorphism, munities (ARIC) cohort, 111 Kucharska-Newton and
and the risk of CAD have also been reported, but data are colleagues assessed the risk of incident CAD among indivi
conflicting.98 These inconclusive findings have produced duals with elevated levels of markers of inflammation and
a general skepticism among investigators about the feasi hemostasis (including fibrinogen, VWF, and FVIIIc)
bility of linking polymorphisms of blood coagulation pro compared with those with normal levels. Third versus first
teins with the prevalence of CAD. Even more importantly tertile hazard ratios for the association between nonfatal
the costbenefit ratio of routine genetic screening of myocardial infarction and fibrinogen were 1.91 (95%CI
patients has not been investigated in any of these studies 1.552.36), for VWF were 1.37 (95%CI 1.131.66), and
and therefore represents a hot topic for futureresearch. for FVIIIc were 1.31 (95%CI 1.081.60).111
The antiphospholipid antibody syndrome (APS)
Acquired risk factors usually describes the association between the presence of
A number of epidemiological studies have identified antiphospholipid (aPL) antibodies (comprising anticardio
several acquired states that might predispose patients to lipin antibodies, anti-2GP1 antibodies and lupus anti
arterial thrombosis.99 These include elevated blood levels coagulants) and the risk of thrombosis. The prevalence of
of homocystein, CRP, fibrinogen, factorVIIc (FVIIc), aPL antibodies in the general population is relatively low
factorVIIIc, or PAI1, the presence of antiphospholipid (15%), but increases substantially inpatients with venous
antibodies in the blood, hereditary thrombophilias, and thrombosis (up to 10%) and in those with systemic lupus
platelet hyper-reactivity.99 At present, clinical evidence for erythematosus (up to 50%).112 Ben-Ami etal. investigated
elevated fibrinogen, CRP (high-sensitivity test; hs-CRP), associations between APS and arterial stenosis.113 They
hyperhomocysteinemia, and antiphospholipid anti found that APS involves arteries of varying sizes, occurs
bodies as potential risk factors for arterial thrombosis at several different locations (with higher prevalence in
is convincing. Data on FVIIc and platelet receptor poly renal, gastrointestinal, and intracranial arteries), and
morphisms are contradictory or lacking.99 Two indepen encompasses pathogenetic mechanisms such as acceler
dent studies failed to observe any significant association ated atherosclerosis, proliferation of smooth muscle cells,
between FVIIc and FVIIa with prevalent cardiovascular and superimposed thrombosis. Notably, acute myocardial
disease.100,101 Similarly, large prospective studies have infarction and stroke accounted for up to 30% of deaths
failed to demonstrate a significant association between in patients with APS.114
any platelet receptor polymorphism investigated and Plasma levels of PAI1 have been studied in various
thromboticoutcomes.102106 clinical settings characterized by acute thrombotic
Findings of a meta-analysis involving 31 prospective complications, such as CAD, ischemic stroke, vascu
studies and a total of 154,211 individuals indicated a signifi lar death, and the metabolic syndrome.46,5759 However,
cant positive association between plasma fibrinogen levels findings are conflicting, possibly owing to concerns
and cardiovascular risk.107 After adjustment for age and sex, about study design, the presence of confounders (such
the hazard ratio for an increase in plasma fibrinogen (per as traditional risk factors), as well as methodological
gram of fibrinogen per liter) was 2.42 (95%CI 2.242.60) and biological issues. For example, plasma PAI1 levels
for CAD, 2.06 (95%CI 1.832.33) for ischemic stroke, do not mirror the local PAI1 release from activated
and for vascular mortality 2.76 (95%CI 2.283.35). platelets during thrombogenesis, the periprocedural
Although the question of whether CRP is causative, platelet activation might spuriously increase PAI1,
or represents an epiphenomenon of underlying chronic and uncertainty still exists as to how to measure PAI1
inflammation, remained unanswered, a meta-analysis of antigen or PAI1 activity. Moreover the number of nega
54 long-term prospective studies involving 160,309 indivi tive studies, in which no association or predictive power
duals concluded that blood hsCRP levels are linearly cor was found, is equal to those reporting a positive associa
related with the risk of cardiovascular disease.108 When tion; therefore, well-conducted prospective studies are
adjusted for age, sex, traditional risk factors, and fibrino needed to clarify whether PAI1 plasma levels influence
gen, the relative risks per threefold increase in hs-CRP the risk of atherothrombosis.98,115116 Nevertheless, the
concentration were 1.23 (95%CI 1.071.42) for CAD, 1.32 potential involvement of PAI1 and other fibrinolytic
(95%CI 1.181.49) for ischemic stroke, and 1.34 (95%CI markers in the plasma in adverse thrombotic events
1.181.52) for vascular mortality. related to modern, drug-eluting coronary stents has
Lhmann etal. performed a systematic overview of renewed the scientific interest in unraveling the molecu
11 reviews and 33 epidemiological studies (prospective lar processes involved in fibrinolysis and in modulating
cohort studies and nested casecontrol studies) in which fibrinolysispharmaceutically.5759
With regards to lipoprotein(a), the important role of this an injured atherosclerotic plaque, the formation of an
unique lipoprotein in atherothrombosis is supported by arterial thrombus involves platelet adhesion and aggre
several lines of evidence, attesting that lipoprotein(a) might gation. This process initially leads to the formation of a
accelerate atherosclerosis (by delivering large amount labile platelet plaque, which is then stabilized by insoluble
ofcholesterol within the plaque, triggering production of fibrin, mainly produced as a result of the activation of the
proinflammatory cytokines, and promoting the recruit coagulation cascade. Factors involved in the formation of
ment of monocytes and the migration of smooth muscle arterial thrombi include GPIb-IXV, GPVI, integrin21,
cells), and that lipoprotein(a) also impairs fibrinolysis GPIIb/IIIa, collagenous plaque components (fibronectin,
(by inhibiting the generation of the tPAfibrin complex collagens, and VWF), and blood coagulation proteins.
through direct interaction with tPA and by enhancing Accumulating evidence also suggests that some inherited
expression of PAI1).95,110 factors related gene polymorphisms and acquired pre
Although plasma fibrinolysis has a central role in art disposing conditions (for example the concentration and
erial thrombosis, we are disappointed by the results of the activity of clotting factors) can contribute to the compo
published studies evaluating the predictive value of plasma sition and size of arterial thrombus. Therefore, although
fibrinolytic parameters for CAD. One reason is the uncer we already have a good basic knowledge of pathological
tainty about what to measure. Proposed markers include arterial thrombus formation, more research is required to
antigens, enzymatic activity, or genetic polymorphisms further elucidate the functions of the many proteins and
of fibrinolytic proteins. Another concern is the inherent cellular elements that have important roles in this process.
limitation of using a simple factorial assessment to quantify A better knowledge of the pathophysiological mechanisms
the complex and dynamic process of plasma fibrinolysis.98 of arterial thrombus formation should enable the develop
So far, no parameter provides a quick and meaningful, ment of new therapeutic approaches to the treatment
individualized assessment of a patients fibrinolytic status as ofatherothrombosis.117
it would be needed in the clinic. Large, prospective studies
are required to examine the predictive value of plasma Review criteria
fibrinolytic markers for CAD, ideally using a simple, rapid,
Relevant articles published between 2001 and 2011
comprehensive, point-of-care test that measures overall were selected from electronic databases (MEDLINE,
plasma fibrinolytic capacity. EMBASE, and Google scholar) using the key words
arterial thrombus formation, mechanisms of
Conclusions thrombosis, pathogenesis of atherosclerosis,
The development of arterial thrombosis is a highly complex pathogenesis of thrombosis, and review. Articles
and dynamic pathological process that differs from that published in languages other than English were excluded
from the analysis.
of venous thrombosis. Originating as a consequence of
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