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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1517-1532
REVIEWARTICLE
From the Department of Hematology, Imperial College School of
Medicine, London, and the Academic Unit of Molecular Vascular Medicine,
University of Leeds, Leeds, United Kingdom.
The development of thrombotic disorders in humans is one of
the most common causes of morbidity and mortality in the Western world.
Thrombotic disease can be classified in broad terms as that which
occurs in the venous system of low flow and pressure or in the
high-flow and pressure arterial system. Certain basic distinctions can
be drawn between arterial and venous thrombosis, such as the
composition of the thrombi (platelet rich in arterial and fibrin rich
in venous) and the presence of vascular wall damage (atheroma) in
arterial thrombosis. However, the distinctions are not absolute, and
there are common underlying mechanisms. Perturbation of hemostasis is
central to the pathogenesis of all thrombosis, even though it differs
in nature depending on location. Transient or long-lasting
environmental influences may play important roles in perturbing
hemostasis and influencing risk for thrombosis in both the venous and
the arterial systems. The term environmental is used in its
broadest sense to embrace changes induced by diverse influences such as
childbirth, hormone ingestion, surgery, diet, and smoking, by
intercurrent disorders such as diabetes mellitus, hypertension and
dyslipidemia, and hyperhomocystinemia, and by local changes to the
vascular wall. Perturbation of hemostasis may also be in part
genetically determined, and, when this is the case, its influence is
potentially profound because of its life-long presence. Because of the
late onset of the majority of thromboses, it is unlikely that genetic
changes could be their sole determinant, and this
points to the importance of gene-environment interactions in disease.
There is a rapidly growing literature on the relationship
between the genetics of hemostatic factors, the environment, and thrombotic occlusion. Most of this literature concerns variation in the
genes for blood coagulation factors, inhibitors, fibrinolytic factors,
and platelet-membrane receptors. The aim of our review is to summarize
this literature, focusing on the common genetic variations (a
prevalence approximately 1/100 or greater is used as a rough, not an
absolute, guide, and the term polymorphism is used regardless
of clinical effect) that could potentially have important influence on
the health of populations. Certain changes, such as partial or total
gene deletions, tend to be of low prevalence and will not be
considered. Furthermore, the specific mutations in certain genes
predisposing to thrombosis are essentially "private" to a
relatively small number of families (such as those in the genes for
antithrombin, protein C, and protein S) and will not be considered. At
its conclusion, an evaluation will be made of the overall importance of
genetics in determining the course of these common disorders, and a
perspective on gene-environment interactions will be presented.
Venous thromboembolic disorders form a spectrum of conditions
characterized by in situ thrombus formation and the variable presence
of embolic manifestations. The clinical presentation depends to a large
extent on the site and extent of thrombus formation and on the
underlying cause. In the absence of genetic deficiencies, thrombosis
occurs in the older population, largely in the context of marked
environmental influences such as surgery, obesity, and underlying
malignancy. In contrast, at the other extreme, familial thrombosis
associated with mutations in genes for protein S, protein C, or
antithrombin is associated with younger age of onset, lesser environmental stimulus, and thrombus formation often in unusual sites.
There is an increasing awareness of the importance of hemostatic mechanisms in the pathogenesis of venous thrombosis. The hemostatic process comprises coagulation and fibrinolytic systems with activators, zymogens, cofactors, surfaces (such as platelets), and inhibitors. The
function and regulation of these composite systems and factors have
been extensively studied. Understanding their functional integration in
vivo, however, still presents a major challenge. A starting point for a
simplified model of integration envisages a balance between
procoagulant (clot-promoting) and anticoagulant (clot-preventing)
mechanisms. This balance serves to prevent an explosive generation of
thrombin when coagulation is triggered. The balance is determined by
the (functional) levels of all coagulation and fibrinolytic factors,
with increases in the levels of coagulation factors and decreases in
the levels of both fibrinolytic factors and natural inhibitors being
procoagulant. The role of inhibitory mechanisms in
preventing venous occlusion was established after the identification of
the link between inherited deficiencies of antithrombin, protein C,
protein S, and venous thrombosis during the 1960s and the 1970s. The
general importance of the anticoagulant pathway involving
protein C and protein S was established by the widespread prevalence
among white populations and the clinical consequences of the phenotype
of activated protein C resistance (APCR) and its main causative gene
mutation, factor V G1691A (factor V Arg506Gln, factor V Leiden). There
has been slower appreciation of the procoagulant effect of increased
levels of coagulation factors in venous disease, but recent work has
highlighted the likely importance of prothrombin and factor VIII levels
in this regard.
Factor V
Prothrombin
Factor XIII Factor XIII is a transamidase comprised of 2 A and 2 B subunits in a tetrameric structure (A2B2) of 320 kd.48 The role of activated factor XIII lies mainly in accelerating the formation of shear- and fibrinolysis-resistant cross-linked fibrin; a deficiency of factor XIII is associated with severe bleeding.48 Thrombin cleaves a 37-amino acid peptide from the A subunit. The gene for the A subunit codes for a polypeptide of 75 kd.49 In excess of 20 mutations have been described in the A subunit gene that relate to factor XIII deficiency by leading to absence of the A subunit.50-55 In addition 4 common coding polymorphic sites have been described at Val34Leu, Pro564Leu, Val650Ile, and Glu651Gln.51,54 The polymorphism coding, G/T, for factor XIII Val34Leu produces a coding change in the A subunit only 3 amino acids from the thrombin cleavage activation site at position Arg37-Gly38.Endothelial cell protein C/activated protein C receptor Endothelial cell protein C/activated protein C receptor (EPCR) is a 43-kd endothelial cell membrane type I intercalated receptor for protein C.60,61 There is a body of evidence accumulating that suggests that this receptor is an important component of the protein C anticoagulant pathway.62,63 It is found predominantly on large vessels and serves to ensure high local concentration of protein C for activation by the thrombin-thrombomodulin complex.64 The gene for the human EPCR contains 4 exons and has a number of potential polymorphic sites.65 An early report (abstract) has identified a 23-bp insertion in exon 3, which duplicates the preceding 23 bases and results in a STOP 6 codons downstream from the insertion point.66 The clinical significance of the insertion was examined in 149 patients with venous thrombosis and 404 controls. A crude OR for this mutation was 4.6 (CI, 1.1 to 19.7), suggesting that gene mutation of EPCR may predispose to venous thrombosis.Thrombomodulin Intuitively, it might be expected that thrombomodulin gene variation could predispose to thrombosis, given the overall importance of the protein C anticoagulant pathway in maintaining blood fluidity. Thrombomodulin is an endothelial cell membrane intercalated proteoglycan of approximately 100-kd. It functions as a thrombin receptor and transforms the specificity of bound thrombin so that it loses its procoagulant functions and acquires a greatly increased ability to activate protein C. Several coding sequence changes have been identified in families by screening for mutations in the thrombomodulin gene.67-69 However, there is still limited information on the effects on function of these genetic changes, and the families have been too small to provide decisive information on the relationship with thrombosis. The only common polymorphism identified, C/T coding for Ala455Val,70 appears not to be associated with thrombosis. It appears that any gene changes altering the function or expression of thrombomodulin are probably private mutations.Factor VIII(-related) Increased factor VIII levels have been shown to be associated with thrombosis in several studies. In the Leiden Thrombophilia Study, factor VIII elevated more than 150 IU/dL, measured as factor VIII coagulant activity, was shown to have an associated relative risk of 4.8 (CI, 2.3 to 10).71 Increased risk for elevated factor VIII has been confirmed by a study of patients referred for unexplained thrombosis who were largely free of markers of inflammation.72 To date, no common genetic variation in the factor VIII gene has been identified that might account for this phenotypic variation.73 However, there is good evidence that factor VIII levels may be genetically determined. Von Willebrand factor (vWF) and blood group are well-known determinants of the factor VIII level in plasma, and factor VIII levels have been shown to cluster in families.74Genes other than those of hemostasis Among the range of factors that can potentially interact with hemostatic genetic determinants, the blood level of homocysteine is of interest in the current context. Homocysteine is a sulfhydryl amino acid arising from the metabolism of methionine. A high level of homocysteine, hyperhomocystinemia, has attracted much recent interest as a potential risk factor for both venous and arterial thrombotic disease, not least because dietary supplementation with folic acid affords a safe and inexpensive therapeutic option. One of the 2 enzymatic pathways of remethylation of homocysteine to methionine involves methylene tetrahydrofolate reductase (MTHFR). The gene for MTHFR contains a common polymorphism, C677T, and this can potentially interact with hemostatic gene polymorphisms. Inconsistent results have been obtained in the numerous published studies, reviewed comprehensibly elsewhere.75 Hyperhomocystinemia appears to be only a weak risk factor for venous thrombosis,76,77 and this may account for the variable outcomes both when the C677T polymorphism has been studied as a sole risk factor and when in combination with hemostatic genetic risk factors.75
Cardiovascular disease is a generalized disorder of the vascular tree characterized by long-term atheromatous plaque formation and culminating in atherothrombotic obstructive lesions that lead to tissue damage. In many subjects there are coexistent atheromatous lesions in the coronary, carotid, aorto-iliac, and femoropopliteal arteries that can present as various syndromes according to the vessel that is predominantly affected by the process. Angina and acute myocardial infarction (MI) are the clinical manifestations of the chronic development of coronary artery atheroma, with the final pathologic process of plaque rupture and coronary thrombosis. The underlying processes that lead to atheroma formation and coronary thrombosis are complex and involve multiple interrelated systems that regulate vasoactivity, adhesion molecules and their ligands, lipid metabolism, and the coagulation and fibrinolytic pathways. A body of evidence implicates underlying insulin resistance with associated clustering of cardiovascular risk in subjects with and without diabetes as 1 of the common factors linking some of these processes.78-80 The mechanisms involved are multifactorial, and effects of insulin/insulin resistance on nitric oxide production, lipid metabolism, hemostasis, and blood flow are implicated in subjects with diabetes and a proportion of subjects without diabetes.
Fibrinogen Relationship between plasma levels and disease, influence of polymorphisms on plasma levels. Of all the components of the coagulation system, elevated fibrinogen has been most consistently associated with occlusive vascular disorders. Investigations such as the Northwick Park Heart Study and the Gothenburg and PROCAM studies have prospectively related fibrinogen to MI and stroke outcomes.81,82,86 Evidence from the Scottish Heart Health Study indicates that increased fibrinogen also clusters with other cardiovascular risk markers, including hypertension, diabetes, smoking, and peripheral vascular disease.87 Fibrinogen provides a link between smoking and the development of arterial disease because of the influence of smoking on fibrinogen levels.88
Polymorphisms and disease.
Although there is compelling evidence of associations between
fibrinogen level and arterial disease and between fibrinogen level and
certain polymorphisms, the relationship between fibrinogen polymorphisms and disease is altogether less clear. Certain studies, some large, suggest an association. In the ECTIM study, a number of
associations between fibrinogen and severity of atheroma, assessed by
coronary angiography, were documented.97 The rarer allele of the 4 Factor VII
Relationship between plasma levels and disease, influence of
polymorphisms on plasma levels.
Interest in the relationship between factor VII and cardiovascular
disease was stimulated by the finding from the Northwick Park Heart
Study that elevated levels were related to fatal but not to nonfatal
MI. In this prospective study of white males (n = 1511) aged 40 to 64 years at the time of recruitment, 109 developed a first major coronary
artery disease event. Factor VIIC (ie, factor VII determined by
clotting assay using factor VII-deficient plasma) was found to be
strongly associated with coronary risk (117% compared with 107%;
P < .001) with a 1 SD increase in factor VII associated
with a 62% increase in risk over the first 5 years of the
study.81 These results are often reported to have been supported by a second prospective study, PROCAM.86,113 In
PROCAM, 130 coronary heart disease events occurred in 8 years of
follow-up. However, in this study the results for factor VII were not
decisive. Factor VIIC was elevated in patients who had coronary events
(112% compared to 109%; P < .023), but in multiple
logistic regression analysis, factor VIIC was not an independent risk
factor for coronary events. A third prospective study, the Edinburgh
Artery Study, also failed to confirm factor VII as an independent
predictor of coronary disease.114 Interestingly, in the
ECTIM study, the controls had uniformly higher levels of factor VII
than the patients, which tended to militate against its major role as a
cardiovascular risk marker.115 A number of other
cross-sectional studies have provided conflicting conclusions about the
importance of factor VII.116-118 A particular complication
with factor VII is the methodology of its assay. The clotting assay,
factor VIIC, reflects the total factor VII antigen, but it can also be
influenced by the amount of factor VII that is activated (factor VIIa)
in the plasma. The latter can be measured directly with an assay that
utilizes truncated tissue factor as stimulant.119 It has
been suggested that the factor VIIC assay used in the Northwick Park
Heart Study is particularly sensitive to factor VIIa. There is,
however, no good evidence that factor VIIa is an informative marker
with respect to the prediction of cardiovascular
disease.120
Polymorphisms and disease.
The relationship of certain of these polymorphisms to disease is highly
controversial. In a study of a cohort of 453 patients with MI and 476 controls from the ECTIM study, the Arg353Gln polymorphism was found to
relate strongly to levels of factor VII in cases and
controls.115 There was, however, no difference in genotype frequencies between these 2 large groups. Similar results were obtained
in a case-control study of 270 patients investigated for chest pain by
coronary angiography.117 A case-control study in Sweden of
94 men with MI before the age of 45 years was reported by Moor et
al.120 Using data from this study, Doggen et
al131 calculated that there was a nonsignificant trend for
an association of Arg353 with MI (OR, 1.81; CI, 0.79 to 4.13). The
largest published case-control study, SMILE, in the Netherlands,
included 560 patients and 644 controls.131 It found the
expected association of factor VII levels with Arg353Gln in the control
samples. However, Arg353 was associated with a reduced, rather than an
increased, risk for MI (OR, 0.80; CI, 0.60 to 1.06), which was more
pronounced in patients younger than 50 (OR, 0.49; CI, 0.28 to 0.84).
Conclusions of this large study are that a genetic propensity to high
factor VII levels is not associated with a risk for MI and that an
elevated factor VII level itself is not a causal determinant. In
contrast to these studies with largely negative results, a study of 165 Italian subjects with familial MI and 225 controls showed that there
are higher risks associated with the common coding allele for both the
Arg353Gln polymorphism and the hypervariable region in intron
7.132 The protection from MI associated with the homozygous Gln allele was large (OR, 0.08; CI, 0.01 to 0.9). It is interesting to
note again (see "Fibrinogen") that this small study derived from
the GISSI 2 population provided strong associations between genotype
and disease, whereas larger studies failed. Why should the same
mutation be highly associated with MI in Italy but be apparently
protective of disease in a study that was 3 times larger in the
Netherlands? The issue of the unique manner of selection of patients in
the Italian study must be considered as a possible influencer of
outcome. Because these patients all had familial arterial disease, it
is highly likely that there are associated important genetic factors
that strengthened any associated risk. Similar overestimates of
strengths of associated risks by family-based studies have been noted
in venous thrombotic disease.133
Factor XIII
Factor V/prothrombin
EPCR/thrombomodulin The 23-bp insertion in the EPCR (see above) has been investigated in a single study of MI and reported in abstract form.66 It was found in 4 of 203 patients and 0 of 195 controls, suggesting an association with MI. Until recently, there has been little published work relating changes in thrombomodulin expression and arterial thrombosis. A large (n = 14,170) case-cohort prospective study of coronary heart disease and atherosclerosis, the ARIC study, has now found an inverse relationship between plasma thrombomodulin levels and risk for incident coronary heart disease.153 This suggests that low thrombomodulin levels could be associated with increased risk for coronary heart disease. Support for genetically determined levels of thrombomodulin has been provided by a recent study of a family with a private mutation in this gene.154 There are 2 polymorphisms in the thrombomodulin gene, the C/T change coding for Ala455Val (mentioned above) and G/A change coding for Ala25Thr.155,156 One report has suggested an association between Ala455Val and MI,157 but this has not been confirmed.158 The Ala25Thr dimorphism has been studied in the SMILE study, and the data are suggestive that it is associated with increased risk for MI, particularly when it interacts with smoking (OR, 8.8; CI, 1.8 to 42.2) or with metabolic risk factors for the disease (OR, 4.4; CI, 0.9 to 21.3).156 There is no biochemical evidence showing that Thr25 alters expression or function of the protein.
tPA tPA is the main endothelial cell-derived blood activator of the fibrinolytic system. It is a 70-kd serine proteinase activator of plasminogen whose catalytic efficiency is greatly increased by the presence of fibrin.159 For many years it was believed that impaired fibrinolysis caused by the decreased function of tPA might be a risk factor for thrombosis. Recent interest has been on elevated, rather than reduced, levels of tPA as a risk marker.160 Both the US Physicians Health and the ECAT prospective studies have found an increased risk for future MI in persons with elevated levels of tPA.85,161 Possible explanations for this apparently paradoxic association are that elevated tPA levels may reflect preexisting disease or that they may be caused by increased PAI 1, with which tPA forms an inactive complex. Certainly, the predictive influence of tPA in patients with angina is greatly influenced by adjustments for insulin resistance, inflammation, and endothelial cell markers.162PAI-1 Relationship between plasma levels and disease, influence of polymorphisms on plasma levels. PAI-1 is a member of the SERPIN family, and its main function is as the fast-acting inhibitor of tPA.168 PAI-1 exists in the circulation in molar excess over tPA, and it is generally accepted that this prevents the development of systemic fibrino(geno)lysis and permits local clot lysis without systemic bleeding.168 It appears that fibrin shields fibrinolytic activators from the inhibitory effects of PAI-1, and it has been suggested that in this way fibrin facilitates its own destruction. In spite of the inherent difficulties that this concept introduces, it seems that elevated concentrations of PAI-1 are fairly consistently associated with vascular risk. High concentrations of PAI-1 occur in the atheromatous plaque,169,170 and these changes are more marked in patients with diabetes. Circulating PAI-1 has been related to vascular outcome in a number of studies.80,171,172 These associations occur during clustering of other vascular risk markers in the presence of insulin resistance with or without diabetes mellitus.78,79,173 It remains to be determined whether the associations result from any causal effect of elevated PAI-1.
Polymorphisms and disease.
In a small study of young Swedish males with premature cardiovascular
disease and controls, there were no differences in prevalence of either
the dinucleotide repeat or the HindIII
genotypes.174 Identification of the promoter 4G/5G site led
to a flurry of publications with a mixture of results. In this study, a
higher prevalence of the 4G allele was observed in the group of young
Swedish males with MI than in controls.184 Similar results
were obtained in a small number of subjects with type 2 diabetes and
myocardial infarction.177 In a mixed-gender population of
453 patients undergoing coronary angiography, of whom 166 had a history
of MI, the 4G allele was significantly associated with PAI-1 levels and
with MI; the relationship with MI and the genotype were strengthened in
those with established atheroma.183 In a study of 1179 healthy subjects and their first-degree relatives, the 4G allele was
associated with significantly higher risk for MI (OR, 1.62; CI, 1.17 to
2.25).188 A small study has reported that the 4G allele is
related to the development of acute coronary syndromes.189
However, other studies, including the large ECTIM,182 the
US Physicians Health Study,190 and SMILE,191
failed to show any relationship between genotype and MI. A recent large
study of 2565 patients undergoing coronary angiography has reported an
association between the 4G allele and coronary artery
disease.192 In the total sample, there was elevated risk
associated with the 4G/4G genotype for coronary artery disease (OR,
1.31; CI, 1.04 to 1.65). The polymorphism was also a risk for the
severity of disease when groups at high risk (smokers, persons with
hypertension) were selected.
The normal functional activity of platelets is dependent on the
presence of platelet-membrane glycoproteins that have an important role
in platelet adhesion and aggregation.195,196 Glycoprotein (Gp) IIb/IIIa (also known as integrin Gp IIb/IIIa
Gp Ib-IX-V complex Four gene products comprise the Gp Ib-IX-V receptor complex.196 Gp Ib , approximately 140-kd, is disulfide
bonded to Gp Ib , approximately 25-kd, and these polypeptides are
noncovalently associated with Gp IX, approximately 22-kd and Gp V,
approximately 82-kd. Two polymorphisms have attracted interest. A
length polymorphism in Gp Ib results from a variable number of
tandem repeats (VNTR) of 39-bp coding for 13 amino acids in the
glycosylated region (macroglycopeptide). Up to 4 polymorphic forms
result, designated D, C, B, A, in order of increasing number of repeats
(1, 2, 3, or 4 repeats). The function of the macroglycopeptide is
thought to be that of a spacer, keeping the ligand-binding region well above the platelet surface. The second polymorphism, C to T at position
3550, results in a Thr145Met substitution and is linked to the HPA-2
alloantigen system.
Gp Ia/IIa complex This collagen receptor consists of an approximately 167-kd (2)
and an approximately 130-kd (1) polypeptide. What has been of great
interest is the finding that though the receptor is expressed at low
density on the platelet surface (1000 to 3000 copies), there is a wide,
approximately 10-fold, variation within normal persons that results in
variability of response to collagen.219 A genetic
association of the density variation with linked sequence polymorphisms
within the 2 gene has been reported. The variation is particularly
associated with a silent exonic dimorphism at position 807, C/T. In a
study of patients with von Willebrand disease (vWD), it was found that
the 807C allele, associated with low receptor density, was higher in
patients with-type I vWD, suggesting it might increase the tendency for
bleeding.220
Genes other than those of hemostasis A consistent finding in case-control and cross-sectional studies has been an association between hyperhomocystinemia and atherothrombotic disease.223,224 This association has not, however, always been found in prospective studies, for reasons that could include nutritional or genetic differences between the populations studied.75 The MTHFR C677T polymorphism has been studied extensively as a possible genetic determinant of the increased risk associated with the phenotype. A meta-analysis of 13 studies of this polymorphism in 3281 patients with cardiovascular disease (and their controls) has failed to support this link between genotype, phenotype, and disease.225
A casual glance at a rapidly expanding literature could easily lead
to the conclusion that we are well on the way to establishing the
genetic basis for vascular disorders, such is the number of polymorphisms that have been investigated (see summary Table
1). There has clearly been appreciable
progress in relation to venous thromboembolic disease whereby the
functional and clinical consequences of certain polymorphisms are
accepted. Venous disease occurs in the context of a low-pressure,
low-flow system in which atheroma does not occur. The most common
genetic risk determinant for venous disease alters the function of the
protein C anticoagulant pathway, whereas other genetic risk factors
alter levels or activities of certain coagulation factors. Although
environmental influences are undoubtedly important, genetic changes can
play a crucial role and even sometimes lead to apparently
spontaneous venous disease.
Submitted September 20, 1999; accepted December 16, 1999.
Supported by grants from the British Heart Foundation and the Stroke Association.
Reprints: David A. Lane, Department of Hematology, Imperial College School of Medicine, Charing Cross Campus, Hammersmith, London W6 8RP, United Kingdom; e-mail: d.lane{at}ic.ac.uk.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
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E. J. Dunn, R. A. Ariens, M. de Lange, H. Snieder, J. H. Turney, T. D. Spector, and P. J. Grant Genetics of fibrin clot structure: a twin study Blood, March 1, 2004; 103(5): 1735 - 1740. [Abstract] [Full Text] [PDF]
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 F. L. Sciacca, E. Ciusani, A. Silvani, E. Corsini, S. Frigerio, S. Pogliani, E. Parati, D. Croci, A. Boiardi, and A. Salmaggi Genetic and Plasma Markers of Venous Thromboembolism in Patients with High Grade Glioma Clin. Cancer Res., February 15, 2004; 10(4): 1312 - 1317. [Abstract] [Full Text] [PDF]
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B. Voetsch and J. Loscalzo Genetic Determinants of Arterial Thrombosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 216 - 229. [Abstract] [Full Text]
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D. Scanavini, D. Girelli, B. Lunghi, N. Martinelli, C. Legnani, M. Pinotti, G. Palareti, and F. Bernardi Modulation of Factor V Levels in Plasma by Polymorphisms in the C2 Domain Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 200 - 206. [Abstract] [Full Text] [PDF]
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 J. A. Lopez, C. Kearon, and A. Y.Y. Lee Deep Venous Thrombosis Hematology, January 1, 2004; 2004(1): 439 - 456. [Abstract] [Full Text] [PDF]
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N. Ameziane, T. Beillat, P. Verpillat, S. Chollet-Martin, M.-C. Aumont, P. Seknadji, M. Lamotte, D. Lebret, V. Ollivier, and D. de Prost Association of the Toll-Like Receptor 4 Gene Asp299Gly Polymorphism With Acute Coronary Events Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): e61 - e64. [Abstract] [Full Text] [PDF]
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H.-C. Huang, G.-Y. Shi, S.-J. Jiang, C.-S. Shi, C.-M. Wu, H.-Y. Yang, and H.-L. Wu Thrombomodulin-mediated Cell Adhesion: INVOLVEMENT OF ITS LECTIN-LIKE DOMAIN J. Biol. Chem., November 21, 2003; 278(47): 46750 - 46759. [Abstract] [Full Text] [PDF]
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 T. Buchholz, P. Lohse, N. Rogenhofer, E. Kosian, R. Pihusch, and C.J. Thaler Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages Hum. Reprod., November 1, 2003; 18(11): 2473 - 2477. [Abstract] [Full Text] [PDF]
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 C. Duggan, K. Marriott, R. Edwards, and J. Cuzick Inherited and Acquired Risk Factors for Venous Thromboembolic Disease Among Women Taking Tamoxifen to Prevent Breast Cancer J. Clin. Oncol., October 1, 2003; 21(19): 3588 - 3593. [Abstract] [Full Text] [PDF]
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W. L. van Heerde, H. Kenis, S. Schoormans, P. Lap, C. P. M. Reutelingsperger, R. Gonzalez-Conejero, J. Corral, V. Roldan, C. Martinez, F. Marin, et al. The -1C>T mutation in the annexin A5 gene does not affect plasma levels of annexin A5 Blood, May 15, 2003; 101(10): 4223 - 4224. [Full Text] [PDF]
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M. Martiskainen, T. Pohjasvaara, J. Mikkelsson, R. Mantyla, T. Kunnas, P. Laippala, E. Ilveskoski, M. Kaste, P.J. Karhunen, and T. Erkinjuntti Fibrinogen Gene Promoter -455 A Allele as a Risk Factor for Lacunar Stroke Stroke, April 1, 2003; 34(4): 886 - 891. [Abstract] [Full Text] [PDF]
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Atherosclerosis, Thrombosis, and Vascular Biology No Evidence of Association Between Prothrombotic Gene Polymorphisms and the Development of Acute Myocardial Infarction at a Young Age Circulation, March 4, 2003; 107(8): 1117 - 1122. [Abstract] [Full Text] [PDF]
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 G. H. Westrich, B. B. Weksler, C. J. Glueck, B. F. Blumenthal, and E. A. Salvati Correlation of Thrombophilia and Hypofibrinolysis with Pulmonary Embolism Following Total Hip Arthroplasty: An Analysis of Genetic Factors J. Bone Joint Surg. Am., December 9, 2002; 84(12): 2161 - 2167. [Abstract] [Full Text] [PDF]
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 F. L Ruberg and J. Loscalzo Prothrombotic determinants of coronary atherothrombosis Vascular Medicine, November 1, 2002; 7(4): 289 - 299. [Abstract] [PDF]
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J. D. Mills, R. A.S. Ariens, M. W. Mansfield, and P. J. Grant Altered Fibrin Clot Structure in the Healthy Relatives of Patients With Premature Coronary Artery Disease Circulation, October 8, 2002; 106(15): 1938 - 1942. [Abstract] [Full Text] [PDF]
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 J.D. Mills, M.W. Mansfield, and P.J. Grant Elevated fibrinogen in the healthy male relatives of patients with severe, premature coronary artery disease Eur. Heart J., August 2, 2002; 23(16): 1276 - 1281. [Abstract] [PDF]
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 C. Infante-Rivard, G.-E. Rivard, W. V. Yotov, E. Genin, M. Guiguet, C. Weinberg, R. Gauthier, and J. C. Feoli-Fonseca Absence of Association of Thrombophilia Polymorphisms with Intrauterine Growth Restriction N. Engl. J. Med., July 4, 2002; 347(1): 19 - 25. [Abstract] [Full Text] [PDF]
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J. D. Mills, M. W. Mansfield, and P. J. Grant Tissue Plasminogen Activator, Fibrin D-Dimer, and Insulin Resistance in the Relatives of Patients With Premature Coronary Artery Disease Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 704 - 709. [Abstract] [Full Text] [PDF]
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 J. B. Braunstein, D. W. Kershner, P. Bray, G. Gerstenblith, S. P. Schulman, W. S. Post, and R. S. Blumenthal Interaction of Hemostatic Genetics With Hormone Therapy : New Insights To Explain Arterial Thrombosis in Postmenopausal Women Chest, March 1, 2002; 121(3): 906 - 920. [Abstract] [Full Text] [PDF]
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M. S. Freeman, M. W. Mansfield, J. H. Barrett, and P. J. Grant Genetic Contribution to Circulating Levels of Hemostatic Factors in Healthy Families With Effects of Known Genetic Polymorphisms on Heritability Arterioscler. Thromb. Vasc. Biol., March 1, 2002; 22(3): 506 - 510. [Abstract] [Full Text] [PDF]
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 J. E Rossouw Hormones, genetic factors, and gender differences in cardiovascular disease Cardiovasc Res, February 15, 2002; 53(3): 550 - 557. [Full Text] [PDF]
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R. Rai, M. Backos, S. Elgaddal, A. Shlebak, and L. Regan Factor V Leiden and recurrent miscarriage--prospective outcome of untreated pregnancies Hum. Reprod., February 1, 2002; 17(2): 442 - 445. [Abstract] [Full Text] [PDF]
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 F Andreotti, I Porto, F Crea, and A Maseri Inflammatory gene polymorphisms and ischaemic heart disease: review of population association studies Heart, February 1, 2002; 87(2): 107 - 112. [Abstract] [Full Text] [PDF]
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D. J. Stearns-Kurosawa, K. Swindle, A. D'Angelo, P. Della Valle, A. Fattorini, N. Caron, M. Grimaux, B. Woodhams, and S. Kurosawa Plasma levels of endothelial protein C receptor respond to anticoagulant treatment Blood, January 15, 2002; 99(2): 526 - 530. [Abstract] [Full Text] [PDF]
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H Douglas, K Michaelides, D A Gorog, E Durante-Mangoni, N Ahmed, G J Davies, and E G D Tuddenham Platelet membrane glycoprotein Ib{alpha} gene -5T/C Kozak sequence polymorphism as an independent risk factor for the occurrence of coronary thrombosis Heart, January 1, 2002; 87(1): 70 - 74. [Abstract] [Full Text] [PDF]
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M.A. Laffan Fibrinogen polymorphisms and disease Eur. Heart J., December 2, 2001; 22(24): 2224 - 2226. [PDF]
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Y. Cadroy, K. S. Sakariassen, J.-P. Charlet, C. Thalamas, B. Boneu, and P. Sie Role of 4 platelet membrane glycoprotein polymorphisms on experimental arterial thrombus formation in men Blood, November 15, 2001; 98(10): 3159 - 3161. [Abstract] [Full Text] [PDF]
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E. Beutler Discrepancies between genotype and phenotype in hematology: an important frontier Blood, November 1, 2001; 98(9): 2597 - 2602. [Abstract] [Full Text] [PDF]
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 C. Meisel, V. Afshar-Kharghan, I. Cascorbi, M. Laule, V. Stangl, S. B. Felix, G. Baumann, J. A. Lopez, I. Roots, and K. Stangl Role of Kozak sequence polymorphism of platelet glycoprotein Ib{alpha} as a risk factor for coronary artery disease and catheter interventions J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1023 - 1027. [Abstract] [Full Text] [PDF]
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H. Weiler, V. Lindner, B. Kerlin, B. H. Isermann, S. B. Hendrickson, B. C. Cooley, D. A. Meh, M. W. Mosesson, N. W. Shworak, M. J. Post, et al. Characterization of a Mouse Model for Thrombomodulin Deficiency Arterioscler. Thromb. Vasc. Biol., September 1, 2001; 21(9): 1531 - 1537. [Abstract] [Full Text] [PDF]
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A. Tripodi and P. M. Mannucci Laboratory Investigation of Thrombophilia Clin. Chem., September 1, 2001; 47(9): 1597 - 1606. [Abstract] [Full Text] [PDF]
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P. Hari, G. K. P. Chemiti, R. S. Lankipalli, P. A. Kyrle, and S. Eichinger High Plasma Levels of Factor VIII and the Risk of Recurrent Venous Thromboembolism N. Engl. J. Med., December 28, 2000; 343(26): 1968 - 1969. [Full Text]
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P. M. Mrozikiewicz, I. Cascorbi, S. Ziemer, M. Laule, C. Meisel, V. Stangl, W. Rutsch, K. Wernecke, G. Baumann, I. Roots, et al. Reduced procedural risk for coronary catheter interventions in carriers of the coagulation factor VII-Gln353 gene J. Am. Coll. Cardiol., November 1, 2000; 36(5): 1520 - 1525. [Abstract] [Full Text] [PDF]
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G. Gunther, R. Junker, R. Strater, R. Schobess, K. Kurnik, A. Kosch, U. Nowak-Gottl, and f. t. C. S. S. Group Symptomatic Ischemic Stroke in Full-Term Neonates : Role of Acquired and Genetic Prothrombotic Risk Factors Stroke, October 1, 2000; 31(10): 2437 - 2441. [Abstract] [Full Text] [PDF]
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J. D. Mills, M. W. Mansfield, and P. J. Grant Tissue Plasminogen Activator, Fibrin D-Dimer, and Insulin Resistance in the Relatives of Patients With Premature Coronary Artery Disease Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 704 - 709. [Abstract] [Full Text] [PDF]
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Top
Introduction
Venous thromboembolic disease
) linked by disulfide bonds. The 3 polypeptides are encoded by 3 fibrinogen genes clustered on the long
arm of chromosome 4.
455 G/A polymorphism (in the 5'
promoter region of the 
some large