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Antithrombotic Drug Therapy in Cardiovascular Disease
The protein S gene is structurally complex and has a pseudogene (a segment of DNA that resembles
a gene, but cannot be transcribed) with high homology which has made genetic analysis more
complicated. The 5¢ end of the gene shows high homology with other vitamin-K-dependent proteins.
Interestingly, only about 50–60% of patients with protein S deficiency have identified genetic muta-
tions (58,59). The majority of genetic variants causing type I protein S deficiency are SNPs and inser-
tions and deletions with at least 33 unique variants identified
(27). Four different mutations have been
identified that cause type II protein S deficiency
(60,61), including two in the propeptide, one in the
EGF domain and one in the second EGF domain. Reports have suggested that type I and type III
protein S deficiency may be phenotypic variants of the same genotype
(62,63). For example, in one
study of French patients with low free protein S, 82% of patients in whom mutations could be identi-
fied had a Ser460Pro SNP
(58), also known as protein S Heerlen (64). However, in this same study,
this SNP had the same frequency in patients with thrombosis as in the general population; hence, its
association with increased thrombotic risk remains to be clarified. The prevalence of familial protein
S deficiency in the general population is approximately 0.03–0.13%
(65) with a prevalence of 7.3%
in patients with VTE
(29). The absolute risk of thrombosis in patients with protein S deficiency has
been estimated at 8.5 times higher as compared with individuals with no defect
(42). Homozygous
protein S deficiency is rare and associated with neonatal purpura fulminans
(66). Although reports of
arterial thrombosis in patients with protein S deficiency are published
(67), larger studies have not
confirmed a role in arterial thrombosis
(68). Clinical diagnosis of protein S deficiency relies on a
functional and immunoassay (Table
10), and as with antithrombin III deficiency, testing for the underlying
genetic variant is not clinically indicated.
Protein C Deficiency
Protein C, a vitamin-K-dependent plasma glycoprotein is the precursor of the serine-proteinase-
activated protein C (APC), which subsequently inactivates coagulation factors Va and VIIIa, an effect
enhanced by protein S. Interestingly, APC has anti-inflammatory activities and protects endothelial
barrier function in reactions mediated by the endothelial protein C receptor (EPCR)
(69). Protein C
deficiency is a heterogeneous disorder inherited in an autosomal dominant fashion, and two subtypes
have been identified
(70). In the more common type I protein C deficiency, there is reduction both in
protein C activity and in protein C antigen, and is characterized by marked phenotypic variability. In
type II protein C deficiency, there is evidence of an abnormal protein C molecule but with normal
protein C antigen. The gene for protein C is located on chromosome 2 and is closely related to the
gene for factor IX
(71). More than a hundred different genetic mutations have been associated with
the two subtypes
(72). There appears to be the presence of a founder effect in Dutch families with
type I deficiency (73).
The prevalence of heterozygous protein C deficiency ranges from 1 in 200–500 in a healthy popula-
tion (74), increasing to 2–5% in a population of patients with VTE (29). Clinically, protein C defi-
ciency presents as VTE, neonatal purpura fulminans (primarily in homozygous or double heterozygous
newborns), warfarin-induced skin necrosis, and has also been linked to fetal loss (75). Warfarin-
induced skin necrosis is an infrequent complication induced by a transient hypercoagulable state; the
initiation of warfarin leads to a decrease in protein C anticoagulant activity, with more pronounced
effects when doses greater than 10 mg of warfarin daily are used. Arterial thrombosis has not been
consistently associated with protein C deficiency, though there have been reports of nonhemorrhagic
stroke in young adults (76). Homozygous protein C deficiency can cause purpura fulminans (caused
by thrombosis of small vessels), occurring soon after birth or in the first year of life; or can result in
milder manifestations similar to those with heterozygous deficiency (77). The median age-of-onset of
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VTE in protein C deficiency is 45 years in unselected patients and 30 years in members of throm-
bophilia families
(78). Recurrent VTE develops in 60% of carriers with VTE. The absolute risk of
thrombosis in patients with protein C deficiency is about sevenfold higher than that of normal subjects
(42,79). However, there is marked variability in families with protein C deficiency, suggesting factors
other than that explained by the genetic defect. One such risk factor for higher risk of VTE is presence
of a second thrombotic defect, especially factor V Leiden. For example, a review of four studies
revealed that 75% of family members who carried two defects suffered VTE, compared with 10–30%
of carriers of only one defect (80).
Protein C deficiency is diagnosed by a variety of immunologic and functional assays
(47). Patients
with a protein C level <55% of normal likely have a genetic abnormality, whereas levels between 55
and 65% are either due to a deficient state or represent lower limits of normal
(81). Warfarin therapy
reduces functional and immunologic measurements of protein C. If it is not possible to stop antico-
agulation, i.e., due to severity of the thrombotic tendency, individuals can be studied while anticoagu-
lated with heparin using protein C antigen level testing. When treating an acute VTE event in patients
with known protein C deficiency, oral anticoagulation should be started only after full heparinization
is achieved. Further, to avoid warfarin-induced skin necrosis, the initial dose of warfarin should be
low and then increased slowly until therapeutic. In patients with heterozygous protein C deficiency
and a history of warfarin-induced skin necrosis, supplemental administration of protein C should be
considered until a stable warfarin dose is achieved (82).
Activated Protein C Resistance (Factor V Leiden)
Dahlbäck and colleagues discovered APCR in 1993 (83) and it is responsible for 20–30% of cases
of VTE. Plasma is diagnosed as “APC resistant” if addition of exogenous APC fails to prolong its
clotting time in an activated partial thromboplastin time (aPTT) assay (83). Factor V is a plasma
glycoprotein cofactor; during coagulation, factor V is converted to factor Va by meizothrombin and/
or factor Xa. Furthermore, factor V is a cofactor in the inactivation of factor VIIIa by activated pro-
tein C. Approximately 90% of cases of VTE due to APC resistance are due to an SNP in the Factor
V gene (G to A at position 1691 in exon 10), resulting in an arginine to glutamine in amino acid 506,
also known as Factor V Leiden (84). Factor V Leiden is the most common cause of VTE, accounting
for 40–50% of cases. The underlying molecular mechanism by which Factor V Leiden causes APCR
is still under biochemical investigation. Factor Va Leiden has been shown to be inactivated more
slowly by APC than normal factor Va, resulting in increased coagulation (85). Furthermore, factor
V Leiden results in decreased anticoagulation by leading to lack of cleavage of factor V at position
506, which would normally serve as a cofactor with APC in degradation in factors VIIIa and Va.
APC resistance can also be caused by the Factor V R2 (H1299R) mutation. The rare R306T (Factor
V Cambridge (86)) and R306G (Factor V Hong Kong (87)) affect the APC cleavage site at Arg306,
conferring only mild APC resistance (88). Factor V Liverpool (Ile359Thr) results in poor APC
cofactor activity for the inactivation of factor VIIIa, as well as reduced APC mediated inactivation
of factor Va (89).
Factor V Leiden has a prevalence of up to 6% in Caucasians, but is much lower in African and
Asian populations (90). In Europeans, the mutation is found in up to 50% of familial thrombotic dis-
orders (84). A study of over 4,000 subjects in the Physicians’ Health Study and Women’s Health
Study found carrier frequencies in Caucasians of 5.3%, in Hispanic Americans of 2.2%, in Native
Americans of 1.25%, in African-Americans of 1.2%, and in Asian Americans of 0.45% (91). It
appears that the mutation originated approximately 30,000 years ago based on haplotype analyses
suggesting evidence for a founder effect (92).
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The transmission is autosomal dominant. This mutation is associated with a significant increase in
thrombotic risk and is found in 20% of patients with thrombophilia (up to 50% in selected patients,
i.e., those with a family history of thrombosis)
(84,93,94). There is evidence that this variant (bal-
anced with the prothrombin 202010A) may reflect a selective advantage in heterozygotes, offering
benefits for reducing blood loss associated with giving birth and trauma
(95), decreased risk of intrac-
ranial hemorrhage
(96), and protecting against blood loss after cardiac surgery (97). Factor V R2 has
not been shown to be associated with an increased risk of VTE, but has been shown to increase Factor
V Leiden-related thrombosis risk in individuals doubly heterozygous at these mutations
(98,99).
Factor V Liverpool has been associated with an increased risk of VTE
(89). Factor V Cambridge and
factor V Hong Kong do not appear to be associated with thrombosis
(100).
The clinical manifestations of factor V Leiden include DVT, pulmonary embolism
(101), as well
as cerebral
(102), mesenteric, and portal vein thrombosis, and may play a role in recurrent fetal loss
(103). In addition, factor V Leiden has been associated with other obstetric complications including
pre-eclampsia, fetal growth restriction, and abruption placenta
(104); however, these associations
need further validation. Interestingly, it appears that the lifetime risk of VTE and the severity of VTE
are less in patients heterozygous for factor V Leiden when compared with patients with the less com-
mon thrombophilias
(42). Factor V Leiden may be associated with increased risk of recurrent VTE;
however, data are conflicting
(105). Factor V Leiden does not appear to be associated with risk of
arterial thrombosis: most studies, including two meta-analyses, have been unable to find a significant
increase in the prevalence of factor V Leiden in patients with myocardial infarction and stroke
(106,107). However, an increased risk of arterial thrombosis may be confined to young female smok-
ers who carry factor V Leiden
(108,109).
Patients with VTE who have other thrombotic defects such as protein C, protein S, or antithrombin
deficiency, and prothrombin gene mutations have an increased prevalence of factor V Leiden, with the
presence of two defects increasing the thrombotic risk in family members up to threefold in comparison
with the risk of a single defect (110,111). In a review of case-control studies of factor V Leiden and
prothrombin G20210A, patients doubly heterozygous for the two mutations had a fourfold increase in
risk of VTE compared with patients heterozygous only for the factor V Leiden mutation (odds ratio 4.9
vs. 20.0)
(112). The risk of VTE has been found to be increased threefold in first-degree relatives who
are carriers of factor V Leiden if factor VIII levels are ³150
IU/dL (113) and also increased in patients
with concomitant factor V deficiency
(114). Patients with non-O blood types have a two to four times
increased risk of VTE in both heterozygous and homozygotes for factor V Leiden
(115). Patients with
concomitant factor V Leiden and hyperhomocysteinemia have an increased risk of VTE
(116). Further,
as shown in Table 4, the risk of VTE is increased with concomitant use of oral contraceptives, hormone
replacement therapy, or pregnancy (117,118) Other concomitant clinical factors may also increase VTE
risk in the presence of factor V Leiden: a prospective study of almost 10,000 Danish patients found that
VTE risk in patients heterozygous or homozygous for factor V Leiden increases with age, smoking,
and increasing body mass index (BMI)
(119).
Other Forms of Activated Protein C Deficiencies
APCR can also occur in the absence of a genetic mutation in factor V, for example, in patients with
cancer, which may contribute to the increased thrombotic incidence in these patients (120); however,
the clinical utility of diagnosing this type of APC resistance is unclear. APC resistance can also be
acquired in those using oral contraceptives or hormone replacement therapy (121). In addition to
mutations in the Factor V gene, activated protein C deficiencies can result from other genetic muta-
tions. The EPCR is a type I transmembrane protein highly expressed on the endothelium of large
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The Genetics of Thrombosis
vessels (122), enhancing the rate of protein C activation (123). Several polymorphisms in the EPCR
gene have been associated with venous and arterial thrombosis by affecting the coupling of protein C
to the EPCR, resulting in an alteration of APC generation
(124). Four haplotypes have been found in
the EPCR gene (H1, H2, H3, H4), which have been associated with VTE, but with varying results.
The H3 haplotype has been associated with an increased risk of VTE (OR: 1.8)
(125), though other
studies have found no increased risk
(126,127). The H1 haplotype, which is tagged by the SNP 4678
G/C (aka rs9574), has been associated with decreased risk of VTE (OR: 0.59)
(126), and with
decreased risk of VTE in carriers of the Factor V Leiden mutation (OR: 0.31)
(128). Another study
evaluated two SNPs in exon 4 of the EPCR gene and found that the 4600AG genotype had signifi-
cantly higher soluble EPCR levels than the AA genotype, though it was not associated with VTE risk,
but that the 4678CC genotype was associated with decreased VTE risk (OR: 0.61)
(126). Further, a
23-bp insertion in exon 3 was shown to be a risk factor for atherothrombotic disease
(129); however,
a subsequent study failed to confirm that association
(130). Further studies are necessary to establish
the importance of the EPCR gene in thrombotic disease.
Prothrombin 20210A
Prothrombin (aka factor II), is the precursor to thrombin, is vitamin K dependent, and plays a key
role in the conversion of fibrinogen to fibrin. In 1996, Poort et
al. described the prothrombin 20210A
mutation in an investigation of patients with a personal and family history of VTE and in healthy
controls: 18% of patients with VTE had the substitution (adenine for guanine at position 20210) com-
pared with an only 1% prevalence in healthy controls
(131). These investigators subsequently con-
ducted a population-based, case-control study which revealed that 6.2% of consecutive patients with
a first DVT carried the G20210A allele as compared with 2.3% of age- and sex-matched control sub-
jects. They further found that a higher level of prothrombin activity itself was associated with
increased risk of VTE and individuals with one copy of the A allele had significantly higher mean
prothrombin levels as compared with individuals with the GG genotype
(131). More recent reports
have found little correlation between this mutation and plasma prothrombin levels. One study did
show a highly significant LOD score between the G20210A mutation and a QTL for prothrombin
activity, and further, that simultaneously accounting for association with the variant completely elimi-
nated the linkage signal suggesting that G20210A is a functional polymorphism
(132).
G20210A represents the second most frequent prothrombotic genetic polymorphism, and like Factor
V Leiden, the transmission is autosomal dominant. The prevalence of this mutation varies widely geo-
graphically. In whites, the prevalence varies from 0.7 to 6.5% (133–135) with an overall prevalence in
one study of 11 centers in nine countries of 2% (134), and is very rare in black and Asian populations.
Carriers of this mutation have a threefold increased risk of VTE (131). Many subsequent reports have
confirmed the role of prothrombin 20210A in risk of DVT and PE, with odds ratios ranging from 2.0
to 5.0 (136–140). For example, in the Leiden Thrombophilia Study, 6.2% patients with DVT had the
G20210A variant compared with 2.3% of healthy matched controls (131), with a 2.8-fold independ-
ently increased risk of VTE across sexes and age groups. Given its strong role in risk of VTE, studies
have investigated the role of this polymorphism in recurrent thrombotic events with some studies show-
ing no association (141) and one meta-analysis suggesting association with recurrent DVT (OR: 1.72;
95% CI: 1.27–2.31) (105). Carriers of this mutation may also have an increased risk of VTE in the
setting of pregnancy, with one study showing that 31% of pregnant or postpartum women with VTE
carried the mutation as compared with 4.2% of controls without VTE (OR: 10.2; 95% CI: 4.0–25.9)
(142). Prothrombin G20210A has also been shown to be a risk factor for cerebral venous thrombosis
with a gene-environment effect concentrated in patients using oral contraceptives (143).
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Antithrombotic Drug Therapy in Cardiovascular Disease
As mentioned previously, given the high frequency of many of the genetic variants associated with
predilection to thrombosis, a number of studies have evaluated whether the coinheritance of two or
more defects increases the likelihood of thrombosis and have found this to be the case. For example,
one study compared the prothrombin G20210A allele in individuals with a history of VTE and found
that 5% of patients carried both factor V Leiden and the prothrombin variant, higher than the expected
population frequency of 0.1% (144). In a study of neonatal thrombosis, there was a very high preva-
lence of concurrent factor V Leiden and prothrombin G201210A mutation
(145). A pooled analysis
of eight case-control studies found that the odds ratio for risk of VTE was 20.0 for double heterozy-
gotes (i.e., patients with both the prothrombin G20210A and factor V Leiden mutations), as compared
with 3.8 to 4.9 in patients with only the prothrombin or factor V Leiden mutations
(112). Of patients
with VTE, 2.2% were double heterozygotes, 12% were factor V Leiden heterozygotes only, and 23%
were prothrombin G20210A heterozygotes only. These results have been replicated in other studies
(133,136,144,146,147). In fact, many investigators now believe that the prothrombin variant is not
sufficient in and of itself to predispose to VTE. To study this, investigators examined 281 patients
referred for thrombosis in Italy and found that risk of VTE associated with this variant was significant
only in the subset of patients with additional risk factors
(147).
The role of the prothrombin G20210A mutation in arterial thrombosis is controversial, with most
studies showing no association or showing association only in the presence of another known risk fac-
tor
(137,148–155). For example, one study found weak association of the mutation with heart disease
in young women (OR: 4.0), but when the variant was present in conjunction with smoking or a meta-
bolic risk factor (obesity, hypertension, hyperlipidemia, or diabetes), the risk of heart disease increased
to 34–43-fold increased risk
(155). Another study showed similar results in men with MI; patients who
smoke and have metabolic risk factors in combination with the genetic variant had a higher risk of MI
compared with noncarriers with the same risk factors (150). The prothrombin G20210A variant has
also been evaluated in relation to risk of ischemic stroke with similarly conflicting data. Most studies
have shown no association (137,152,156), but one study in 72 young patients with no traditional risk
factors found a 3.8-fold risk of ischemic stroke associated with the heterozygous mutation
(157).
There have been very few descriptions of individuals homozygous for prothrombin G20210A;
these have shown marked variation in the clinical manifestation ranging from ischemic stroke (157)
to no clinical manifestations
(158). Other mutations have been identified in the prothrombin gene
including C20209T and A19911G, with varying reports about their association with VTE risk
(159,160). Tables 4.4 and 4.5 detail the prevalence of Factor V Leiden and prothrombin gene muta-
tions in different populations, illustrating its relative abundance in patients with VTE
(161). In sum-
mary, these studies suggest that the prothrombin G20210A variant may be a VTE susceptibility
variant, but with significant contributions from other genetic, molecular, and clinical risk factors.
Hyperhomocysteinemia
Homocystinuria is a rare autosomal recessive hereditary disease resulting in extremely high plasma
and urine homocysteine concentrations and clinical manifestations including thromboembolic disease
and premature atherosclerosis. In contrast to this very rare condition, 5–7% of the population mani-
fests less marked plasma homocysteine elevations (162), and evidence suggests that moderate hyper-
homocysteinemia is a risk factor for VTE and atherosclerosis (163). There are several mechanisms by
which hyperhomocysteinemia may play a role in thrombotic risk. A recent study in apolipoprotein-E-
deficient mice suggests that hyperhomocysteinemia results in endothelial dysfunction and subsequent
accelerated carotid artery thrombosis (164). Another study in mice suggests that susceptibility to arte-
rial thrombosis with hyperhomocysteinemia may involve oxidative stress and impairment of the
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The Genetics of Thrombosis
protein C anticoagulant pathway (165). In addition to nutritional deficiencies, certain medications
(166), chronic kidney failure, and cigarette smoking (167), genetics have been shown to cause eleva-
tions in plasma homocysteine concentrations. MTHFR (5,10-methylenetetrahydrofolate reductase) is
an enzyme that catalyzes the conversion of homocysteine to methionine. The thermolabile T allele of
the MTHFR gene SNP C677T results in an amino acid change from alanine to valine in the MTHFR
gene, reducing its efficiency by half, and is associated with elevated homocysteine levels in individu-
als with low folate intake
(168). The prevalence of the mutation is 5–14% in a general population
(169). Although it appears that hyperhomocysteinemia is a risk factor for VTE (163) and recurrent
VTE
(170), there are conflicting results about the prothrombotic role of the C677T polymorphism
(reviewed in Ray et
al. (171)). Regardless, this mutation plays much less of a role than the 20210A
and Factor V Leiden mutations in thrombosis risk.
The MTHFR C677T variant has also been implicated to a variable degree in arterial thrombosis. In
a meta-analysis of greater than 11,000 individuals homozygous for the thermolabile variant of
MTHFR and over 12,000 matched controls enrolled in 40 observational studies, patients with the TT
genotype had moderate but statistically significant increased risk of coronary heart disease as com-
pared with controls (OR: 1.16; 95% CI: 1.05–1.28) (172). Another meta-analysis suggested interna-
tional geographic variations in risk conferred by the MTHFR variant, with no association in North
American, European, and Australian populations, but evidence of a relationship in Middle Eastern
and Asian populations
(173). One explanation for this heterogeneity may be due to differences in
folate status: the North American studies were conducted where there was greater use of vitamin B
and folate supplementation or fortification. Hence, it appears that the effect of the MTHFR variant has
minimal effect on risk of cardiovascular disease in populations with adequate folate levels.
Lupus Anticoagulant/Antiphospholipid Antibodies
The antiphospholipid syndrome is defined by the clinical manifestation of venous or arterial thrombo-
sis, recurrent fetal loss, or thrombocytopenia coupled with the presence in the serum of at least one type
of antiphospholipid antibody. Lupus anticoagulants are one of a group of antiphospholipid antibodies and
are common in patients with the antiphospholipid syndrome. They are associated with thromboembolism,
recurrent spontaneous abortion, and thrombocytopenia (174) but lupus anticoagulants are also present in
1–5% of healthy individuals. Relatives of probands with antiphospholipid antibody syndrome are more
likely to have aPL, and there is a strong association between aPL and HLA types (175,176). Therefore,
studies have attempted to identify genetic variants that may interact with, or operate in the background
of, antiphospholipid antibodies. One study found that the P-selectin Pro715 allele was not present in
patients with lupus anticoagulant who suffered arterial thrombosis (but was slightly more frequent in
patients with VTE), whereas the CA repeat polymorphism in the 3¢-noncoding region of CD154 was
associated with risk of development of arterial thrombosis (177). The authors suggest that these genetic
variants can differentiate between risk of venous and arterial thrombosis in patients with lupus anticoagu-
lant. Studies have also shown that the concurrent presence of other genetic mutations including factor V
Leiden, the prothrombin G20210A mutation, and APCR increases the risk of antiphospholipid-associated
VTE (178,179). Further studies of the genetics of this disease are necessary.
Other Genetic Factors Associated with VTE
Tissue-factor pathway inhibitor (TFPI) plays a major role in the inhibition of the extrinsic coagula-
tion pathway (180). The Pro15Leu SNP in TFPI has been shown to be a risk factor for VTE (181);
however, subsequent studies did not confirm this association (182). Thrombomodulin, a component
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of the protein C anticoagulant pathway, is a transmembrane protein synthesized by endothelial cells
and acts as a receptor for thrombin and as cofactor of thrombin in the activation of protein C. Several
missense mutations in the thrombomodulin gene have been identified in patients with VTE
(183–186);
however, the relationship between these variants and risk of VTE remains unclear. Variants in the
thrombomodulin gene have also inconsistently been associated with coronary heart disease and/or MI
(187–195). A recently published large-scale study of genetic variants in DVT found variants within
several genes to be associated with DVT in three case-control datasets, including CYP4V2, SERPINC1,
GP6
(196). Further studies of these various genetic variants are necessary to establish their role in
VTE risk.
Laboratory Assays and Diagnostic Testing for Hereditary VTE
Table 10 presents an overview of the various laboratory assays for the more commonly tested
genetic thrombophilias. The primary screening tests for APC resistance are aPTT-based assays. In
such, the aPTT is done with and without a standardized amount of APC. The two generated clotting
times are then converted to an APC ratio which is compared to the normal range or by normalizing to
the APC resistance ratio from normal pooled plasma. This test is not valid in patients receiving
anticoagulants, in patients with a baseline abnormal aPTT due to other coagulation defects, and has
not been validated in patients with acute thrombotic events or pregnant women (197). In second-
generation functional assays, patient plasma is diluted in a sufficient volume of factor-V-deficient
plasma, and then an aPTT-based assay or a tissue factor-dependent factor V assay is performed (198).
This assay can be performed in patients receiving anticoagulants and in those with abnormal baseline
aPTT due to other coagulation defects. Factor V Leiden specifically can be detected by a genetic test
in DNA extracted from peripheral blood mononuclear cells to detect the substitution of A for G at
nucleotide 1691 in the factor V gene, which results in the Arg506Gln mutation in the factor V protein
and hence loss of an Mn1I cleavage site (84).
Similarly, the G20210A gene mutation is usually identified in DNA extracted from peripheral
blood mononuclear cells using PCR-based methods. Plasma prothrombin assays are not diagnostic for
this mutation. For diagnosis of hyperhomocysteinemia, there are sensitive assays that allow quantifi-
cation of total plasma homocysteine concentrations. Normal values range from 5 to 15 mmol/L, with
moderate hyperhomocysteinemia defined as 15–30
mmol/L, intermediate defined as 30–100 mmol/L,
and severe hyperhomocysteinemia defined as >100
mmol/L (199). However, identification of the
MTHFR genotype is not cost effective and the clinical utility is uncertain.
GENETIC VARIANTS IN ARTERIAL THROMBOTIC DISORDERS
The clinical manifestations of arterial thrombosis are diverse. For example, acute thrombosis at the
site of a ruptured, lipid-rich atherosclerotic plaque is thought to be the precipitating event underlying
development of acute MI, ischemic stroke, or peripheral arterial disease (PAD) (200). Given that
almost half of all thrombotic events occur in patients without traditional cardiovascular risk factors
(201), there have been extensive efforts in elucidating novel risk factors, including genetic risk factors,
for arterial thrombosis (reviewed in Voetsch and Loscalzo (202)). Hundreds of genetic variants have
been implicated in CAD and arterial thrombotic risk, and an exhaustive review is beyond the scope
of this chapter. An overview of the most relevant and validated prothrombotic genetic variants is pre-
sented in Table 7. Overall, few (if any) genetic variants contribute significantly to risk of arterial
thrombotic disorders and in general, clinical testing of these variants is not indicated except in certain
subgroups of patients (summarized as follows and in Fig. 1).
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Table 7
Genetic factors implicated in arterial thromboembolism
Gene Variant Function (if known) Phenotype
Fibrinogen b (1) Bc/I
(2) Arg448Lys
(3) −455G/A
(1) Increases fibrinogen level
(2) Alters nuclear protein binding; changes
fibrin structure/function
(3) Increased transcription of b-fibrinogen (206)
MI, atheroma progression, lacunar
infarcts (207–215) (conflicting
results)
Fibrinogen a Thr312Ala Results in more extensive a-chain crosslinking
and thicker clot fibers (216)
Poststroke mortality in pts with Afib
(217,219); venous thromboembolism
(218)
Factor VII (1) Arg353Gln(2) Hypervariable
region 4 (HVR4)
Higher levels of factor VII MI
Factor XIIIA Val34Leu Changes FXIII activation rate and fibrin
structure/function
MI (8,358)
Fibrinogen Aa Thr312Ala Changes fibrin structure/function and FXIII
crosslinking
Atrial fibrillation (417)
Thrombomodulin Ala455Val, Ala25Thr, −33 G/A Unknown MI, CAD, though reports inconsistent
(187–195)
GPIIIa Leu33Pro (PlA2) Results in conformational change in disulfide
loop important for fibrinogen binding (418)
CAD, stroke, MI, venous thrombosis
(237–242,418)
Glycoprotein Ia-IIa
(a2b1 integrin)
C807T Affects a2b1 integrin density on platelets and
collagen receptor activity (259,260)
MI and stroke, particularly in young
patients (263–265), results
contradictory (266,267)
Glycoprotein Ib-V-IX (1) HPA-2 (C3550T), VNTR (1) Poorly defined (1) MI and stroke, results contradictory
(242,251–256)
(2) Kozak sequence (T/C
dimorphism at nucleotide -5)
(2) More efficient mRNA translation and
increased levels of Iba receptor on platelet
surface (Afshar-Kharghan V, 186)
(2) MI (258)
Plasminogen activator
inhibitor-1 (PAI-1)
4G/5G promoter indel 4G allele associated with higher PAI-1 levels CAD, MI (270–274,278), dialysis
access thrombosis (interaction with
TGF-b1 haplotype) (419)
Tissue-type
plasminogen
activator (t-PA)
(1) 311-bp Alu indel in intron 8 Associated with t-PA release (1–2) MI (280,284,285), ischemic
stroke (286)
(3) Ischemic stroke (420)
(2) −7351C/T
(3) rs7007329-rs8178750
haplotype
(continued)
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Antithrombotic Drug Therapy in Cardiovascular Disease
Gene Variant Function (if known) Phenotype
Thrombin-activatable
fibrinolysis inhibitor
(TAFI)
Ala147Thr Associated with plasma TAFI antigen levels Angina, MI (289,290)
MTHFR 677 C/T Leads to thermo liability of the enzyme CAD, MI, stroke (292,293,421)
Endothelial nitric
oxide synthase
(eNOS)
(1) VNTR in intron 4 and 13 (1) Unknown (1) MI, CAD (298)
(2) Promoter SNPs (−786 T/C,
−922 A/G, −1468 T/A)
(2) −786 T/C results in reduction in eNOS
promoter activity
(2) Coronary spasm, reduced cerebral
blood flow, CAD, endothelial
dysfunction (299–302)
P-selectin PSGL-1 VNTR Coronary stent thrombosis (422)
IL-6 (1) −572G→C
(2) −174G→C
(1) Ischemic stroke (308)
(2) MI, stroke, CAD (423–425)
Von Willebrand factor
(vWF) (426)
1798 C/G Coronary artery disease, advanced
atherosclerosis
Factor V Factor V Leiden Conflicting results: MI, ischemic
stroke, peripheral vascular disease
(109,145,220–223)
Prothrombin G20210A Controversial and conflicting association
with MI (137,148–155,427),
ischemic stroke (137,152,156,157),
cryptogenic stroke (428), peripheral
vascular disease
MTHFR C677T MI, ischemic stroke, peripheral vascular
disease (172,220,291–294)
Fucosyltransferase 3 T59G Atherothrombotic disease (429)
Tissue factor I1208D Lower levels of circulating tissue factor
(d allele) (235)
Protective against VTE, no association
with coronary disease (235)
Paraoxonase Various Various Coronary artery disease, MI
(303,305–307)
ALOX5AP/LTA4 Various Involved in leukotriene pathway Coronary artery disease, MI (17,430)
CDKN2A/CDKN2B Several SNPs adjacent to
CDKN2A/CDKN2B genes
Unknown Coronary artery disease, MI (25,309)
Endothelial protein C
receptor (EPCR)
23-bp insertion in exon 3 Unknown Atherothrombotic disease, reports
contradictory (129,130)
Table 7
(continued)
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The Genetics of Thrombosis
Genetic Variants In Hemostatic System Genes
Fibrinogen
Fibrinogen is the precursor of fibrin and fibrinogen levels influence platelet aggregation. Elevated
fibrinogen levels have been associated with MI, stroke, and PAD
(203,204), with a meta-analysis
showing an overall twofold increased risk of cardiovascular disease in healthy and high-risk subjects
(205). Genetic factors are estimated to contribute to approximately 50% of variability in fibrinogen
levels
(202). Variants in the genes encoding the three pairs of fibrinogen polypeptide chains (a, b, and g)
have been studied in relation to arterial thrombotic risk, with most studies focusing on variants within
the gene encoding b-fibrinogen: −148C/T, −455G/A (HaeIII), BclI (in 3¢ untranslated region), and
−854G/A. The −455G/A and BclI variants are in linkage disequilibrium (i.e., are correlated) with each
other. The AA genotype of the −455G/A SNP has been associated with 10% higher fibrinogen levels
compared with the GG genotype (202). Studies have further shown that the A allele binds less well
to a putative repressor protein complex, resulting in increased fibrinogen-b chain transcription (206).
However, the association between this fibrinogen gene variant and risk of arterial thrombosis remains
unclear, with some studies showing an association and others showing none
(207–213). A systematic
review of the association of this SNP revealed that homozygosity for the −455A allele was marginally
protective against acute MI (OR: 0.66; 95% CI: 0.44–0.99) (214); but in another study, this allele was
associated with a 2.5-fold increase in risk of multiple cerebral lacunar infarcts but not with large-
artery strokes (215). A variant in the a-fibrinogen gene Thr312Ala results in more extensive a-chain
crosslinking and thicker fibers with clot formation (216), and has been shown to be associated with
mortality rates after stroke (217) and VTE (218). However another study showed no association with risk
of MI (219). These widely conflicting results suggest there is little if any role for fibrinogen variants
in thrombotic disorder risk.
Factor V Leiden and Prothrombin G20210A
The Factor V Leiden and prothrombin G20210A SNPs have been examined for association with
arterial thrombotic disorders in numerous studies (reviewed in a meta-analysis by Kim and Becker
Fig. 1. Proposed criteria for the selection of patients in whom it may be justified to perform testing for underlying
thrombophilic conditions (Factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations) (Reproduced
with permission from Andreotti et
al. (358)).
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