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Antithrombotic Drug Therapy in Cardiovascular Disease
have not been performed making it difficult to establish guidelines for management of patients with
a genetic variant and thrombosis. Patients with VTE and an inherited thrombophilia are usually
treated with oral anticoagulants for a minimum of 6–12 months with a goal INR of 2.0–3.0. Long-
term treatment following this period is dependent on the number of recurrences and the number of
genetic defects found. These decisions are complicated by the fact that risk of recurrence varies
depending on the genetic defect.
In patients with factor V Leiden, long-term (indefinite) oral anticoagulation should be considered
in those with recurrent VTE, multiple thrombophilic disorders, coexistent risk factors (i.e., prolonged
immobility), and in patients who are homozygous for the mutation. Long-term anticoagulation is not
indicated in all patients after first DVT who are heterozygous for factor V Leiden as shown in several
studies
(363,364), including the Leiden Thrombophilia study of patients with a first DVT where the
risk of recurrent VTE was similar in patients with and without an underlying inherited thrombophilic
defect
(364). For other inherited thrombophilias, in general, long-term (i.e., indefinite) anticoagula-
tion is not indicated except in the setting of (1) recurrent spontaneous thromboses (or one spontaneous
thrombosis in the case of antithrombin III deficiency or antiphospholipid syndrome); (2) one sponta-
neous life-threatening thrombosis; (3) one spontaneous thrombosis at an unusual site (i.e., mesenteric
or cerebral vein); or (4) one spontaneous thrombosis in the setting of more than one inherited genetic
defect (146,362,365).
Management of Pregnancy
Anticoagulation in pregnant women with a known inherited thrombophilic defect is controversial
and should be considered on an individual-by-individual basis. Small, observational studies have
suggested that prophylactic antithrombotic therapy is beneficial in such women (366,367), and one
randomized trial has shown benefit
(368). In this study, 160 women heterozygous for factor V
Leiden or prothrombin G20210A mutations, or with protein S deficiency, who had had one unex-
plained pregnancy loss after 10 weeks of gestation were randomized to aspirin (100 mg daily) or
low-molecular-weight heparin from 8 to 37 weeks of gestation. They found that women treated
with enoxaparin had a higher live birth rate than those treated with aspirin (86.3% vs. 28.8%; OR:
15.5 (95% CI: 7–34), as well as higher birth weights and lower rate of fetal growth restriction.
Therefore, women with high-risk thrombophilia (antithrombin III deficiency, factor V Leiden or
prothrombin G20210A homozygotes, or compound heterozygotes for factor V Leiden and pro-
thrombin) should be considered for treatment with prophylactic dose anticoagulation with heparin
during pregnancy and postpartum. In the setting of high-risk thrombophilia and a personal or strong
family history of VTE, therapeutic dose anticoagulation with heparin should be considered. Women
with lower risk thrombophilia (heterozygous factor V Leiden or prothrombin G20210A, protein C
or S deficiency) should be managed depending on their personal history of thrombotic events; if
they have a personal history of thrombotic events, they should be considered for prophylaxis during
pregnancy and postpartum.
Other Management Considerations
In general, oral contraceptives should not be started or continued after a thrombotic episode
regardless of the presence of an inherited thrombophilic defect. Women with a family history of
multiple thromboses (especially those occurring at a younger age) should be cautioned about the
significant danger of oral contraceptive use. Testing for hereditary thrombophilias may be useful in
this group to help in decision making about contraceptive use (369). Women heterozygous for factor
V Leiden should be discouraged against use of oral contraceptives, though it is not an absolute
contraindication.
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The Genetics of Thrombosis
COMPLEX DISEASE GENETICS
Until the mid- to late 1990s, textbooks listed only a small number of single-gene defects associated
with thrombosis. The focus was primarily on Mendelian genetics, where there were single genes with
strong effects and predictable patterns of inheritance and high penetrance. Methods for identifying
such genes have been used to identify Mendelian diseases of the hemostatic system, with results pri-
marily in disorders of bleeding as opposed to disorders of thrombosis. For example, there exists a rare
inherited bleeding disorder, combined deficiency of factors V and VII (F5F8D), where patients show
a marked reduction in plasma levels of factors V and VIII. The gene underlying this disorder (LMAN1)
was identified using family-based genetic analyses
(370,371). The gene for the rare disease familial
thrombotic thrombocytopenic purpura (TTP) was also identified using similar methods in rare patients
with the disorder
(372).
However, the publication of the completed draft sequence of the human genome (Human Genome
Project (1)) and the rapid development of genomic technologies have served to expand the focus of
human genetics beyond Mendelian traits to a deeper understanding of complex disease genetics. In
contrast to Mendelian genetics, complex genetic diseases are usually characterized by multiple genes,
each with modest effects, potentially unclear modes of inheritance, lower penetrance, and are the
result of a complex interplay of gene–gene and gene–environment interactions. Thrombotic disorders
have many of these characteristics. The diagnosis and therapy of most inherited thrombotic and hem-
orrhagic disorders is made more complex by the presence of incomplete penetrance and variable
expressivity (10).
Gene–Environment Interactions
As reviewed under individual genetic variants, there are several known gene–environment inter-
actions for risk of thrombotic disease. For example, in individuals who are heterozygous for the
Factor V Leiden variant, oral contraceptive use or being post partum conferred an additional rela-
tive risk of 6.0, increasing to a relative risk of 60 if the individuals also carried the prothrombin
202010A variant
(373). Another study has clearly shown an incrementally increased risk of throm-
boembolism in carriers of this variant who smoked and were overweight
(119). Interactions have
been shown between factor V Leiden, smoking, and increased risk of stroke
(108); and between
prothrombin G20210A carriership and use of hormone replacement therapy in risk of MI in post-
menopausal women (374).
Vascular-Bed Specific Factors
One can view the local vascular bed as an environment, which may interact with the underlying
genetic architecture of a given individual to result in disease. For example, it is a well-recognized
feature of thrombophilias that there is focal and vascular-bed-specific expression of thrombosis.
This suggests that local regulatory pathways and intrinsic vessel-determined responses to pro-
thrombotic stimuli are in play (375). Studies have shown that endothelial cells from different
vascular beds exhibit distinct phenotypes, including differences in signaling pathways (376);
mitosis rates (377); growth responses (378); and in expression of nitric oxide synthase, von
Willebrand factor, and tissue-type plasminogen activator (379–382). Furthermore, relationships
between vascular endothelial cells and surrounding tissues may be important in site-specific
responses to prothrombotic stimuli (183,379,383,384). Clinically, this can manifest with site-
specific thrombotic complications (Table 11) (375). Therefore, screening, diagnostic testing, and
management should include consideration of a patient/vascular-bed-specific approach rather than
a more generalized strategy.
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Antithrombotic Drug Therapy in Cardiovascular Disease
Table 11
Factors in vascular bed-specific thrombosis (Reproduced with permission from Edelberg et al. (375))
Organ bed
Heart Lung Spleen Kidney Brain
Clinical disorders/
associated
syndromes
Myocardial infarction, acute
coronary
syndromes
Pulmonary hypertension,
pulmonary embolism/
infarction
Splenic
infarction
Nephropathy, renal
thrombosis
Stroke
Clinically associated
factors
Activated factor IX peptide,
Factor XIIa, Fibrinogen,
Plasminogen activator
inhibitor-1, Tissue-type
plasminogen activator
antigen, von Willebrand
factor
Fibrinopeptide A,
Hereditary
spherocytosis,
Soluble
thrombomodulin
Protein C Sickle
cell anemia
Factor V Leiden,
Homocysteine,
Plasminogen
activator
inhibitor-1 4G/4G
Antithrombin III,
Factor V Leiden,
Homocysteinuria
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The Genetics of Thrombosis
Gene–Gene Interactions
As reviewed earlier, given the high frequency of many of the genetic variants associated with
predilection to thrombosis, a number of studies have evaluated and confirmed that the coinheritance
of two or more defects increases the likelihood of thrombosis, including factor V Leiden and Protein
C
(385), factor V Leiden and antithrombin (386), factor V Leiden and protein S deficiency (111), and
others
(387). 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 vari-
ant, higher than the expected population frequency of 0.1%
(144). Another study evaluated simultane-
ously the effects of variants covering four thrombosis genes (factor V, intercellular adhesion molecular
1 (ICAM1), protein C, and thrombomodulin) with cardiovascular disease risk
(388). They found that
several combinations of variants within these genes were associated with cardiovascular events, sug-
gesting that variants may act in combination to increase risk. Another study of five functional hemo-
static polymorphisms found an interaction of factor XIII and prothrombin polymorphisms in risk of
premature MI
(389). In individuals with anticardiolipin antibodies, there appears to exist an incremen-
tal risk of thrombotic events as the number of concomitant risk factors increases (i.e., factor V Leiden,
MTHFR C677T, prothrombin 20210A, etc.), with an odds ratio of 1.46 per each additional prothrom-
botic risk factor
(390). These reports highlight that thrombosis is a complex genetic trait and is a
polygenic disorder. Continued advances in human genetics will most likely highlight more gene–gene
and gene–environment interactions in venous and arterial thrombosis.
Beyond Genetics
Transcriptomics
In this era of complex disease genetics, evaluation and understanding of processes distal to DNA
are vital for dissecting the complex interplay between genes, and between genes and environment, to
result in health and disease. Transcriptomics refers to large-scale gene-expression profiling which
allows simultaneous detection of thousands of different genes on one single “chip.” Application of
such technology to thrombotic disorders is demonstrated by a study performed at Duke University
where Potti et
al. (391) examined gene-expression profiles in patients with anticardiolipin antibodies
and identified expression “signatures” composed of 50 genes whose expression patterns were able to
discriminate and predict those who would suffer subsequent thrombotic events in these patients
(Fig.
2). Hence, these technologies hold promise in developing novel diagnostic tools for determining
which patients may be at risk and potentially intervening prior to a clinical event. For example, the
Bloodomics project at Cambridge University has as its primary objective to discover genetic markers
within platelets that predict arterial thrombotic risk (392).
Proteomics
There exists significant structural homology among coagulation factors. For example, in a study of
a group of healthy subjects participating in the Leiden Thrombophilia Study (393), investigators
found clustering of plasma concentrations of vitamin-K-dependent factors (II, VII, IX, X); of factors
XI and XII; and factors V and VIII clustered with fibrinogen and d-dimer. The anticoagulant factors
(proteins C and S, antithrombin III) clustered together (393). These results of several independent
clusters suggest that the basis for individual fluctuations in plasma levels may lie outside the genes
coding for these factors. Thus, evaluating the coagulation and fibrinolytic pathways behind DNA is
important; gene sequences cannot fully predict the complex structure of proteins, nor their function
or dysfunction. For example, regulation of proteins occurs beyond the level of DNA through post-
translational modification and protein–protein interactions. Proteomics has therefore emerged as a
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Antithrombotic Drug Therapy in Cardiovascular Disease
key component of the molecular characterization of complex diseases, and is defined as the identifica-
tion and functional characterization of the full complement of proteins expressed by complex biologi-
cal systems. Furthermore, post-translational modification of proteins may be involved in the
pathogenesis and clinical manifestation of thrombophilias. For example, if thrombomodulin is oxi-
dized at methionine residue 388, its capacity to downregulate coagulation is reduced (through acti-
vated protein C), but its capacity to inhibit fibrinolysis is unchanged (through thrombin activatable
fibrinolysis inhibitor) (394). Modification of the amino acid side chain of apoprotein B on low-density
lipoprotein results in its oxidation and renders it prothrombotic (395). A study has shown correlation
between the oxidative state of plasma proteins and several markers of thrombin generation and
activity (396). Advancing technological platforms including mass spectrometry have facilitated
Fig. 2. Gene-expression profiles that classify and predict APS phenotype.
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high-throughput proteomic evaluation of plasma and serum. With the use of such technologies, we
will be able to further understand the role of known coagulation proteins and potentially novel pro-
teins in thrombotic risk.
Considerations In Genomic Studies
With the increasing use of emerging genomic technologies in thrombotic disease research, clini-
cians and researchers must be aware of potential pitfalls and issues in conducting and interpreting
such studies. Over the past decade hundreds of association studies have been published for association
of genetic variants with thrombotic risk though few have been consistently replicated. Positive asso-
ciations can be the result of a true association, but can also be due to type I error (observing an asso-
ciation when one does not exist, for example, if one evaluates several variants, a proportion will be
positively associated purely by chance); differing phenotype definitions; linkage disequilibrium
(where the genetic variant is linked to the true etiologic variant); confounders; or population stratifica-
tion (spurious association due to underlying differences in race/ethnicity or other factors). These
considerations need to be carefully addressed in association studies. Investigators should also evaluate
a given candidate gene systematically, assessing both known functional and nonfunctional variants,
and should consider potential gene–gene and gene–environment interactions. The functional signifi-
cance of associated genetic variants should then be assessed to understand and further confirm the
etiologic role of the variant. Reviews of such issues in conduction genetic studies have been published
(397). Studies of transcriptomics and large-scale proteomics must pay careful attention to the analytic
issues prompted by analysis of tens of thousands of variables usually with small sample sizes.
Integration of the different platforms is vital to fully understanding thrombotic risk in a “systems biol-
ogy” approach, but provides further analytic challenge. Finally, the clinical relevance of these studies
must be evaluated, including consideration of whether the genetic variant (or gene-expression profile,
protein, etc.) adds to what is known from clinical factors; whether testing would lead to a change in
patient management; and attention to cost effectiveness of testing. In particular, carefully conducted
clinical trials showing utility of testing for genomic markers are necessary prior to initiating wide-
spread testing in clinical practice. Only with such diligence will genomic research in thrombotic
diseases lead to the eventual goal of “personalized medicine” where genes, gene expression, and other
molecular information are used in conjunction with clinical information to stratify disease or select
specific medications and/or therapies to benefit one particular individual.
CONCLUSIONS
Herein we have reviewed the current state of the genetics of thrombosis. The past decade has spurred
an explosion of studies of the genetic basis of complex diseases such as venous and arterial thrombosis.
Coupled with great strides in molecular technologies, the next decade holds much promise for further
understanding of the underlying genetic and molecular architecture of thrombosis risk.
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