Reviews: Inherited Risk Factors For Venous Thromboembolism

REVIEWS
Inherited risk factors for venous

thromboembolism
Ida Martinelli, Valerio De Stefano and Pier M. Mannucci
Abstract | Venous thromboembolism (VTE) has important heritable components. In the past 20 years,
knowledge in this field has greatly increased with the identification of a number of gene variants causing
hypercoagulability. The two main mechanisms are loss-of-function of anticoagulant proteins and gain-of-
function of procoagulants, the latter owing to increased synthesis or impaired downregulation of a normal
protein or, more rarely, to synthesis of a functionally hyperactive molecule. Diagnosis of thrombophilia is useful
to determine the causes of VTE, recognizing that this multifactorial disease can also be influenced by various
acquired factors including cancer, surgery, trauma, prolonged immobilization, or reproduction-associated
risk factors. Diagnosis of inherited thrombophilia rarely affects the acute or long-term management of VTE.
However, the risk of recurrent VTE is increased in anticoagulant-deficient patients and in homozygotes for
gain-of-function mutations. Screening for inherited thrombophilia in thrombosis-free individuals is indicated
only for relatives of a proband who is anticoagulant-deficient or has a family history of VTE. In families
with thrombophilia and VTE, primary antithrombotic prophylaxis during risk situations lowers the rate of
incident VTE. In this Review, we discuss the main causes of inherited thrombophilia, the associated clinical
manifestations, and the implications for antithrombotic prophylaxis in the affected individuals.
Martinelli, I. et al. Nat. Rev. Cardiol. 11, 140–156 (2014); published online 14 January 2014; doi:10.1038/nrcardio.2013.211
Introduction
Venous thromboembolism (VTE), which encompasses replacement therapy (HRT).2,6–11 The familial segrega-
deep-vein thrombosis (DVT) and pulmonary embo- tion of VTE as a heritable phenotype has been estimated
lism, is the most-common vascular disease after coro- to be between 52% and 62% under non-Mendelian and
nary artery and cerebrovascular diseases.1 The clinical Mendelian assumptions, respectively.12 A family history
consequences of VTE include death, VTE recurrence, of VTE has been consistently reported to be a risk factor
post-thrombotic syndrome, and bleeding complica- for VTE per se.13–15 On the other hand, documented inher-
tions owing to anticoagulant therapy. In the USA, the ited thrombophilia (hypercoagulability), and particularly
incidence of first VTE per 1,000 person-years has been its interaction with acquired factors, is an important
estimated to be 1.61 (1.17 for DVT alone and 0.45 for determinant of VTE.16
pulmonary embolism, with or without associated DVT).2 In this Review, we examine the main causes of inher-
In Europe, a similar incidence of VTE of 1.5 per 1,000 ited thrombophilia, and their associated clinical mani-
Angelo Bianchi
Bonomi Hemophilia person-years has been reported in community studies.3–5 festations. We also discuss the indications for laboratory
and Thrombosis VTE is predominant in older age-groups—the inci- screening to identify individuals who carry thrombophilia-
Center, Fondazione
IRCCS Ca’ Granda,
dence of VTE per 1,000 person-years is 0.08 for men causing mutations, and the implications for primary and
Ospedale Maggiore and 0.12 for women aged <40 years, 1.69 for men and secondary antithrombotic prophylaxis.
Policlinico, Via Pace 9, 1.00 for women aged 40–60 years, 4.24 for men and 3.16
20122 Milan, Italy
(I. Martinelli). for women aged 60–80 years, and 7.65 in men and 8.22 Definition of thrombophilia
Institute of Hematology, in women aged >80 years.3 The term thrombophilia describes a tendency to develop
Catholic University,
Largo A. Gemelli 8,
VTE is a multifactorial disorder resulting from the VTE on the basis of a hypercoagulable state, owing to
I‑00168 Rome, Italy interaction between an array of acquired and genetic inherited or acquired disorders of blood coagulation or
(V. De Stefano). factors. In addition to ageing, the main acquired fibrinolysis. In 1937, Nygaard and Brown introduced the
Scientific Direction,
Fondazione IRCCS risk factors for VTE (Box 1) include history of VTE, term “essential thrombophilia” in a report on five patients
Ca’ Granda, Ospedale superficial vein thrombosis (SVT), surgery, trauma, con- with vascular disease.17 After the connection between
Maggiore Policlinico,
Via F. Sforza 28,
finement to bed, malignant neoplasms with or without thrombophilia and heritability of VTE was clinically
20122 Milan, Italy chemotherapy, major illnesses, insertion of a central described in 1956,18 the deficiencies of antithrombin,
(P. M. Mannucci).
venous catheter or pacemaker, and limb paresis, as protein C, and protein S were documented as the first rare
Correspondence to: well as pregnancy, oral contraceptive use and hormone causes of inherited thrombophilia.19–22 These plasmatic
P. M. Mannucci defects hamper the two main regulatory pathways of coag-
piermannuccio.
mannucci@ Competing interests ulation: the inhibition of serine proteases by antithrombin,
policlinico.mi.it The authors declare no competing interests. and that of the nonenzymatic cofactors VIIIa and Va by
140 | MARCH 2014 | VOLUME 11 www.nature.com/nrcardio

© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Key points Box 1 | Acquired risk factors for VTE

■■ Knowledge about the spectrum of genetic abnormalities causing thrombophilia Permanent
has greatly expanded in the past 20 years ■■ Increasing age
■■ These abnormalities increase the risk of venous thromboembolism (VTE) by ■■ Family history of VTE
causing blood hypercoagulability through the impairment of natural anticoagulant ■■ History of VTE or superficial vein thrombosis
pathways or the potentiation of procoagulants ■■ Obesity (BMI >30 kg/m2)
■■ VTE risk is higher in carriers of natural anticoagulant deficiencies, homozygous ■■ Cancer (brain, breast, gastrointestinal, lung, lymphoma,
defects, and multiple abnormalities (severe thrombophilia) than in heterozygotes pancreatic, renal, prostate) with or without surgery
for factor V Leiden and prothrombin 20210A (mild thrombophilia) and chemotherapy
■■ Family history of VTE is a strong risk factor for VTE regardless of the presence ■■ Myeloproliferative neoplasms
of known VTE susceptibility genes ■■ Major illness (autoimmune diseases, Behçet disease,
■■ Thrombophilia screening is useful in some instances to inform the optimum chronic renal disease, COPD, inflammatory bowel
duration of secondary prophylaxis in patients who have developed VTE and are disease, multiple sclerosis, neurological disease with
at high risk of recurrence limb paresis, rheumatoid arthritis)
■■ Thrombosis-free individuals in risk-enhancing situations (pregnancy, oral ■■ Congestive cardiac failure
contraceptive use, hormone replacement therapy, orthopaedic surgery) do not ■■ Cardiovascular disease (CHD, stroke, TIA)
require thrombophilia screening, except in families with natural anticoagulant ■■ Lupus anticoagulant and antiphospholipid antibodies
deficiencies or history of VTE ■■ Paroxysmal nocturnal haemoglobinuria and other
haemolytic anaemias
■■ Varicose veins
Transient
activated protein C (APC) and its cofactor protein S.23,24 In
■■ Confinement to bed
the 1990s, two gene polymorphisms—factor V G1691A ■■ Current smoking status
Leiden (FVL), which causes resistance to the anticoagulant ■■ Standing for >6 h per day
action of APC, and prothrombin G20210A (PT20210A), ■■ Long-distance travel (>6 h)
which is often associated with a high plasma level of ■■ Violent effort or muscular trauma
prothrombin, were recognized as more-common causes ■■ Plaster cast of the lower extremities
of thrombophilia than deficiencies in antithrombin, ■■ Infectious disease
protein C, or protein S.25–27 ■■ Recent* hospital admission
■■ Recent* hip fracture, hip surgery, or both
■■ Recent* major surgery (abdominal, neurological, pelvic
Known mechanisms of thrombophilia or thoracic)
Inherited thrombophilia can be caused by two main ■■ Recent* splenectomy
mechanisms: the loss-of-function of endogenous anti- ■■ Central venous catheter or pacemaker
coagulants (including deficiency or dysfunction of ■■ Current use of antipsychotic drugs, tamoxifen,
antithrombin, protein C, or protein S) and gain-of- l‑asparaginase, or thalidomide
function of procoagulant factors. Gain-of-function in ■■ Exposure to ambient air pollution

blood coagulation can be caused by increased synthesis Sex-associated
of a normal protein (such as PT20210A, and also fibrin ■■ Current use of oral contraceptives
■■ Current use of hormone replacement therapy
ogen and factors VIII, IX, X, and XI, the genetic deter-
■■ Pregnancy, particularly in women aged >35 years,
minants of which are only partially known), impaired parity >1, or weight gain >21 kg
downregulation of a normal protein (such as FVL) or, ■■ Pre-eclampsia (with or without foetal growth restriction)
rarely, by synthesis of a functionally hyperactive mol- ■■ Assisted reproductive techniques
ecule (for example, factor IX Padua). A third mechanism ■■ Twin pregnancy
of thrombophilia is hypofibrinolysis (Box 2). ■■ Puerperium, particularly in women with postpartum
haemorrhage or Caesarean section
Loss-of-function mechanisms *The term recent usually refers to the past 3 months, although
some epidemiological studies define triggering events as
Antithrombin deficiency those occurring within 3–6 weeks prior to VTE. Abbreviations:
Antithrombin, a member of the serine protease inhibitor CHD, coronary heart disease; COPD, chronic obstructive
pulmonary disease; TIA, transient ischaemic attack; VTE,
(serpin) superfamily synthesized in the liver, regulates venous thromboembolism.
coagulation by forming a 1:1 covalent complex with
thrombin, factor Xa, and other activated procoagulants,
including factors XIIa, XIa, IXa, and VIIa. The rate of (Table 1).31 In type I, both antithrombin activity and
interaction with target proteases is accelerated by heparin antigen level are low in plasma owing to a lack of protein
(Figure 1).23 In the general population, the estimated production or secretion by the mutant allele. In type II,
prevalence of antithrombin deficiency ranges from five low antithrombin activity contrasts with normal antigen
to 17 per 10,000 individuals,28,29 and in patients with VTE levels, indicating functional defects in the molecule.
is around 1%.30 Type II can be further subdivided into three subtypes
More than 250 gene variations have been identified in characterized by impairment of the enzyme reactive
antithrombin deficiency, including missense and non- site, of the heparin-binding site, or by pleiotropic defects
sense point mutations, insertions, and deletions.31 Two affecting antigen concentration and heparin binding or
types of antithrombin deficiency can be distinguished, enzyme activity.31 The only individuals homozygotic
both inherited in an autosomal-dominant fashion for antithrombin deficiency described so far carry
NATURE REVIEWS | CARDIOLOGY VOLUME 11 | MARCH 2014 | 141

REVIEWS
Box 2 | Mechanisms associated with thrombophilia heterozygous protein C deficiency does not cause embry-
onic death, although newborns with these disorders
Known mechanisms
often develop purpura fulminans characterized by severe
Loss-of-function
■■ Antithrombin deficiency thrombosis of the small vessels, resulting in cutaneous
■■ Protein C deficiency and subcutaneous ischaemic necrosis.36
■■ Protein S deficiency Similarly to antithrombin deficiency, protein C def
Gain-of-function iciency can be divided into two subtypes (Table 1). 37
■■ Factor V Leiden Type I is the most common, and is characterized by a
■■ Prothrombin G20210A parallel reduction in plasma antigen level and activity,
■■ High factor VIII level reflecting a reduced synthesis of functional protein. The
■■ Non‑O blood group rarer type II is characterized by normal antigen level with
■■ Dysfibrinogenaemia
reduced functional activity, reflecting normal synthesis
Postulated mechanisms of a dysfunctional protein. More than 200 mutations
■■ Low tissue factor pathway inhibitor level
in the PROC gene have been reported.37 In type I, the
■■ High fibrinogen level
■■ High factor IX level
majority of mutations are of the missense variety, leading
■■ High factor X level to premature termination of synthesis or disruption of
■■ High factor XI level protein folding; deletions and insertions occur with
■■ Resistance to antithrombin lower frequency (~10%).37 In type II, missense muta-
■■ Global hypofibrinolysis tions are located mainly in the γ‑carboxyglutamic acid
■■ High thrombin activatable fibrinolysis inhibitor level and protease domains.37
■■ Hyperhomocysteinaemia
Protein S deficiency
XII XIIa
Protein S acts as a cofactor for APC, enhancing its capac-
ity to inactivate factors Va and VIIIa.24 Approximately
60% of protein S is bound to the complement C4b-
XI XIa
binding protein, and only the remaining 40% is func-
tionally active.24 In addition, protein S acts as cofactor
IX IXa
of tissue factor pathway inhibitor (TFPI) in the inhib
VIIIa Heparin ition of factor Xa.38 Protein S and TFPI circulate as a
X Xa Antithrombin
complex in plasma,38 which could explain the covariance
of protein S and TFPI levels39 and the low levels of TFPI in
VII VIIa patients who are protein S deficient.40 In the general pop-
Va ulation, protein S deficiency has been detected in up to 10
Prothrombin Thrombin
(II) (IIa) in 10,000 individuals,41 whereas the prevalence in patients
with VTE is 2%, similar to that of protein C deficiency.30
Three subtypes of inherited protein S deficiency
Endothelium have been identified (Table 1): type I (low total and free
Figure 1 | Anticoagulant mechanisms of antithrombin, antigen levels, reduced activity), type II (normal total
which mainly inhibits factor IIa and factor Xa, but also and free antigen levels, reduced activity), and type III
factors VIIa, IXa, XIa, and XIIa. The rate of interaction with (normal total antigen level, and reduced free antigen
target proteases is accelerated by heparin. Solid lines level and activity). 42 The PROS1 gene database lists
denote activation and broken lines inhibition (dashed lines, almost 200 different mutations associated with protein S
strong inhibition; dotted lines, weak inhibition). deficiency, the majority being missense mutations or
short deletions or insertions. Large deletions or inser-
heparin-binding site defects, suggesting that the other tions account for <4% of patients with protein S defi-
subtypes are associated with embryonic lethality.32,33 ciency.43 Type I and type III account for 95% of patients
with protein S deficiency, and often occur together in the
Protein C deficiency same family as phenotypic variants of the same genetic
Protein C is a natural anticoagulant protein that is acti- defect (mixed type I/III deficiency).44,45 Most mutations
vated when thrombin is generated, this process being associated with type I or type III deficiencies are distrib-
accelerated by the complex formed by thrombin with uted throughout the whole gene. Frequently, no mutation
an endothelial protein C receptor and thrombomodulin in the PROS1 gene is found in type III; therefore, other
(Figure 2).24 Protein C inactivates factor Va through an gene variations are thought to affect protein S concentra-
initial cleavage at Arg506, which is required for exposure tion in these patients, the most likely candidate being
of the cleavage sites at Arg306 and Arg679.24 Protein C the complement C4b-binding protein gene (C4BPA).43
deficiency is inherited as an autosomal-dominant trait,20 Type III is often associated with the PROS1 Ser460Pro
and heterozygous deficiency has been found in 14–50 (Heerlen) mutation, with no increased risk of thrombo-
per 10,000 adult individuals in the general popula- sis,46 and conflicting results have been reported about the
tion34,35 and in 3% of patients with VTE.30 In contrast risk of VTE in carriers of other type III deficiencies.47,48
to antit hrombin deficiency, homozygous or double In type II deficiency, PROS1 mutations mainly affect the

REVIEWS
Table 1 | Abnormalities caused by loss-of-function of anticoagulant proteins than in noncarriers, the wide range of prothrombin
levels between healthy individuals precludes the use of
Deficiency Antigen level* Activity
this intermediate phenotype to identify mutation car-
Antithrombin riers.27 According to the Hardy–Weinberg equilibrium,
Type I Low Low (with or without heparin) homozygosity for PT20210A mutation can be expected
Type II (reactive-site defect) Normal Low (with or without heparin) in 4 in 10,000 individuals.57
Type II (heparin-binding-site Normal Low with heparin, or normal
defect) with no heparin added‡ High factor VIII level
Type II (pleiotropic effects) Decreased Low (with or without heparin)
Factor VIII deficiency in patients with haemo-
philia A is known to cause a severe bleeding diathesis.
Protein C
Evidence exists that the converse is also true, and that
Type I Low Low a high factor VIII level in the plasma is a risk factor for
Type II Normal Low VTE.58–63 This finding was first reported in the Leiden
Protein S Thrombophilia Study,58,59 in which a factor VIII level
Type I Low total and free antigen Low
>50 UI/dl detected in 25% of patients with VTE was asso-
ciated with a 4.8‑fold increased risk of VTE. Inherited
Type II Normal total and free Low
antigen factors are likely to be important in the mechanism of a
persistently high factor VIII level.60–62 For example, in
Type III Normal total and low Low
free antigen a study of patients with a high factor VIII level, 40% of
their first-degree relatives also had a factor VIII level
*In general, heterozygote carriers show ‘low’ (~50% of the normal) or ‘decreased’ (50–70% of the normal)
antigen and/or activity levels, and homozygote carriers nearly undetectable levels. To discriminate >75th percentile of the normal distribution, in asso
between different types of deficiencies, protein activity is tested first and, if low, antigen level is then
tested. ‡Laboratory testing for type II antithrombin deficiency is made with and without added heparin, to
ciation with an increased risk of both VTE and art
discriminate reactive-site (low antithrombin activity in plasma in both instances) from heparin-binding-site erial thrombosis.62 In a large family study, the relative
defect (low activity only with heparin added).
risk of VTE was 7.1‑fold higher in individuals with a
high (>150 IU/dl) factor VIII level than in those with
γ‑carboxyglutamic acid protein and the pro-epidermal lower levels.63 Although strong indirect evidence exists
growth factor 4 domain essential for the APC cofactor that genetic mechanisms are involved in determining a
function of protein S.43 high factor VIII level, the genetic basis remains largely
unknown. Intermediate phenotypes such as APC resist-
Gain-of-function mechanisms ance and factor VIII plasma levels have been linked to a
Factor V Leiden quantitative trait locus on chromosome 18, but no candi-
The FVL missense mutation (Arg506Gln) causes date haemostasis-associated gene that might affect APC
factor V resistance to the anticoagulant action of APC.26 resistance or factor VIII levels was identified.64 Moreover,
Other point mutations in the F5 gene occur at Arg306, 92714C>G (rs1800291), a gene polymorphism encoding
another APC cleavage site, replaced by a glycine residue in the B‑domain substitution Asp1241Glu in the F8 gene, is
factor V Hong Kong,49 and a threonine residue in factor V associated with increased factor VIII levels.65
Cambridge. 50 These factor V variants cause varying
degrees of APC resistance, intermediate between those of ABO blood group
FVL and wild-type factor V, perhaps explaining why the An individual’s ABO blood group is the most-common
associated thrombotic risk is lower than that with FVL.51 genetic risk factor for VTE. The effect of ABO blood
FVL is inherited as an autosomal-dominant trait and is group on the risk of VTE is believed to be mediated by
present almost exclusively among white individuals, with a levels of von Willebrand factor (VWF) and factor VIII,
prevalence of 5% for heterozygous FVL in the general pop- as discussed above. Factor VIII, a glycoprotein synthe-
ulation and 18% among patients with VTE.52 Homozygous sized and released into the bloodstream by liver sinu-
FVL occurs in approximately 10 in 10,000 individuals in soidal cells, circulates mainly in complex with VWF.
the population, and 1% in patients with VTE.53 Levels of VWF and factor VIII are ~25% higher in indi-
viduals of non‑O blood groups than in those with blood
Prothrombin G20210A group O.66 The effect of ABO blood group on VWF (and,
A heterozygous G to A nucleotide transition at position therefore, on its complex companion factor VIII) seems
20210 in the 3'-untranslated region of the prothrombin to be caused by a direct effect, rather than by linkage dis-
(F2) gene (PT20210A) is often associated with a high equilibrium with other VWF regulatory genes.67 Indeed,
plasma level of prothrombin. 27 This mutation can changes in the glycan composition of VWF driven by dif-
increase the risk of VTE by increasing thrombin gener ferent ABO alleles not only influence plasma levels of this
ation54 or inhibiting factor Va inactivation by APC,55 thus platelet-adhesive moiety, but also have differential effects
creating APC resistance. PT20210A is found in 2% of on its rate of proteolysis by the VWF cleaving protease
white individuals in the general population, and in 6% ADAMTS‑13 (a disintegrin and metalloproteinase with
of patients with VTE.27 The mutation is slightly more thrombospondin motifs 13).68 These phenotypic effects
common in southern than northern Europe, a gradient have been shown to influence the risk of VTE. In a meta-
opposite to that of FVL.56 Although PT20210A hetero analysis involving >10,000 patients, the prevalence of
zygotes have a prothrombin plasma level 30% higher non‑O blood group was twice as high in patients with

REVIEWS
Postulated mechanisms of thrombophilia

IXa
Low TFPI level
VIIIa Free protein S Tissue factor pathway inhibitor (TFPI) inhibits blood
X Xa Protein coagulation by forming a quaternary complex with acti-
Ca
vated factor X, activated factor VII, and tissue factor.83
Va In plasma, 90% of TFPI is truncated and bound to
lipoproteins, whereas 10% is free full-length TFPI. 83
Prothrombin Thrombin Protein
(II) (IIa) C Although a low level of TFPI has been reported to be a
Ca2+
Thrombomodulin EPCR weak risk factor for first or recurrent VTE,84–86 this asso-
ciation was not confirmed in a multivariable analysis of
Endothelium a population-based cohort study.87 The genetic basis for
a low TFPI level is uncertain, and the studies in which
Figure 2 | Anticoagulant mechanisms of the protein C– the relationship between polymorphisms in the TFPI
protein S system. Protein S acts as a cofactor of protein C gene, TFPI level, and risk of VTE have been investigated
and the complex inhibits factors VIIIa and Va. Protein C is are inconclusive.88
activated by the EPCR bound to the complex thrombin
(factor IIa)–thrombomodulin. Solid lines denote activation
and broken lines inhibition. Abbreviations: EPCR, endothelial
Gain-of-function mechanisms
protein C receptor; Protein Ca, activated protein C. High plasma levels of procoagulants, such as fibrin
ogen and factors IX, X, and XI, increase the risk of VTE
and should, therefore, be included among the gain-of-
VTE than in healthy control individuals.69 Furthermore, function thrombophilia abnormalities (Box 2). However,
the risk of VTE in individuals with thrombophilia and whereas a high factor VIII level has been widely repli-
non‑O blood group is up to 23.2‑fold higher than in cated as risk factor,58,59 evidence for the other factors is
those without thrombophilia and blood group O. 70–73 more limited.89–92 The magnitude of the increased risk of
However, in some studies non‑O blood group remained VTE ranges from 1.6‑fold for plasma factor X levels >90th
significantly associated with the risk of VTE even after percentile, to fourfold for a f ibrinogen level >5.0 g/l.89–92
adjustment for factor VIIII levels, suggesting that other The genetic basis of high levels of these procoagulants is
factors might be involved in the association between partially known. An A>G sequence variant in the F9 gene
ABO blood group and thrombotic risk.71,72 (rs6048; factor IX Malmö) is associated with VTE, but
the mechanism remains unknown.93,94 A gain-of function
Dysfibrinogenaemia mutation in the F9 gene (R338L; factor IX Padua) was
Heritable dysfibrinogenaemia is associated with abnor- detected in some members of a single family who had
mal fibrinogen function, presenting as reduced activity VTE and extremely high plasma factor IX activity (eight-
in coagulation assays contrasting with normal plasma times the normal level) contrasting with normal antigen.95
concentrations of immunoreactive fibrinogen.74 The This mutation is extremely rare or ‘private’, because it
prevalence of heritable dysfibrinogenaemia is 1.5 per has not been found in other cohorts of patients with
10,000 individuals undergoing routine coagulation VTE.96,97 Finally, a novel gain-of-function mechanism
laboratory testing.75 Abnormal bleeding is identified in called resistance to antithrombin has been identified,
approximately 25% of the affected individuals and VTE caused by point mutations at the prothrombin Arg596
in 20%; the remaining 55% are asymptomatic.76,77 Rarely, residue leading to disruption of thrombin–antithrombin
heritable dysfibrinogenaemia has been associated with binding and impaired inhibition by antithrombin of the
arterial thrombosis, skin necrosis, and recurrent mis mutant thrombin.98,99
carriage.76 Heritable dysfibrinogenaemia has been linked
to >100 nucleotide variations in the fibrinogen genes.77,78 Hypofibrinolysis
Mutations have been detected in all three fibrinogen VTE can also be induced by hypofibrinolysis (Box 2),
genes (FGA, FGB, and FGG), producing a variety of as measured with a global test, such as the clot lysis
thrombophilia mechanisms: defective thrombin binding time. 100,101 A high plasminogen activator inhibitor 1
to fibrin leading to an elevated level of this enzyme, defec- (PAI‑1) level is among the main determinants of pro-
tive function of the abnormal fibrin in the activation of longed clot lysis time.102 A deletion/insertion (4G/5G)
fibrinolysis induced by tissue plasminogen activator, polymorphism in the promoter region of the PAI‑1 gene
and abnormal fibrinogen polymerization increasing the (SERPINE1) is associated with an increased plasma
resistance of fibrin fibres to plasmin degradation.76–80 level of PAI‑1 in carriers of the 4G allele.103 In a meta-
Homozygous carriers of the C10034T allele of the FGG analysis, Tsantes et al. found a marginally increased risk
gene, present in ~5% of the general population, have of unexplained VTE associated with the 4G allele com-
a twofold increased risk of VTE,81,82 possibly owing to pared with the 5G allele (OR 1.1),104 but this finding was
decreased levels of the fibrinogen γ chain, which con- not replicated in prospective studies.105 Finally, a high
tains a high-affinity thrombin-binding site that acts as an plasma level of thrombin-activatable fibrinolysis inhib
inhibitor of thrombin.81 The aforementioned mechanisms itor (TAFI; also known as carboxypeptidase B2) was
lead to an excess of circulating thrombin or to an excess associated with a 1.7‑fold increased risk of first DVT;106
of fibrin, producing an overall gain-of-function effect. higher TAFI levels were also found in carriers of FVL

REVIEWS
who had developed VTE than in their asymptomatic study (1,398 cases and 1,757 controls).93 Further stages
relatives.107 Interindividual variations of TAFI levels are of genotyping showed that five SNPs located in the
genetically determined, and several single nucleotide CYP4V2/KLKB1/F11 gene cluster, as well as one SNP in
polymorphisms (SNPs) in the promoter region of the the GP6 gene, one SNP in the SERPINC1 gene, and one
TAFI gene (CPB2) are associated with an increased level SNP in the F5 gene, were consistently but weakly asso
of this enzyme.108 ciated with VTE, with small odds ratios (1.10–1.49).93,120
In other GWAS, only SNPs in known susceptibility
Hyperhomocysteinaemia genes (F5, ABO, FGG, and F11) reached statistical sig-
Homocysteine is formed from the demethylation of nificance.121–124 Finally, a genome-wide linkage study
dietary methionine, and its level in the plasma is con- conducted on 438 siblings who had developed VTE at a
trolled by two metabolic pathways: remethylation to young age revealed five SNPs on chromosome 7 that were
methionine or trans-sulphuration to cysteine. Hyper associated with VTE, but which were not replicated in the
homocysteinaemia owing to defective methionine frame of the Leiden Thrombophilia Study.125
metabolism is associated with a mildly increased risk of The results of GWAS suggest that additional common
atherosclerosis, arterial occlusive diseases, and VTE. 109 variants do exist, but have a modest effect on the risk of
A meta-analysis showed that hyperhomocysteinaemia VTE and are of little clinical utility. However, the find-
is associated with an estimated 2.9‑fold increase in the ings from GWAS can provide preliminary information
risk of VTE.110 Factors that influence the homocysteine for additional analysis that prioritize the constellations of
level are acquired and genetic, including deficiencies results and clarify the roles of common variants, although
in folate, vitamins B6 or B12, and reduced activity of statistical approaches in this setting have limitationsand
methylenetetrahydrofolate reductase or other enzymes are associated with analytical challenges.126,127
involved in the metabolic pathway. 109 However, the Technological advances in DNA sequencing tech-
degree of inheritance of hyperhomocysteinaemia is niques have dramatically enhanced whole-genome or
low, emphasizing the more-important role of environ- whole-exome sequencing capacity. The sequencing
mental causes.111 The pathomechanisms of thrombosis approach affords identification of common as well as
in hyperhomocysteinaemia are unclear, and whether rare variants. Efforts are ongoing to apply the whole-
hyperhomoc ysteinaemia is a biological marker or a exome sequencing approach to delineate the genetic
direct aetiological agent in the development of throm- causes of common forms of Mendelian diseases, par-
bosis remains to be demonstrated.112 What is certain, ticularly those with an autosomal-dominant pattern of
however, is that laboratory investigation of hyper inheritance and complex traits. However, the enorm
homocysteinaemia in patients with VTE should include ous genetic diversity of humans, and the presence of
measurement of the intermediate phenotype (that is, a very large number of variants in each genome, in
serum homocysteine levels as the result of the interaction conjunction with incomplete penetrance of the causa-
between genetic and acquired [dietary] factors), rather tive variants pose substantial difficulties in establish-
than the methylenetetrahydrofolate reductase genotype, ing clear genotype–phenotype co-segregation.127 For
as shown in a large population-based study and in two example, the HIVEP1 locus on chromosome 6p24.1 was
meta-analyses.113–115 identified in a GWAS as a susceptibility locus for VTE,
although this locus seems to be outside the traditional
Novel thrombophilia markers from GWAS coagulation–fibrinolysis pathway.128
In general, linkage studies performed in families with
VTE have been disappointing,116–118 perhaps because Clinical manifestations of thrombophilia
each family might harbour a different private mutation Deep-vein thrombosis and pulmonary embolism
in a specific susceptibility gene. Therefore, the rarity of The most-common clinical manifestation associated
mutations renders the combination of these pedigrees with inherited thrombophilia is DVT of the lower
inadequate to identify VTE susceptibility abnormal limbs with or without pulmonary embolism. In general,
ities widely diffuse in the population. On the other in large case–control studies, the overall risk of these
hand, these studies have been successful in the identi- clinical manifestations of VTE was twofold to seven-
fication of quantitative trait loci that explain, at least in fold higher in carriers of any thrombophilic disorder
part, the natural variations in plasma levels of the most- than in nonc arriers.27,53,93,129 Furthermore, two large
important coagulation proteins.119 A newer approach meta-analyses, in which only FVL and PT20210A were
consists of genome-wide association studies (GWAS) evaluated, showed a threefold to fourfold increased
into the association between common genetic variations, risk of DVT or pulmonary embolism for thrombo-
mostly represented by SNPs, and thrombotic risk in case– philia heterozygotes, and a sixfold to 11‑fold increased
control studies of VTE. The first large-scale GWAS had risk for homozygotes.114,115 Although DVT and pul-
a multistage design.93 In the first stage, 19,682 SNPs were monary embolism are commonly thought to be differ-
genotyped in pooled DNA samples (443 cases and 453 ent manifestations of the same disease and to share the
controls) from the Leiden Thrombophilia Study, resulting same risk factors, FVL is consistently associated with a
in 1,206 SNPs significantly associated with VTE. These higher risk of DVT than of pulmonary embolism.130–135
1,206 SNPs were then replicated in the study population Nevertheless, survivorship bias among FVL carriers,
of the Multiple Environmental and Genetic Assessment owing to an excess of fatal pulmonary embolism, was

REVIEWS
excluded by an autopsy study. 136 Thus, to explain this and mesenteric vein thrombosis.8 The most-common
curious differential effect (often referred to as the ‘FVL predisposing conditions are liver cirrhosis and chronic
paradox’),131 FVL has been hypothesized to be associated myeloproliferative neoplasms, but the risk factors cited
with the formation of venous thrombi more compact above for cerebral vein thrombosis are also encountered.8
and resistant to fibrinolysis and, therefore, less prone to The close relationship between myeloproliferative neo-
embolization than the thrombi in patients without FVL. plasms and splanchnic vein thrombosis is confirmed by
However, the reason for this discrepancy between the two the high prevalence of the JAK2 V617F somatic muta-
main clinical manifestations of VTE is not due exclusively tion.146 Inherited thrombophilia is another relevant risk
to blood hypercogulability. In fact, this difference does factor, as a high prevalence of the PT20210A mutation,
not apply to other thrombophilic abnormalities, whereas but not FVL, has been consistently reported in patients
different levels of risk of DVT or pulmonary embolism with PVT, 147–149 whereas FVL is more common than
have been reported in many acquired c onditions that PT20210A in the Budd–Chiari syndrome.150,151 Case–
predispose to VTE.137 control studies have shown an eightfold increased risk of
PVT for PT20210A,147 and an 11‑fold increased risk of the
Superficial vein thrombosis Budd–Chiari syndrome for FVL.150 According to a meta-
Thrombosis of the superficial veins is a common disease, analysis, the risk of PVT is increased fourfold among
reported in 3–11% of the population, but its exact annual carriers of PT20210A, and threefold in carriers of FVL.148
incidence remains to be determined.138 Although varicose
veins are the main cause, other underlying conditions Veins of the upper extremities
(such as malignancy, or autoimmune diseases) should be Between 5% and 10% of all cases of DVT involve the
sought in patients with idiopathic, migrant, or recurrent subclavian, axillary, or brachial veins.8 Approximately
SVT developing in nonvaricose veins. In selected patients 75% of cases are secondary to direct injuries to these
referred to specialized thrombosis centres, the distribu- veins owing to central catheter or pacemaker insertion
tion of inherited thrombophilia is similar in patients or cancer, and the remaining 25% of cases are caused
with SVT as in those with DVT.139,140 A case–control by pinching of the axillary–subclavian vein at the level
study showed that the risk of SVT not associated with of the thoracic outlet by muscular and osteotendineous
varicose veins, malignancy, or autoimmune diseases was structures induced by abduction and extension of the
increased sixfold in carriers of FVL, fourfold in carriers arm (Paget–Schroetter or effort syndrome).8 A few cases
of PT20210A, and 13‑fold for patients with antithrombin, are apparently unprovoked, and a study suggested a role
protein C, or protein S deficiencies together.139 for inherited thrombophilia, with a fivefold increased
risk with PT20210A and deficiencies of antithrombin,
Venous thrombosis at unusual sites protein C, or protein S together, and a sixfold increased
Venous thrombosis can develop at sites other than the risk with FVL.152
deep or superficial veins of the lower limbs and the pul-
monary circulation—in the cerebral sinuses, the splanch- Retinal veins
nic veins, the deep veins of the upper extremities, and Retinal vein thrombosis occurs in the central retinal vein
the retinal veins. Although rare, these thrombotic events with an annual incidence of 1.3 per 10,000 individuals,
are associated with substantial morbidity and mortal- or in a branch retinal vein with an annual incidence of
ity, and thrombophilia seems to have an important 20 per 10,000 individuals.153 The incidence of retinal vein
mechanistic role.8 thrombosis increases with age, and is unilateral in the vast
majority of patients.153 A number of studies conducted
Cerebral veins in the past decade have produced conflicting results
Two-thirds of adults who have thrombosis of the cerebral regarding the association between inherited thrombo-
veins are women of fertile age141 who use oral contra philia and retinal vein thrombosis. A meta-analysis from
ceptives, which is the most-common risk factor and 2005 did not show a significant association between FVL
associated with a sixfold increased risk of the disease.142 or PT20210A and retinal vein thrombosis,154 whereas a
Inherited thrombophilia is another risk factor for cer- moderately increased risk associated with FVL was found
ebral vein thrombosis, with an increase in the relative in a subsequent review.155 By contrast, meta-analyses
risk of approximately fourfold and 10‑fold for FVL or have established the presence of antiphospholipid anti-
PT20210A heterozygosity, respectively.142–144 A synergis- bodies and mild hyperhomocysteinaemia as risk factors
tic interaction exists between oral contraceptive use and for retinal vein thrombosis.154,156
mild thrombophilia.143 The puerperium period is a time
of increased risk of cerebral vein thrombosis, particularly Tailoring primary prophylaxis of VTE
among women from low-income countries.145 Other risk Risk grading of inherited thrombophilia
factors include chronic myeloproliferative neoplasms, Family history of VTE is per se a strong risk factor for
head infection or trauma, and autoimmune diseases.8 VTE in the general population.13–15 Therefore, regardless
of the presence of other known risk factors, family studies
Splanchnic veins are the most-appropriate tool to investigate the risk and
Thombosis of the splanchnic veins encompasses portal incidence of VTE in carriers of thrombophilia versus
vein thrombosis (PVT), the Budd–Chiari syndrome, noncarriers. These studies, conducted among individuals

REVIEWS
Table 2 | Antithrombotic management of thrombophilia

Type of Cause of thrombophilia Primary prophylaxis Acute treatment Secondary prophylaxis
thrombophilia
Severe Deficiencies in Screening asymptomatic relatives of carriers of Special measures for Indefinite duration of
antithrombin, severe thrombophilia; antithrombotic prophylaxis antithrombin or protein C anticoagulant treatment
protein C, or protein S; during exposure to risk-enhancing situations deficiency in case of after an unprovoked or
any homozygous (surgery, confinement to bed, plaster cast); life-endangering VTE event life-endangering VTE event
abnormality; multiple counselling about risk associated with oestrogen–
abnormalities progestogen treatment; antithrombotic prophylaxis
in pregnancy and puerperium
Mild Heterozygous FVL; Screening asymptomatic relatives of patients with Standard antithrombotic Standard duration of
heterozygous PT20210A family history of VTE; antithrombotic prophylaxis treatment antithrombotic treatment
during exposure to risk-enhancing situations
(surgery, confinement to bed, plaster cast);
counselling about risk associated with oestrogen–
progestogen treatment; antithrombotic prophylaxis
in pregnancy if additional risk factors are present;
antithrombotic prophylaxis in puerperium
Abbreviations: FVL, factor V Leiden; PT, prothrombin; VTE, venous thromboembolism.
with a shared genetic background, consistently indicate the incidence of VTE is much lower, ranging from 0.2 to
that a risk gradient exists—the risk is higher in those with 2.3 per 100 person-years.178 Although inherited thrombo
antithrombin, protein C, protein S deficiencies, homo philia is typically associated with the occurrence of VTE
zygous FVL or PT20210A, or multiple abnormalities in young people, advanced age is a prominent risk factor
(severe thrombophilia; Table 2) than in heterozygotes for for mild thrombophilia.53,179,180 In a family cohort, median
FVL or PT20210A (mild thrombophilia; Table 2).63,157–176 age at onset of first VTE in relatives of probands with
Carriers of antithrombin, protein C, or protein S defi- a hereditary deficiency in antithrombin, protein C,
ciencies have a fourfold to 30‑fold increased risk of VTE or protein S was 29 years (range 5–60 years) in anti
compared with noncarriers. The highest incidence of thrombin deficiency; 31 years (range 16–63 years) in
0.9–4.0 per 100 person-years is observed in carriers protein C deficiency; and 31 years (range 16–64 years)
of antithrombin deficiency (Table 3).63,157–176 Patients with in protein S deficiency.173 In another large family cohort,
type II heparin binding site defects are the exception, relatives of probands with thrombosis and a thrombo-
with only a 5–10% probability of developing VTE.32,33 philic defect, who themselves had an antithrombin,
On the other hand, carriers of mild thrombophilic protein C, or protein S deficiency, had VTE at a younger
traits have a twofold to sevenfold increased risk of VTE, age (median 29 years) than those with FVL, PT20210A, or
with a much lower incidence of events than those with an elevated level of factor VIII (median 40 years).63
severe thrombophilia (0.14–0.67 per 100 person-years
for FVL; 0.05–0.42 per 100 person-years for PT20210A; Benefits of familial thrombophilia screening
Table 3).63,157–176 Even low–borderline plasma levels of The main theoretical argument in favour of screen-
antithrombin, protein C, and protein S are associated ing asymptomatic relatives of patients with inherited
with a twofold increased risk of VTE, to the same degree thrombophilia is the possibility of identifying a need
as that of mild thrombophilia.177 for primary anticoagulant prophylaxis during situ
Importantly, thrombophilia markers cannot be inter- ations that increase the risk of VTE, such as low-risk
preted in isolation, because interactions with other surgery, pregnancy, and the puerperium period, and
genetic and acquired risk factors (Box 1) are important are not routinely covered by prophylaxis (Box 1). Some
determinants of the overall risk of VTE.16 For example, in data exist to support this approach. In a retrospective
a large family study, carriers of antithrombin, protein C, study of 238 individuals with antithrombin, protein C,
or protein S deficiency, FVL, or PT20210A who had or protein S deficiencies, the incidence of VTE during
additional abnormalities (such as high levels of TAFI or 121 pregnancies and 89 surgical interventions without
factors VIII, IX, or XI, or hyperhomocysteinaemia) had antithrombotic prophylaxis before diagnosis of thrombo
a twofold to sixfold higher incidence of VTE than those philia was overall 29.2%. 181 By contrast, short-term
without such additional abnormalities.63 Moreover, in VTE prophylaxis administered to asymptomatic rela-
retrospective 164,166,167,170,173 and prospective 157,158,161,163 tives during risk-enhancing situations after diagnosis
family studies of patients with inherited antithrombin, of thrombophilia failed in preventing VTE in 12.5% of
protein C, or protein S deficiencies, approximately half individuals.182 This benefit of anticoagulant prophylaxis
of VTE events were also associated with a concomi- was confirmed in prospective cohorts of patients with
tant acquired risk factor. During exposure to acquired the same deficiencies.158,161,163 Sanson et al. reported
risk factors, the incidence of VTE in patients with anti that the incidence of VTE during risk-enhancing situ
thrombin, protein C, or protein S deficiencies is estimated ations was 16.7% without and 4.5% with antithrombotic
to be as high as 1.2–8.1 per 100 person-years, whereas in prophylaxis.158 In another study, the annual incidence of
mild thrombophilia with exposure to acquired risk factors VTE secondary to the exposure to acquired risk factors

REVIEWS
Table 3 | Incidence of VTE in studies of families with thrombophilia

Reference (year) Study information Incidence of VTE per 100 person-years (where available,
the relative risk vs noncarriers is in brackets)
Relatives/ Observation Antithrombin Protein C Protein S FVL PT20210A Multiple defects
carriers years deficiency deficiency deficiency
Prospective studies
Pabinger (1994)157 93/44 211 NA 2.5 2.2 NA NA NA
Sanson (1999)158 735/208 611 4.0 1.0 0.7 NA NA NA
Middeldorp (2001) 159
855/470 1,564 NA NA NA 0.58 §
NA NA
Simioni (2002)160 561/313 1,255 NA NA NA 0.67 NA NA
Vossen (2005)161 575‡ 3,283 1.7 0.7 0.8 0.1 NA NA
Coppens (2006) 162* 464/236 1,816 NA NA NA NA 0.37 (3.1)
§
NA
Mahmoodi (2010)163 382/149 3,472 2.29§ (10.2) 0.95§ (4.1) 1.55§ (9.6) NA NA NA
Retrospective studies
Lijfering (2009)63* 2,479/1,528 NA 1.77§ (28.2) 1.52§ (24.1) 1.90§ (30.6) 0.49§ (7.5) 0.34§ (5.2) NA
Martinelli (1998)164* 723/396 NA 1.0 (8.1) 0.72 (7.4) 0.78 (10.4) 0.25 (4.6) NA NA
Middeldorp (1998) 165
437/236 12,240 NA NA NA 0.45 (4.2)
§
NA NA
Bucciarelli (1999)166 513‡ 19,542 1.07 0.54 0.50 0.30 NA 0.67
Simioni (1999)167 793/405 19,685 0.87 (10.6)|| 0.43 (10.6)|| 1.65 (10.6)|| 0.28 (2.8) NA NA
Lensen (2000) 168
197/108 8,760 NA NA NA 0.34 (2.9) NA NA
Martinelli (2000)169* 1,093/640 43,208 NA NA NA 0.19 (2.9) 0.13 (2.0) 0.42 (6.4)
Tirado (2001) 170
722/435 NA 2.94 (10.6) 0.36 (6.4) 1.04 (7.6) 0.31 (6.2) 0.23 (4.2) NA
Bank (2004)171* 407/209 12,085 NA NA NA NA 0.35 (1.9) NA
Tormene (2004)172 294/152 8,347 NA NA NA NA 0.11 (1.7) NA
Brouwer (2006) 173
468/224 4,174 1.94 (18.3) 1.58 (16.2) 1.50 (16.2) NA NA NA
Couturaud (2006)174 553/322 17,532 NA NA NA 0.43 (2.5) NA NA
Rossi (2011)175 1,088/625 40,405 0.92 (12.8) 0.12 (5.1)|| 0.12 (5.1)|| 0.14 (2.3)¶ 0.05 (0.6)¶ 0.24/0.19/0.58#
Holzhauer (2012) 176
533/146 18,278 2.82 (25.7)** 2.82 (25.7)** 2.82 (25.7)** 0.25 (1.7) 0.42 (2.6) 2.33 (19.6)
*Including probands with a history of VTE or arterial thrombosis. ‡Recruitment limited to carrier relatives of patients with VTE diagnosed with thrombophilia. §Observation period starting from
14–15 years of age. ||Relative risk calculated on the total carriers of antithrombin, protein C, and protein S deficiencies. ¶Homozygotes excluded. #Incidence estimated in double heterozygotes
for FVL and PT20210A, homozygotes for FVL or PT20210A, and in carriers of other multiple abnormalities. **Incidence for antithrombin, protein C, and protein S deficiencies combined.
Abbreviations: FVL, factor V Leiden; NA, data not available; PT, prothrombin; VTE, venous thromboembolism.
was 0.84% before and 0.58% after diagnosis of thrombo- not been associated with thrombotic risk in population-
philia.163 Among asymptomatic heterozygotes for FVL, based studies.34,35,187 As regards antithrombin deficiency,
the incidence of VTE during risk-enhancing situations in a large cohort of healthy blood donors, all the individ
was 27.1% without and 9.1% with prophylaxis.160 On uals with rare type I deficiency (prevalence 2.1 in 10,000
the other hand, in a prospective family study, no VTE individuals) had a family history of VTE, whereas those
events occurred in PT20210A heterozygotes exposed to with the more-common type II heparin binding site mild
risk-enhancing situations, independent of low molecular defect (prevalence 14.5 in 10,000 individuals) did not.29
weight heparin (LMWH) prophylaxis.162
On the whole, screening for thrombophilia in Disadvantages of thrombophilia screening
asymptomatic relatives of patients with severe thrombo- Unrestricted thrombophilia screening in asymptomatic
philia seems to be useful. As regards mild thrombophilia, individuals in the general population who are exposed
strong evidence exists in favour of screening among rela- to situations that increase the risk of VTE, such as oral
tives of FVL carriers with VTE, whereas the evidence contraceptive use, during pregnancy, or major ortho-
is weaker for screening relatives of PT20210A carriers paedic surgery is not justified. The reason is not because
with VTE (Table 2). The risk of VTE has been consist- screening is not cost-effective188 (the cost of genetic
ently reported to be higher in asymptomatic carriers of testing will decrease substantially in the next few years),
mild thrombophilia who have a family history of VTE, but mainly because thrombophilia is a risk factor, not
than in those with no family history (Box 3).13,175,183 In a disease, and many carriers (particularly of gain-of-
family studies of severe thrombophilia, up to 60% of function mutations) remain asymptomatic for their life-
individuals with a relative who has an antithrombin, time. For example, the prevalence of FVL and PT20210A
protein C, or protein S deficiency develop VTE.48,184–186 among centenarians, a paradigm of successful ageing,
On the other hand, protein C or protein S deficiency has is similar to that in the general population.189 Another

REVIEWS
drawback of unrestricted thrombophilia screening is that Box 3 | Family history for risk assessment of VTE227,228
individuals labelled as ‘carriers’ could experience insur-
Advantages
ance discrimination and emotional upset owing to an
■■ Family history of VTE is per se a strong risk factor for
overestimated perception of genetic risk, while receiving VTE in the general population, as well as in carriers of
no real benefit in terms of health care.190 On the other inherited thrombophilia
hand, a negative result in thrombophilia screening does ■■ Medical interview should focus on the occurrence
not exclude inherited abnormalities that are currently of VTE events among first-degree and second-degree
unknown, and should not provide false reassurance for relatives
patients or clinicians. Furthermore, counselling for car- ■■ Questions should focus on the circumstances of
the actual VTE event, its objective diagnosis, and
riers of thrombophilic abnormalities should emphasize
subsequent therapy
that, despite an increased relative risk of VTE with respect
Disadvantages
to the age-adjusted incidence in the general population,
■■ Sensitivity of family history (presence of disease in
the annual incidence of VTE among these individuals relatives) is less accurate than specificity (absence
rarely exceeds 1% (Table 3).63,157–176 Moreover, counselling of disease)
and information given to patients should be based on the ■■ Accuracy is greater for information from first-degree
absolute, rather than the relative, risk of VTE. than more-distant relatives
■■ The unsatisfactory sensitivity of family history, and failure
Management of VTE to report VTE in relatives, can lead to underestimation
Acute treatment of risk
Abbreviation: VTE, venous thromboembolism.
Initial treatment of acute VTE, consists of unfractionated
heparin or LMWH, followed by vitamin K antagonists
(VKAs) or perhaps one of the direct oral anticoagulants from that of VKAs.199 Postmarketing reports will help
(apixaban, dabigatran, edoxaban or rivaroxaban), and to define precisely the risk–benefit profile of such drugs.
should be the same for patients with or without inher- With this background, many studies have addressed
ited thrombophilia. Accordingly, laboratory screening the role of inherited thrombophilia in predicting the
for inherited abnormalities is not warranted during the likelihood of VTE recurrence. For heterozygous FVL
acute phase of VTE. However, antithrombin deficiency or PT20210A, these studies were summarized in three
should be ruled out as soon as possible, because of the meta-analyses, revealing a ~1.5‑fold increased risk of
possible partial resistance of these patients to the anti- VTE recurrence for either mutation.200–202 Such a mod-
coagulant action of heparins, which can be overcome estly increased risk of recurrent VTE contrasts with a
by increasing drug dosages.191 Furthermore, the use of higher risk with severe thrombophilia. In retrospective
antithrombin concentrates can be considered in individ- studies, the risk of recurrent VTE in patients with an
uals deficient in antithrombin to treat life-threatening antithrombin deficiency was increased by 1.9‑fold to
VTE (pulmonary embolism, cerebral vein thrombosis, 2.6‑fold,196,203 and the annual incidence per 100 person-
splanchnic vein thrombosis) until stable anticoagulation years was 10 for antithrombin, 6 for protein C, and 8.4
is reached (Table 2).192 Similarly, in severe (homozygous) for protein S deficiencies.204 In a prospective study, the
protein C deficiency, replacement therapy with protein C incidence of recurrent VTE per 100 person-years was
concentrates should be given in patients with purpura 10.5 in patients with antithrombin deficiency, but only
fulminans, and during the transition from heparins to 3.5 in those with FVL.205 A systematic review showed that
VKAs, until stable anticoagulation is reached and the homozygous FVL was associated with a 2.6‑fold increased
risk of warfarin-induced skin necrosis is minimized.193,194 risk of recurrent VTE.200 Given the low absolute number
of recurrent VTE events among carriers of mild thrombo
Secondary prophylaxis philia, laboratory screening is of little use in the clinical
After a first episode of VTE, the duration of secondary management of the large majority of patients with VTE.
prophylaxis with VKAs or direct oral anticoagulants Although data stem from small, noncontrolled studies,
should be determined, balancing the risk of haemor- the detection of severe thrombophilia in at least 10% of all
rhagic complications with that of a second VTE event. patients with VTE who could be at increased risk of VTE
The cumulative rate of recurrence is as high as 40% recurrence, should not be overlooked (Table 2).
within 10 years of the first VTE; the rate is lower in The literature on laboratory screening after VTE
patients with VTE associated with trauma or surgery contains contrasting guidelines and recommend
(11.4%) or reproduction-associated risk factors (20.3%), ations, which were reviewed by De Stefano and Rossi in
and higher in those with unprovoked VTE (52.6%).195 2013.206 Screening seems to be appropriate in patients
This finding is consistent with observations in other who develop VTE at a young age and in those with
prospective cohorts of patients with VTE.196,197 The inci- unprovoked events, mainly to determine the patho
dence of major bleeding during treatment with VKAs mechanism of VTE rather than to tailor therapeutic strat-
(1.1 per 100 person-years) should also be considered.198 egies. Furthermore, diagnosis of severe thrombophilia
The introduction of direct oral anticoagulants into clini- can give important information on the optimal duration
cal practice is unlikely to reduce the bleeding risk in this of anticoagulant treatment.207 This information is crucial
setting, as the relative risk of major bleeding with these for patients with thrombosis at life-endangering sites,
drugs observed in most clinical trials is not different because international guidelines recommend indefinite

REVIEWS
Table 4 | Risk of VTE among users of OC or HRT with or without inherited thrombophilia
Thrombophilia OC RR in Absolute risk Absolute risk HRT RR in Absolute risk Absolute risk
users* case–control per person-years per person-years users§ case–control per person-years per person-years
studies (estimated‡) (observed in studies (estimated‡) (observed in
family studies||) family studies||)
None No 1.0 1.8/10,000 0.2/100 No 1.0 1.0/1,000 NA
None Yes 2.0–9.0 0.4–1.6/1,000 0–0.5/100 Yes 2.1–3.2 2.1–3.2/1,000 0
AT deficiency Yes 12.6 2.3/1,000 5.1–10.0/100 Yes NA NA NA
PC deficiency Yes 6.3 1.2/1,000 0–7.1/100 Yes NA NA NA
PS deficiency Yes 4.9 0.9/1,000 2.4–4.2/100 Yes NA NA NA
Heterozygous FVL Yes 11.3–34.7 2.0–6.2/1,000 0.5–2.0/100 Yes 6.7–15.5 0.7–1.5/100 2.9/100
Heterozygous Yes 5.1–16.0 0.9–2.9/1,000 0–0.2/100 Yes 2.9 0.3/100 0
PT20210A
Homozygous FVL Yes NA NA NA Yes NA NA NA
Homozygous Yes NA NA NA Yes NA NA NA
PT20210A
*Age <40 years. ‡Estimated as relative risk × VTE incidence in the general population (that is, 1.8 per 10,000 in women of fertile age, and 1.0 per 1,000 in women aged 40–60 years). §Age
>40 years. ||Families with the index case diagnosed with thrombophilia after VTE. Abbreviations: AT, antithrombin; FVL, factor V Leiden; HRT, hormone replacement therapy; NA, data not available;
OC, oral contraceptives (combined); PC, protein C; PS, protein S; PT, prothrombin; RR, relative risk; VTE, venous thromboembolism.
anticoagulation in the presence of persistent risk factors factors compared with either of the risk factors consid-
(severe thrombophilia) particularly for cerebral208 and ered alone.213 However, the expected final incidence of
portal vein thrombosis.209 VTE in the general population among unselected car-
riers does not exceed 6.2 events per 1,000 woman-years
Sex-associated differences in VTE (Table 4).213 Therefore, screening has a limited role in
Sex-associated risk factors are important components of women with no personal or family history of VTE.188
the clinical spectrum of VTE. Men have a 2.1‑fold higher By contrast, among oral contraceptive users who are
risk of first VTE210 and a 1.5‑fold to 1.8‑fold higher risk of asymptomatic carriers of inherited thrombophilia and
recurrent VTE211,212 than women without reproduction- belong to families with a history of VTE, the incidence of
associated risk VTE factors (such as oral contraceptive VTE is much higher: four to 10 events per 100 woman-
use or pregnancy). Currently, the well-established, but years for antithrombin, protein C, or protein S deficien-
mechanistically unexplained, increased risk of VTE cies,163,214 and up to two events per 100 woman-years for
recurrence in men has not led guideline committees to FVL159,165,167 (Table 4). Therefore, screening women who
recommend a different intensity or duration of secondary are relatives of symptomatic carriers of thrombophilia
prophylaxis after the first VTE episode. (especially severe thrombophilia) before prescribing oral
contraceptives can be beneficial.
Oestrogen–progestogen therapies The absolute incidence of VTE among women using
Whether laboratory screening for inherited thrombo HRT is higher than among users of oral contraceptives,
philia should be carried out in women initiating owing to their older age.215 Therefore, this therapy is asso-
oe strogen–progestogen therapies is an important ciated with an increased risk of VTE among thrombophilic
issue. In the general population, the incidence of VTE women.215 Accordingly, unrestricted or family-history-
is approximately 1.8 per 10,000 woman-years among driven thrombophilia screening before prescribing HRT
women of fertile age, and 1.0 per 1,000 woman-years has been proposed.188 However, this suggestion remains to
between the ages of 40 and 60 years.3 The use of com- be confirmed by ad hoc-designed studies.
bined oral contraceptives is associated with a twofold to
ninefold increased risk of VTE.11 The risk is associated Pregnancy
with the oestrogen dose, but the type of progestogen The rate of clinically relevant maternal bleeding asso
also affects the risk of VTE. Specifically, the oral contra ciated with the use of LMWH has been estimated to be
ceptives containing the progestogens desogestrel or as high as 2%, which in most individuals is associated
gestodene (the so-called third-generation compounds) with the delivery (1%) or to wound haematoma (0.6%).216
seem to be associated with a twofold increased risk of Pregnant women with asymptomatic inherited thrombo
VTE compared with those containing levonorgestrel philia have a significantly increased risk of VTE only if
(a second-generation compound).11 Therefore, the abso- they have a family history of VTE or severe thrombo-
lute incidence of VTE among women using oral contra- philia. For these women, antenatal LMWH prophy-
ceptives is expected to vary between 0.4 and 1.6 per 1,000 laxis is recommended in most guidelines.217–220 On the
woman-years (Table 4). A supra-additive effect for risk other hand, antenatal clinical surveillance is thought to
of VTE was observed between the use of oral contracep- be sufficient for pregnant women with mild thrombo
tives and presence of inherited thrombophilia, being philia, owing to the low rate of pregnancy-related VTE
increased by twofold to fivefold in women with both risk associated with FVL or PT20210A.221,222 In these women,

REVIEWS
Table 5 | Laboratory assays for diagnosis of inherited thrombophilia226 a generic diagnosis of unprovoked or idiopathic throm-
Abnormality Assay* Disadvantages bosis. However, astute clinicians are aware that VTE is a
truly multifactorial disease, and that concomitant causes
Antithrombin deficiency Heparin cofactor Anti-factor Xa assays can miss
activity against some type II defects; heparin other than inherited thrombophilia must always be
factor IIa or Xa binding-site defects are missed investigated, particularly when only mutations associated
(a heparin-free test is needed) with mild thrombophilia are identified.
Protein C deficiency Amidolytic assay Some rare type II variants are On the other hand, laboratory screening for thrombo-
with snake venoms missed (a clot-based test is needed) philia abnormalities is not without disadvantages. The
as activators diagnosis of a genetic defect carries multiple psycho
Protein S deficiency Free antigen assay Type II is missed (a clot-based test logical implications for the affected individuals, as well as
is needed) for their families. Testing children of thrombophilia car-
Factor V Leiden DNA assay Activated protein C resistance riers does not make sense, because their risk is inherently
not associated with factor V Leiden low owing to their young age and they would be unable
is missed
to understand the difference between risk and disease.
Prothrombin G20210A DNA assay Activated protein C resistance
In this Review, we were cautious in recommending
not associated with prothrombin
G20210A is missed screening for thrombophilia in asymptomatic individ
uals. The main indication for screening is for members
High factor VIII level One-stage clotting Increased during acute-phase
assay response of kindreds with a family history for VTE, because this
risk factor is undoubtedly highly relevant. Little need
Dysfibrinogenaemia Immunoassay Fibrinogen antigen and activity
combined with a levels are method-dependent exists for screening before pregnancy or at the time of
clot-based test prescribing hormonal therapy, except in the presence
Hyperhomocysteinaemia Fasting plasma Evaluation of folate and vitamin B6 of a family history of VTE and in selected older women
homocysteine assay and B12 status is advised starting HRT.
*Acquired conditions that can cause of misleading test results: liver disease (decreased antithrombin, Does the potential exist for discovery of novel genetic
protein C, protein S, acquired dysfibrinogenaemia); proteinuria, inflammatory bowel disease, or prolonged
heparin treatment (decreased antithrombin); vitamin K antagonist use (decreased protein C, protein S);
markers of thrombophilia? We believe that the vast
pregnancy or oestrogen use (decreased protein S, increased factor VIII); acute phase reactions (decreased majority of genetic defects have already been identified,
free protein S, increased factor VIII); kidney dysfunction or hypothyroidism (increased homocysteine);
homocysteine levels are influenced by many drugs.109 at least pertaining to variants characterized by a high
prevalence in the population, coupled with a minor
increase in VTE risk, such as the gain-of-function muta-
antenatal LMWH prophylaxis should be considered only tions or the ABO genes. On the other hand, in many
in the presence of additional risk factors (family history patients with VTE, a marker of thrombophilia is not
of VTE, confinement to bed, obesity, age >35 years, detected even after laboratory investigation (Table 5).
gross varicose veins) and discussed with an expert in the GWAS have been rather disappointing, identifying only
field.217–220,223 After delivery, antithrombotic prophylaxis already known variants or variants with low additional
with LMWH is recommended for the whole 6‑week potency in risk evaluation. Perhaps the new and develop-
puerperium period in asymptomatic carriers of severe ing methods of deep DNA sequencing might, in patients
thrombophilia.217–220,223 For carriers of mild thrombo- with idiopathic VTE, identify a few very rare variants
philia, recommendations for LMWH prophylaxis are associated with high risk of thrombosis. However, we
not uniform, ranging from at least 7 days postpartum,218 should consider that the still-unexplained heritabil-
to up to 6 weeks,217,219,223 to only for women presenting ity of VTE might reside in gene elements that do not
with additional risk factors.218,220 In sharp contrast, the change DNA sequence, but rather influence expression
American College of Chest Physicians guidelines suggest and regulation.
antenatal clinical surveillance only in almost all asympto
matic carriers of inherited thrombophilia, consider-
ing LMWH prophylaxis only for homozygous carriers Review criteria
of FVL or PT20210A with a family history of VTE. 224
The information for this Review article was retrieved by
Moreover, prophylaxis in the puerperium period is searching the MEDLINE database for relevant studies
advised only for women with a family history of VTE.224 published in English up to November 2013, using
This restrictive view has been critically discussed by as key words the MeSH terms and other pertinent
De Stefano and colleagues.225 terms. The main search terms were: “thrombosis”,
“deep vein thrombosis”, “pulmonary embolism”,
Conclusions “venous thromboembolism”, “inherited thrombophilia”,
“risk factors”, “prevention” or “prophylaxis” and all
Half a century after the first description of antithrombin
the abnormalities known or postulated as cause of
deficiency, knowledge on the genetic basis of thrombo- hypercoagulability. We considered only full-text papers,
philia has dramatically improved. This knowledge has including electronic early-release publications. No meeting
allowed us to understand the pathomechanisms of VTE, abstracts were included. We included retrospective and
particularly in young people and in the apparent absence prospective population-based, case–control, and family
of risk factors. We are convinced that unravelling the studies as well as narrative reviews and meta-analyses.
causes of a severe disease such as VTE is important, and A complementary manual search of the reference lists of
patients are eager to understand their condition beyond relevant articles was also performed.

REVIEWS
1. van Schouwenburg, I. M. et al. Increased risk of deficiency of protein S. N. Engl. J. Med. 311, inhibitor type 1. J. Thromb. Haemost. 6, 393–395
arterial thromboembolism after a prior episode 1525–1528 (1984). (2008).
of venous thromboembolism: results from the 22. Schwarz, H. P., Fischer, M., Hopmeier, P., 40. Castoldi, E., Simioni, P., Tormene, D., Rosing, J. &
Prevention of REnal and Vascular ENd stage Batard, M. A. & Griffin, J. H. Plasma protein S Hackeng, T. M. Hereditary and acquired protein S
Disease (PREVEND) Study. Br. J. Haematol. 159, deficiency in familial thrombotic disease. Blood deficiencies are associated with low TFPI levels in
216–222 (2012). 64, 1297–1300 (1984). plasma. J. Thromb. Haemost. 8, 294–300 (2010).
2. Cushman, M. et al. Deep vein thrombosis 23. Roemisch, J., Gray, E., Hoffmann, J. N. 41. Beauchamp, N. J., Dykes, A. C., Parikh, N.,
and pulmonary embolism in two cohorts: the & Wiedermann, C. J. Antithrombin: a new look at Tait, R. C. & Daly, M. E. The prevalence of, and
longitudinal investigation of thromboembolism the actions of a serine protease inhibitor. Blood molecular defects underlying, inherited protein S
etiology. Am. J. Med. 117, 19–25 (2004). Coagul. Fibrinolysis 13, 657–670 (2002). deficiency in the general population. Br. J.
3. Nordström, M., Lindblad, B., Bergqvist, D. & 24. Dahlbäck, B. & Villoutreix, B. O. The Haematol. 125, 647–654 (2004).
Kjellstöm, T. A. prospective study of the incidence anticoagulant protein C pathway. FEBS Lett. 42. Lane, D. A. et al. Inherited thrombophilia: part 1.
of deep-vein thrombosis within a defined urban 579, 3310–3316 (2005). Thromb. Haemost. 76, 651–662 (1996).
population. J. Intern. Med. 232, 155–160 (1992). 25. Dahlbäck, B., Carlsson, M. & Svensson, P. J. 43. García de Frutos, P., Fuentes-Prior, P., Hurtado, B.
4. Oger, E. for the EPI-GETBP Study Group. Familial thrombophilia due to a previously & Sala, N. Molecular basis of protein S
Incidence of venous thromboembolism: unrecognized mechanism characterized by poor deficiency. Thromb. Haemost. 98, 543–556
a community-based study in Western France. anticoagulant response to activated protein C: (2007).
Thromb. Haemost. 83, 657–660 (2000). prediction of a cofactor to activated protein C. 44. Zöller, B., García de Frutos, P. & Dahlbäck, B.
5. Naess, I. A. et al. Incidence and mortality of Proc. Natl Acad. Sci. USA 90, 1004–1008 (1993). Evaluation of the relationship between protein S
venous thrombosis: a population-based study. 26. Bertina, R. M. et al. Mutation in blood and C4b-binding protein isoforms in hereditary
J. Thromb. Haemost. 5, 692–699 (2007). coagulation factor V associated with resistance protein S deficiency demonstrating type I and
6. Heit, J. A. et al. Risk factors for deep vein to activated protein C. Nature 369, 64–67 type III deficiencies to be phenotypic variants of
thrombosis and pulmonary embolism: (1994). the same genetic disease. Blood 85, 3524–3531
a population-based case–control study. Arch. 27. Poort, S. R., Rosendaal, F. R., Reitsma, P. H. (1995).
Intern. Med. 160, 809–815 (2000). & Bertina, R. M. A common genetic variation in 45. Simmonds, R. E. et al. Genetic and phenotypic
7. Samama, M. M. An epidemiologic study of risk the 3'-untranslated region of the prothrombin analysis of a large (122-member)
factors for deep vein thrombosis in medical gene is associated with elevated plasma protein S‑deficient kindred provides an
outpatients: the Sirius study. Arch. Intern. Med. prothrombin levels and an increase in venous explanation for the familial coexistence of type I
160, 3415–3420 (2000). thrombosis. Blood 88, 3698–3703 (1996). and type III plasma phenotypes. Blood 89,
8. Martinelli, I. & De Stefano, V. Rare thromboses 28. Wells, P. S. et al. Prevalence of antithrombin 4364–4370 (1997).
of cerebral, splanchnic and upper-extremity deficiency in healthy blood donors: a cross- 46. Bertina, R. M. et al. Heerlen polymorphism of
veins. A narrative review. Thromb. Haemost. 103, sectional study. Am. J. Hematol. 45, 321–324 protein S, an immunologic polymorphism due to
1136–1144 (2010). (1994). dimorphism of residue 460. Blood 76, 538–548
9. Ocak, G. et al. Risk of venous thrombosis in 29. Tait, R. C. et al. Prevalence of antithrombin (1990).
patients with major illnesses: results from the deficiency in the healthy population. Br. J. 47. Libourel, E. J. et al. Protein S type III deficiency
MEGA study. J. Thromb. Haemost. 11, 116–123 Haematol. 87, 106–112 (1994). is no risk factor for venous and arterial
(2013). 30. De Stefano, V., Finazzi, G. & Mannucci, P. M. thromboembolism in 168 thrombophilic families:
10. Greer, I. A. Thrombosis in pregnancy: updates Inherited thrombophilia: pathogenesis, clinical a retrospective study. Blood Coagul. Fibrinolysis
in diagnosis and management. Hematology Am. syndromes, and management. Blood 87, 16, 135–140 (2005).
Soc. Hematol. Educ. Program 2012, 203–207 3531–3544 (1996). 48. Castoldi, E. et al. Similar hypercoagulable
(2012). 31. Lane, D. A., Kunz, G., Olds, R. J. & Thein, S. L. state and thrombosis risk in type I and type III
11. Battaglioli, T. & Martinelli, I. Hormone therapy Molecular genetics of antithrombin deficiency. protein S‑deficient individuals from families
and thromboembolic disease. Curr. Opin. Blood Rev. 10, 59–74 (1996). with mixed type I/III protein S deficiency.
Hematol. 14, 488–493 (2007). 32. Finazzi, G., Caccia, R. & Barbui, T. Different Haematologica 95, 1563–1571 (2010).
12. Heit, J. A. et al. Familial segregation of venous prevalence of thromboembolism in the subtypes 49. Chan, W. P., Lee, C. K., Kwong, Y. L., Lam, C. K.
thromboembolism. J. Thromb. Haemost. 2, of congenital antithrombin III deficiency: & Liang, R. A novel mutation of Arg306 of
731–736 (2004). review of 404 cases. Thromb. Haemost. 58, factor V gene in Hong Kong Chinese. Blood 91,
13. Bezemer, I. D., van der Meer, F. J., 1094 (1987). 1135–1139 (1998).
Eikenboom, J. C., Rosendaal, F. R. & Doggen, C. J. 33. Rossi, E. et al. Report of a novel kindred with 50. Williamson, D., Brown, K., Luddington, R.,
The value of family history as a risk indicator for antithrombin heparin-binding site variant (47 Arg Baglin, C. & Baglin, T. Factor V Cambridge:
venous thrombosis. Arch. Intern. Med. 169, to His): demand for an automated progressive a new mutation (Arg306 Thr) associated with
610–615 (2009). antithrombin assay to detect molecular variants resistance to activated protein C. Blood 91,
14. Zöller, B., Li, X., Sundquist, J. & Sundquist, K. with low thrombotic risk. Thromb. Haemost. 98, 1140–1144 (1998).
Parental history and venous thromboembolism: 695–697 (2007). 51. Norstrøm, E., Thorelli, E. & Dahlbäck, B.
a nationwide study of age-specific and sex- 34. Tait, R. C. et al. Prevalence of protein C Functional characterization of recombinant FV
specific familial risks in Sweden. J. Thromb. deficiency in the healthy population. Thromb. Hong Kong and FV Cambridge. Blood 100,
Haemost. 9, 64–70 (2011). Haemost. 73, 87–93 (1995). 524–530 (2002).
15. Sørensen, H. T. et al. Familial risk of venous 35. Miletich, J., Sherman, L. & Broze, G. Jr. Absence 52. De Stefano, V., Chiusolo, P., Paciaroni, K.
thromboembolism: a nationwide cohort study. of thrombosis in subjects with heterozygous & Leone, G. Epidemiology of factor V Leiden:
J. Thromb. Haemost. 9, 320–324 (2011). protein C deficiency. N. Engl. J. Med. 317, clinical implications. Sem. Thromb. Haemost. 24,
16. Rosendaal, F. R. Venous thrombosis: 991–996 (1987). 367–379 (1998).
a multicausal disease. Lancet 353, 1167–1173 36. Marciniak, E., Wilson, H. D. & Marlar, R. A. 53. Rosendaal, F. R., Koster, T., Vandenbroucke, J. P.
(1999). Neonatal purpura fulminans: a genetic disorder & Reitsma, P. H. High risk of thrombosis in
17. Nygaard, K. K. & Brown, G. E. Essential related to the absence of protein C in blood. patients homozygous for factor V Leiden
thrombophilia: report of five cases. Arch. Intern. Blood 65, 15–20 (1985). (activated protein C resistance). Blood 85,
Med. 59, 82–106 (1937). 37. Reitsma, P. H. et al. Protein C deficiency: 1504–1508 (1995).
18. Jordan, F. L. & Nandorff, A. The familial tendency a database of mutations, 1995 update. On behalf 54. Kyrle, P. A. et al. Clinical studies and thrombin
in thrombo-embolic disease. Acta Med. Scand. of the Subcommittee on Plasma Coagulation generation in patients homozygous or
156, 267–275 (1956). Inhibitors of the Scientific and Standardization heterozygous for the G20210A mutation in the
19. Egeberg, O. Inherited antithrombin deficiency Committee of the ISTH. Thromb. Haemost. 73, prothrombin gene. Arterioscler. Thromb. Vasc.
causing thrombophilia. Thromb. Diath. Haemorrh. 876–889 (1995). Biol. 18, 1287–1291 (1998).
13, 516–530 (1965). 38. Hackeng, T. M., Maurissen, L. F., Castoldi, E. 55. Smirnov, M. D., Safa, O., Esmon, N. L.
20. Griffin, J. H., Evatt, B., Zimmerman, T. S., & Rosing, J. Regulation of TFPI function by & Esmon, C. T. Inhibition of activated protein C
Kleiss, A. J. & Wideman, C. Deficiency of protein C protein S. J. Thromb. Haemost. 7 (Suppl. 1), anticoagulant activity by prothrombin. Blood 94,
in congenital thrombotic disease. J. Clin. Invest. 165–168 (2009). 3839–3846 (1999).
68, 1370–1373 (1981). 39. Dahm, A. E., Sandset, P. M. & Rosendaal, F. R. 56. Rosendaal, F. R. et al. Geographic distribution of
21. Comp, P. C. & Esmon, C. T. Recurrent venous The association between protein S levels and the 20210 G to A prothrombin variant. Thromb.
thromboembolism in patients with a partial anticoagulant activity of tissue factor pathway Haemost. 79, 706–708 (1998).

REVIEWS
57. Bosler, D., Mattson, J. & Crisan, D. Phenotypic 74. Cunningham, M. T., Brandt, J. T., Laposata, M. 92. de Visser, M. C., Poort, S. R., Vos, H. L.,
heterogeneity in patients with homozygous & Olson, J. D. Laboratory diagnosis of Rosendaal, F. R. & Bertina, R. M. Factor X levels,
prothrombin 20210AA genotype. A paper dysfibrinogenemia. Arch. Pathol. Lab. Med. 126, polymorphisms in the promoter region of
from the 2005 William Beaumont Hospital 499–505 (2002). factor X, and the risk of venous thrombosis.
Symposium on Molecular Pathology. J. Mol. 75. Mathonnet, F. et al. Three new cases of Thromb. Haemost. 85, 1011–1017 (2001).
Diagn. 8, 420–425 (2006). dysfibrinogenemia: Poissy III, Saint-Germain I 93. Bezemer, I. D. et al. Gene variants associated
58. Koster, T., Blann, A. D., Briët, E., and Tahiti. Thromb. Res. 103, 201–207 (2001). with deep vein thrombosis. JAMA 299,
Vandenbroucke, J. P. & Rosendaal, F. R. Role 76. Haverkate, F. & Samama, M. Familial 1306–1314 (2008).
of clotting factor VIII in effect of von Willebrand dysfibrinogenemia and thrombophilia. Report on 94. Bezemer, I. D. et al. F9 Malmö, factor IX and
factor on occurrence of deep-vein thrombosis. a study of the SSC Subcommittee on Fibrinogen. deep vein thrombosis. Haematologica 94,
Lancet 345, 152–155 (1995). Thromb. Haemost. 73, 151–161 (1995). 693–699 (2009).
59. Jenkins, P. V., Rawley, O., Smith, O. P. 77. Hanss, M. & Biot, F. A database for human 95. Simioni, P. et al. X‑linked thrombophilia with a
& O’Donnell, J. S. Elevated factor VIII levels and fibrinogen variants. Ann. N. Y. Acad. Sci. 936, mutant factor IX (factor IX Padua). N. Engl. J. Med.
risk of venous thrombosis. Br. J. Haematol. 157, 89–90 (2001). 361, 1671–1675 (2009).
653–663 (2012). 78. Groupe d’Etudes sur l’Hemostase et la 96. Mazetto Bde, M. et al. Prevalence of
60. Kamphuisen, P. W. et al. Familial clustering Thrombose (GEHT). Le Site Francophone de factor IX‑R338L (factor IX Padua) in a cohort of
of factor VIII and von Willebrand factor levels. l’Hémostase. Base de données des variants patients with venous thromboembolism and mild
Thromb. Haemost. 79, 323–327 (1998). du Fibrinogène [online], http://www.geht.org/ elevation of factor IX levels. Thromb. Res. 126,
61. Kamphuisen, P. W. et al. Heritability of elevated databaseang/fibrinogen/ (2013). e165 (2010).
factor VIII antigen levels in factor V Leiden 79. Marchi, R. et al. Fibrinogen Caracas V, an 97. Koenderman, J. S., Bertina, R. M., Reitsma, P. H.
families with thrombophilia. Br. J. Haematol. 109, abnormal fibrinogen with an Aalpha 532 Ser Cys & de Visser, M. C. Factor IX‑R338L (factor IX
519–522 (2000). substitution associated with thrombosis. Padua) screening in a Dutch population of
62. Bank, I. et al. Elevated levels of FVIII:C within Thromb. Haemost. 84, 263–270 (2000). sibpairs with early onset venous
families are associated with an increased risk 80. Kotlín, R. et al. Two cases of congenital thromboembolism. Thromb. Res. 128, 603
for venous and arterial thrombosis. J. Thromb. dysfibrinogenemia associated with thrombosis (2011).
Haemost. 3, 79–84 (2005). —Fibrinogen Praha III and Fibrinogen Plzen. 98. Miyawaki, Y. et al. Thrombosis from a prothrombin
63. Lijfering, W. M. et al. Selective testing for Thromb. Haemost. 102, 479–486 (2009). mutation conveying antithrombin resistance.
thrombophilia in patients with first venous 81. Uitte de Willige, S. et al. Genetic variation in the N. Engl. J. Med. 366, 2390–2396 (2012).
thrombosis: results from a retrospective family fibrinogen gamma gene increases the risk for 99. Djordjevic, V. et al. A novel prothrombin mutation
cohort study on absolute thrombotic risk for deep venous thrombosis by reducing plasma in two families with prominent thrombophilia—
currently known thrombophilic defects in 2479 fibrinogen γ' levels. Blood 106, 4176–4183 the first cases of antithrombin resistance in a
relatives. Blood 113, 5314–5322 (2009). (2005). Caucasian population. J. Thromb. Haemost. 11,
64. Soria, J. M. et al. A new locus on chromosome 82. Grünbacher, G. et al. The fibrinogen gamma 1936–1939 (2013).
18 that influences normal variation in activated (FGG) 10034C>T polymorphism is associated 100. Lisman, T., de Groot, P. G., Meijers, J. C.
protein C resistance phenotype and factor VIII with venous thrombosis. Thromb. Res. 121, & Rosendaal, F. R. Reduced plasma fibrinolytic
activity and its relation to thrombosis 33–36 (2007). potential is a risk factor for venous thrombosis.
susceptibility. Blood 101, 163–167 (2003). 83. Crawley, J. T. & Lane, D. A. The haemostatic role Blood 105, 1102–1105 (2005).
65. Viel, K. R. et al. A sequence variation scan of the of tissue factor pathway inhibitor. Arterioscler. 101. Meltzer, M. E., Lisman, T., Doggen, C. J.,
coagulation factor VIII (FVIII) structural gene and Thromb. Vasc. Biol. 28, 233–242 (2008). de Groot, P. G & Rosendaal, F. R. Synergistic
associations with plasma FVIII activity levels. 84. Dahm, A., Rosendaal, F. R., Andersen, T. O. effects of hypofibrinolysis and genetic and
Blood 109, 3713–3724 (2007). & Sandset, P. M. Tissue factor pathway inhibitor acquired risk factors on the risk of a first venous
66. Gill, J. C., Endres-Brooks, J., Bauer, P. J., anticoagulant activity: risk for venous thrombosis. PLoS Med. 5, e97 (2008).
Marks, W. J. Jr & Montgomery, R. R. The effect thrombosis and effect of hormonal state. Br. J. 102. Meltzer, M. E. et al. Venous thrombosis risk
of AB0 blood group on the diagnosis of von Haematol. 132, 333–338 (2006). associated with plasma hypofibrinolysis is
Willebrand disease. Blood 69, 1691–1695 85. Dahm, A. et al. Low levels of tissue factor explained by elevated plasma levels of TAFI and
(1987). pathway inhibitor (TFPI) increase the risk of PAI‑1. Blood 116, 113–121 (2010).
67. Souto, J. C. et al. Functional effects of the ABO venous thrombosis. Blood 101, 4387–4392 103. Dawson, S. J. et al. The two allele sequences of
locus polymorphism on plasma levels of von (2003). a common polymorphism in the promoter of the
Willebrand factor, factor VIII, and activated 86. Hoke, M. et al. Tissue factor pathway plasminogen activator inhibitor 1 (PAI‑1) gene
partial thromboplastin time. Arterioscler. Thromb. inhibitor and the risk of recurrent venous respond differently to interleukin‑1 in HepG2
Vasc. Biol. 20, 2024–2028 (2000). thromboembolism. Thromb. Haemost. 94, cells. J. Biol. Chem. 268, 10739–10745 (1993).
68. Sodetz, J. M., Pizzo, S. V. & McKee, P. A. 787–790 (2005). 104. Tsantes, A. E. et al. Association between the
Relationship of sialic acid to function and in vivo 87. Zakai, N. A., Lutsey, P. L., Folsom, A. R., plasminogen activator inhibitor‑1 4G/5G
survival of human factor VIII/vonWillebrand factor Heckbert, S. R. & Cushman, M. Total tissue polymorphism and venous thrombosis. A meta-
protein. J. Biol. Chem. 252, 5538–5546 (1977). factor pathway inhibitor and venous thrombosis: analysis. Thromb. Haemost. 97, 907–913
69. Dentali, F. et al. Non‑O blood type is the the Longitudinal Investigation of (2007).
commonest genetic risk factor for VTE: results Thromboembolism Etiology. Thromb. Haemost. 105. Ridker, P. M., Hennekens, C. H., Lindpaintner, K.,
from a meta-analysis of the literature. Semin. 104, 207–212 (2010). Stampfer, M. J. & Miletich, J. P. Arterial and
Thromb. Hemost. 38, 535–548 (2012). 88. Opstad, T. B., Eilertsen, A. L., Høibraaten, E., venous thrombosis is not associated with the
70. Morelli, V. M., De Visser, M. C., Vos, H. L., Skretting, G. & Sandset, P. M. Tissue factor 4G/5G polymorphism in the promoter of the
Bertina, R. M. & Rosendaal, F. R. AB0 blood pathway inhibitor polymorphisms in women with plasminogen activator inhibitor gene in a large
group genotypes and the risk of venous and without a history of venous thrombosis and cohort of US men. Circulation 95, 59–62 (1997).
thrombosis: effect of factor V Leiden. J. Thromb. the effects of postmenopausal hormone therapy. 106. van Tilburg, N. H., Rosendaal, F. R.
Haemost. 3, 183–185 (2005). Blood Coagul. Fibrinolysis 21, 516–521 (2010). & Bertina, R. M. Thrombin activatable
71. Ohira, T. et al. AB0 blood group, other risk factors 89. Koster, T. et al. Factor VII and fibrinogen levels fibrinolysis inhibitor and the risk for deep vein
and incidence of venous thromboembolism: as risk factors for venous thrombosis. A case– thrombosis. Blood 95, 2855–2859 (2000).
the Longitudinal Investigation of control study of plasma levels and DNA 107. Libourel, E. J. et al. Co-segregation of
Thromboembolism Etiology (LITE). J. Thromb. polymorphisms: the Leiden Thrombophilia Study thrombophilic disorders in factor V Leiden
Haemost. 5, 1455–1461 (2007). (LETS). Thromb. Haemost. 71, 719–722 (1994). carriers; the contributions of factor VIII, factor XI,
72. Cohen, W. et al. AB0 blood group and 90. Meijers, J. C., Tekelenburg, W. L., Bouma, B. N., thrombin activatable fibrinolysis inhibitor and
von Willebrand factor levels partially explained Bertina, R. M. & Rosendaal, F. R. High levels of lipoprotein(a) to the absolute risk of venous
the incomplete penetrance of congenital coagulation factor XI as a risk factor for venous thromboembolism. Haematologica 87,
thrombophilia. Arterioscler. Thromb. Vasc. Biol. thrombosis. N. Engl. J. Med. 342, 696–701 1068–1073 (2002).
32, 2021–2028 (2012). (2000). 108. Henry, M. et al. Identification of polymorphisms
73. Spiezia, L. et al. AB0 blood groups and the risk 91. van Hylckama Vlieg, A., van der Linden, I. K., in the promoter and the 3' region of the TAFI
of venous thrombosis in patients with inherited Bertina, R. M. & Rosendaal, F. R. High levels of gene: evidence that plasma TAFI antigen levels
thrombophilia. Blood Transfus. 11, 250–253 factor IX increase the risk of venous thrombosis. are strongly genetically controlled. Blood 97,
(2013). Blood 95, 3678–3682 (2000). 2053–2058 (2001).

REVIEWS
109. Eldibany, M. M. & Caprini, J. A. 126. Cantor, R. M., Lange, K. & Sinsheimer, J. S. 143. Martinelli, I., Battaglioli, T., Pedotti, P.,
Hyperhomocysteinemia and thrombosis: Prioritizing GWAS results: a review of statistical Cattaneo, M. & Mannucci, P. M.
an overview. Arch. Pathol. Lab. Med. 131, methods and recommendations for their Hyperhomocysteinemia in cerebral vein
872–884 (2007). application. Am. J. Hum. Genet. 86, 6–22 (2010). thrombosis. Blood 102, 1363–1366 (2003).
110. Ray, J. G. Meta-analysis of hyperhomocysteinemia 127. Marian, A. J. Molecular genetic studies of 144. Wysokinska, E. M. et al. Thrombophilia
as a risk factor for venous thromboembolic complex phenotypes. Transl. Res. 159, 64–79 differences in cerebral venous sinus and lower
disease. Arch. Intern. Med. 158, 2101–2106 (2012). extremity deep venous thrombosis. Neurology
(1998). 128. Morange, P. E. et al. A follow-up study of a 70, 627–633 (2008).
111. Martinelli, I., Bucciarelli, P., Zighetti, M. L., genome-wide association scan identifies a 145. Treadwell, S. D., Thanvi, B. & Robinson, T. G.
Cafro, A. & Mannucci, P. M. Low risk of susceptibility locus for venous thrombosis on Stroke in pregnancy and the puerperium.
thrombosis in family members of patients with chromosome 6p24.1. Am. J. Hum. Genet. 86, Postgrad. Med. J. 84, 238–245 (2008).
hyperhomocysteinaemia. Br. J. Haematol. 117, 592–595 (2010). 146. De Stefano, V. & Martinelli, I. Abdominal
709–711 (2002). 129. van der Meer, F. J., Koster, T., Vandenbroucke, J. P., thromboses of splanchnic, renal and ovarian
112. Clarke, R. et al. Effects of lowering homocysteine Briet, E. & Rosendaal, F. R. The Leiden veins. Best Pract. Res. Clin. Haematol. 25,
levels with B vitamins on cardiovascular Thrombophilia Study (LETS). Thromb. Haemost. 253–264 (2012).
disease, cancer, and cause-specific mortality: 78, 631–635 (1997). 147. Primignani, M. et al. Risk factors for
meta-analysis of 8 randomized trials involving 130. Manten, B., Westendorp, R. G., Koster, T., thrombophilia in extrahepatic portal vein
37,485 individuals. Arch. Intern. Med. 170, Reitsma, P. H. & Rosendaal, F. R. Risk factor obstruction. Hepatology 41, 603–608 (2005).
1622–1631 (2010). profiles in patients with different clinical 148. Dentali, F., Galli, M., Gianni, M. & Ageno, W.
113. Bezemer, I. D., Doggen, C. J., Vos, H. L. manifestations of venous thromboembolism: Inherited thrombophilic abnormalities and risk of
& Rosendaal, F. R. No association between the a focus on the factor V Leiden mutation. Thromb. portal vein thrombosis: a meta-analysis. Thromb.
common MTHFR 677C T polymorphism and Haemost. 76, 510–513 (1996). Haemost. 99, 675–682 (2008).
venous thrombosis: results from the MEGA 131. Bounameaux, H. Factor V Leiden paradox: risk 149. Plessier, A. et al. Acute portal vein thrombosis
study. Arch. Intern. Med. 167, 497–501 (2007). of deep-vein thrombosis but not of pulmonary unrelated to cirrhosis: a prospective multicenter
114. Gohil, R., Peck, G. & Sharma, P. The genetics embolism. Lancet 356, 182–183 (2000). follow-up study. Hepatology 51, 210–218
of venous thromboembolism. A meta-analysis 132. Rossi, E., Za, T., Ciminello, A., Leone, G. (2010).
involving approximately 120,000 cases and & De Stefano, V. The risk of symptomatic 150. Janssen, H. L. et al. Factor V Leiden mutation,
180,000 controls. Thromb. Haemost. 102, pulmonary embolism due to proximal deep prothrombin gene mutation, and deficiencies in
360–370 (2009). venous thrombosis differs in patients with coagulation inhibitors associated with Budd–
115. Simone, B. et al. Risk of venous different types of inherited thrombophilia. Chiari syndrome and portal vein thrombosis:
thromboembolism associated with single and Thromb. Haemost. 99, 1030–1034 (2008). results of a case–control study. Blood 96,
combined effects of factor V Leiden, prothrombin 133. van Stralen, K. J. et al. Mechanisms of the 2364–2368 (2000).
20210A and methylenetethraydrofolate factor V Leiden paradox. Arterioscler. Thromb. 151. Darwish Murad, S. et al. Etiology, management,
reductase C677T: a meta-analysis involving over Vasc. Biol. 28, 1872–1877 (2008). and outcome of the Budd–Chiari syndrome. Ann.
11,000 cases and 21,000 controls. Eur. J. 134. Mäkelburg, A. B. et al. Different risk of deep vein Intern. Med. 151, 167–175 (2009).
Epidemiol. 28, 621–647 (2013). thrombosis and pulmonary embolism in carriers 152. Martinelli, I., Battaglioli, T., Bucciarelli, P.,
116. Souto, J. C. et al. Genetic susceptibility to with factor V Leiden compared with non-carriers, Passamonti, S. M. & Mannucci, P. M. Risk
thrombosis and its relationship to physiological but not in other thrombophilic defects. Results factors and recurrence rate of primary deep vein
risk factors: the GAIT study. Am. J. Hum. Genet. from a large retrospective family cohort study. thrombosis of the upper extremities. Circulation
67, 1452–1459 (2000). Haematologica 95, 1030–1033 (2010). 110, 566–570 (2004).
117. Hasstedt, S. J. et al. Genome scan of venous 135. Dentali, F. et al. Role of factor V Leiden or 153. Laouri, M., Chen, E., Looman, M. & Gallagher, M.
thrombosis in a pedigree with protein C G20210A prothrombin mutation in patients with The burden of disease of retinal vein occlusion:
deficiency. J. Thromb. Haemost. 2, 868–873 symptomatic pulmonary embolism and deep review of the literature. Eye 25, 981–988
(2004). vein thrombosis: a meta-analysis of the (2011).
118. Wichers, I. M. et al. Assessment of coagulation literature. J. Thromb. Haemost. 10, 732–737 154. Janssen, M. C., den Heijer, M., Cruysberg, J. R.,
and fibrinolysis in families with unexplained (2012). Wollersheim, H. & Bredie, S. J. Retinal vein
thrombophilia. Thromb. Haemost. 101, 465–470 136. Kuismanen, K., Savontaus, M. L., Kozlov, A., occlusion: a form of venous thrombosis or a
(2009). Vuorio, A. F. & Sajantila, A. Coagulation factor V complication of atherosclerosis? A meta-
119. Reitsma, P. H. & Rosendaal, F. R. Past and future Leiden mutation in sudden fatal pulmonary analysis of thrombophilic factors. Thromb.
of genetic research in thrombosis. J. Thromb. embolism and in a general northern European Haemost. 93, 1021–1026 (2005).
Haemost. 5 (Suppl. 1), 264–269 (2007). population sample. Forensic Sci. Int. 106, 71–75 155. Rehak, M. et al. The prevalence of activated
120. Bezemer, I. D., Bare, L. A., Arellano, A. R., (1999). protein C (APC) resistance and factor V Leiden
Reitsma, P. H. & Rosendaal, F. R. Updated 137. van Langevelde, K., Flinterman, L. E., is significantly higher in patients with retinal
analysis of gene variants associated with deep van Hylckama Vlieg, A., Rosendaal, F. R. vein occlusion without general risk factors:
vein thrombosis. JAMA 303, 421–422 (2010). & Cannegieter, S. C. Broadening the factor V case–control study and meta-analysis. Thromb.
121. Trégouët, D. A. et al. Common susceptibility Leiden paradox: pulmonary embolism and deep- Haemost. 99, 925–929 (2008).
alleles are unlikely to contribute as strongly as vein thrombosis as 2 sides of the spectrum. 156. McGimpsey, S. J., Woodside, J. V., Cardwell, C.,
the FV and AB0 loci to VTE risk: results from a Blood 120, 933–946 (2012). Cahill, M. & Chakravarthy, U. Homocysteine,
GWAS approach. Blood 113, 5298–5303 138. Decousus, H. et al. Epidemiology, diagnosis, methylenetetrahydrofolate reductase C677T
(2009). treatment and management of superficial-vein polymorphism, and risk of retinal vein occlusion:
122. Germain, M. et al. Genetics of venous thrombosis of the legs. Best Pract. Res. Clin. a meta-analysis. Ophthalmology 116,
thrombosis: insights from a new genome wide Haematol. 25, 275–284 (2012). 1778–1787 (2009).
association study. PLoS ONE 6, e25581 (2011). 139. Martinelli, I. et al. Genetic risk factors for 157. Pabinger, I. et al. The risk of thromboembolism
123. Heit, J. A. et al. A genome-wide association study superficial vein thrombosis. Thromb. Haemost. in asymptomatic patients with protein C and
of venous thromboembolism identifies risk 82, 1215–1217 (1999). protein S deficiency: a prospective cohort study.
variants in chromosomes 1q24.2 and 9q. 140. Margaglione, M. et al. Inherited thrombophilic Thromb. Haemost. 71, 441–445 (1994).
J. Thromb. Haemost. 10, 1521–1531 (2012). risk factors in a large cohort of individuals 158. Sanson, B. J. et al. The incidence of venous
124. Tang, W. et al. A genome-wide association study referred to Italian thrombophilia centers: distinct thromboembolism in asymptomatic carriers of
for venous thromboembolism: the extended roles in different clinical settings. Haematologica a deficiency of antithrombin, protein C, or
cohorts for heart and aging research in genomic 86, 634–639 (2001). protein S: a prospective cohort study. Blood 94,
epidemiology (CHARGE) consortium. Genet. 141. Stam, J. Thrombosis of the cerebral vein and 3702–3706 (1999).
Epidemiol. 37, 512–521 (2013). sinuses. N. Engl. J. Med. 352, 1791–1798 159. Middeldorp, S. et al. A prospective study of
125. de Visser, M. C. et al. Genome-wide linkage (2005). asymptomatic carriers of the factor V Leiden
scan in affected sibling pairs identifies 142. Dentali, F., Crowther, M. & Ageno, W. mutation to determine the incidence of venous
novel susceptibility region for venous Thrombophilic abnormalities, oral thromboembolism. Ann. Intern. Med. 135,
thromboembolism: Genetics in Familial contraceptives, and risk of cerebral vein 322–327 (2001).
Thrombosis study. J. Thromb. Haemost. 11, thrombosis: a meta-analysis. Blood 107, 160. Simioni, P. et al. Incidence of venous
1474–1484 (2013). 2766–2773 (2006). thromboembolism in asymptomatic family

REVIEWS
members who are carriers of factor V Leiden: thromboembolism is dependent on the clinical the use of antithrombin concentrates and
a prospective cohort study. Blood 99, 1938–1942 phenotype of the proband. Thromb. Haemost. prothrombin complex concentrates. Blood
(2002). 106, 646–654 (2011). Transfus. 7, 325–334 (2009).
161. Vossen, C. Y. et al. Risk of a first venous 176. Holzhauer, S. et al. Inherited thrombophilia in 193. Marlar, R. A., Montgomery, R. R. &
thrombotic event in carriers of a familial children with venous thromboembolism and Broekmans, A. W. Diagnosis and treatment of
thrombophilic defect: the European Prospective the familial risk of thromboembolism: an homozygous protein C deficiency. Report of the
Cohort on Thrombophilia (EPCOT). J. Thromb. observational study. Blood 120, 1510–1515 Working Party on Homozygous Protein C Deficiency
Haemost. 3, 459–464 (2005). (2012). of the Subcommittee on Protein C and Protein S.
162. Coppens, M. et al. A prospective cohort study 177. Bucciarelli, P. et al. Low borderline plasma levels International Committee on Thrombosis and
on the absolute incidence of venous of antithrombin, protein C and protein S are risk Haemostasis. J. Pediatr. 114, 528–534 (1989).
thromboembolism and arterial cardiovascular factors for venous thromboembolism. J. Thromb. 194. De Stefano, V. et al. Replacement therapy with
disease in asymptomatic carriers of the Haemost. 10, 1783–1791 (2012). a purified protein C concentrate during initiation
prothrombin 20210A mutation. Blood 108, 178. Middeldorp, S. & van Hylckama Vlieg, A. of oral anticoagulation in severe protein C
2604–2607 (2006). Does thrombophilia testing help in the clinical congenital deficiency. Thromb. Haemost. 70,
163. Mahmoodi, B. K. et al. A prospective cohort management of patients? Br. J. Haematol. 143, 247–249 (1993).
study on the absolute risks of venous 321–335 (2008). 195. Prandoni, P. et al. The risk of recurrent venous
thromboembolism and predictive value of 179. Ridker, P. M. et al. Age-specific incidence rates of thromboembolism after discontinuing
screening asymptomatic relatives of patients venous thromboembolism among heterozygous anticoagulation in patients with acute proximal
with hereditary deficiencies of protein S, carriers of factor V Leiden mutation. Ann. Intern. deep vein thrombosis pulmonary embolism.
protein C or antithrombin. J. Thromb. Haemost. 8, Med. 126, 528–531 (1997). A prospective cohort study in 1,626 patients.
1193–1200 (2010). 180. De Stefano, V. et al. Different circumstances Haematologica 92, 199–205 (2007).
164. Martinelli, I. et al. Different risks of thrombosis of the first venous thromboembolism among 196. Baglin, T., Luddington, R., Brown, K. & Baglin, C.
in four coagulation defects associated with younger or older heterozygous carriers of the Incidence of recurrent venous thromboembolism
inherited thrombophilia: a study of 150 families. G20210A polymorphism in the prothrombin in relation to clinical and thrombophilic risk
Blood 92, 2353–2358 (1998). gene. Haematologica 88, 61–66 (2003). factors: prospective cohort study. Lancet 362,
165. Middeldorp, S. et al. The incidence of venous 181. De Stefano, V. et al. Thrombosis during pregnancy 523–526 (2003).
thromboembolism in family members of patients and surgery in patients with congenital deficiency 197. Christiansen, S. C., Cannegieter, S. C., Koster, T.,
with factor V Leiden mutation and venous of antithrombin III, protein C, protein S. Thromb. Vandenbroucke, J. P. & Rosendaal, F. R.
thrombosis. Ann. Intern. Med. 128, 15–20 Haemost. 71, 799–800 (1994). Thrombophilia, clinical factors, and recurrent
(1998). 182. De Stefano, V. et al. Clinical manifestations venous thrombotic events. JAMA 293,
166. Bucciarelli, P. et al. Risk of venous and management of inherited thrombophilia: 2352–2361 (2005).
thromboembolism and clinical manifestations retrospective analysis and follow-up after 198. Palareti, G. et al. Bleeding complications of oral
in carriers of antithrombin, protein C, protein S diagnosis of 238 patients with congenital anticoagulant treatment: an inception-cohort,
deficiency, or activated protein C resistance: deficiency of antithrombin III, protein C, prospective collaborative study (ISCOAT). Lancet
a multicenter collaborative family study. protein S. Thromb. Haemost. 72, 352–358 348, 423–428 (1996).
Arterioscler. Thromb. Vasc. Biol. 19, 1026–1033 (1994). 199. Fox, B. D., Kahn, S. R., Langleben, D.,
(1999). 183. Bucciarelli, P. et al. Influence of proband’s Eisenberg, M. J. & Shimony, A. Efficacy and
167. Simioni, P. et al. Incidence of venous characteristics on the risk of venous safety of novel oral anticoagulants for treatment
thromboembolism in families with inherited thromboembolism in relatives with factor V of acute venous thromboembolism: direct and
thrombophilia. Thromb. Haemost. 81, 198–202 Leiden or prothrombin G20210A adjusted indirect meta-analysis of randomised
(1999). polymorphisms. Blood 122, 2555–2561 (2013). controlled trials. BMJ 345, e7498 (2012).
168. Lensen, R. P., Bertina, R. M., de Ronde, H., 184. Demers, C., Ginsberg, J. S., Hirsh, J., 200. Segal, J. B. et al. Predictive value of factor V
Vandenbroucke, J. P. & Rosendaal, F. R. Venous Henderson, P. & Blajchman, M. A. Thrombosis Leiden and prothrombin G20210A in adults
thrombotic risk in family members of unselected in antithrombin‑III‑deficient persons. Report of with venous thromboembolism and in family
individuals with factor V Leiden. Thromb. a large kindred and literature review. Ann. Intern. members of those with a mutation: a systematic
Haemost. 83, 817–821 (2000). Med. 116, 754–761 (1992). review. JAMA 301, 2472–2485 (2009).
169. Martinelli, I. et al. The risk of venous 185. van Boven, H. H., Vandenbroucke, J. P., Briët, E. 201. Ho, W. K., Hankey, G. J., Quinlan, D. J.
thromboembolism in family members with & Rosendaal, F. R. Gene–gene and gene– & Eikelboom, J. W. Risk of recurrent venous
mutations in the genes of factor V or environment interactions determine risk of thromboembolism in patients with common
prothrombin or both. Br. J. Haematol. 111, thrombosis in families with inherited thrombophilia: a systematic review. Arch. Intern.
1223–1229 (2000). antithrombin deficiency. Blood 94, 2590–2594 Med. 166, 729–736 (2006).
170. Tirado, I. et al. Contribution of prothrombin (1999). 202. Marchiori, A., Mosena, L., Prins, M. H.
20210A allele and factor V Leiden mutation to 186. Allaart, C. F. et al. Increased risk of venous & Prandoni, P. The risk of recurrent venous
thrombosis risk in thrombophilic families with thrombosis in carriers of hereditary protein C thromboembolism among heterozygous carriers
other hemostatic deficiencies. Haematologica deficiency defect. Lancet 341, 134–138 (1993). of factor V Leiden or prothrombin G20210A
86, 1200–1208 (2001). 187. Pintao, M. C. et al. Protein S levels and the risk mutation: a systematic review of prospective
171. Bank, I. et al. Prothrombin 20210A mutation: of venous thrombosis: results from the MEGA studies. Haematologica 92, 1107–1114 (2007).
a mild risk factor for venous thromboembolism case–control study. Blood 122, 3210–3219 203. De Stefano, V. et al. The risk of recurrent
but not for arterial thrombotic disease and (2013). venous thromboembolism in patients with
pregnancy-related complications in a family 188. Wu, O. et al. Screening for thrombophilia in inherited deficiency of natural anticoagulants
study. Arch. Intern. Med. 164, 1932–1937 high‑risk situations: a meta-analysis and cost- antithrombin, protein C, and protein S.
(2004). effectiveness analysis. Br. J. Haematol. 131, Haematologica 91, 695–698 (2006).
172. Tormene, D., Simioni, P., Pagnan, A. 80–90 (2005). 204. Brouwer, J. L. et al. High long-term absolute
& Prandoni, P. The G20210A prothrombin gene 189. Mari, D., Mannucci, P. M., Duca, F., Bertolini, S. risk of recurrent venous thromboembolism in
mutation: is there room for screening families? & Franceschi, C. Mutant factor V (Arg506Gln) in patients with hereditary deficiencies of
J. Thromb. Haemost. 2, 1487–1488 (2004). healthy centenarians. Lancet 347, 1044 (1996). protein S, protein C or antithrombin. Thromb.
173. Brouwer, J. L., Veeger, N. J., Kluin‑Nelemans, H. C. 190. van El, C. G. & Cornel, M. C. for the ESHG Public Haemost. 101, 93–99 (2009).
& van der Meer, J. The pathogenesis of venous and Professional Policy Committee. Genetic 205. Vossen, C. Y. et al. Recurrence rate after a first
thromboembolism: evidence for multiple testing and common disorders in a public health venous thrombosis in patients with familial
interrelated causes. Ann. Intern. Med. 145, framework. Recommendations of the European thrombophilia. Arterioscler. Thromb. Vasc. Biol.
807–815 (2006). Society of Human Genetics. Eur. J. Hum. Genet. 25, 1992–1997 (2005).
174. Couturaud, F. et al. Incidence of venous 19, 377–381 (2011). 206. De Stefano, V. & Rossi, E. Testing for inherited
thromboembolism in first-degree relatives of 191. Schulman, S. & Tengborn, L. Treatment of thrombophilia and consequences for
patients with venous thromboembolism who venous thromboembolism in patients with antithrombotic prophylaxis in patients with
have factor V Leiden. Thromb. Haemost. 96, congenital deficiency of antithrombin III. Thromb. venous thromboembolism and their relatives.
744–749 (2006). Haemost. 68, 634–636 (1992). A review of the Guidelines from Scientific
175. Rossi, E. et al. In families with inherited 192. Liumbruno, G., Bennardello, F., Lattanzio, A., Societies and Working Groups. Thromb. Haemost.
thrombophilia the risk of venous Piccoli, P. & Rossetti, G. Recommendations for 110, 697–705 (2013).

REVIEWS
207. National Institute for Health and Care cohort study. Arch. Intern. Med. 167, 282–289 Leiden and prothrombin G20210A. J. Thromb.
Excellence. Clinical Guideline 144: venous (2007). Haemost. 6, 494–498 (2008).
thromboembolic diseases. The management of 215. Wu, O. Postmenopausal hormone replacement 223. McLintock, C. et al. Recommendations for the
venous thromboembolic diseases and the role therapy and venous thromboembolism. Gend. prevention of pregnancy-associated venous
of thrombophilia testing [online], http:// Med. 2 (Suppl. A), S18–S27 (2005). thromboembolism. Aust. N. Z. J. Obstet. Gynaecol.
guidance.nice.org.uk/CG144 (2012). 216. Greer, I. A. & Nelson-Piercy, C. 52, 3–13 (2012).
208. Einhäupl, K. et al. EFNS guideline on the Low‑molecular‑weight heparins for 224. Bates, S. M. et al. American College of Chest
treatment of cerebral venous and sinus thromboprophylaxis and treatment of venous Physicians. VTE, thrombophilia, antithrombotic
thrombosis in adult patients. Eur. J. Neurol. 17, thromboembolism in pregnancy: a systematic therapy, and pregnancy: antithrombotic therapy
1229–1235 (2010). review of safety and efficacy. Blood 106, and prevention of thrombosis, 9th ed: American
209. DeLeve, L. D., Valla, D. C. & Garcia-Tsao, G. 401–407 (2005). College of Chest Physicians evidence-based
for the American Association for the Study 217. Lussana, F. et al. Screening for thrombophilia clinical practice guidelines. Chest 141 (2 Suppl.),
Liver Diseases. Vascular disorders of the liver. and antithrombotic prophylaxis in pregnancy: e691S–e736S (2012).
Hepatology 49, 1729–1764 (2009). guidelines of the Italian Society for Haemostasis 225. De Stefano, V., Grandone, E. & Martinelli, I.
210. Roach, R. E., Lijfering, W. M., Rosendaal, F. R., and Thrombosis (SISET). Thromb. Res. 124, Recommendations for prophylaxis of pregnancy-
Cannegieter, S. C. & le Cessie, S. Sex difference e19–e25 (2009). related venous thromboembolism in carriers of
in risk of second but not of first venous 218. Royal College of Obstetricians and inherited thrombophilia. Comment on the 2012
thrombosis: paradox explained. Circulation Gynaecologists. Reducing the risk of thrombosis ACCP guidelines. J. Thromb. Haemost. 11,
http://dx.doi.org/10.1161/ and embolism during pregnancy and the 1779–1781 (2013).
CIRCULATIONAHA.113.004768. puerperium. Green-Top Guideline No. 37a 226. Johnson, N. V., Khor, B. & Van Cott, E. M.
211. McRae, S., Tran, H., Schulman, S., Ginsberg, J. [online], http://www.rcog.org.uk/files/ Advances in laboratory testing for thrombophilia.
& Kearon, C. Effect of patient’s sex on risk of rcog-corp/GTG37aReducingRiskThrombosis.pdf Am. J. Hematol. 87, S108–S112 (2012).
recurrent venous thromboembolism: a meta- (2009). 227. Frezzato, M., Tosetto, A. & Rodeghiero, F.
analysis. Lancet 368, 371–378 (2006). 219. Scottish Intercollegiate Guidelines Network. Validated questionnaire for the identification
212. Douketis, J. et al. Risk of recurrence after Prevention and management of venous of previous personal or familial venous
venous thromboembolism in men and women: thromboembolism: a national clinical guideline. thromboembolism. Am. J. Epidemiol. 143,
patient level meta-analysis. BMJ 342, d813 SIGN publication 122 [online], http:// 1257–1265 (1996).
(2011). www.sign.ac.uk/pdf/sign122.pdf (2010). 228. Wilson, B. J. et al. Systematic review: family
213. Wu, O. et al. Oral contraceptives, hormone 220. Lockwood, C. & Wendel, G. for the Committee on history in risk assessment for common
replacement therapy, thrombophilias and risk of Practice Bulletins—Obstetrics. Practice bulletin diseases. Ann. Intern. Med. 151, 878–885
venous thromboembolism: a systematic review: no. 124: inherited thrombophilias in pregnancy. (2009).
the Thrombosis: Risk and Economic Obstet. Gynecol. 118, 730–740 (2011).
Assessment of Thrombophilia Screening 221. Tormene, D. et al. The G20210A prothrombin Author contributions
(TREATS) study. Thromb. Haemost. 94, 17–25 variant and the risk of venous thromboembolism All the authors researched data for the article and
(2005). or fetal loss in pregnant women: a family study. contributed substantially to the discussion of content.
214. van Vlijmen, E. F. et al. Oral contraceptives and J. Thromb. Haemost. 5, 2193–2196 (2007). I. Martinelli wrote the first draft of the article;
the absolute risk of venous thromboembolism 222. Martinelli, I. et al. The risk of first venous V. De Stefano and P. M. Mannucci contributed to
in women with single or multiple thrombophilic thromboembolism during pregnancy and writing subsequent drafts. All the authors reviewed/
defects: results from a retrospective family puerperium in double heterozygotes for factor V edited the manuscript before submission.


Reviews: Inherited Risk Factors For Venous Thromboembolism

Uploaded by

Copyright:

Available Formats

Reviews: Inherited Risk Factors For Venous Thromboembolism

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Reviews: Inherited Risk Factors For Venous Thromboembolism

Uploaded by

Copyright:

Available Formats

REVIEWS

Inherited risk factors for venous

140 | MARCH 2014 | VOLUME 11  www.nature.com/nrcardio

Key points Box 1 | Acquired risk factors for VTE

function of procoagulant factors. Gain-of-function in ■■ Exposure to ambient air pollution

NATURE REVIEWS | CARDIOLOGY VOLUME 11 | MARCH 2014 | 141

142 | MARCH 2014 | VOLUME 11  www.nature.com/nrcardio

NATURE REVIEWS | CARDIOLOGY VOLUME 11 | MARCH 2014 | 143

Postulated mechanisms of thrombophilia

144 | MARCH 2014 | VOLUME 11  www.nature.com/nrcardio

NATURE REVIEWS | CARDIOLOGY VOLUME 11 | MARCH 2014 | 145

146 | MARCH 2014 | VOLUME 11  www.nature.com/nrcardio

Table 2 | Antithrombotic management of thrombophilia

NATURE REVIEWS | CARDIOLOGY VOLUME 11 | MARCH 2014 | 147

Table 3 | Incidence of VTE in studies of families with thrombophilia

148 | MARCH 2014 | VOLUME 11  www.nature.com/nrcardio

NATURE REVIEWS | CARDIOLOGY VOLUME 11 | MARCH 2014 | 149

150 | MARCH 2014 | VOLUME 11  www.nature.com/nrcardio

NATURE REVIEWS | CARDIOLOGY VOLUME 11 | MARCH 2014 | 151

152 | MARCH 2014 | VOLUME 11  www.nature.com/nrcardio

NATURE REVIEWS | CARDIOLOGY VOLUME 11 | MARCH 2014 | 153

154 | MARCH 2014 | VOLUME 11  www.nature.com/nrcardio

NATURE REVIEWS | CARDIOLOGY VOLUME 11 | MARCH 2014 | 155

156 | MARCH 2014 | VOLUME 11  www.nature.com/nrcardio

You might also like

140 | MARCH 2014 | VOLUME 11 www.nature.com/nrcardio

142 | MARCH 2014 | VOLUME 11 www.nature.com/nrcardio

144 | MARCH 2014 | VOLUME 11 www.nature.com/nrcardio

146 | MARCH 2014 | VOLUME 11 www.nature.com/nrcardio

148 | MARCH 2014 | VOLUME 11 www.nature.com/nrcardio

150 | MARCH 2014 | VOLUME 11 www.nature.com/nrcardio

152 | MARCH 2014 | VOLUME 11 www.nature.com/nrcardio

154 | MARCH 2014 | VOLUME 11 www.nature.com/nrcardio

156 | MARCH 2014 | VOLUME 11 www.nature.com/nrcardio