Expert Review of Hematology

ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: https://www.tandfonline.com/loi/ierr20

Thrombophilia, risk factors and prevention

Elena Campello, Luca Spiezia, Angelo Adamo & Paolo Simioni

To cite this article: Elena Campello, Luca Spiezia, Angelo Adamo & Paolo Simioni
(2019): Thrombophilia, risk factors and prevention, Expert Review of Hematology, DOI:
10.1080/17474086.2019.1583555

To link to this article: https://doi.org/10.1080/17474086.2019.1583555

Accepted author version posted online: 18

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Publisher: Taylor & Francis

Journal: Expert Review of Hematology

DOI: 10.1080/17474086.2019.1583555
Thrombophilia, risk factors and prevention
Elena Campello, Luca Spiezia, Angelo Adamo, Paolo Simioni*
Haemorrhagic and Thrombotic Diseases Unit, Department of Medicine (DIMED), Padova
University Hospital, Italy

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*Corresponding author:

Paolo Simioni,
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Haemorrhagic and Thrombotic Diseases Unit, Department of Medicine, Padova University

Hospital, Via Ospedale Civile 105, 35100 Padova, Italy
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Telephone (+39) 049 8212667

Fax (+39) 049 8212651
Email: paolo.simioni@unipd.it
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Abstract

Introduction: Fifty-three years after the first description of an inherited prothrombotic

condition (antithrombin deficiency), our knowledge on hereditary and acquired causes of

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hypercoagulability that can predispose carriers to venous thromboembolism (VTE) has

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greatly improved.

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Areas covered: Main causes of hereditary thrombophilia are summarized alongside new
prothrombotic mutations recently discovered. The main causes of acquired thrombophilia,

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and namely, antiphospholipid antibody syndrome and hyperhomocysteinemia, are also
discussed together with other common acquired prothrombotic states characterized by an
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increase of procoagulant factors and/or a decrease of natural anticoagulants. Finally,
suggestions for thromboprophylaxis in carriers of hereditary thrombophilia according to
current guidelines/evidence are made for the most challenging high-risk situations (i.e.
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surgery, pregnancy, contraception, cancer, economy class syndrome) as well as for the
prevention of post-thrombotic syndrome.
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Expert opinion: A carrier of inherited thrombophilia should be evaluated in the framework

of other (genetic and/or acquired) coexisting risk factors for first or recurrent VTE when
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assessing the need and duration of prevention (primary prophylaxis). Prevention strategies
should be tailored to each patient and every situational risk factor. The knowledge of the
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carriership status of severe thrombophilia in the proband can be important to provide

asymptomatic relatives with adequate counseling on thrombophilia screening or primary
thromboprophylaxis.
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Keywords: deep vein thrombosis, inherited and acquired thrombophilia, pregnancy,

pulmonary embolism, thromboprophylaxis, venous thromboembolism.
1. Introduction

In 1856, Virchow postulated alterations in the blood hypercoagulability as one of the

pathomechanisms that can lead to thrombosis [1]. Nowadays, the term “hypercoagulable

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state” is used as synonym of pre-thrombotic state even though the majority of patients with

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hypercoagulability will never develop thrombosis. The genetic mutations responsible for

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inherited hypercoagulability were mainly studied in families with a high incidence of
thrombotic manifestations [2]. Acquired diseases may also result in coagulation changes

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that may predispose to a thrombotic tendency. Thrombophilia may therefore be defined as
either an inherited or acquired abnormality of the haemostasis predisposing the affected
subjects to venous and/or arterial thrombosis [3, 4] (Table 1). The focus of this review is to
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evaluate the current knowledge on inherited and acquired thrombophilia and to summarize
of the main pathophysiologic pathways and prevention strategies for thrombosis.
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Anticoagulant therapy and secondary presentation in patients with thrombophilia will not
be treated.
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2. Inherited thrombophilia
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Inherited thrombophilia is a genetic propensity to develop venous thromboembolism

(VTE). The most frequent causes are the factor V Leiden and the prothrombin gene
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mutation G20210A, accounting for about 50% to 70% of the diagnosed genetic
thrombophilia. The less frequent but more severe defects of antithrombin (AT), protein C
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(PC) and protein S (PS) account for most of the remaining cases of diagnosed genetic
thrombophilia [5, 6, 7, 8]. More recently, new genetic defects responsible for severe
thrombophilia have been identified, and namely, pseudo-homozygosity for activated
protein C (APC) resistance, the hyperfunctional factor IX Padua, and the resistance to AT
[9, 10, 11]. And last but not least, ABO blood group is the most common genetic risk factor
for VTE [12]. Figure 1 summarizes known and currently diagnosed hereditary
thrombophilias. There is a large number of families (about 30-40%) with symptomatic
thrombophilia in which none of the known inherited conditions is identified. This
unexplained thrombophilia is very likely to be due to genetic mutations that are still
unknown.

2.1 Most frequent inherited thrombophilias – Factor V Leiden and prothrombin G20210A
mutations

Factor V Leiden (FVL) and prothrombin G20120A are inherited mutations resulting in the
so-called “gain-of function” for the correspondent procoagulant factors. FVL is an
autosomal dominant disorder related to a missense mutation in the F5 gene at G1691A

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which substitutes the amino acid glutamine for arginine at position 506 (R506Q) [13]. This

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missense mutation (Arg506Gln) causes factor V resistance to inactivation by APC [14].

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Several point mutations in the F5 gene causing APC resistance have been identified in
different populations, including Arg306→Thr (FV Cambridge), Arg306→Gly (FV Hong

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Kong), Ile359→Thr (FV Liverpool), Glu666→Asp (mechanism unknown), and Ala512→Val
(FV Bonn) [15, 16, 17]. Nevertheless, FVL is responsible for about 95% of cases of APC
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resistance. FVR2 (H1299R) also exhibits reduced APC cofactor activity and can cause
mild APC resistance, showing a lower thrombotic risk as compared to FVL [15, 18]. The
prothrombin mutation — G to A nucleotide change at 20210 in the 3'-untranslated region
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of the prothrombin (F2) gene (PT G20210A) — leads to an impaired F2 3’-end cleavage
signal, resulting in RNA accumulation and thus, increased prothrombin synthesis [19]. This
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mutation can increase plasma levels of prothrombin by approximately 30% in

heterozygotes and 70% in homozygotes. However, in many cases the presence of this
mutation is not associated with increased levels of prothrombin and the reverse is also
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true. PT G20210A predisposes to VTE either by promoting thrombin generation or by

inhibiting factor Va inactivation by APC, thus creating indirectly APC resistance [20, 21].
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Other still undefined mechanisms could contribute to the risk of thrombosis in carriers of
PT G20210A including other genetic lesions which could be in linkage disequilibrium with
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PT G20210A mutation. From the clinical point of view, FVL currently represents the most
common known hereditary defect predisposing to VTE: heterozygotes showed an
increased annual risk of VTE from 1 in 1,000 to 3-8 in 1,000, whereas homozygotes
exhibited an annual risk of 80 in 1,000 [22, 23]. As for PT G20210A, heterozygous carriers
present with an increased risk for VTE, with a relative risk (RR) of 2 to 3, overall slightly
lower than the risk associated with FVL [24, 25, 26]. In homozygous individuals the risk
has not clearly defined yet but in a recent study a RR of 5 (95% CI 2.1–11.92) was shown
compared to non-carriers [25]. Interestingly enough, carriers of both mutations (double
heterozygous for FVL and prothrombin mutation) have been reported to present with a six-
time higher VTE risk than their non-carrier relatives, even though a recent meta-analysis
found the risk of double heterozygosity to be similar to that observed in FVL alone [27, 28].
These discrepancies may be related mainly to the selection of the populations and to
different study design.

2.2 Most severe inherited thrombophilia – loss-of-function of endogenous anticoagulants

Antithrombin is one of the most important natural anticoagulants of the coagulation system
that inhibits several activated factors including thrombin, factor IXa, Xa, XIa and XIIa.

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Heterozygous mutations in the AT gene can result in AT defects that are characterized by

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reduced inhibition of factor Xa and thrombin and, as a consequence, by increased

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thrombin generation and activity [2]. More than 250 genetic lesions have been identified in
patients with AT defects, including missense and nonsense point mutations, small or large

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insertions and deletions [29]. The two more common types of defects are the so-called
“Type I”, a quantitative defect resulting in a decreased synthesis of a functional protein;
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and Type II, a qualitative defect with normal levels of an abnormal protein with impaired
functional activity. Type II is further divided into three subtypes related to impair binding to
the enzyme reactive sites; subtype IIb is due to mutations in the heparin-binding sites;
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subtype IIc is characterized by pleiotropic defects affecting both antigen concentration and
heparin binding site or binding to enzyme reactive sites [29, 30]. Cases of homozygous AT
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defects were rarely reported so far mainly involving the heparin-binding site, indicating that
homozygosity for type I or other type II subtypes is associated with embryonic lethality [31,
32]. The absolute risk of a first VTE in asymptomatic carriers of AT deficiency belonging to
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families with a symptomatic proband is approximately 2% per year [26, 30]. A large
population-based study showed that AT deficiency was associated with a five-fold (95% CI
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0.7– 34) increased risk of a first episode of deep venous thrombosis [33].

Protein C and protein S are vitamin K-dependent glycoproteins synthesized in the liver.
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The activated form of protein C (APC) is an important natural anticoagulant that, along with
its co-factor PS, decreases thrombin generation by inhibiting factors Va and VIIIa [34].
Therefore, inherited deficiencies of each of the two determine increased thrombin
generation and predisposition to thrombosis. Protein C deficiency is inherited as an
autosomal dominant trait, and is classified into type I (quantitative) and type II (qualitative)
defects [4, 35]. Unlike AT deficiency, homozygous or double heterozygous PC deficiency
does not determine fetal death, but newborns with these severe thrombophilic conditions
may develop purpura fulminans characterized by severe thrombosis of small dermal
vessels, resulting in the ischaemic necrosis of extremities [36]. More than 200 mutations,
mostly missense, in the PC gene (PROC) have been described so far responsible for the
different types of defects [37].

Protein S circulates in a free form (~40%) or bound to complement C4b-binding protein

(~60%). Bound protein S has no protein C co-factor activity [38]. Inherited PS deficiency
has been classified as type I (low plasma levels of total and free antigen as well as
reduced functional activity), type II (normal plasma levels of total and free antigen and

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reduced functional activity; or dysfunctional PS), and type III (normal or near normal

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plasma levels of total antigen and reduced free antigen and functional activity) [2, 4]. More
than 200 different mutations in the PROS1 gene responsible for PS defects have been

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identified, mostly being missense mutations or short deletions or insertions [4]. From the

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clinical point of view, heterozygous PC deficiency is associated with a 4- to 6.5-fold
increased risk of VTE, while homozygous deficiency results in severe thrombotic
complications in the foetus, neonates or children, as mentioned previously [26]. The risk of
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VTE associated with PS deficiency is still a matter of debate: family studies have
suggested a risk comparable to that observed in PC deficiency, but population studies
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suggest a lower risk [26]. As in PC deficiency, homozygous PS deficiency may cause
severe purpura fulminans in neonates.
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2.3 ABO blood group

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Non-O blood group can be considered the most frequent genetic risk factor associated
with VTE. The prothrombotic effect is probably carried by increased levels of von
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Willebrand factor (VWF) and factor VIII, as mean levels of these factors are ~25% higher
in individuals with non-O blood groups than in those with O-blood group [39]. The
underlying mechanism for high VWF levels is the addition of A and B antigens to the
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specific H oligosaccharides of VWF by means of glycosyltransferase enzymes, resulting in

increased plasma levels of this protein. Additionally, changes in the sugar composition of
VWF due to different ABO alleles affect the rate of cleavage by the VWF-cleaving protease
ADAMTS-13 [40]. However, other factors might also be involved, since non-O blood
groups remained significantly associated with the risk of VTE even after adjustment for
factor VIIII levels [4]. Many clinical trials have previously documented a higher risk of VTE
in non-O blood subjects. Wu and colleagues performed a meta-analysis which selected
4709 VTE cases from 21 studies, and found an OR of 1.79 (95% confidence interval [CI]
1.56-0.05) in non-O versus O status [12]. A further meta-analysis considering 38 studies,
hence 10,305 VTE cases, reported that non-O blood groups increase approximately
twofold the risk of VTE (OR 2.08; 95%CI 1.83–2.37) [41]. Furthermore, the hazard of VTE
in individuals with hereditary thrombophilia and with non-O blood groups is up to 23.2-fold
higher than that observed in those without thrombophilia and with O blood group [42].

2.4 Novel gain-of-function mechanisms

It can happen that heterozygous FVL carriers present with a concomitant heterozygous F5

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gene mutation responsible for FV deficiency, resulting in the 50% of FV plasma levels

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being all FVL. This is the case of the so-called pseudo-homozygous FVL which show a

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severe APC resistance and a stronger tendency towards thrombosis as compared to
heterozygous FVL alone [9]. In pseudo-homozygotes, APC-resistance levels are

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consistent with homozygosity though DNA testing shows heterozygous FVL. This
discrepancy between the genotype (heterozygous FVL) and the laboratory (severe APC
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resistance) or clinical phenotypes (severe thrombotic tendency) should prompt further
analyses to exclude the presence of pseudo-homozygosity. Indeed, the thrombotic risk in
pseudo-homozygous patients is as high as that observed in homozygous individuals [43].
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High plasma levels of procoagulants, such as factor VIII, IX, X, XI, and fibrinogen can
increase the risk of VTE and should therefore be included among the gain-of-function
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thrombophilia abnormalities [4]. However, the genetic basis behind elevated levels of
these procoagulants is only partially known. The extent of the increased risk of VTE
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ranges from 1.6-fold for plasma factor X levels >90th percentile, to fourfold for a fibrinogen
level >5.0 g/l [4]. More specifically, individuals with sustained elevations of factor VIII (i.e.
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serum concentrations ≥150 IU/dL) have a reported RR of VTE 5 times that observed in
those with levels <100 IU/dL [44]. The same FVIII elevation found among first-degree
relatives could indicate a hereditary transmission. A genetic polymorphism in the low-
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density lipoprotein receptor-related protein 1 (LRP1 663C>T) has been showed to be

associated with high levels of factor VIII. The carriers had a 3-fold enhanced VTE risk
regardless of other prothrombotic risk factors [45]. Moreover, the gene polymorphism
encoding the B-domain substitution Asp1241Glu in the F8 gene (92714C>G) has been
reported to be associated with elevated factor VIII levels [46].

Levels of FIX antigen >129 U/dl are associated with a 2.3-fold increased risk of VTE
(95%CI, 1.6-3.5) [47]. Factor IX Malmö is an A>G sequence variant (rs6048) in the F9
gene associated with VTE, although the prothrombotic mechanism remains unknown [48].
Factor IX Padua is a gain-of-function mutation in the F9 gene (R338L) discovered by our
group, which was detected in some components of a single family symptomatic for VTE
and carrying extremely high plasma factor IX activity (eight times the normal levels)
contrasting with normal antigen levels [10]. The mutation has not been reported in other
cohorts of patients with VTE so far [49].

Elevations of factor XI >90th percentile were found to be an independent risk factor for VTE
with a 2-fold increased risk [50]. No genetic mutations responsible for increased FXI levels

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have been identified so far.

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A novel gain-of-function mechanism defined as “resistance to antithrombin” has been

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identified in families with thrombophilia. The molecular basis is a missense mutation at the
prothrombin Arg596 residue (exon 14) leading to a defect of thrombin–antithrombin

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binding and impaired inhibition by AT of the mutated thrombin [51]. The first prothrombin
mutation causing antithrombin-resistance was reported in 2012 (Prothrombin Yukuhashi)
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[51]. Subsequently, similar cases were recorded in Serbia, India and Italy [52, 53, 54]. The
five families carry three different mutations on the same Arginine 596, and namely:
Prothrombin Yukuhashi Arg596Leu [51], Prothrombin Belgrade and Amrita Arg596Gln [52,
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54] and Prothrombin Padua 2, Arg596Trp [53]. Point mutations of prothrombin Arg596
have been identified in several thrombotic patients of different race and ethnicity
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worldwide. However, the real incidence of these mutations and the associated thrombotic
risk have not been clearly defined yet. It is worth mentioning that these novel hereditary
mechanisms of thrombophilia are rare and currently do not affect much the clinical
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practice. However, clinicians should think even to these novel mutations or to other new
potential genetic mechanisms when approaching patients or families with unexplained
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history of recurrent VTE.

3. Acquired thrombophilia
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The term thrombophilia also includes the hypercoagulable states caused by acquired
disorders of haemostasis. Acquired disorders can foster a prothrombotic state via elevated
procoagulant factors, reduced anticoagulants, pro-inflammtory/autoimmune mechanisms,
as well as multiple alterations in homeostatic regulation of blood coagulation. The main
acquired disorders associated to thrombophilia are antiphospholipid antibody syndrome,
hyperomocisteinaemia, transiently/permanently increased levels of procoagulant factors,
and finally, decreased levels of natural anticoagulants.
3.1 Antiphospholipid antibody syndrome

The antiphospholipid antibody syndrome (APS) is an immune-mediated disease

characterized by thrombotic and/or obstetrical events [55]. Thrombotic APS is
characterized by venous, arterial, or microcirculation thrombosis; whereas obstetrical APS
is determined by foetal loss after the 10th week of gestation, recurrent early miscarriages,
intrauterine growth restriction, or severe preeclampsia. This disease is caused by
antibodies directed against membrane anionic phospholipids (i.e. antiphospholipids

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antibodies [aPL], mainly anticardiolipin and antiphosphatidylserine antibodies) or their

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associated plasma proteins, mainly beta-2 glycoprotein I (β2GPI), or the presence of a
lupus anticoagulant (LAC). A diagnosis of APS is made if at least one of the above

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mentioned clinical manifestations occurs and at least one of the laboratory antibodies is

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identified in two or more occasions [56]. The main prothrombotic mechanism in APS
involves the binding of aPL to β2GPI on cellular surfaces leading to the following
consequences: i) up-regulation of the expression of potentially prothrombotic adhesion
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molecules on the cell-surface (e.g. E-selectin, tissue factor); ii) down-regulation of tissue
factor pathway inhibitor activity; iii) impairment of APC activity; iv); hypofibrinolysis (via
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reduction of tissue plasminogen activator-tPA activity); v) complement activation [55, 57].
The risk of a first VTE among asymptomatic subjects who are positive for LAC,
anticardiolipin, and anti–β2GPI antibodies — so-called triple positive patients — is 5.3%
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per year. Importantly, 44% of triple positive APS patients will undergo recurrent thrombosis
over a 10-year follow-up period (notwithstanding anticoagulant therapy) [58].
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3.2 Hyperhomocysteinaemia
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The amino acid homocysteine is formed from the demethylation of methionine and its
plasma levels depend on two main mechanisms: remethylation to methionine (by
methionine synthase which requires both vitamin B12 and N5-methyltetrahydrofolate
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reductase activity) or trans-sulphuration to cysteine (by cystathionine β-synthase which

requires vitamin B6) [3]. Both genetic and acquired factors concur to plasma homocysteine
levels. Genetic factors include mutations in the N5-methyltetrahydrofolate reductase
(thermolabile variant of MTHFR) and cystathionine β-synthase genes. On the other hand,
acquired conditions comprise deficiencies of folate, vitamin B12 or B6, hypothyroidism,
psoriasis, chronic renal failure, inflammatory bowel diseases, rheumatoid arthritis, organ
transplantation, antifolate drugs (e.g. anticonvulsants, l-dopa, niacin, methotrexate,
thiazides, and cyclosporine A), or B12 antagonists (e.g. nitrous oxide). Acquired moderate
hyperhomocysteinaemia may also stem from lifestyle risk factors, such as physical
inactivity, smoking, coffee consumption, and physiologic variables (increasing age,
postmenopausal status, and male gender). Hyperhomocysteinaemia is associated with a
mildly increased risk of atherosclerosis, arterial occlusive disorders and VTE [59]. A meta-
analysis showed that hyperhomocysteinaemia correlates with an estimated 2.9-fold
increased risk of VTE [60]. The degree of inheritance of hyperhomocysteinaemia is low,
suggesting a bigger role for environmental causes [61]. As the matter of fact, the
presence of the thermolabile variant of MTHFR in the absence of hyperhomocysteinaemia,

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is not associated with an increased risk of thrombosis [61].

3.3 Acquired high levels of coagulation factors and anticoagulants deficiency

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The levels of pro- and anticoagulant factors are genetically controlled though they can be

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influenced by age and acquired conditions, and mostly inflammation [3]. Indeed, the
majority of the acquired risk factors for thrombosis — surgery, trauma, acute medical
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conditions, inflammation, malignancy and myeloproliferative disorders, obesity — are
characterized by elevated levels of procoagulant factors, particularly factor VIII. Moreover,
acquired risk factors for thrombosis, and namely pregnancy, hormonal therapy, cancer,
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nephrotic syndrome are also associated with reduced anticoagulant factors levels. Table 2
summarizes the risks of VTE in acquired thrombophilic conditions while showcasing the
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trend of pro- and anticoagulant factors levels. Particularly, the hypercoagulability observed
in pregnancy is due to increased levels of VWF, fibrinogen, factors VII, VIII, X; decreased
PS and acquired APC resistance [62]. The mechanism underlying hypercoagulability in
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cancer is quite complex [63, 64]. Briefly, tissue factor is highly expressed in tumor cells;
activated platelets release procoagulant microvesicles (MV) providing a procoagulant
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surface; natural anticoagulants levels are also frequently reduced. VTE is a frequent
leading cause of death in cancer, and occurs in about 20% of all cases [62].
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Myeloproliferative neoplasms have a high incidence of both venous (10%) and arterial
thrombotic complications (3%). The main causes of hypercoagulability are the following:
endothelial dysfunction, leukocytosis, vascular cell activation, high platelet-induced
thrombin generation, decreased levels of PS (possibly due to absorption on the expanded
blood cell surfaces) and acquired APC resistance, as well as elevated plasma viscosity
[65].

4. Prevention in hereditary thrombophilia

Each of the aforementioned thrombophilic traits contributes to increasing the thrombotic
risk; it is higher in patients with AT, PC, PS deficiencies, homozygous FVL or PT 20210A,
or concomitant alterations (severe thrombophilia) than in heterozygotes for FVL or PT
20210A (mild thrombophilia). Overall, hereditary thrombophilia reportedly increases the
RR of VTE by a factor of ~ 4 to 30. The highest incidence of 0.9–4.0 per 100 person-years
is observed in carriers of AT deficiency [3, 4], with the exception of type II heparin binding
site defects featured by reduced probability of developing VTE unless homozygous defects
are present. Conversely, mild thrombophilia confers a 2- to 7-fold increased risk of VTE

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(0.14–0.67 per 100 person-years for FVL; 0.05–0.42 per 100 person-years for prothrombin
mutation) [3, 4]. Interestingly, low borderline levels of AT, PC, and PS also have been

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associated with a twofold increased risk of VTE, comparable with that of mild
thrombophilia [66].

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VTE can be considered like a double- or triple-hit process, which means a single risk factor
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(e.g., heterozygous FVL) will provide an element of risk that is unlikely to singlehandedly
cause thrombosis, but an additional risk factor (e.g., surgery) may provide the trigger for
overt thrombosis to occur [67]. Indeed, carriers may remain asymptomatic for many years,
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suggesting that the development of VTE may require further triggering factors. In family
studies conducted on carriers of natural anticoagulants deficiencies, about half of
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thrombotic events were triggered by a concomitant acquired risk factor [4]. Thus,
interactions between genetic and acquired risk factors should be considered to determine
the overall prothrombotic profile of patients.
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Indeed, the incidence of VTE in patients with AT, PC, or PS defects with exposure to
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acquired risk factors is estimated to be 1.2–8.1 per 100 person-years, whereas said
incidence in mild thrombophilia is much lower during exposure to acquired risk factors,
around 0.2-2.3 per 100 person-years [2]. First of all, a positive familial history of VTE is
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“per se” a strong risk factor for VTE and should be always taken into consideration when
evaluating a patient’s thrombotic risk. The second element is age; in fact, in family cohort
studies, carriers of AT, PC, or PS defects, exhibited VTE at a younger age (median 29
years) than those with FVL or PT G20210A (median 40 years) [44, 68]. Recent findings
from our group showed that circulating MVs may also concur to the occurrence of VTE in
hereditary thrombophilic carriers — both in mild and severe states — as well as in APS
[69, 70, 71]. Circulating MVs, which may constitute an epiphenomenon of the
thrombophilic state itself, could be up-regulated in acute conditions thus enhancing the
overall hypercoagulable state up to the threshold of VTE occurrence [69, 70, 71].
Surgery, immobilization, and pregnancy are some of the additional risk factors for
thrombosis that may prompt to consider thromboprophylaxis in patients with hereditary
thrombophilia. Here, we summarize the latest evidence on prevention of VTE in
thrombophilia patients in the most common high-risk situations.

5. Prevention of surgery- related VTE

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Because of the risk of bleeding complications that can occur during thromboprophylaxis,
the risk-benefit ratio of antithrombotic therapy as primary prevention for surgery-related

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VTE in at-risk patients need to be carefully assessed. In 2012, the American College of
Chest Physicians (ACCP) Guidelines suggest the use of thromboprophylaxis with low-

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molecular-weight heparin (LMWH) after general and abdominal-pelvic surgery in patients
at moderate risk for VTE (~3.0%; Caprini score 3-4) who did not present with a high risk for
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major bleeding [72]. The Caprini Scoring system is a tool to identify patients at increased
postoperative risk for VTE [73]. Interestingly enough, 3 points were assigned to the
presence of FVL or PT G20201A, LAC, elevated anticardiolipin antibodies, elevated serum
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homocysteine, or other congenital or acquired thrombophilia. Accordingly, pharmacological

thromboprophylaxis could be indicated in patients otherwise considered at low risk for VTE
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[74]. Interestingly, a positive family history of VTE represents itself an additional risk factor
(3 points in Caprini score), irrespective of a confirmed thrombophilic state. Thus, the
detection of inherited thrombophilia is not likely to make a significant contribution to the
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stratification of the risk if family history of VTE is already present. Likewise, there is still no
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evidence that modality and duration of thromboprophylaxis should be different in subjects

with or without inherited thrombophilia. It is worth mentioning however, that some authors
empirically recommend higher doses of heparin (whichever formulation) in AT-deficient
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patients, potentially at risk of heparin resistance, and a longer duration of postoperative

prophylaxis because of the presence of the severe thrombophilic defect [75]. Similarly,
data gathered from case reports suggest replacement therapy using AT concentrates [30]
to maintain AT plasma levels closer to normal. Clark et al. [76] described the successful
management of 3 patients with AT deficiency undergone coronary artery bypass surgery
using a preoperative loading dose of AT on the evening before surgery, followed by
reduced doses for 5 to 7 days postoperatively. In addition, all patients received
postoperative heparin and no thrombotic complications occurred [76]. Moreover, AT
replacement therapy could be given when the use of standard thromboprophylaxis is
precluded by a high risk of bleeding or in patients at highest risk of VTE (e.g., orthopedic
or abdominal/pelvic cancer surgeries) carrying hereditary AT deficiency, although either
doses or duration of replacement therapy are still undefined [75, 77]. The use of plasma-
derived protein C concentrates has also been suggested in patients with (severe) PC
deficiency undergoing surgery [78].
The ACCP guidelines suggest the use of mechanical prophylaxis (i.e. elastic stockings or
intermittent pneumatic compression) in addition to pharmacological prophylaxis after

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general and abdominal-pelvic surgery in individuals at high risk for VTE (~6.0%; Caprini
score ≥5). [72].

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6. Prevention of pregnancy-related VTE
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Decisions whether using of prophylactic anticoagulation during pregnancy to prevent VTE
depend on the benefit-risk ratio. The rate of clinically relevant maternal bleeding due to the
LMWH use is about 2%, mainly associated with the delivery (1%) or wound haematoma
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(0.6%) [79]. On the other hand, in a systematic review of 9 case-control studies (n=2526
patients) considering the association between thrombophilia and pregnancy-associated
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VTE, the highest risk was associated to homozygous FVL or PTG20201A [80].
Deficiencies of AT, PC, and PS were associated with moderate risk increases, while
pregnant women with mild thrombophilias presented with a lower risk of VTE. Considering
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a basal incidence of VTE complications during pregnancy of about 1/1000 deliveries, the
calculated absolute risks suggest a low prothrombotic profile (0.5–1.2% of affected
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pregnancies) for most inherited thrombophilias, except homozygotes for FVL or PT

G20201A where the risk estimate increases to approximately 4% [81]. Needless to say,
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this observation can be influenced by the prevalence of thrombophilic defects which is

higher for the less severe thrombophilic conditions and lower for the more severe defects.
Interestingly, a positive family history of VTE confers a two- to four-fold increased risk for
VTE, depending on the number of symptomatic relatives, while thrombophilic women with
asymptomatic family have a lower risk of VTE [81]. Regarding acquired thrombophilias,
although less studied, repeated aPL positivity is associated with an increased risk of VTE
[82]. The risk of pregnancy-related VTE in women with aPL and without previous VTE is
uncertain. It is worth mentioning that thrombophilia screening is not recommended as a
routine initial test in pregnancy or as prenatal/newborn screening; however women should
undergo an individualized VTE risk profile assessment both prior to pregnancy, as well as
once pregnancy is achieved and throughout pregnancy as soon as new clinical situations
arise [81].

In summary, pregnant women with asymptomatic inherited thrombophilia have a

significantly increased risk of VTE particularly if they have a positive family history of VTE
or severe thrombophilia (i.e. homozygous FVL or PTG20201A, double heterozigosity,
natural anticoagulant defects). Most guidelines recommend antenatal LMWH prophylaxis

t
in those cases [4, 81, 83, 84, 85]. Conversely, antenatal clinical surveillance is believed to

ip
be sufficient for pregnant women with mild thrombophilia, and clinicians should consider
antenatal LMWH prophylaxis only in the presence of additional risk factors (positive family

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history, hypo mobility, obesity, age >35 years, gross varicose veins) [4]. As for post-

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partum, antithrombotic LMWH prophylaxis is recommended for 4-6 weeks in carriers of
severe thrombophilia. The same is true of mild thrombophilia, even though data are
inconsistent, with antithrombotic prophylaxis ranging from at least 7 days to up to 6 weeks
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post-partum but only for women carrying additional risk factors [4]. ACCP guidelines are
more restrictive in thromboporophylaxis indications pointing out the positive family history
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more than the carriership of thrombophilia [86]. When the decision is made to use
antepartum prophylaxis, it should be initiated early in the pregnancy. Finally, prophylaxis is
recommended after caesarean delivery in case of a known thrombophilia. As for AT
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deficiency, it has been recommended that AT concentrate be administered prior to delivery

and during post-partum if the expectant mother recently experienced an acute VTE event
pt

or has a history of VTE. Indeed, it was reported that in AT-deficient patients with recent or
recurrent thrombosis, the administration of AT during labor successfully prevented
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thrombotic recurrences; this is a period during which administration of anticoagulation may

be dangerous [30].
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7. Prevention of VTE induced by oestrogen–progestogen therapies

Combined oral contraceptives (COC) therapy can increase the risk of VTE by two to
ninefold. This is due both to the dose of oestrogen and the type of progestogen contained
in the preparations. The so called “third-generation pills” containing desogestrel or
gestodene are associated with a twofold increased risk of VTE compared to levonorgestrel
(present in the “second-generation” pills) [87]. Additionally, the most recent “fourth-
generation” type of COC containing progestins such as drospirenone, nomegestrol acetate
or dienogest present with 3-fold increased risk of VTE compared to the second-generation
pills [88]. A multiplicative effect of COC use and inherited thrombophilia on the risk of VTE
was observed, with a two to fivefold increase in women with both risk factors versus either
risk factor considered individually [89]. Interestingly, a recent study on pre-menopausal
women showed a statistically significant interaction between COC use and presence of
FVL on VTE risk (OR 1.37, 95%CI 1.06–1.77). This interaction appeared higher for
drospirenone (OR 1.99 [95%CI 1.18–3.38]) or third-generation cyproterone acetate users
(OR 1.71 [95%CI 1.20–2.45]), but not significant for 1st or 2nd COC users [90]. Recently,
WHO Medical Eligibility Criteria confirmed that COC use in women with hereditary

t
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thrombophilias is associated with an unacceptable health (life threatening) risk [91]. A
recent meta-analysis regarding 12 case–control and three cohort studies showed that mild

cr
thrombophilia increased the risk of VTE in COC users by 6-fold (RR 5.89; 95%CI 4.21–
8.23) (14 studies considered), while the presence of severe thrombophilia enhanced the

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risk in COC users by approximately 7-fold (RR 7.15; 95%CI 2.93–17.45) (3 studies
considered) [89]. VTE incidence in COC users with mild thrombophilia was 0.49 (95%CI
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0.18–1.07) to 2.0 (0.3–7.2) per 100 pill-years; it was 0.86 (95%CI, 0.10–3.11) per 100 pill-
years in COC users double heterozygous or homozygous for FVL or PT G20201A and 4.3
(95%CI 1.4–9.7) to 4.62 (95%CI 2.5–7.9) per 100 pill-years in COC users who were
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carriers of AT, PC or PS defects. These results confirm that COC should not be
administered to women with severe hereditary thrombophilia, including asymptomatic
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women. Possible options with similar contraceptive efficacy include progestogen-only pills,
intrauterine devices (IUDs) containing only levonorgestrel and Cu-IUDs containing at least
300 mm2 Cu [89]. Thrombophilia screening is not generally recommended before the use
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of oral contraceptives/hormone replacement therapy/other selective estrogen receptor

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modulators, as it is not cost-effective and may increase patient anxiety. However, a

clinician should bear in mind that screening and identification of asymptomatic women who
are family members of symptomatic carriers of thrombophilia (particularly severe
Ac

thrombophilia) before prescribing oral contraceptives can be beneficial. By contrast, the

additive VTE risk of oral contraceptives in mild thrombophilia is maintained to be modest.
In women with known mild thrombophilia, detailed counseling on all contraceptive options
is strongly recommended to supply them all the elements to decide whether the increased
risk of VTE related to oral contraceptives use, albeit modest, is balanced by the benefit
coming from the chosen strategy. In the absence of other risk factors — family history,
body mass index, others — COCs are often prescribed in asymptomatic carriers of mild
thrombophilia when reliable alternative contraceptives are refused/not tolerated, bearing
also in mind that in these patients the risk of pregnancy-related VTE outweighs the COC-
associated VTE risk. In such cases, COCs with the lowest prothrombotic profile are
recommended as the first choice (i.e. levonorgestrel, norgestimate- or norethisterone-
containing COCs with a low ethinylestradiol amount [≤35 micrograms]). As far as
thrombophilia screening is concerned, it is generally not recommended to test
asymptomatic women from families with known mild thrombophilia [92] but a clear
evidence on the benefit-risk ratio of such an approach is still lacking . As a consequence, it
is recommended to fully inform those women on the implications of screening so that they

t
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can knowingly decide whether or not to be tested.

8. Prevention of cancer-associated thrombosis

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A few studies evaluating the role of FVL and PT G20210A on the risk of cancer-associated

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thrombosis have been published [93]. Overall, despite conflicting results, it would appear
that cancer patients carrying either of these mutations tend to show an increase risk of
an
thrombosis. In a case–control study by Blom et al. [94] on 205 adult cancer patients, the
risk of VTE was 2-fold higher in patients with than those without FVL (adjusted OR: 2.2
[95%CI 0.3-17.8]). Moreover, patients with cancer and PT G20210A had an OR for VTE of
M
4.1 (95%CI 0.3-60.8) compared with those without mutation. In a study by a Turkish group,
the prevalence of FVL was significantly higher (30.2%) in cancer patients with VTE
ed

compared to those without VTE (3.7%, p <0.001) [95], while no significant difference in the
prevalence of PT G20210A was observed. Particularly, patients with cancer and central
venous catheters (CVC) who had inherited thrombophilia showed increased risk of VTE. In
pt

a meta-analysis by Dentali et al. [96] including 10 studies (211 cases and 860 controls)
increased risk of CVC-related thrombosis in carriers of FVL [OR 4.6 (95%CI 2.6-8.1)] and
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PT G20210A [OR 4.9 (95%CI 1.7-14.3)], respectively was shown. The measured
attributable risk of CVC-related thrombosis was 13.1% and 4.5% for FVL and PT
Ac

G20210A, respectively. In carriers with FVL receiving allogeneic bone marrow

transplantation, the risk of CVC-associated thrombosis was increased by 7-fold
independently of the administration of thromboprophylaxis [95]. Similar data were obtained
in FVL carriers affected by breast cancer [97]. Furthermore, in women with FVL,
thrombotic events occurred mainly during the first 6 months of adjuvant therapy with
tamoxifen [22]. In a cohort of 175 patients with gastrointestinal adenocarcinoma, 17.9% of
the patients with VTE were heterozygotes for FVL versus 4.8% of those without VTE (p =
.026, OR 4.4), whereas heterozygosity for PT G20210A did not affect the incidence of
thrombosis [22]. More recently, FVL was found to be associated with the occurrence of
VTE in metastatic colorectal cancer treated with first-line chemotherapy plus bevacizumab
(only at univariate analysis) [98]. No specific association between AT, PC, and PS
hereditary deficiencies and cancer-associated thrombosis has been described so far, with
the only exception of children with acute lymphoblastic leukemia (ALL). In a meta-analysis
performed by Caruso et al. [99] based on 17 prospective studies and 1,752 children with
ALL, the rate of VTE was 5.2%. Thrombophilia (FVL, PTG20210A, MTHFR genotype,
elevated lipoprotein, deficiencies of PC, PS, AT,) was evaluated in 557 children (5 studies)
out of 1,752 and the thrombotic risk in ALL patients with thrombophilia rose up

t
ip
approximately 8-fold (RR 8.5, 95%CI 4.4–17.4). Even though data are still limited, it
appears that thrombophilia could increase the risk of cancer-associated thrombosis.

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However, inherited thrombophilia testing is not currently recommended in the strategies of
prophylaxis and treatment of VTE in cancer patients.

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9. Prevention of economy class syndrome
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The ‘economy class syndrome’ is defined as the occurrence of thrombotic complications
during long-haul flights that manifest mainly in passengers travelling in economy class. In
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normal healthy individuals the estimated absolute risk of VTE on flights lasting more than 4
h was about 1 in 6000 [100]. In a meta-analysis [101] of 14 studies including 4055 cases of
ed

VTE occurred during both air and overland trips lasting up to 8 h and with a follow-up time
post-journey ranging from two to eight weeks, the overall RR of VTE was 2.8 [95%CI 2.2–
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3.7] with an approximate 18% increase in the risk at each increment of 2 h in travel time.
This risk increased up to 26% if only air travels were considered. In travellers with
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thrombophilia, the risk of VTE was 16.8 times higher (95%CI 3.8–74.7) than in non-
thrombophilic, non-travelers, accounting for a synergistic interaction [102]. In the case of
thrombophilia, antithrombotic measures are of paramount importance. Travellers should
Ac

be informed of the potential thrombotic risks, encouraged to exercise regularly with short
walks along the aisles, and avoid dehydration [100]. The Aerospace Medical Association
(AsMA) published guidelines on optimal antithrombotic prophylaxis in subjects who travel
by air and patients with known thrombophilia is considered at high risk for thrombosis
[103]. Recommendations for travellers with high thrombotic risk on flights lasting over 8 h
are: avoidance of constrictive clothing around the lower extremities or waist; adequate
hydration; repeated calf muscle contraction. A perceived higher risk of VTE may prompt
active thromboprophylaxis measures such as properly fitted below-knee compressive
stockings (15-30 mmHg of pressure at the ankle) or a single prophylactic dose of LWMH,
injected prior to departure.

10. Prevention of post-thrombotic syndrome

Post-thrombotic syndrome (PTS), the most common chronic complication of deep vein
thrombosis (DVT), causes chronic limb pain, swelling and leg ulcers, which reduces the
quality of life of affected patients [104]. Previous studies reported that 20–50% of patients
with DVTs developed PTS [104]. A study by our group considering 191 patients with

t
thrombophilia and 339 without, showed that the adjusted HR for the development of PTS

ip
in thrombophilic versus non-thrombophilic patients was 1.23 (95%CI, 0.92–1.64) [42].

cr
Specifically, the adjusted HR for the development of PTS in carriers was 0.42 (95%CI,
0.20–0.88; P = 0.02) for FVL, 0.81 (0.36–1.37) for LAC, 0.96 (0.29–3.82) for PC

us
deficiency, 1.08 (0.29–2.70) for PS deficiency, and 1.33 (0.68–2.58) for PT G20210A. Of
the two patients with AT deficiency, neither developed PTS. A meta-analysis by
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Rabinovich et al. [105] considered 16 studies (13 assessing FVL, 10 PT G20210A, 5 PC
and PS deficiencies, 3 AT deficiency, 4 elevated FVIII, and 6 aPL). The Authors confirmed
that none of the studies acknowledged any of the thrombophilias as predictive of PTS.
M
Unexpectedly, FVL and PT G20210A even appeared to protect against PTS in studies
including patients with first and recurrent DVT events, and studies in which over 50% of
ed

patients had an unprovoked event. A very recent Japanese Registry gathered data on
1218 patients with DVT who completed 3 years of follow-up [104]. The Authors showed
that chronic kidney disease (OR 2.21, 95% CI 1.45–3.39), leg swelling (OR 4.15, 95%CI
pt

2.25–7.66), no transient risk factors for VTE (OR 2.39, 95%CI 1.55–3.67), active cancer
(OR 3.66, 95%CI 2.30–5.84), and thrombophilia (OR 2.07, 95%CI 1.06–4.04) were
ce

independent risk factors for the development of PTS. Patients with thrombophilia were 79
(6.1%) and, interestingly, they considered only severe thrombophilia (APS; PC, PS and AT
Ac

deficiencies). This is the only study where severe thrombophilia appears to be associated
with the development of PTS. At the moment, the association between thrombophilia and
PTS is not deemed important enough to warrant a thrombophilia screening or different
secondary prophylaxis strategies in thrombophilic carriers. Needless to say, this
conclusion is based on low levels of evidence due to the lack of properly designed studies.
Finally, a recent study by our group suggested that non-O blood type might be a risk factor
for the development of PTS, as individuals with non-O blood group were associated with a
significantly higher PTS occurrence (HR 1.53, 95% CI, 1.05–2.24; p = 0.028) than O group
[106]. Although larger studies are needed to confirm our results, blood group might be an
additional element to take into account in the evaluation of the strategies to prevent PTS.

11. Expert Opinion

Fifty-three years following the first description of a hereditary prothrombotic condition (AT
deficiency) we have greatly increased our knowledge on both hereditary and acquired
causes of hypercoagulability which can temporary or long-life predispose carriers to VTE.

t
Focusing on hereditary thrombophilia, currently available data uncovered a thrombotic risk

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gradient from carriers of natural anticoagulant deficiencies and in the presence of

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homozygous defects or multiple abnormalities (severe thrombophilia) to heterozygotes for
FVL and prothrombin G20210A (mild thrombophilia). Additionally, novel prothrombotic

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hereditary conditions have been recently described and the thrombotic risk conferred by
them is still unknown. Among the most common acquired prothromboitc conditions,
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clinicians have to consider APS and hyperhomocisteinaemia, as well as all the conditions
characterized by a temporary acquired increase in procoagulant and/or decrease in
anticoagulant factors. Importantly, the management of a patient with a thrombophilic
M
condition should take into consideration other (genetic and/or acquired) coexisting risk
factors for first or recurrent VTE in order to determine the necessity and duration of
ed

prevention (primary prophylaxis). The main role of the clinicians is to individualize case-by-
case the approach for the prevention of VTE and consider each patient’s risk taking into
account strong situational risk factors (e.g., surgery, pregnancy, therapies, etc.). Notably,
pt

the susceptibility to VTE is modulated by the presence or absence of a family history of

VTE, thus family history plays an important role in the evaluation of a patient’s risk profile.
ce

In addition, the knowledge of the carriership status of the so-called severe thrombophilia
can be important to properly counsel asymptomatic relatives — particularly women of
Ac

childbearing age — on thrombophilia screening or primary prophylaxis. Finally, there is no

consensus on some hot-topic issues such as care of fertile-age women to date. In these
situations, counseling by qualified clinicians addressing the associated risks-benefit ratio
and the available prevention strategies are strongly suggested in order to provide these
women an aware choice.

Novel severe thrombophilic conditions have been identified in the last few years, and
namely, factor IX Padua [10], prothrombin Yukuhashi [52], prothrombin Belgrade [52],
prothrombin Amrita [54], and prothrombin Padua 2 [53]. Even more new genetic defects
predisposing to thrombosis are likely to be discovered soon. The discovery of novel
genetic mutations undoubtedly opens new doors to understanding the mechanisms of
thrombosis. Studies on thrombophilia need to be conducted anew, taking into account a
more thorough evaluation and definition of thrombophilia. Granted, we now possess a
wealth of knowledge as it pertains to the slight impact of mild thrombophilias on the overall
thrombotic risk; nevertheless, there are still areas of doubt and uncertainty regarding
severe and novel thrombophilia. Future research projects should focus on identifying novel
thrombophilic factors in order to explain (and possibly prevent) more cases of unprovoked

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thrombosis, and to clarify the molecular mechanisms underlying the complex interaction
between genetic and environmental risk factors for thrombosis. Finally, the more favorable

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safety and efficacy profiles of direct oral anticoagulants recently introduced in clinical
practice should be considered in the light of future strategies for prevention and treatment

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of VTE in patients with inherited or acquired thrombophilia.

Article Highlights
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• Thrombophilia is a clinical condition defined as either an inherited or acquired
abnormality of haemostasis predisposing to venous thromboembolism (VTE).
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• Hereditary and acquired thrombophilia determine a prothrombotic state. Acquired

disorders foster a prothrombotic state via elevated procoagulant factors, reduced
ed

anticoagulants, pro-inflammatory/autoimmune mechanisms.

• Hereditary thrombophilia is divided into mild or severe according to the thrombotic

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risk associated with the genetic abnormalities.

• New genetic gain-of-functions defects responsible for severe thrombophilia have

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been identified, and namely, pseudo-homozygosity for activated protein C

resistance, factor IX Padua and resistance to antithrombin.
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• Individual’s ABO blood group is the most common genetic risk factor for VTE to
remember.

• The main acquired thrombophilia conditions are antiphospholipid antibody

syndrome, hyperomocisteinemia, acquired increased levels of procoagulant factors
and/or decreased levels of natural anticoagulants.
 • A subject with thrombophilia should be evaluated in the framework of other (genetic
and/or acquired) coexisting risk factors for first or recurrent VTE when assessing
the need and duration of prevention (primary prophylaxis).

Funding

This paper was not funded.

Declaration of conflicts of interest

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The authors have no relevant affiliations or financial involvement with any organization or

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entity with a financial interest in or financial conflict with the subject matter or materials

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discussed in the manuscript. This includes employment, consultancies, honoraria, stock
ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to

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disclose.

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Table 1. Increased thrombotic risk in hereditary and acquired thrombophilia

Thrombophilia Relative risk for a first VTE

(compared to community controls)

Hereditary thrombophilia

Factor V Leiden

Heterozygous 3-7x

Homozygous 80x

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Prothrombin G20210A

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Heterozygous 2-3x

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Homozygous 5x

Double heterozygosity (FVL and prothrombin G20210A) 6x

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AT deficiency 5x

Protein C deficiency 4-6.5x

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Protein S deficiency 1-3x

Pseudohomozygous FVL 80x

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Factor IX Padua 10x

AT resistance 2-3x

Non-0 blood type 2x

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Factor VIII ≥150 IU/dL 3-5x

Factor IX ≥129 IU/dL 2.3x

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Factor XI ≥121 IU/dL 2x

Acquired thrombophilia
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Antiphospholipid antibody syndrome 3-10x

Hyperhomocysteinaemia 1.5-3x
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Adapted from [2-4, 62], Phillippe HM et al. Inherited Thrombophilia. J Pharm Pract. 2014; 27(3) 227-233;
Makris M. Thrombophilia: grading the risk. Blood. 2009;113(21):5038-9; Bauer KA et al. Overview of the
causes of venous thrombosis. www.uptodate.com ©2018 UpToDate.

AT: antithrombin; FVL: factor V Leiden; VTE: venous thromboembolism.

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Table 2. Thrombotic risk in acquired thrombophilia and main hypercoagulable changes in
coagulation pathways

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Acquired thrombophilia Relative risk Haemostatic changes
for a first VTE

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Surgery 1.7-2.8x • release or exposure of TF
• ↓ AT
Trauma 3-5x • hypofibrinolysis (↑ PAI-1)
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• ↑ procoagulant factors (fibrinogen, VII, VIII,
X, vW)
Pregnancy 5-50x • ↓ protein S
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• acquired APC resistance

• ↓ protein S
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• ↓ TFPI

• release of TF
Oestrogen–progestogen therapies 2-9x
• ↑ procoagulant factors
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• ↓ anticoagulant factors
Cancer 4-7x • platelet activation
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• ↑ procoagulant factors
• ↓ protein S
• acquired APC resistance
• ↑ platelet-induced thrombin generation
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• Hypofibrinolysis (↑ prothrombin fragment

Myeloproliferative neoplasms 3x F1+F2, ↓ tPA)
• Haemoconcentration

• ↑ procoagulant factors (fibrinogen, VII, VIII,

X, vW)
• hypofibrinolysis (↑ PAI-1)
Economy class syndrome 2-4x • ↑ platelet aggregation
Obesity (BMI ≥30 Kg/m2) 2-3x

Adapted from [62-65,98], Sandor T. Travel thrombosis: pathomechanisms and clinical aspects.
Pathophysiology. 2008;15(4):243–52; Bauer KA et al. Overview of the causes of venous thrombosis.
www.uptodate.com ©2018 UpToDate.

TF: tissue factor; AT: antithrombin; PAI-1: plasminogen activator inhibitor-1; BMI: body mass index; vW: von
Willebrand; APC: activated protein C; TFPI: tissue factor pathway inhibitor, tPA: tissue plasminogen
activator.

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