INTRODUCTION Inherited thrombophilia is a genetic tendency to venous thromboembolism.

Factor V Leiden is the most common cause of the syndrome accounting for 40 to 50 percent of
cases. The prothrombin gene mutation, deficiencies in protein S, protein C, and antithrombin
account for most of the remaining cases, while rare causes include the dysfibrinogenemias. The
total incidence of an inherited thrombophilia in subjects with a deep vein thrombosis ranges from 24
to 37 percent overall compared with about 10 percent in controls. (See "Overview of the causes of
venous thrombosis", section on 'Inherited thrombophilia'.)
This review will discuss the usefulness of screening for these conditions in various asymptomatic
populations [1,2]. The diagnostic approach to the patient presenting with thrombosis and
management of inherited thrombophilias are discussed separately. (See "Evaluating patients with
established venous thromboembolism for acquired and inherited risk factors" and "Management of
inherited thrombophilia".)
GENERAL SCREENING ISSUES Screening techniques are used clinically to identify individuals
at risk for a preventable disease or complication. Reliable assays are now available to test for the
presence of the various causes of inherited thrombophilia (table 1).
However, unselected population-based screening for inherited thrombophilia is not recommended
because of three salient factors:
The low frequency of the symptomatic condition in the general population
The low penetrance of the symptomatic condition among carriers of the most common
thrombophilic conditions (eg, factor V Leiden and prothrombin G20210A mutations), AND
The lack of a safe, cost-effective, long-term method of prophylaxis if an abnormality is found.
Patients with a family history of thrombosis are at increased risk for a mutation. However, a simple
positive history is not a reliable criterion to select patients for screening. This was illustrated in a
report of 101 patients who had their first and single thromboembolic event while using oral
contraceptives [3]. A family history of thrombosis in a first-degree relative had a positive predictive
value of only 14 percent for factor V Leiden.
The usefulness of screening for hereditary thrombophilia has been considered in family members of
patients with a history of venous thromboembolism (VTE) and a thrombophilic defect, especially
antithrombin, protein S, or protein C deficiencies. As examples:
In a report of 150 pedigrees with factor V Leiden or antithrombin, protein C, or protein S
deficiency, the lifetime probability of developing thrombosis compared with those with no
defect was 8.5 times higher for carriers of protein S deficiency, 8.1 for antithrombin deficiency,
7.3 for protein C deficiency, and 2.2 for carriers of factor V Leiden [4]. Similar conclusions
were reached in a systematic literature review that did not include this study [5].
A retrospective cohort study of 2479 relatives of individuals with thrombosis and a
thrombophilic defect found that relatives who shared an inherited defect in protein S, protein
C, or antithrombin had an annual risk of VTE of 1.5 to 1.9 percent and a cumulative VTE
incidence of 55 percent at 10 years; individuals who shared other thrombophilic defects with
the index case had lower cumulative risks (eg, 7 percent for factor V Leiden and 11 percent for
prothrombin mutations) [6].

A prospective observational study of 206 pediatric patients <18 years, found that 27 percent
of first and second degree relatives had an inherited thrombophilia, the most common of which
was heterozygosity for the factor V Leiden mutation (57 percent) [7]. Of these relatives with
inherited thrombophilia, 23 percent (33 of 146) had VTE. In contrast, only 3.6 percent of
relatives without an inherited defect had VTE. The risk of clinically important thrombophilia
was greatest in individuals with protein S, protein C, and antithrombin mutations and least with
factor V Leiden mutations.
Since the genetic pattern for the inherited thrombophilias is autosomal dominant, one-half of the
relatives of each patient with thrombosis and hereditary thrombophilia will carry the same defect.
However, the value of screening for the presence of a defect remains controversial. The following
sections provide arguments for and against such screening.
Arguments against screening Identification via screening of an inherited thrombophilia would
theoretically permit the institution of prophylactic anticoagulation, either permanently or during highrisk situations. However, there are no data that justify the risks of long-term or permanent
prophylactic anticoagulation in the asymptomatic individual (ie, an individual who has not had a
thromboembolic event).
As examples, two studies of the incidence of thromboembolic disease in family members of patients
with factor V Leiden suggest that neither of these strategies would be of value [8,9]. In a
retrospective, blinded analysis, the incidence of VTE was assessed in 437 first-degree relatives of
112 symptomatic heterozygotes and 30 relatives of six homozygotes [8]. The annual incidence of
thromboembolism in relatives of heterozygous patients was 0.45 percent in those with the mutation
and 0.1 percent in those without the mutation; 20 percent of the episodes were related to surgery
and 30 percent to pregnancy or the use of oral contraceptives.
The 0.35 percent difference between the two groups suggests that approximately 300 women would
have to be treated (and suffer the risks and problems of anticoagulation) in an attempt to prevent
one episode of VTE per year. This absolute benefit does not appear to justify life-long
anticoagulation. It was also estimated that, if all identified pregnant carriers were treated with
anticoagulant prophylaxis, treatment would be given unnecessarily in 98 percent of pregnant
carriers who would be exposed to the risks of bleeding, bone loss, and thrombocytopenia. Similarly,
if all potential users of oral contraceptives were screened and then discouraged from use of the
drugs if they tested positive, 333 women would be identified for every episode of VTE prevented.
Similar arguments against screening for the prothrombin G20210A mutation have been presented,
in which the annual incidence of thromboembolism in relatives of heterozygous patients was 0.37
percent in those with the mutation and 0.12 percent in those without the mutation [10].
Arguments in favor of screening Although prophylactic anticoagulation in the asymptomatic
individual (ie, an individual who has not had a thromboembolic event) cannot be universally justified,
there are certain potential high-risk situations (eg, major surgery, trauma, immobilization for >7
days, pregnancy and puerperium) which can be identified by screening of relatives and which may
prompt consideration of prophylactic treatment [11,12].
In addition, individuals can be educated about precautions and early symptoms. As an example,
women can be made aware of the risk/benefit ratio associated with oral contraceptives and
hormone replacement therapy and make more informed decisions [13]. This applies particularly to

individuals who are heterozygous for protein C, protein S, and antithrombin deficiency, conditions
that appear to have a three- to fourfold higher thrombosis risk than heterozygous factor V Leiden
[4,12]. (See "Menopausal hormone therapy and cardiovascular risk".)
SCREENING FOR SPECIFIC INHERITED THROMBOPHILIAS
Factor V Leiden Factor V Leiden is the most common inherited thrombophilia. This topic is
discussed separately. (See "Factor V Leiden and activated protein C resistance: Clinical
manifestations and diagnosis".)
Homozygosity and multiple defects Rarely, an asymptomatic high risk homozygote with the
factor V Leiden or prothrombin G20210A mutation can be diagnosed by family screening.
Infrequently, a second hereditary defect, particularly factor V Leiden, is identified in a patient with
one of the other inherited thrombophilic defects. (See "Overview of the causes of venous
thrombosis".)
Carriers of two defects seem to be at a higher risk for thrombosis than their relatives with a single
defect. In one review of four studies, approximately 75 percent of the family members who were
carriers of two defects had experienced thrombosis compared with 10 to 30 percent of the carriers
of a single defect [14]. However, these data may reflect an artificially elevated risk based on
reporting bias.
The lack of utility of screening asymptomatic relatives of homozygous probands with a negative
family history of venous thromboembolism (VTE) is supported by a study that retrospectively
evaluated the risk of VTE in family members of individuals with inherited defects [15]. This study
found that VTE was less likely in homozygotes for factor V Leiden or prothrombin G20210A with a
negative family history of VTE than in individuals who were heterozygous for an inherited defect
with a positive family history of VTE (adjusted hazard ratio [HR] 1.3; 95% CI 1.3-5.4 and HR 4.1;
95% CI 1.2-14.7, respectively).
Management of individuals with homozygosity or compound heterozygosity for inherited
thrombophilias is discussed separately. (See "Management of inherited thrombophilia", section on
'Argument against long-term therapy' and "Management of inherited thrombophilia", section on
'Surgery' and "Inherited thrombophilias in pregnancy", section on 'Prevention of VTE'.)
Protein C deficiency Patients with protein C deficiency are at potential risk of warfarin-induced
skin necrosis and should be aware of this diagnosis, if present. In a patient with thrombosis who is
known to be protein C deficient, oral anticoagulation should be started under the cover of full
heparinization. If used, the dose of warfarin should be increased gradually, starting from a relatively
low dose (eg, 2 mg/day). (See "Protein C deficiency: Clinical manifestations and diagnosis", section
on 'Warfarin-induced skin necrosis'.)
Antithrombin deficiency Pregnant women with hereditary antithrombin (formerly called
antithrombin III) deficiency have an unusually high risk for thromboembolism. One study, for
example, evaluated 78 women with inherited deficiency in antithrombin, protein S, or protein C [16].
Deep vein thrombosis occurred in 18 percent of patients with type I antithrombin deficiency during
pregnancy and in 33 percent in the postpartum period. By comparison, thrombosis during
pregnancy occurred in only 7 percent of patients with protein C deficiency and in none of the
patients with protein S deficiency. Thrombosis in the postpartum period occurred in 19 percent of

protein C and 17 percent of protein S deficient patients. (See "Antithrombin (AT III) deficiency:
Clinical manifestations and diagnosis".)
As a result, women with antithrombin deficiency should receive anticoagulant prophylaxis with low
molecular weight (LMW) heparin during pregnancy and for six weeks postpartum. (See "Inherited
thrombophilias in pregnancy" and "Use of anticoagulants during pregnancy and postpartum".)
Recommendation We believe that the benefits of screening are likely to be significant in the
asymptomatic family member with thrombophilia only if there is a strong family history of VTE (ie,
multiple first-degree relatives with thrombotic events prior to age 50) [6]. Following an informed
discussion with such patients with VTE and thrombophilia, we recommend screening first-degree
family members for the identified defect. How this should be performed is discussed separately.
(See "Evaluating patients with established venous thromboembolism for acquired and inherited risk
factors", section on 'Hypercoagulable tests'.)
We do not recommend screening for high homocysteine levels or presence of the MTHFR variant in
any setting.
In patients with thrombophilia who have had a VTE but have no family history, the benefit of
screening first-degree family members is not established. An individualized approach should be
taken to testing such individuals after discussing the potential benefits and risks and taking personal
preference into account.
SCREENING IN HIGH RISK SITUATIONS
Oral contraceptives We typically do not screen women taking oral contraceptives (OCs) or
considering their use for inherited thrombophilia unless a blood relative has inherited thrombophilia
and clinical thromboembolic disease. This issue is discussed in detail separately.
(See "Contraceptive counseling for women with inherited thrombophilias".)
Pregnancy The overall maternal death rate due to pulmonary embolism in the United States is
estimated at 1.2 per 100,000 [17]. In a study of over 72,000 deliveries, the incidence of deep vein
thrombosis alone was much higher at 71 per 100,000 deliveries; factor V Leiden accounted for 8
percent of the patients with thrombosis [18]. If one-half of the fatal pulmonary emboli were to occur
in the 10 percent of women with factor V Leiden, the risk would be approximately 1 in 13,000. This
is lower than the risk of fatal bleeding or intracranial bleeding that leads to lifelong handicap [19];
the latter risk has been estimated at about 0.5 patients per 100 treatment years or 1 in 2000
mothers anticoagulated for at least six weeks [20]. (See "Inherited thrombophilias in pregnancy".)
Thus, screening all pregnant women for an inherited thrombophilia is not recommended [19,21].
Obstetric complications In addition to an association with venous thrombosis, inherited
thrombophilia has also been linked to obstetric complications such as second and third trimester
fetal loss, which are associated with intervillous or spiral artery thrombosis and inadequate placental
perfusion. The value of screening women with one of these complications is uncertain.
(See "Inherited thrombophilias in pregnancy".)
DEFECTS FOR WHICH SCREENING IS NOT HELPFUL There are some defects for which
screening is not indicated in asymptomatic individuals. We also do not alter management if

screening for these defects has been conducted and abnormalities are found, based on lack of
evidence that risk is significantly increased or that anticoagulation reduces risk.
Homocysteine and the MTHFR variant There is no clinical rationale for measurement of fasting
plasma homocysteine levels or for assaying for presence of the MTHFR 677C>T variant in
asymptomatic individuals, and we never order this testing to evaluate venous or arterial thrombosis.
(See "Overview of homocysteine", section on 'Screening for hyperhomocysteinemia'.)
If the patient has had this biochemical or genetic testing and findings are abnormal, we counsel that
the result is of no clinical significance, and relatives should not be tested.
Elevated coagulation factor levels Elevated levels of several procoagulant coagulation factors
may increase risk for a first episode of venous thromboembolism; elevated factor VIII level is the
strongest of these risk factors. It has not been determined whether there is a genetic basis for these
elevations. Furthermore, factor VIII assays are not standardized for this purpose, and the factor VIII
level above which there is an increased risk may differ substantially between populations. Thus, it is
not useful to measure the levels of these factors in asymptomatic individuals. We recommend
against screening relatives for such abnormalities, even if a first degree relative has been found to
have an abnormally high level of a coagulation factor.
SUMMARY
Inherited thrombophilia is a genetic tendency to venous thromboembolism (VTE). Common
causes include Factor V Leiden (the most common condition), the prothrombin gene mutation,
and deficiencies in protein S, protein C, and antithrombin.
Unselected population-based screening for inherited thrombophilic states is not
recommended because of their low frequency, low penetrance, and lack of a safe, costeffective, long-term method of prophylaxis if an abnormality is found. Specifically, there are no
data that justify the risks of prophylactic anticoagulation in the asymptomatic patient with
inherited thrombophilia. (See 'Arguments against screening' above.)
The benefits of screening are likely to be significant in the asymptomatic family member with
thrombophilia only if there is a strong family history of VTE (ie, multiple first-degree relatives
with thrombotic events prior to age 50); such histories are more common in patients with
deficiencies of antithrombin, protein C, or protein S.
However, in certain high thrombotic risk situations (eg, major surgery, trauma, immobilization
for >7 days, pregnancy and puerperium), screening for inherited thrombophilia, if present, may
prompt consideration of prophylactic treatment or alteration in the type/duration of
antithrombotic prophylaxis. These scenarios include (see 'Screening for specific inherited
thrombophilias' above and 'Screening in high risk situations' above):
Presence of homozygosity for the Factor V Leiden or prothrombin gene mutations or
multiple thrombophilic defects
Initiation of vitamin K antagonists in patients with protein C deficiency given potential for
the rare complication of warfarin-induced skin necrosis
Consideration of antithrombin concentrate administration in antithrombin deficiency in
the peri-partum period in pregnant women or in conjunction with surgical procedures
when anticoagulants cannot be safely administered (eg, during delivery or immediately
following neurosurgery or spinal surgery)

We typically do not screen women taking oral contraceptives for inherited thrombophilia
unless a first-degree relative has inherited thrombophilia and clinical thromboembolic disease.
(See "Contraceptive counseling for women with inherited thrombophilias".)
Management of individuals with inherited thrombophilia is discussed separately.
(See "Management of inherited thrombophilia".)
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