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2226 Part XII: Hemostasis and Thrombosis Chapter 130: Hereditary Thrombophilia 2227

thromboembolic disease have not been able to sufficiently adjust for in some scenarios could be cost-effective, the underlying assumptions
known and unknown confounders. Moreover, acute myocardial infarc- from inconsistent observational studies seriously hamper their inter-
tion and ischemic stroke may cause acute-phase reactions that tran- pretation. 91,92 Second, although the psychological impact and conse-
siently increase FVIII levels, hampering interpretation of case-control quences of knowing that one is a carrier of a (genetic) thrombophilic
or retrospective cohort studies. However, patients with hemophilia A, a defect are considered limited, a qualitative study described several neg-
genetic cause of decreased FVIII levels, have an approximate 80 percent ative effects of both psychological and social origins. 93,94 Difficulties in
lower risk of death from ischemic heart disease, indicating a potential obtaining life or disability insurance are frequently encountered by indi-
causal relation between FVIII levels and arterial thrombosis. 82 viduals who are known carriers of thrombophilia, regardless of whether
Mild hyperhomocysteinemia and MTHFR 677TT have been they are symptomatic or asymptomatic. Third, the most compelling
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extensively studied in relation to arterial thromboembolic disease. A argument against testing is the potential false reassurance that may arise
meta-analysis of studies that included more than 5000 patients with from a negative thrombophilia test for individuals who come from fam-
ischemic heart disease and more than 1000 patients with ischemic stroke ilies with a thrombotic tendency. For example, Table 130–4 indicates
demonstrated a significant correlation between homocysteine level and that in these families, women without thrombophilia have a markedly
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the risk of arterial thrombosis. The risk increase in was higher in ret- increased risk of oral contraceptive-related VTE compared to pill users
rospective studies than in prospective studies in which homocysteine from the general population (0.7 percent in women with a natural anti-
levels are measured before the thrombotic episodes. This could, in part, coagulant deficiency versus 0.04 percent per year of use), reflecting a
be explained by the observed association between hyperhomocysteine- selection of families with a strong thrombotic tendency in which yet
mia and other well-known risk factors for arterial cardiovascular dis- unknown thrombophilias have co-segregated.
ease, including smoking, chronic inflammatory disorders, and renal The following paragraphs discuss the potential scenarios for
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failure. Like with elevated FVIII levels, it is uncertain whether studies thrombophilia testing in more detail.
that investigate the relation between homocysteine and arterial cardio-
vascular disease have been able to sufficiently adjust for confounding
variables. The association between MTHFR 677TT and ischemic heart TESTING FOR THROMBOPHILIA TO
disease has shown mixed results with no association in studies in North
American patients and a modest 16 percent risk increase in studies in MODIFY THE RISK OF A FIRST VENOUS
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European patients. It was initially hypothesized that this difference is THROMBOEMBOLISM
attributable to a lower dietary folate intake in Europe. However, this Having a family history of VTE is a poor predictor of the presence of
hypothesis conflicts with the results of trials in patients with vascular thrombophilia. 69,95 Still, a potential advantage of testing patients with
disease in whom homocysteine lowering with folic acid and B vitamins VTE for thrombophilia may be the identification of asymptomatic fam-
did not reduce the risk of recurrent episodes. 66 ily members in order to take preventive measures if tested positive, and
to withhold such measures if relatives have tested negative. An impor-
PREGNANCY COMPLICATIONS tant requisite is that a test result indeed dichotomizes carriers and non-
carriers in terms of their risk for a first episode of VTE.
Although many studies have observed a relationship between heredi- Based on the absolute risks for a first episode of VTE
tary thrombophilia and pregnancy complications, including recurrent (see Table 130–4), it is clear that the 1 to 3 percent annual major bleed-
miscarriage, late pregnancy loss, preeclampsia, intrauterine growth ing risk associated with continuous oral anticoagulant treatment out-
restriction, and placental abruption, this should be regarded as contro- weighs the risk of VTE. 96,97 Table 130–4 also shows that during high-risk
versial. Most associations are modest in strength and vary with type of situations such as surgery, immobilization, trauma, pregnancy, and the
thrombophilia and type of pregnancy complication. 8,85,86 Furthermore, postpartum period, and during the use of oral contraceptives, the abso-
the most recent and larger prospective cohort studies found lower ORs lute risk is generally low, with the exception of women with a natural
for hereditary thrombophilia than older and smaller case-control stud- anticoagulant deficiency who use oral contraceptives or are pregnant.
ies, which may point to a bias in the observed associations. 8,87,88 The Estimates of the effect of avoidance of oral contraceptives on the
mechanisms of how thrombophilia would lead to pregnancy compli- number of prevented episodes of VTE by means of thrombophilia
cations remain largely unknown. It is unlikely that mere hypercoagula- testing can be calculated for women who have a positive first-degree
bility with thrombosis of placental vasculature is the pathophysiologic relative with VTE in whom the thrombophilic defect is known. To
98
substrate for an association with thrombophilia. Animal and in vitro avoid one VTE event, 28 women with antithrombin, protein C or pro-
studies have implicated a role for both procoagulant and inflammatory tein S deficiency, and a positive family history for VTE would need
pathways in pregnancy failure and interesting effects of acetylsalicylic to refrain from oral contraceptives, and to identify these women, 56
acid (ASA) and heparin. For instance, in a murine high-risk preg- female relatives would need to be tested. For factor V Leiden or the
89
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nancy model, heparin rescued factor V Leiden–associated placental prothrombin 20210A mutation, approximately 333 women would need
failure, but this was independent of anticoagulation. 90 to avoid oral contraceptives and 666 female relatives would need to be
tested. Although the number of tested women for the natural deficien-
cies seems quite acceptable, the major argument against this scenario is
CLINICAL IMPLICATIONS OF that a normal level of antithrombin, protein C, or protein S in women
THROMBOPHILIA INCLUDING TESTING from these families does not exclude a strongly increased risk of VTE
during oral contraceptive use, as compared to the general population
GENERAL CONSIDERATIONS OF (see Table 130–4). The same, but to a lesser extent, is true for women
from thrombophilic families who do not carry either the factor V
THROMBOPHILIA TESTING Leiden or prothrombin mutation, but here also the number needed to
Several arguments against testing for thrombophilia should be consid- screen is unacceptably high.
ered. First, an obvious disadvantage of testing for thrombophilia is the Table 130–5 indicates the estimated number needed to test to ini-
10
high cost. Although two studies concluded that testing for thrombophilia tiate prophylactic measurements around pregnancy, again applicable

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