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2224 Part XII: Hemostasis and Thrombosis Chapter 130: Hereditary Thrombophilia 2225

The association between homocysteine levels is again under scrutiny in heterozygotes. Likewise, patients with combined thrombophilic disor-
newer studies. The single largest case-control study of more than 4000 ders have a higher risk of VTE than those with a single defect. One can
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patients with a first VTE found no association between MTHFR 677TT estimate the absolute risk of VTE by multiplying the relative risk with
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and VTE. Furthermore, a family study of probands with mild hyperho- the absolute incidence in cohorts from the general population, in which
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mocysteinemia and venous or arterial thrombosis found that the asso- the risk of first VTE is approximately 0.2 to 0.3 per 100 person-years.
ciation between homocysteine and VTE disappeared after adjustment Because this may however lead to imprecise estimates, it is prefera-
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for FVIII levels. Finally, homocysteine lowering by B vitamins did not ble to use absolute risk estimates derived from cohort studies. Retro-
reduce the incidence of recurrent events both in patients with VTE as well spective cohort studies may produce less-reliable incidence estimates
as in patients with arterial cardiovascular disease. 65,66 As a result of these because retrospective studies carry the risk of (unconscious) selection
studies, homocysteine testing (either its levels of polymorphisms) as part of patients and data and the clinical diagnosis of VTE may not have
of a thrombophilia panel has been largely abandoned. been confirmed by objective tests. Prospective cohort studies of asymp-
tomatic carriers of hereditary thrombophilic defects are probably better
PITFALLS IN LABORATORY TESTING FOR suited to estimate the true incidence of thrombosis in thrombophilic
HEREDITARY THROMBOPHILIA patients. It is important to note that cohort studies have been mainly
performed in relatives of (consecutive) patients with a particular throm-
Testing for hereditary thrombophilia is performed in many patients, bophilic defect. Absolute risk estimates from family studies are higher
or family members of patients, with various thromboembolic diseases than from population based studies. Even in the absence of any hered-
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or pregnancy complications. However, it is important to realize that itary thrombophilia, the risk of VTE is still twofold increased in first
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many acquired, often transient, conditions may affect the test results. degree family members of patients with VTE. This suggests cosegre-
Most known is the use of VKAs, which reduces the levels of anticoag- gation of other, unmeasured or unknown thrombophilias. Table 130–4
ulant factors protein C and protein S, which can thereby mimic severe presents absolute risk estimates for a first-episode VTE for asymptom-
deficiencies. Another example is pregnancy that reduces free protein S atic carriers with a family history of VTE. These risk estimates can be
levels and increases APC resistance and FVIII levels. However, other used to counsel both affected and unaffected family members about
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factors can also affect test results and should be considered in the inter- their risk of VTE. These studies also provide absolute risk estimates for
pretation of results or, better yet, in the timing of testing. Table 130–2 VTE associated with exogenous additional risk factors such as surgery,
presents an overview of acquired conditions that can yield false-positive trauma or immobilization, and pregnancy or use of hormonal contra-
thrombophilia tests. For deficiencies of the natural anticoagulants as ception (Table 130–4). These incidences are derived from retrospective
well as for elevated FVIII levels, repeated testing should be performed to family studies, as prospective studies are limited by shorter followup
exclude spuriously abnormal tests. Genetic testing for deficiencies of the duration and reduced power.
natural anticoagulants is not performed because of the large number of
known mutations. The hereditary nature of deficiencies must be estab- Thrombophilia and the Risk of Recurrent Venous
lished by confirming the abnormality in a first-degree family member. Thromboembolism
Regardless of thrombophilia, the absolute risk of a recurrent episode is
HEREDITARY THROMBOPHILIA AND much higher than the risk of a first episode of VTE. The most impor-
tant determinant of recurrence is the presence of transient clinical risk
THE RISK OF DISEASE factors during the time of the first episode. After an unprovoked first
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episode of VTE, the risk of recurrence is approximately 10 percent in
VENOUS THROMBOEMBOLISM the first year after cessation of anticoagulation and approximately 5 per-
The relative risk of a first episode of VTE in individuals with a form of cent per year thereafter. The risk is lower after VTE that was associated
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common hereditary thrombophilia ranges from 2 to 11 (Table 130–3). with a transient risk factor, with an incidence in the first 2 years of 0.7
These figures were derived from family and population-based cohort percent per year for surgery-provoked VTE and 4.2 percent per year for
or case-control studies. Individuals homozygous for the prothrombin VTE provoked by estrogen use, pregnancy, temporary immobilization,
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G20210A or factor V Leiden mutations are at higher risk for VTE than or trauma. Other determinants for recurrence are male sex, proximal

TABLE 130–3. Relative Risk Estimates for Common Hereditary Thrombophilias and Venous or Arterial Thrombosis and
Pregnancy Complications
Relative Risk
First VTE Recurrent VTE Arterial Thrombosis Pregnancy Complications
Antithrombin deficiency 5–10 1.9–2.6 No association 1.3–3.6
Protein C deficiency 4–6.5 1.4–1.8 No consistent association 1.3–3.6
Protein S deficiency 1–10 1.0–1.4 No consistent association 1.3–3.6
Factor V Leiden 3–5 1.4 1.3 1.0–2.6
Prothrombin G20210A 2–3 1.4 0.9 0.9–1.3
Persistently elevated FVIII 2–11 6–11 – 4.0
Mild hyperhomocysteinemia 2.5–2.6 2.6–3.1 – No consistent association
FVIII, factor VIII; VTE, venous thromboembolism.
Risk estimated are derived from studies reviewed in detail elsewhere. 11

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