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CHAPTER 130 published cases on the familial tendency in thromboembolic dis-
2
ease. The term thrombophilia was then used to describe patients with
HEREDITARY prominent manifestations of venous thromboembolism (VTE; venous
thrombosis in any site or pulmonary embolism) such as recurrent
THROMBOPHILIA spontaneous VTE, VTE at young age, a strong family history of VTE,
or thrombosis in an unusual site, such as the splanchnic veins or cere-
bral sinuses. Currently, the term thrombophilia is generally used for
laboratory abnormalities, usually in the coagulation system, which
Saskia Middeldorp and Michiel Coppens increase the risk of VTE. Thrombophilia can be either acquired or
hereditary. An example of acquired thrombophilia is the antiphospho-
lipid syndrome, which is characterized by a tendency toward venous
or arterial thrombosis or pregnancy complications, in combination
SUMMARY with persistent lupus anticoagulant or antibodies to cardiolipin or
β -glycoprotein-1 (Chap. 131). Furthermore, there are many acquired
2
Thrombophilia refers to laboratory abnormalities that increase the risk of and transient conditions that lead to a prothrombotic state, including
venous thromboembolism (VTE). Over the last several decades numer- cancer, surgery, strict immobilization, pregnancy and the postpartum
ous factors have been identified. The most prevalent examples of hered- period, and the use of estrogen-containing medication, such as oral
itary forms of thrombophilia include the factor V Leiden and prothrombin contraceptives and hormone replacement therapy.
G20210A mutations; deficiencies of the natural anticoagulants antith- Patients with hereditary thrombophilia have an increased risk
rombin, protein C, and protein S; persistently elevated levels of coagulation of developing VTE and just like in patients without thrombophilia,
factor VIII; and mild hyperhomocysteinemia. Taken together, some form approximately half of patients will develop their first episode in rela-
of hereditary thrombophilia can be identified in more than 50 percent of tion to an acquired prothrombotic risk factor. Moreover, despite
young age being a criterion for thrombophilia and the mean age at
patients with VTE who are without obvious reasons for VTE, such as trauma time of a first thrombosis being approximately 10 years lower than in
or prolonged stasis. Moreover, hereditary thrombophilia has been associ- the general population, the majority of patients with thrombophilia
ated with arterial cardiovascular disease and obstetric complications such will have the first episode later in life. The theoretical concept is that
3
as (recurrent) pregnancy loss and preeclampsia. The high yield of throm- patients with thrombophilia have an intrinsic prothrombotic state,
bophilia testing has led to widespread testing for these abnormalities in which in itself is insufficient to cause thrombosis, but may lead to
patients. Nevertheless, thrombophilia testing remains a topic of ongoing an event when superimposed upon (clinical) risk factors, including
debate, mostly because of the lack of therapeutic consequences. While increasing age. 3
hereditary thrombophilia is a clear risk factor for a first VTE, the risk for The role of hereditary thrombophilia in arterial cardiovascular
4,5
recurrent episodes is hardly increased compared with nonaffected patients disease has been extensively studied. Most of those studies did not
and prolonged anticoagulation is not warranted unless VTE is recurrent. demonstrate significant associations between hereditary thrombophilia
A similar lack of therapeutic consequences applies to patients with arterial and arterial disease with the exception of patients with events before the
age of 55 years. Moreover, the relative risk increase was very modest
5
cardiovascular disease and women with obstetric complications. Throm- (odds ratios [OR] of 1.1 to 1.8) in studies that did find significant asso-
bophilia testing in asymptomatic relatives of patients with VTE may be use- ciations, indicating that hereditary thrombophilia is not a major risk
ful in families with antithrombin, protein C, or protein S deficiency, or for factor for arterial cardiovascular disease. 4
siblings of patients who are homozygous for factor V Leiden, and is limited Like the acquired antiphospholipid syndrome, most hereditary
to women who intend to become pregnant or who would like to use oral thrombophilias are also modestly associated with pregnancy related
contraceptives. Careful counseling with knowledge of absolute risks helps disorders such as (recurrent) miscarriage, stillbirth, intrauterine growth
patients to making an informed decision in which their own preferences can retardation, preeclampsia and the hemolysis, elevated liver enzymes,
be taken into account. and low platelets (HELLP) syndrome of pregnancy, although for later
pregnancy complications this association is controversial. 6–8
In the past decades, hereditary thrombophilia has evolved from a
very rare genetic disorder to a prevalent trait. This evolution is a direct
To our knowledge, the term thrombophilia was first used by Nygaard consequence of increasing insight into the blood coagulation system,
and Brown in 1937, when they described sudden occlusion of large as well as advanced genetic research tools that allowed the search for
arteries, sometimes with coexistent venous thrombosis. In 1956, abnormalities in candidate coagulation proteins and their encoding
1
Jordan and Nandorff extensively reviewed their own and previously genes. At present, some form of thrombophilia can be identified in
about half of the patients presenting with VTE. Likely inspired by
the high yield of thrombophilia testing, testing has increased tre-
9
mendously for various indications, but whether the results of such
tests help in the clinical management of patients has still not been
Acronyms and Abbreviations: 95% CI, 95% confidence interval; APC, activated settled. 10,11 This chapter provides an overview of the most impor-
protein C; ASA, acetylsalicylic acid; HELLP, hemolysis, elevated liver enzymes, low tant hereditary thrombophilias and of the history of thrombophilia
platelets; LMWH, low-molecular-weight heparin; MTHFR, methylenetetrahydro- research. It reviews the risks associated with the most commonly
folate reductase; OR, odds ratio; VKA, vitamin K antagonist; VTE, venous thromboem- tested thrombophilias and provides guidance on the indications and
bolism; VWF, von Willebrand factor. potential implications of the results of thrombophilia testing in vari-
ous patient groups.

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