Williams Manual of Pregnancy Complications, 23 ed.

CHAPTER 53. Inherited Thrombophilias

There are several important regulatory proteins that act as inhibitors at strategic sites in the coagulation cascade (see Figure 53-1). Inherited or acquired deficiencies of these inhibitory proteins—collectively referred to as thrombophilias—can lead to hypercoagulability and recurrent venous thromboembolism. Although collectively present in about 15 percent of white European populations, these disorders are responsible for more than half of all thromboembolic events during pregnancy.

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FIGURE 53-1 Overview of the inherited thrombophilias and their effect(s) on the coagulation cascade. (Reproduced, with permission, from Cunningham FG, Leveno KJ, Bloom SL, et al (eds). Williams Obstetrics. 23rd ed. New York, NY: McGraw-Hill; 2010. Adapted from Seligsohn U, Lubetsky A: Genetic susceptibility to venous thrombosis. N Engl J Med 344:1222, 2001.)

The antiphospholipid syndrome is an acquired coagulation disorder whereas antithrombin deficiency, protein C deficiency, protein S deficiency, Factor V Leiden mutation, prothrombin G20210A mutation and hyperhomocysteinemia are inherited. Considerable attention has been directed recently toward a possible relationship between certain pregnancy complications and these coagulation disorders. Many thrombophilias have been variably linked to preeclampsia and eclampsia, and especially the HELLP syndrome; fetal-growth restriction; placental abruption; recurrent abortion; and stillbirth.

Antiphospholipid antibodies are autoantibodies that are detected in about 2 percent of patients who have nontraumatic venous thrombosis. They may also be found in association with systemic lupus erythematosus. Patients with moderate-to-high levels of these antibodies may have the antiphospholipid syndrome, which is associated with a number of clinical features including venous and arterial thromboembolism. While this most commonly involves the lower extremities, the syndrome should be considered in women with thromboses in unusual sites, such as the postal, mesenteric, splenic, subclavian, and cerebral veins. Antiphospholipid antibodies are also a predisposing factor for arterial thromboses. In fact, they account for up to 5 percent of arterial strokes in otherwise healthy young women. Thromboses may occur in relatively unusual locations such as the retinal, subclavian, brachial, or digital arteries.

Diagnosis and treatment of the antiphospholipid syndrome is discussed in Chapter 54.

ANTITHROMBIN DEFICIENCY

The primary function of the enzyme thrombin is clot formation. One of the most important inhibitors of this process is antithrombin. Antithrombin deficiency may result from numerous mutations that are almost always autosomal dominant. Homozygous antithrombin deficiency is lethal.

Although rare, affecting as few as 1 in 5000 individuals, antithrombin deficiency is the most thrombogenic of the heritable coagulopathies. Indeed, the lifetime risk of thrombosis is 50 to 90 percent with a 50- to 60-percent risk during pregnancy and a 33-percent risk during the puerperium. The antithrombin-deficient pregnant woman is treated with adjusted-dose heparin prophylaxis regardless of whether she has had a prior thrombosis.

PROTEIN C DEFICIENCY

When thrombin is bound to thrombomodulin on endothelial cells of small vessels, its procoagulant activities are neutralized (see Figure 53-1). It also activates protein C—a natural anticoagulant—that in the presence of protein S, controls thrombin generation by inactivating factors Va and VIIIa.

More than 160 different protein C gene mutations have been described. The prevalence of protein C deficiency is 2 to 5 per 1000, and inheritance is autosomal dominant. The risk of thromboembolism in pregnant women is between 3 and 20 percent and most occur during the puerperium. Approximately half of heterozygotes will suffer venous thrombotic episodes by adulthood.

PROTEIN S DEFICIENCY

This circulating anticoagulant is activated by protein C to decrease prothrombin generation. Protein S deficiency is measured by antigenically determined free, functional, and total S levels. All three of these levels decline substantively during normal pregnancy—in some cases by 50 percent. Protein S deficiency is caused by one of several autosomal dominant mutations with an aggregate prevalence of about 0.8 per 1000. There are three types of deficiency that correlate with correspondingly decreased free, functional, or total protein S levels. Thus, because all three are already decreased, diagnosis during pregnancy is difficult.

The lifetime risk of thromboembolism in patients with protein S deficiency is about 50 percent. The risk during pregnancy may be as high as 6 percent, and like protein C deficiency, the risk is even higher—up to 22 percent—during the puerperium.

FACTOR V LEIDEN MUTATION (ACTIVATED PROTEIN C RESISTANCE)

This is the most prevalent of the known thrombophilic syndromes. It is characterized by resistance of plasma to the anticoagulant effects of activated protein C (see Figure 53-1). The most common cause is the factor V Leiden mutation—named after the city where it was described. This missense mutation in the factor V gene results in a substitution of glutamine for arginine at position 506 in the factor V polypeptide, which confers resistance to degradation by activated protein C. The unimpeded abnormal factor V protein retains its procoagulant activity and predisposes to thrombosis.

Heterozygosity for factor V Leiden mutation is found in 20 to 40 percent of nonpregnant patients with thromboembolic disease. Homozygous inheritance of two aberrant copies is rare and increases the risk of thrombosis by more than 100-fold.

Resistance to activated protein C is measured by bioassay. Resistance is normally increased after the first trimester due to alterations in other coagulation proteins. Thus, during pregnancy, DNA analysis for the factor V Leiden mutation is instead used. Activated protein C resistance can also be caused by the antiphospholipid syndrome as well as other genetic defects in the factor V molecule.

The Maternal-Fetal Medicine Units Network conducted a prospective observational study of the factor V Leiden mutation in nearly 5200 pregnant women. The heterozygous carrier incidence was 2.7 percent. Of the three pulmonary emboli and one deep venous thrombosis (0.8 per 1000 pregnancies), none were among these carriers. There was no increased risk for preeclampsia, placental abruption, or fetal-growth restriction in heterozygous women. The investigators concluded that universal prenatal screening for the Leiden mutation, as well as prophylaxis for carriers without a prior venous thromboembolism, are not indicated. Women who are homozygous for the factor V Leiden mutation should be given adjusted-dose heparin prophylaxis during pregnancy.

PROTHROMBIN G20210A MUTATION

This missense mutation in the prothrombin gene leads to excessive accumulation of prothrombin, which then may be converted to thrombin. Found in approximately 2 percent of the white population, it is extremely uncommon in nonwhites. The mutation is associated with a two- to threefold lifetime risk of thromboembolism. Case-control studies suggest that the relative risk of thromboembolism is increased 3- to 15-fold during pregnancy. Homozygous women are given adjusted-dose heparin prophylaxis.

When coinherited with the factor V Leiden mutation, patients with a G20210A mutation are at increased risk for thromboembolism. Doubly heterozygous individuals have a 2.6-fold increased risk of recurrence relative to those with the Leiden mutation alone. These carriers of both mutations are candidates for lifelong anticoagulation after a first episode.

HYPERHOMOCYSTEINEMIA

High homocysteine concentrations activate factor V in endothelial cells, which inhibits the activation of protein C with an increased risk for thrombosis (see Figure 53-1). During pregnancy, the risk of thrombosis is increased two- to threefold. The coinheritance of hyperhomocysteinemia with either the factor V Leiden or prothrombin G20210A mutation further increases the risk. Hyperhomocysteinemia also increases the lifetime risk for premature atherosclerosis as well as fetal neural tube defects.

Hyperhomocysteinemia is diagnosed by elevated fasting levels. During normal pregnancy, mean concentrations are decreased and a fasting cutoff level of more than 12 μmol/L is used to define hyperhomocysteinemia during pregnancy. Low-dose prophylaxis is recommended in women who had a prior venous thromboembolism.

HOW TO TEST FOR INHERITED THROMBOPHILIAS

Test recommended for diagnoses of the inherited thrombophilias are summarized in Table 53-1. Whenever possible, laboratory testing should be performed remote (after 6 weeks) from the thrombotic event and while the patient is not pregnant and not taking anticoagulation or hormonal therapy.

TABLE 53-1. How to Test for Inherited Thrombophilias

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PREVENTION OF THROMBOEMBOLISM

The decision to treat with anticoagulation during pregnancy or postpartum is influenced by the venous thromboembolism history, severity of the inherited thrombophilia and additional risk factors. The American Congress of Obstetricians and Gynecologists has delineated recommendation for thrombophylaxis in nine different clinical scenarios for inherited thrombophilias. The reader is referred to Practice Bulletin No. 113, July 2010, on Inherited Thrombophilias in Pregnancy.


For further reading in Williams Obstetrics, 23rd ed.,

see Chapters 47, “Thromboembolic Disorders,” and 54, “Connective Tissue Disorders.”