Guidance for the evaluation and treatment of hereditary and acquired thrombophilia

Of the many factors which predict the risk of recurrent thrombosis after an initial event, the presence of provoking factors is the most important [12, 20]. Thrombosis following a major provocation, such as major surgery in the preceding 3 months, carries a short term relative risk of recurrence of 0.5 or less compared to the absence of an identifiable provocation [20]. A large prospective registry offered patients with VTE the opportunity to be screened for hereditary thrombophilia. The risk of recurrence following an episode of provoked VTE was very low, and recurrence rates did not differ among those with or without a hereditary thrombophilia [35]. A large case–control study and another prospective registry yielded similar results [16, 22]. Therefore, the risk:benefit balance favoring time-limited anticoagulation remains the same, regardless of the presence of a thrombophilia. There is the potential for patient harm if thrombophilia testing is performed after a provoked VTE event, as healthcare providers may overestimate the risk of recurrence and prescribe extended duration anticoagulation, subjecting patients to the unnecessary risk of bleeding [36, 37]. Other published guidelines broadly agree that thrombophilia testing does not assist with clinical decision making in cases of provoked VTE and should not be performed [21, 25, 38, 39]. The American Society of Hematology (ASH) and the Society for Vascular Medicine (SVM) recommended against testing in such cases in their Choosing Wisely© initiatives [36, 37].

A positive thrombophilia evaluation is not a sufficient basis to offer extended anticoagulation following an episode of provoked VTE.

The absolute risk for recurrent VTE among patients with unprovoked thrombosis is higher than among those with provoked VTE, with 5-year risk approaching 30 % unless extended-duration anticoagulant therapy is provided [20, 40]. Current guidelines from the American College of Chest Physicians (ACCP) recommend extended duration anticoagulation (anticoagulation with no planned stop date) after unprovoked VTE unless the risk of bleeding is high or this is contrary to the patient’s values and preferences [20]. However, anticoagulant medications confer an increased risk of major bleeding, inconvenience to patients, and not all patients will go on to develop recurrent thrombosis. Therefore it would be desirable to offer extended anticoagulation only to those who would benefit from it. Thrombophilia testing has been suggested as a means to identify these patients. However, a large registry did not demonstrate a difference in rates of recurrent VTE in patients who were tested for thrombophilia versus those who were not, although the number of patients with AT, PC, PS deficiencies or compound heterozygosity for FVL/PGM was limited [35]. Several prospective registries and case–control studies revealed clinically insignificant differences in the VTE recurrence rates for those with or without a hereditary thrombophilia [16, 22, 41, 42]. Some thrombophilias, including APS, confer a higher risk of recurrence than others (Table 2) and support the decision for extended anticoagulation. However, if a patient will remain on indefinite anticoagulation based on the known recurrence rate for unprovoked VTE, then thrombophilia testing may not add additional utility. Therefore, the value of testing is likely limited to patients who would stop anticoagulants unless they are at even higher risk of recurrence than the initial unprovoked event would predict. There are also potential risks to thrombophilia testing after unprovoked VTE. Negative testing for thrombophilia may falsely reassure clinicians that the risk of recurrent VTE is low after an unprovoked VTE, leading to cessation of anticoagulation in patients at high risk for recurrence [43]. Conversely, finding a thrombophilia in a patient at high bleeding risk may lead to continued anticoagulation, due to an overestimation of the risk conferred by the condition. Other published guidelines vary regarding thrombophilia testing after unprovoked VTE [15, 38]. The National Institute for Health and Clinical Excellence (NICE) guidelines discourage testing for FVL and PGM, and suggest selective testing for other conditions [21]. The ACCP guideline lists thrombophilias among factors which “…predict risk of recurrence, but not strongly or consistently enough to influence recommendations on duration of therapy” [20]. Several risk prediction models (which do not include thrombophilia testing) have been proposed to help inform decisions regarding duration of anticoagulation after unprovoked VTE; though some were derived in populations which intentionally excluded patients with known deficiency of PS, PC, AT and with APS [8, 44, 45]. As direct acting oral anticoagulants (DOACs) may confer a lower risk of bleeding than warfarin during extended therapy, the barriers to extended anticoagulation may be lessened, perhaps further decreasing the utility of thrombophilia status to inform clinical decisions. Other factors, such as the degree of post-thrombotic symptoms, D dimer levels after a minimum of 3 months of anticoagulant therapy, and residual vein thrombosis may also modify the risk of recurrence [46‐48].

If a patient with unprovoked VTE and low bleeding risk is planning to stop anticoagulation, test for thrombophilia (Table 2) if test results would change this decision.

A negative thrombophilia evaluation is not a sufficient basis to stop anticoagulants following an episode of unprovoked VTE in a patient with low bleeding risk and willingness to continue therapy.

Heterozygosity for FVL or PGM does not increase the predicted risk of recurrence after unprovoked VTE to a clinically significant degree.

See Chapter 3, “Guidance for the treatment of DVT and PE” for guidance on determining duration of anticoagulant therapy following unprovoked VTE.

An additional rationale for hereditary thrombophilia testing of patients with VTE is to identify conditions which can lead to screening of asymptomatic family members. Except for temporary prophylaxis during certain high risk situations, anticoagulation for primary prevention of thrombosis is not advocated regardless of the genetic defect because the risk of bleeding may be higher than the absolute risk of a first thrombotic event [19, 49‐51]. However, it is argued that people who know their genotype may be more likely to use preventive strategies in situations where the risk of thrombosis is elevated, such as during hospitalization, following major surgery, and during long distance travel. A large screening study of family members of VTE patients revealed that asymptomatic carriers of a hereditary thrombophilic defect were at excess risk of thrombosis, with risks varying by disorder [52]. However, a family history of thrombosis alone carries an increased risk, even in the absence of an identifiable thrombophilia [43, 53‐55]. Therefore, negative thrombophilia screening does not equate to normal VTE risk. The impact of family screening on behavior was explored in a cohort of 382 first degree family members of patients with VTE and hereditary thrombophilia, who were tested and followed over about 9 years [32]. Twice as many thrombophilia carriers used prophylaxis in risk situations. The rate of provoked VTE was higher in the group with thrombophilia (0.58 %/year in those with hereditary thrombophilia; 0.24 %/year in those without) although this difference did not reach statistical significance (p = 0.08). This study suggested a potential harm from screening, as it demonstrated that family members who tested negative for a thrombophilic defect were less likely to use prophylaxis. Published guidelines vary substantially in regard to utility of family screening [21, 25, 38, 39].

As a family history of VTE confers an excess risk of thrombosis, relatives should be counseled regarding use of prophylaxis in high risk situations.

Thrombophilias act synergistically with the pro-thrombotic effects of estrogen-containing medications [19]. Therefore, identification of a hereditary thrombophilia by family testing could result in choice of an alternate method of contraception, or foregoing hormone replacement therapy (HRT), thus avoiding the associated risk of thrombosis. While the presence of thrombophilia significantly increases the relative risk of a thrombotic event during use of an estrogen-containing medication, the absolute risk remains low (Table 2). This is especially true for oral contraceptives (OCPs), which are generally used by younger women with a very low baseline risk for VTE. Studies focused on testing for thrombophilia in the general female population have suggested little utility and lack of cost-effectiveness. For example, an economic modeling study calculated that more 10,000 women would have to be screened for FVL, and 500 women with the condition would have to avoid OCPs in order to prevent one thrombotic event [56]. Over 92,000 FVL carriers would have to be identified and avoid OCPs to prevent one fatal pulmonary embolism (PE), at a cost of over $300 million [57]. Testing only patients with a family history would likely increase test yield and improve cost-effectiveness [56]. However, family history of VTE in one or more first degree relatives predicts an elevated risk of estrogen-associated VTE, regardless of whether thrombophilia is present [25, 53, 58]. Therefore it is possible that women with negative tests could be falsely reassured, and use estrogen in spite of an increased thrombosis risk. Other published guidelines vary significantly regarding family screening for the purposes of primary prevention in women contemplating estrogens. The NICE guidelines recommend against screening [21]. Medication package inserts contain precautions regarding estrogen-containing contraceptives in women with a family history of VTE. Intrauterine devices, including those which elute progestin, are a contraceptive option that does not increase the risk for thrombosis [31]. While HRT prescriptions have declined based on an unfavorable balance of risks and benefits [59], women with a family history of VTE who strongly desire HRT may mitigate VTE risk with use of a transdermal preparation [60].

Limits/exceptions

If a woman contemplating estrogen use has a first-degree relative with VTE and a known hereditary thrombophilia (Table 2), test for that thrombophilia if the result would change the decision to use estrogen.

Family history of VTE in a first degree relative predicts an excess risk of thrombosis with estrogen use, even when thrombophilia testing is negative.

Pregnancy is a period of particularly high risk for thrombosis, causing a relative risk increase of 5–10 times baseline [61]. The presence of a thrombophilic defect amplifies this risk several-fold further (Table 2). Thrombophilia screening, if performed, would be most applicable to the setting of primary prevention, as women with a prior VTE that was unprovoked, or provoked by pregnancy or an OCP, merit prophylaxis regardless of thrombophilia status [25, 62]. A personal history of a prior VTE provoked by surgery or trauma does not significantly increase the risk of VTE during pregnancy; and no special prophylaxis measures are indicated ante-partum [25, 62‐64]. Pregnant patients with a first degree family member who has had VTE do not appear to have an excess risk of thrombosis in the absence of thrombophilia; therefore testing may be more likely to distinguish women at low or higher thrombosis risk [65, 66]. Screening of unselected pregnant women was not found to be cost-effective in a modeling analysis despite the assumption that all women who tested positive would use both antenatal and post-partum prophylaxis [19]. However, restricting testing to women with a first degree family member with VTE improved cost-effectiveness. A recent multinational prospective, randomized, open-label trial compared prophylaxis with dalteparin versus no prophylaxis in 289 pregnant women with thrombophilia who were at increased risk of placenta-mediated pregnancy complications, VTE, or both. Antepartum prophylactic dalteparin did not reduce the occurrence of VTE, pregnancy loss, or placenta-mediated pregnancy complications, but increased minor bleeding. All participants received post-partum prophylaxis with dalteparin [67]. Systematic reviews have concluded that the evidence supporting management decisions for pregnant patients with FVL or PGM is low [68], and that practitioners are often uncertain how to best manage these patients [27]. There are potential harms to testing. As prophylaxis is generally recommended only to women who harbor less common thrombophilias (see Chapter 6) [25, 62, 63], a large number of women must be screened to detect each case, resulting in significant expense [19]. Also, as homozygosity for FVL is one of the higher-risk conditions in pregnancy, screening will identify many heterozygotes in order to detect the few homozygotes of interest. The heterozygotes may experience worry, emotional distress or challenges with insurability [28‐30], while gaining little or no utility from the information obtained. Other published guidelines vary in suggesting broad [15] or selective [25, 63] screening of relatives of patients with VTE who are contemplating pregnancy; and several guidelines advocate prophylaxis of pregnant women in the presence of certain thrombophilias [24, 62, 63, 69‐71]; though the evidence underlying these recommendations has been questioned [68].

If a woman contemplating pregnancy has a first-degree relative with VTE and a known hereditary thrombophilia (Table 2), test for that thrombophilia if the result would change VTE prophylaxis decisions.

Women with a personal history of unprovoked, estrogen-associated or pregnancy associated VTE already carry an indication for prophylaxis, and are unlikely to benefit from thrombophilia testing.

Women with multiple family members affected by VTE are more likely to carry a higher risk thrombophilia such as AT deficiency which may impact prophylaxis decisions.

See Chapter 6, “Guidance for the treatment of obstetric-associated VTE” for regimens recommended for prophylaxis based on history and thrombophilia status.

Genotype-based tests (such as those for FVL and PGM) and antibody titers (for cardiolipin and beta-2 glycoprotein I) can be performed accurately at any point in the care of a patient. Certain assays for lupus anticoagulants can be performed in the presence of heparins but others may return a false-positive result. A clinician contemplating this test should verify the assay used by the local laboratory before performing the test in the setting of therapy with heparin or low-molecular weight heparin. The remaining thrombophilia tests are influenced by the presence of acute thrombosis or anticoagulant therapy. Therefore, it is best to avoid testing for these thrombophilias in the setting of an acute VTE or while a patient is on an anticoagulant [31]. In the patient with VTE in whom thrombophilia testing has been chosen (see above), either deferring testing until anticoagulation has been stopped, or a two-stage approach is reasonable. In the two-stage approach, tests for thrombophilia that can be reliably done on anticoagulation (FVL, PGM, cardiolipin and beta-2 Glycoprotein-I antibodies) are performed before stopping anticoagulation. If these tests are normal, anticoagulation is discontinued and the remaining thrombophilia tests (lupus anticoagulant, PC, PS and AT) are performed. A final decision on disposition of anticoagulation can then be made on the basis of results. The time that anticoagulation must be interrupted before testing can take place is controversial, and may vary according to the anticoagulant being used [25, 26, 72]. One approach is to perform testing following a 2–4-week period off anticoagulation, which would match the common timing for D-dimer assessment if this is also being performed to assist in decision-making [46]. In the primary prevention setting, it is important to note that pregnancy strongly influences PS activity. It is unclear what PS activity value is diagnostic of deficiency in the pregnant patient, but thresholds have been suggested [24]. When testing is chosen (see above), testing prior to pregnancy is preferred [24]. Regardless of when tested, PS deficiency is difficult to diagnose, and clinicians should be familiar with the limitations of different assays, and consider seeking expert consultation to confirm this diagnosis [73]. It is important to note that the results of thrombophilia tests are frequently misinterpreted by physicians [26] so correct timing of testing and careful interpretation are essential [31, 74].