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Abstract

Keywords

hormone therapy hormone replacement therapy oral contraceptive ProC&reg Global assay thrombophilic risk factor thrombosis venous thromboembolism

‘Although screening of women for thrombophilia prior to prescribing hormone therapy still remains debatable, application of global assays is expected to markedly improve cost-effectiveness in this setting.’

Over 100 million women worldwide use hormone therapy (HT), that is, oral contraceptives (OCs) or hormone replacement therapy (HRT); however, the use of HT is associated with an increased risk of venous thrombo-embolism (VTE), including deep-vein thrombosis, pulmonary embolism and cerebral vein thrombosis [1 –3]. While the risk is low in absolute terms, OCs are the major cause of thrombotic events in young women [1].

The increased risk of VTE is most probably due to the administration of exogenous estrogens, which leads to procoagulant changes [1,2]. The risk is still present with low-dose OCs (second and third generations; 20–30 mg of the estrogen ethinylestradiol) used currently, and with HRT preparations, which contain even lower dosages of estrogen and progestin compared with OC. HRT increases the risk of VTE by 2–3-fold compared with women without HT [4]. The risk is higher during the first year of HT use (up to 1/1000/year), with the use of a third-generation OC (desogestrel or gestodene instead of levonorgestrel or norgestrel) and among women with thrombophilic risk factors [1].

Thrombophilic risk factors

Thrombophilic risk factors are disorders of the hemostatic mechanisms that are likely to predispose to VTE [5]. Heritable thrombophilic risk factors include deficiencies of the natural anticoagulants antithrombin, protein C and protein S, and common genetic mutations, such as factor V Leiden, which is a point mutation at cleavage site 506 that renders factor V resistant to degradation by activated protein C (APC) [6]. The prothrombin G20210A mutation increases the risk of VTE via elevation of prothrombin levels [7], and the thermolabile variant of the methylene tetrahydrofolate reductase is associated with hyperhomocysteinemia [8].

Other relatively common thrombophilic risk factors, which have heritable and acquired components, include lupus anticoagulant, elevated levels of plasma factor VIII, hyperhomocysteinemia and acquired APC resistance [5].

Thrombophilic risk factors, hormone therapy & the risk of venous thrombosis

VTE is a multicausal disease in which acquired risk factors such as age, cancer, pregnancy and HT, together with inherited thrombophilic risk factors, significantly increase the risk of developing VTE. The use of HT is associated with an acquired hypercoagulable state due to decreased plasma levels of protein S [4,9], increased resistance to APC [10,11], and increased levels of prothrombin, factors VII, VIII and X, and fibrinogen [12]. Therefore, the combination of HT use and thrombophilic risk factors has a synergistic effect on the risk of VTE. Women heterozygous for factor V Leiden who are using an OC have a 20–30-fold increased risk of VTE compared with those without factor V Leiden who do not use an OC [13]. Homozygosity for factor V Leiden leads to a 50–100-fold increased risk of VTE [14].

‘The ProC® Global assay is a global coagulation test that evaluates the protein C anticoagulant pathway and has emerged as an important test in the evaluation of the thrombophilic risk of VTE.’

A recent meta-analysis showed significant associations between OC use and the risk of VTE in women with factor V Leiden (odds ratio [OR]: 15.6; 95% confidence interval [CI]: 8.7–28.15); deficiencies of antithrombin (OR: 12.6; 95% CI: 1.4–115.8), protein C (OR: 6.3; 95% CI: 1.7–23.9) or protein S (OR: 4.9; 95% CI: 1.4–17.1); elevated levels of factor VIII (OR: 8.8; 95% CI: 4.1–18.7) and factor V Leiden and prothrombin G20210A (OR: 7.8; 95% CI: 1.6–37.4). For HRT, a significant association was found in women with factor V Leiden (OR: 13; 95% CI: 4.3–40.5) [15].

Another meta-analysis found a high risk of cerebral vein thrombosis in women with a prothrombin G20210A mutation or with hyperhomocysteinemia using OC compared with healthy controls (OR: 9.3; 95% CI: 5.6–14.7; p < 0.001 and OR: 4.1; 95% CI: 2.5–6.5; p < 0.001, respectively) [3].

In addition, a study of unselected relatives with various thrombophilic defects found that the synergistic effect of OCs for VTE appeared even higher for deficiencies of protein C, protein S and antithrombin than for factor V Leiden [16].

These findings support the presence of interactions between thrombophilic risk factors and VTE among women using HT and emphasize the need for identification of women at high risk of VTE before administration of HT.

ProC® Global assay evaluates abnormalities in the protein C pathway

Since defects in the protein C anticoagulant pathway, including protein C and protein S deficiencies and APC resistance with or without factor V Leiden, are major risk factors of VTE [17], a screening assay for this pathway could be potentially useful in the identification of women with increased risk of VTE during treatment with HT. ProC® Global assay (Dade Behring, Marburg, Germany), developed for evaluation of the protein C pathway, utilizes the protein C activator of Agkistrodon contortrix contortrix venom, which activates endogenous protein C in the detected plasma sample. The endogenous APC activity is measured by an activated partial thromboplastin time base-clotting assay. The clotting time is measured with and without protein C activation and the ratio between these times is calculated and expressed by the protein C activation time – normalized ratio (PCAT-NR) [18,19].

The ProC Global assay revealed a high sensitivity for detection of protein C deficiency, APC resistance and factor V Leiden mutation but controversial sensitivity for protein S deficiency [19 –21].

In multicenter studies, abnormal ProC Global assay results were found to be associated with first episode of VTE [22,23] and recurrent VTE [24]. Furthermore, abnormal ProC Global assay results were found to be more common (70%) in women with pregnancy loss, pre-eclampsia, and hemolytic anemia, elevated liver enzymes and low platelet count (HELLP) syndrome compared with healthy women without these complications [25,26].

‘Following a thorough personal and family medical history prior to the initiation of HT in any woman, we suggest screening for thrombophilic risk factors using three tests: ProC Global assay prothrombin G20210A mutation and level of homocysteine.’

ProC Global assay in women with a history of VTE while using hormone therapy

Recently, ProC Global assay was evaluated in 32 women with a history of VTE while using HT compared with 56 healthy controls not using HT, matched by patient's age at blood sampling; and 40 healthy controls using HT, matched by age and HT at patient's VTE event [27]. Abnormal ProC Global assay results were detected in 72% of patients compared with 9% of controls matched by age at the time of blood sampling (OR: 26; 95% CI: 7–106; p < 0.001) and 22.5% of controls matched by HT and age at the time of a VTE event (OR: 9; 95% CI: 2.7–30; p < 0.001) [27].

In this study, of the variables that are risk factors for VTE, such as age, HT use or thrombophilic risk factor, abnormal ProC Global assay results were found by the multivariate analysis to be the variable most commonly associated with VTE in women receiving HT (estimated OR: 15.8; 95% CI: 4.2–59.0; p < 0.001). These results suggest that ProC Global assay can potentially serve as a diagnostic tool for evaluating the risk of VTE in women prior to HT administration. Moreover, within this group of patients with a history of VTE while using HT, abnormal PCAT-NR levels were documented at the same proportions in patients with (75%) and without (67%) a known thrombophilic risk factor, suggesting that abnormal results of the ProC Global assay may be considered as a new risk factor in women with or without thrombophilia who are at risk of developing VTE while receiving HT.

Is the identification of women at high risk of VTE before administration of hormone therapy justifiable?

According to a recent systematic review by the WHO Collaborating Center in Reproductive Health, a greater risk of VTE was found only in OC users with factor V Leiden mutation when compared with nonusers who have the mutation (risk ratio: 1.3–25.1), and the evidence for other thrombophilic risk factors was much weaker [28]. If all women were screened for thrombophilic risk factors before using OCs, 3–6% of them would be denied OCs while preventing only a very small number of VTE events [28]. Therefore, the Expert Working Group for medical eligibility criteria for contraceptive use issued a clarification with the recommendation that “routine screening is not appropriate because of the rarity of the conditions and the high cost of screening” [28].

‘The future of medicine lies in the prevention rather than in the treatment of symptomatic disease.’

The Expert Working Group also recommended that women with a known thrombophilic risk factor should not use combined hormonal contraceptive methods (WHO Category 4), but can use progestogen-only methods, including levonorgestrel-releasing intrauterine devices (WHO Category 2).

A recent cost-effectiveness analysis conducted by the Thrombosis: Risk and Economic Assessment of Thrombophilia Screening Study of the UK NHS revealed that universal screening of women prior to prescribing HRT was the most cost-effective strategy (incremental cost-effectiveness ratio [ICER]: £6824). By contrast, universal screening of women prior to prescribing combined OCs was the least cost-effective strategy (ICER: £202,402) [15]. Selective thrombophilia screening based on previous personal and/or family history of VTE was more cost-effective than universal screening in all the patient groups evaluated. However, these cost-effectiveness analyses related to full thrombophilic risk factor detection.

Despite these findings, it is clear that identification of women at risk of thrombosis before exposure to HT, that is, OCs or HRT, is important for prevention and management of VTE events. Application of global assays such as ProC Global assay is expected to markedly increase the cost-effectiveness of universal screening for thrombophilic risk factors.

ProC Global assay is a global coagulation test that evaluates the protein C anticoagulant pathway and has emerged as an important test in the evaluation of the thrombophilic risk of VTE [22 –24], and, according to our recent results [27], can serve as an important test before administration of HT.

A thorough personal medical and family history of VTE and gestational vascular complications is advisable before prescribing HT. If the personal and family history is positive, evaluation of all thrombophilic risk factors is advisable. If personal and family history is negative, since antithrombin deficiency is very rare in the healthy population, we suggest evaluating the risk of VTE by limited testing. As the most common risk factors of VTE are located in the protein C pathway, we suggest testing ProC Global assay as well as prothrombin G20210A mutation and homocysteine level in healthy women prior to administration of HT.

Future perspective

The future of medicine lies in the prevention rather than in the treatment of symptomatic disease. Identification of individuals at high risk of VTE before exposure to acquired hypercoagulable states, such as long-haul flights, pregnancy or HT, is necessary. Following a thorough personal and family medical history prior to the initiation of HT in any woman, we suggest screening for thrombophilic risk factors using three tests: ProC Global assay, prothrombin G20210A mutation and level of homocysteine.

Prospective studies should focus on evaluating the cost-effectiveness of screening for these tests in populations stratified for risk of VTE.

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Identifying Women at High Risk of Venous Thrombosis before Administration of Hormone Therapy

Abstract

Keywords

Thrombophilic risk factors

Thrombophilic risk factors, hormone therapy & the risk of venous thrombosis

ProC® Global assay evaluates abnormalities in the protein C pathway

ProC Global assay in women with a history of VTE while using hormone therapy

Is the identification of women at high risk of VTE before administration of hormone therapy justifiable?

Future perspective

References