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8 The patient with thrombophilia
Yorain Sri Ranjan and Ying C. Cheong
Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK; Complete Fertility Centre, Princess Anne Hospital, Southampton, UK
Case History: A 35‐year‐old solicitor with a 3‐year history of unexplained subfertility presented for IVF treatment. She had a deep venous thrombosis (DVT) when she was 22 years old whilst taking the oral contraceptive pill. All investigations for thrombophilia were then negative. She is fit and well. Her body mass index (BMI) is 35; she is a nonsmoker and only drinks alcohol socially. Her partner is 34 years old and is fit and well. He has a normal semen analysis. The patient and her husband have come for a consultation regarding their IVF treatment but are concerned about the risks associated with her previous DVT.
Background
Thromboembolism is a rare complication of ovarian stimulation for IVF. The incidence has been estimated to be 1.6 per 100,000 cycles [1], and the majority of cases of thromboembolism reported in the literature are associated with the presence of risk factors for thromboembolic disease [2]. A 2017 systematic review has demonstrated that the frequency of venous thromboembolism (VTE) during pregnancy in patients after IVF, with or without ovarian hyperstimulation syndrome (OHSS), varies between 0.8 and 25 per 1,000 cycles (cf. 0.17–2.5 per 1,000 for natural pregnancies) [3]. Furthermore, in women who experience OHSS in fresh IVF cycles, there is almost a 100‐fold increased risk of VTE in the first trimester, as compared with natural conception [4]. It is therefore important to identify women at increased risk of this complication in order to provide appropriate counseling and management, and to allow preventative steps to be taken where necessary. Venous thrombosis is a potentially serious disorder which may often lead to post‐thrombotic syndrome causing chronic morbidity. Because women undergoing IVF are generally young and active, this may afflict their lives for many years.
The pathogenesis of venous thrombosis is complex and not completely understood. Ovarian stimulation results in a hyperestrogenic state, which has been thought to be associated with hypercoagulability and increased risk of deep venous thrombosis (DVT). However, in recent years a number of studies have shown changes in coagulation during IVF treatment to be modest [5,6]. Recent data suggest that hyperestrogenism related to ovarian stimulation is not associated with the coagulation abnormalities observed with high estrogen‐content oral contraceptives, and therefore does not significantly increase the potential for thrombus formation. During down‐regulation and luteal support the changes in plasma levels of anticoagulant proteins are virtually negligible. The only coagulation variable that may change considerably during IVF treatment is activated protein C resistance; patients resistant to activated protein C have been shown to be at greater risk of thrombosis during ovarian stimulation. The prothrombotic state appears to be most significant after the administration of human chorionic gonadotropin (hCG). Following hCG administration, levels of fibrinogen and factors II, V, VII, VIII and IX are elevated. In one study, activation of the coagulation cascade system was observed to occur within 2 days after hCG, reaching a maximum approximately 8 days following hCG administration [7]. Activation of these systems was observed to continue for more than 3 weeks when pregnancy was established. The predominant contribution of hCG rather than estradiol in the pathogenesis of VTE after ovarian stimulation is also supported by the clinical observation that in frozen thawed cycles where only estradiol is used, the risk of VTE is comparable to natural conceptions [4].
All patients proceeding to IVF treatment should be individually assessed for their risk of thrombotic complications (Table 8.1) [8].
Thrombotic disorders
Inherited thrombophilia
Fifteen to 25% of Caucasian populations have thrombophilic risk factors. Heritable thrombophilias include deficiencies of the endogenous anticoagulants, antithrombin, protein C and protein S, and genetic mutations in procoagulant factors such as factor V Leiden and prothrombin G20210A, and the thermolabile (C677T) variant of the methylene tetrahydro‐folate reductase (MTHFR) gene. The prevalence of these thrombophilias is variable, with significant ethnic variation. For example, 2–7% of Western European populations are heterozygous for factor V Leiden and prothrombin G20210A compared with less than 1% of Chinese.
Table 8.1 Risk factors for venous thromboembolism (VTE) [8].
| History markers | |
|---|---|
| Previous venous or arterial thromboembolism | |
| Obesity (body mass index ≥30 kg/m2) | |
| Gross varicose veins | |
| Previous/current intravenous drug abuse | |
| Age over 35 years | |
| Parity >=3 | |
| Smoker | |
| Ovarian hyperstimulation syndrome | |
| Dehydration | |
| Immobility | |
| Prolonged bed rest | |
| Prolonged travel | |
| Medical conditions (such as infections, malignancies, cardiac conditions, active systemic lupus erythematosus, inflammatory bowel disease, sickle cell disease, type 1 diabetes with nephropathy, nephrotic syndrome etc.) | |
| Inherited thrombophilia | Odds ratio for VTE (95% confidence interval) |
| Factor V Leiden heterozygous | 9.2 (5.44–12.70) |
| Factor V Leiden homozygous | 34.40 (9.86–120.05) |
| Antithrombin deficiency | 4.69 (1.30–16.96) |
| Protein C deficiency | 4.76 (2.15–10.57) |
| Prothrombin G20210A heterozygous | 6.80 (2.46–19.77) |
|
Prothrombin
| |