I. D. Walker

Increased fetal loss in women with heritable thrombophilia.

BACKGROUND A successful outcome of pregnancy requires an efficient uteroplacental vascular system. Since this system may be compromised by disorders of haemostasis associated with a prothrombotic state, we postulated that maternal thrombophilia might be a risk factor for fetal loss. We studied the relation between heritable thrombophilic defects and fetal loss in a cohort of women with factor V Leiden or deficiency of antithrombin, protein C, or protein S. METHODS We studied 1384 women enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). Of 843 women with thrombophilia 571 had 1524 pregnancies; of 541 control women 395 had 1019 pregnancies. The controls were partners of male members of the EPCOT cohort or acquaintances of cases. We analysed the frequencies of miscarriage (fetal loss at or before 28 weeks of gestation) and stillbirth (fetal loss after 28 weeks of gestation) jointly and separately. FINDINGS The risk of fetal loss was increased in women with thrombophilia (168/571 vs 93/395; odds ratio 1.35 [95% Cl 1.01-1.82]). The odds ratio was higher for stillbirth than for miscarriage (3.6 [1.4-9.4] vs 1.27 [0.94-1.71]). The highest odds ratio for stillbirth was in women with combined defects (14.3 [2.4-86.0]) compared with 5.2 (1.5-18.1) in antithrombin deficiency, 2.3 (0.6-8.3) in protein-C deficiency, 3.3 (1.0-11.3) in protein-S deficiency, and 2.0 (0.5-7.7) with factor V Leiden. The corresponding odds ratios for miscarriage in these subgroups were 0.8 (0.2-3.6), 1.7 (1.0-2.8), 1.4 (0.9-2.2), 1.2 (0.7-1.9), and 0.9 (0.5-1.5). Significantly more pregnancy terminations had been done in women with thrombophilia than in controls (odds ratio 2.9 [1.8-4.8]); this discrepancy was apparent in nine of 11 participating centres and for all thrombophilia subgroups. INTERPRETATION Women with familial thrombophilia, especially those with combined defects or antithrombin deficiency, have an increased risk of fetal loss, particularly stillbirth. Our findings have important implications for therapy and provide a rationale for clinical trials of thromboprophylaxis for affected women with recurrent fetal loss.

Clinical guidelines for testing for heritable thrombophilia

Trevor Baglin, Elaine Gray, Mike Greaves, Beverley J. Hunt, David Keeling, Sam Machin, Ian Mackie, Mike Makris, Tim Nokes, David Perry, R. C. Tait, Isobel Walker and Henry Watson Addenbrooke’s Hospital, Cambridge, NIBSC, South Mimms, University of Aberdeen, Aberdeen, Guy’s and St Thomas’, London, Churchill Hospital, Oxford, University College Hospital, London, Royal Hallamshire Hospital, Sheffield, Derriford Hospital, Plymouth, Glasgow Royal Infirmary, Glasgow and Aberdeen Royal Infirmary, UK

A study of Protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state.

Total Protein S (tPS) and free Protein S (fPS) antigen levels were measured in 3788 healthy blood donors. Men had higher levels of both parameters than women (P < 0·001). Age had no effect on tPS in men, although there was a slight reduction in fPS levels with increasing age. In women increasing age was associated with a significant increase in tPS levels (P < 0·001) but had no effect on fPS after adjustment for menopausal state. Oral contraceptive pill (OCP) use significantly lowered tPS but had no effect on fPS. In post‐menopausal women, hormone replacement therapy (HRT) use had no statistically significant effect on either tPS or fPS. Donors with tPS or fPS levels in the lowest percentile (n = 56) were retested; only nine with repeat low levels were identified, eight of whom had persistently low levels over a 4–7‐year follow‐up. Acquired deficiency was excluded. When possible, family studies were performed, leading to an estimate of prevalence of familial PS deficiency of between 0·03% and 0·13% in the general population.

Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT)

Summary.  Background: Reliable risk estimates for venous thrombosis in families with inherited thrombophilia are scarce but necessary for determining optimal screening and treatment policies. Objectives: In the present analysis, we determined the risk of a first venous thrombotic event in carriers of a thrombophilic defect (i.e. antithrombin‐, protein C‐ or protein S deficiency, or factor V Leiden). Patients and methods: The asymptomatic carriers had been tested prior to this study in nine European thrombosis centers because of a symptomatic carrier in the family, and were followed prospectively for 5.7 years on average between March 1994 and January 2001. Annually, data were recorded on the occurrence of risk situations for venous thrombosis and events (e.g. venous thrombosis, death). Results: Twenty‐six of the 575 asymptomatic carriers (4.5%) and seven of the 1118 controls (0.6%) experienced a first deep venous thrombosis or pulmonary embolism during follow‐up. Of these events, 58% occurred spontaneously in the carriers compared with 43% in the controls. The incidence of first events was 0.8% per year (95% CI 0.5–1.2) in the carriers compared with 0.1% per year (95% CI 0.0–0.2) in the controls. The highest incidence was associated with antithrombin deficiency or combined defects, and the lowest incidence with factor V Leiden. Conclusions: The incidence of venous events in asymptomatic individuals from thrombophilic families does not exceed the risk of bleeding associated with long‐term anticoagulant treatment in the literature (1–3%).

Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series

Objectives To assess the use of low molecular weight heparin for the treatment of venous thromboembolism in pregnancy.

Recurrence Rate After a First Venous Thrombosis in Patients With Familial Thrombophilia

Objective—Few comprehensive data are available on the recurrence rate of venous thrombosis in carriers of thrombophilic defects from thrombophilic families. We prospectively determined the recurrence rate after a first venous thrombotic event in patients with familial thrombophilia attributable to factor V Leiden or deficiencies of protein C, S, or antithrombin. Methods and Results—Data were gathered during follow-up on the occurrence of risk situations, anticoagulation treatment, and events (eg, venous thrombosis, hemorrhage). Over a mean follow-up period of 5.6 years, 44 of the 180 patients with familial thrombophilia who did not use long-term anticoagulation experienced a recurrent venous thromboembolic event (5.0%/year; 95% CI 3.6 to 6.7) compared with 7 of the 124 patients on long-term anticoagulation (1.1%/year; 95% CI 0.4 to 2.2). Spontaneous events occurred less often in patients on long-term anticoagulation (57%) than in patients without long-term anticoagulation (75%). The highest recurrence rate was found among men with a deficiency in natural anticoagulants or multiple defects and women with antithrombin deficiency. Although long-term anticoagulation treatment decreased the incidence of recurrent events by 80%, it also resulted in a risk of major hemorrhage of 0.8% per year. Conclusions—Extra care after a first event is required for men with a deficiency in natural anticoagulants or multiple defects and women with antithrombin deficiency.

Prothrombin 20210 G→A, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy

Over 50 unselected women with maternal venous thromboembolism were screened for the prothrombin 20210 G→A and MTHFR C677T mutations, in addition to screening for other thrombophilias. The prevalence of thrombophilia in these women was compared with its prevalence in the general population in our area. The prothrombin (OR 4.4; 95% CI 1.2‐16) and factor V Leiden (OR 4.5; 95% CI 2.1‐14.5) mutations were more common in our patients, compared with the general population, whereas women homozygous for the C677T mutation in the methylene tetrahydrofolate reductase gene (OR 0.45; 95% CI 0.13‐1.58) were not. It is recommended that women with a personal or strong family history of venous thromboembolism should be screened for the prothrombin mutation either before or early in pregnancy, in addition to screening for other thrombophilias. Screening for the MTHFR mutation does not appear to identify women at increased risk of maternal venous thrombosis.

Familial thrombophilia and lifetime risk of venous thrombosis

Summary  Background : We started a large multicenter prospective follow‐up study to provide reliable risk estimates of venous thrombosis in families with various thrombophilic defects.

Hereditary thrombophilia and fetal loss: a prospective follow-up study

Summary.  Background: As the placental vessels are dependent on the normal balance of procoagulant and anticoagulant mechanisms, inherited thrombophilia may be associated with fetal loss. Objectives: We performed a prospective study to investigate the relation between inherited thrombophilia and fetal loss, and the influence of thromboprophylaxis on pregnancy outcome. Patients and methods: Women were enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). These included women with factor (F)V Leiden or a deficiency of antithrombin, protein C or protein S. Controls were partners or acquaintances of thrombophilic individuals. A total of 191 women (131 with thrombophilia, 60 controls) had a pregnancy outcome during prospective follow‐up. Risk of fetal loss and effect of thromboprophylaxis were estimated by frequency calculation and Cox regression modelling. Results: The risk of fetal loss appeared slightly increased in women with thrombophilia without a previous history of fetal loss who did not use any anticoagulants during pregnancy (7/39 vs. 7/51; relative risk 1.4; 95% confidence interval 0.4, 4.7). Per type of defect the relative risk varied only minimally from 1.4 for FV Leiden to 1.6 for antithrombin deficiency compared with control women. Prophylactic anticoagulant treatment during pregnancy in 83 women with thrombophilia differed greatly in type, dose and duration, precluding solid conclusions on the effect of thromboprophylaxis on fetal loss. No clear benefit of anticoagulant prophylaxis was apparent. Conclusions: Women with thrombophilia appear to have an increased risk of fetal loss, although the likelihood of a positive outcome is high in both women with thrombophilia and in controls.

The role of inherited thrombophilia in venous thromboembolism associated with pregnancy

Venous thromboembolism is an important cause of maternal morbidity and mortality. The puerperium should be regarded as the period of greatest risk. However, fatalities in early pregnancy emphasise the need to assess thrombotic risk at all stages of pregnancy. In many cases those at increased risk are potentially identifiable on clinical grounds alone such as those with a personal or family history of venous thromboembolism, obesity, or surgery. Identification of women with multiple clinical risks for thrombosis during pregnancy remains the key to reducing the incidence of this condition. In women who present with a personal or family history of proven venous thromboembolism, thrombophilia screening should be performed in early pregnancy, since the results may influence subsequent management during pregnancy. The investigation and management of patients considered at increased risk of venous thrombosis during pregnancy requires close liaison between obstetricians and haematologists familiar with this rapidly expanding and complex field of thrombophilia.