Concerns about the ALIFE2 Trial.

We have several concerns about the conclusions of the ALIFE2 study by Siobhan Quenby and colleagues.1Quenby S Booth K Hiller L et al.Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): an international open-label, randomised controlled trial.Lancet. 2023; 402: 54-61Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar First, even if low-molecular-weight heparin (LMWH) does not reduce recurrent pregnancy loss, it should also be prescribed for the purpose of preventing venous thromboembolism (ie, deep vein thrombosis and pulmonary embolism). The fact that women with inherited thrombophilia have a high risk of venous thromboembolism during pregnancy is well known. As per the 2018 guidelines for venous thromboembolism by the American Society of Hematology,2Bates SM Rajasekhar A Middeldorp S et al.American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.Blood Adv. 2018; 2: 3317-3359Crossref PubMed Scopus (294) Google Scholar pooled absolute risks are particularly high in women with antithrombin deficiency or factor V Leiden homozygous mutation (antepartum risk 6·86%; 95% CI 1·04–15·83%). Women with thrombophilia should receive LMWH, as the 2018 guidelines recommend. The benefit would be a risk reduction of 75% in thromboembolism. The 2018 guidelines also showed that risk of antepartum bleeding was not significantly increased.2Bates SM Rajasekhar A Middeldorp S et al.American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.Blood Adv. 2018; 2: 3317-3359Crossref PubMed Scopus (294) Google Scholar Second, in Quenby and colleagues’ Article,1Quenby S Booth K Hiller L et al.Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): an international open-label, randomised controlled trial.Lancet. 2023; 402: 54-61Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar 30 (19%) of the 162 participants in the standard care group also received LMWH during pregnancy due to the needs of thromboprophylaxis, which seriously affected the results of the study. Third, 44 (13%) of 326 women had diagnosed protein S deficiency, usually defined as protein S concentrations below 60%. However, previous studies have suggested protein S deficiency is prevalent in the general population.3Tang L Jian XR Hamasaki N et al.Molecular basis of protein S deficiency in China.Am J Hematol. 2013; 88: 899-905Crossref PubMed Scopus (30) Google Scholar Only protein S concentrations below 30% confer a mildly increased risk for venous thromboembolism (relative risk 1·48; 95% CI 1·08–2·04).4Alhenc-Gelas M Plu-Bureau G Horellou MH Rauch A Suchon P PROS1 genotype phenotype relationships in a large cohort of adults with suspicion of inherited quantitative protein S deficiency.Thromb Haemost. 2016; 115: 570-579Crossref PubMed Google Scholar The cutoff value for identifying individuals at increased risk was far below the lower limit of the normal range. Therefore, most individuals with protein S deficiency are not susceptible to thromboembolism and should not be considered as thrombophilic. Lastly, LMWH exerts anticoagulant effects through interaction with antithrombin.5Croles FN Lukens MV Mulder R de Maat MPM Mulder AB Meijer K Monitoring of heparins in antithrombin-deficient patients.Thromb Res. 2019; 175: 8-12Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar People with antithrombin deficiency are heparin resistant and standard LMWH doses always lead to under treatment. A dose-adjusted anticoagulation strategy should be further investigated for people with thrombophilia. We declare no competing interests. Concerns about the ALIFE2 trial – Authors’ replyWe thank the authors for their interest in our study, ALIFE2.1 We agree with Bingwen Eugene Fan that few women in the study had antithrombin deficiency, and Liang V Tang and colleagues, who state that low-molecular-weight heparin (LMWH) thromboprophylaxis should be considered in women with inherited thrombophilia and pregnancy. We excluded women for whom thromboprophylaxis was indicated throughout pregnancy as per local interpretations of international guidelines. The American Society of Hematology's 2018 guideline does not recommend antepartum thromboprophylaxis for women with antithrombin deficiency who have no family history of venous thromboembolism. Full-Text PDF