{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T16:09:29Z","timestamp":1770998969978,"version":"3.50.1"},"reference-count":53,"publisher":"Elsevier BV","issue":"2","license":[{"start":{"date-parts":[[2007,4,1]],"date-time":"2007-04-01T00:00:00Z","timestamp":1175385600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2007,4,1]],"date-time":"2007-04-01T00:00:00Z","timestamp":1175385600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Seminars in Hematology"],"published-print":{"date-parts":[[2007,4]]},"DOI":"10.1053\/j.seminhematol.2007.01.005","type":"journal-article","created":{"date-parts":[[2007,4,12]],"date-time":"2007-04-12T07:13:10Z","timestamp":1176361990000},"page":"93-97","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":26,"title":["Pregnancy Failure and Heritable Thrombophilia"],"prefix":"10.1053","volume":"44","author":[{"given":"Saskia","family":"Middeldorp","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1053\/j.seminhematol.2007.01.005_bib1","first-page":"516","article-title":"Inherited antithrombin III deficiency causing thrombophilia","volume":"13","author":"Egeberg","year":"1965","journal-title":"Thromb Diath Haemorrh"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib2","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1172\/JCI110385","article-title":"Deficiency of protein C in congenital thrombotic disease","volume":"68","author":"Griffin","year":"1981","journal-title":"J Clin Invest"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib3","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1056\/NEJM198412133112401","article-title":"Recurrent venous thromboembolism in patients with a partial deficiency of protein S","volume":"311","author":"Comp","year":"1984","journal-title":"N Engl J Med"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib4","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/369064a0","article-title":"Mutation in blood coagulation factor V associated with resistance to activated protein C","volume":"369","author":"Bertina","year":"1994","journal-title":"Nature"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib5","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1073\/pnas.90.3.1004","article-title":"Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C","volume":"90","author":"Dahlback","year":"1993","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib6","doi-asserted-by":"crossref","first-page":"3698","DOI":"10.1182\/blood.V88.10.3698.bloodjournal88103698","article-title":"A common genetic variation in the 3\u2032-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis","volume":"88","author":"Poort","year":"1996","journal-title":"Blood"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib7","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1161\/01.ATV.14.7.1080","article-title":"High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis","volume":"14","author":"Falcon","year":"1994","journal-title":"Arterioscler Thromb"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib8","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1055\/s-0037-1615380","article-title":"Hyperhomocysteinemia and venous thrombosis: A meta-analysis","volume":"80","author":"den Heijer","year":"1998","journal-title":"Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib9","doi-asserted-by":"crossref","first-page":"226","DOI":"10.7326\/0003-4819-145-3-200608010-00011","article-title":"Trials that matter: Should we routinely measure homocysteine levels and \u201ctreat\u201d mild hyperhomocysteinemia?","volume":"145","author":"Rosenberg","year":"2006","journal-title":"Ann Intern Med"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib10","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1182\/blood-2006-04-014654","article-title":"Homocysteine lowering by B vitamins and the secondary prevention of deep-vein thrombosis and pulmonary embolism","volume":"109","author":"den Heijer","year":"2007","journal-title":"Blood"},{"issue":"suppl 1","key":"10.1053\/j.seminhematol.2007.01.005_bib11","first-page":"P0481","article-title":"Absolute risk of venous and arterial thromboembolism associated with mild hyperhomocysteinemia","volume":"3","author":"Van de Poel","year":"2005","journal-title":"J Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib12","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1159\/000065076","article-title":"Common C677T polymorphism of the methylenetetrahydrofolate reductase gene and the risk of venous thromboembolism: Meta-analysis of 31 studies","volume":"32","author":"Ray","year":"2002","journal-title":"Pathophysiol Haemost Thromb"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib13","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/S0140-6736(95)90166-3","article-title":"Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis","volume":"345","author":"Koster","year":"1995","journal-title":"Lancet"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib14","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1055\/s-0037-1614985","article-title":"Familial clustering of factor VIII and von Willebrand factor levels","volume":"79","author":"Kamphuisen","year":"1998","journal-title":"Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib15","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/j.1538-7836.2004.01033.x","article-title":"Elevated levels of FVIII:c within families are associated with an increased risk for venous and arterial thrombosis","volume":"3","author":"Bank","year":"2005","journal-title":"J Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib16","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1046\/j.1365-2141.2000.02091.x","article-title":"Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia","volume":"109","author":"Kamphuisen","year":"2000","journal-title":"Br J Haematol"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib17","doi-asserted-by":"crossref","first-page":"3008","DOI":"10.1093\/humrep\/dei167","article-title":"Updated and revised nomenclature for description of early pregnancy events","volume":"20","author":"Farquharson","year":"2005","journal-title":"Hum Reprod"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib18","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/S0140-6736(06)69204-0","article-title":"Recurrent miscarriage","volume":"368","author":"Rai","year":"2006","journal-title":"Lancet"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib19","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1053\/beog.2000.0124","article-title":"Genetic aspects of miscarriage","volume":"14","author":"Goddijn","year":"2000","journal-title":"Baillieres Best Pract Res Clin Obstet Gynaecol"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib20","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1111\/j.1538-7836.2006.01753.x","article-title":"International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)","volume":"4","author":"Miyakis","year":"2006","journal-title":"J Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib21","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1055\/s-0038-1650282","article-title":"The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women","volume":"75","author":"Sanson","year":"1996","journal-title":"Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib22","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/S0140-6736(96)04125-6","article-title":"Increased fetal loss in women with heritable thrombophilia","volume":"348","author":"Preston","year":"1996","journal-title":"Lancet"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib23","doi-asserted-by":"crossref","first-page":"736","DOI":"10.7326\/0003-4819-130-9-199905040-00013","article-title":"Increased risk for fetal loss in carriers of the factor V Leiden mutation","volume":"130","author":"Meinardi","year":"1999","journal-title":"Ann Intern Med"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib24","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/S0140-6736(03)12771-7","article-title":"Thrombophilic disorders and fetal loss: A meta-analysis","volume":"361","author":"Rey","year":"2003","journal-title":"Lancet"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib25","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/j.1365-2141.2005.05847.x","article-title":"Thrombophilia in pregnancy: A systematic review","volume":"132","author":"Robertson","year":"2006","journal-title":"Br J Haematol"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib26","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1055\/s-0037-1613083","article-title":"Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: Results from a large population-based study and systematic review","volume":"87","author":"Morrison","year":"2002","journal-title":"Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib27","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1191\/0961203302lu266oa","article-title":"Biology and pathology of the placenta in relation to antiphospholipid antibody-associated pregnancy failure","volume":"11","author":"Sebire","year":"2002","journal-title":"Lupus"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib28","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.fertnstert.2004.07.978","article-title":"Antiphospholipid antibodies prevent extravillous trophoblast differentiation","volume":"83","author":"Quenby","year":"2005","journal-title":"Fertil Steril"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib29","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ajog.2004.09.029","article-title":"Heparin and aspirin attenuate placental apoptosis in vitro: Implications for early pregnancy failure","volume":"192","author":"Bose","year":"2005","journal-title":"Am J Obstet Gynecol"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib30","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nm825","article-title":"The thrombomodulin-protein C system is essential for the maintenance of pregnancy","volume":"9","author":"Isermann","year":"2003","journal-title":"Nat Med"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib31","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1136\/bmj.314.7076.253","article-title":"Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies)","volume":"314","author":"Rai","year":"1997","journal-title":"BMJ"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib32","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1097\/00006250-200212000-00032","article-title":"Antiphospholipid syndrome in pregnancy: A randomized, controlled trial of treatment","volume":"100","author":"Farquharson","year":"2002","journal-title":"Obstet Gynecol"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib33","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/j.fertnstert.2004.11.002","article-title":"Antiphospholipid antibodies associated with recurrent pregnancy loss: Prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin","volume":"83","author":"Noble","year":"2005","journal-title":"Fertil Steril"},{"issue":"2","key":"10.1053\/j.seminhematol.2007.01.005_bib34","doi-asserted-by":"crossref","DOI":"10.1002\/14651858.CD002859.pub2","article-title":"Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant","author":"Empson","year":"2005","journal-title":"The Cochrane Database of Systematic Reviews"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib35","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1067\/mob.2000.106754","article-title":"Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid antibody syndrome?","volume":"183","author":"Pattison","year":"2000","journal-title":"Am J Obstet Gynecol"},{"issue":"suppl","key":"10.1053\/j.seminhematol.2007.01.005_bib36","doi-asserted-by":"crossref","first-page":"627S","DOI":"10.1378\/chest.126.3_suppl.627S","article-title":"Use of antithrombotic agents during pregnancy","volume":"126","author":"Bates","year":"2004","journal-title":"Chest"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib37","doi-asserted-by":"crossref","DOI":"10.1111\/j.1538-7836.2005.01417.x","article-title":"Thrombophilia and pregnancy outcomes","volume":"3","author":"Pabinger","year":"2005","journal-title":"J Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib38","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1046\/j.1538-7836.2003.00504.x","article-title":"Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications\u2014Yes","volume":"1","author":"Brenner","year":"2003","journal-title":"J Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib39","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1046\/j.1538-7836.2003.00503.x","article-title":"Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications\u2014No","volume":"1","author":"Middeldorp","year":"2003","journal-title":"J Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib40","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1093\/humrep\/17.2.442","article-title":"Factor V Leiden and recurrent miscarriage\u2014Prospective outcome of untreated pregnancies","volume":"17","author":"Rai","year":"2002","journal-title":"Hum Reprod"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib41","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1111\/j.1538-7836.2006.01839.x","article-title":"The natural course of women with recurrent fetal loss","volume":"4","author":"Lindqvist","year":"2006","journal-title":"J Thromb Haemost"},{"issue":"suppl","key":"10.1053\/j.seminhematol.2007.01.005_bib42","article-title":"Natural course of the subsequent pregnancy after a single loss in women with and without the factor V Leiden or prothrombin 20210A mutations","author":"Coppens","year":"2006","journal-title":"Blood"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib43","doi-asserted-by":"crossref","first-page":"3695","DOI":"10.1182\/blood-2003-12-4250","article-title":"Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder","volume":"103","author":"Gris","year":"2004","journal-title":"Blood"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib44","doi-asserted-by":"crossref","first-page":"3413","DOI":"10.1182\/blood-2004-06-2121","article-title":"Important publication missing key information","volume":"104","author":"Rodger","year":"2004","journal-title":"Blood"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib45","first-page":"3413","article-title":"Response: Thromboprophylaxis for first fetal loss","volume":"104","author":"Gris","year":"2004","journal-title":"Blood"},{"issue":"2","key":"10.1053\/j.seminhematol.2007.01.005_bib46","doi-asserted-by":"crossref","DOI":"10.1002\/14651858.CD004734.pub2","article-title":"Anticoagulants for the treatment of recurrent pregnancy loss in women without antiphospholipid syndrome","author":"DiNisio","year":"2005","journal-title":"The Cochrane Database of Systematic Reviews"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib47","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/j.1538-7836.2004.01090.x","article-title":"Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: The LIVE-ENOX study","volume":"3","author":"Brenner","year":"2005","journal-title":"J Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib48","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/j.1538-7836.2005.01155.x","article-title":"Low molecular weight heparin for repeated pregnancy loss\u2014Is it based on solid evidence?","volume":"3","author":"Lindqvist","year":"2005","journal-title":"J Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib49","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1111\/j.1538-7836.2005.01288.x","article-title":"The use of LMWH in pregnancies at risk: New evidence or perception?","volume":"3","author":"Middeldorp","year":"2005","journal-title":"J Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib50","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.fertnstert.2005.12.068","article-title":"A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages","volume":"86","author":"Dolitzky","year":"2006","journal-title":"Fertil Steril"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib51","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1001\/archinte.164.17.1932","article-title":"Prothrombin 20210A mutation: A mild risk factor for venous thromboembolism but not for arterial thrombotic disease and pregnancy-related complications in a family study","volume":"164","author":"Bank","year":"2004","journal-title":"Arch Intern Med"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib52","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1160\/TH04-03-0198","article-title":"Unselected women with elevated levels of factor VIII:c or homocysteine are not at increased risk for obstetric complications","volume":"92","author":"Middeldorp","year":"2004","journal-title":"Thromb Haemost"},{"key":"10.1053\/j.seminhematol.2007.01.005_bib53","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/S0015-0282(00)01595-8","article-title":"Hyperhomocysteinemia and recurrent early pregnancy loss: A meta-analysis","volume":"74","author":"Nelen","year":"2000","journal-title":"Fertil Steril"}],"container-title":["Seminars in Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0037196307000066?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0037196307000066?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T06:18:55Z","timestamp":1758521935000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0037196307000066"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,4]]},"references-count":53,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2007,4]]}},"alternative-id":["S0037196307000066"],"URL":"https:\/\/doi.org\/10.1053\/j.seminhematol.2007.01.005","relation":{},"ISSN":["0037-1963"],"issn-type":[{"value":"0037-1963","type":"print"}],"subject":[],"published":{"date-parts":[[2007,4]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Pregnancy Failure and Heritable Thrombophilia","name":"articletitle","label":"Article Title"},{"value":"Seminars in Hematology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1053\/j.seminhematol.2007.01.005","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Copyright \u00a9 2007 Elsevier Inc. All rights reserved.","name":"copyright","label":"Copyright"}]}}