title: Heparin elevates circulating soluble fms-like tyrosine kinase-1 immunoreactivity in pregnant women receiving anticoagulation therapy.
abstract: BACKGROUND
  Alterations in circulating levels of pro- and antiangiogenic factors have been associated with adverse pregnancy outcomes. Heparin is routinely administered to pregnant women, but without clear knowledge of its impact on these factors.
  
  
  RESULTS
  We conducted a longitudinal study of 42 pregnant women. Twenty-one women received prophylactic heparin anticoagulation, and 21 healthy pregnant women served as controls. Compared with gestational age-matched controls, heparin treatment was associated with increased circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1) in the third trimester (P<0.05), in the absence of preeclampsia, placental abruption, or fetal growth restriction. Heparin had no effect on circulating levels of vascular endothelial growth factor, placenta growth factor, or soluble endoglin as assessed by ELISA. In vitro, low-molecular weight and unfractionated heparins stimulated sFlt-1 release from placental villous explants, in a dose- and time-dependent manner. This effect was not due to placental apoptosis, necrosis, alteration in protein secretion, or increased transcription. Western blot analysis demonstrated that heparin induced shedding of the N-terminus of Flt-1 both in vivo and in vitro as indicated by a predominant band of 100-112 kDa. By using an in vitro angiogenesis assay, we demonstrated that serum of heparin-treated cases inhibited both basal and vascular endothelial growth factor-induced capillary-like tube formation.
  
  
  CONCLUSIONS
  Heparin likely increases the maternal sFlt-1 through shedding of the extracellular domain of Flt-1 receptor. Our results imply that upregulation of circulating sFlt-1 immunoreactivity in pregnancy is not always associated with adverse outcomes, and that heparin's protective effects, if any, cannot be explained by promotion of angiogenesis.
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Rosenberg
authors.forename: Irina A
authors.initials: IA
authors.lastname: Buhimschi
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lockwood
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Paidas
authors.forename: Antonette T
authors.initials: AT
authors.lastname: Dulay
authors.forename: Wenda
authors.initials: W
authors.lastname: Ramma
authors.forename: Sonya S
authors.initials: SS
authors.lastname: Abdel-Razeq
authors.forename: Guomao
authors.initials: G
authors.lastname: Zhao
authors.forename: Shakil
authors.initials: S
authors.lastname: Ahmad
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
authors.forename: Catalin S
authors.initials: CS
authors.lastname: Buhimschi
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005260:Female; D005966:Glucuronidase / Q000097:blood; D006493:Heparin / Q000008:administration & dosage*; D006801:Humans; D008137:Longitudinal Studies; D010920:Placenta / Q000166:cytology; D000072483:Placenta Growth Factor; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic / Q000097:blood / Q000453:epidemiology / Q000517:prevention & control*; D011256:Pregnancy Outcome / Q000453:epidemiology; D011257:Pregnancy Proteins / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D013927:Thrombosis / Q000097:blood / Q000453:epidemiology / Q000517:prevention & control*; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood* / Q000235:genetics; D055815:Young Adult; D000099175:Heparanase
chemical_list: D000925:Anticoagulants; D015951:Factor Xa; D065427:Factor Xa Inhibitors; D005966:Glucuronidase; D006493:Heparin; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D000099175:Heparanase; C000608036:PGF protein, human; C467484:VEGFA protein, human; C501162:FLT1 protein, human