Heparin elevates circulating soluble fms-like tyrosine kinase-1 immunoreactivity in pregnant women receiving anticoagulation therapy

Victor A. Rosenberg, Irina A. Buhimschi, Charles J. Lockwood, Michael J. Paidas, Antonette T. Dulay, Wenda Ramma, Sonya S. Abdel-Razeq, Guomao Zhao, Shakil Ahmad, Asif Ahmed, Catalin S. Buhimschi

Research output: Contribution to journalArticle

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.

Methods and 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.
LanguageEnglish
Pages2543-2553
Number of pages11
JournalCirculation
Volume124
Issue number23
DOIs
Publication statusPublished - 6 Dec 2011

Fingerprint

Vascular Endothelial Growth Factor Receptor-1
Heparin
Pregnant Women
Therapeutics
Vascular Endothelial Growth Factor A
Abruptio Placentae
Low Molecular Weight Heparin
Third Pregnancy Trimester
Pregnancy Outcome
Fetal Development
Pre-Eclampsia
Gestational Age
Longitudinal Studies
Necrosis
Up-Regulation
Western Blotting
Enzyme-Linked Immunosorbent Assay
Mothers
Apoptosis
Pregnancy

Keywords

  • anticoagulation
  • angiogenesis
  • sFlt-1
  • heparin
  • pregnancy

Cite this

Rosenberg, V. A., Buhimschi, I. A., Lockwood, C. J., Paidas, M. J., Dulay, A. T., Ramma, W., ... Buhimschi, C. S. (2011). Heparin elevates circulating soluble fms-like tyrosine kinase-1 immunoreactivity in pregnant women receiving anticoagulation therapy. Circulation, 124(23), 2543-2553. https://doi.org/10.1161/CIRCULATIONAHA.111.046821
Rosenberg, Victor A. ; Buhimschi, Irina A. ; Lockwood, Charles J. ; Paidas, Michael J. ; Dulay, Antonette T. ; Ramma, Wenda ; Abdel-Razeq, Sonya S. ; Zhao, Guomao ; Ahmad, Shakil ; Ahmed, Asif ; Buhimschi, Catalin S. / Heparin elevates circulating soluble fms-like tyrosine kinase-1 immunoreactivity in pregnant women receiving anticoagulation therapy. In: Circulation. 2011 ; Vol. 124, No. 23. pp. 2543-2553.
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Rosenberg, VA, Buhimschi, IA, Lockwood, CJ, Paidas, MJ, Dulay, AT, Ramma, W, Abdel-Razeq, SS, Zhao, G, Ahmad, S, Ahmed, A & Buhimschi, CS 2011, 'Heparin elevates circulating soluble fms-like tyrosine kinase-1 immunoreactivity in pregnant women receiving anticoagulation therapy' Circulation, vol. 124, no. 23, pp. 2543-2553. https://doi.org/10.1161/CIRCULATIONAHA.111.046821

Heparin elevates circulating soluble fms-like tyrosine kinase-1 immunoreactivity in pregnant women receiving anticoagulation therapy. / Rosenberg, Victor A.; Buhimschi, Irina A.; Lockwood, Charles J.; Paidas, Michael J.; Dulay, Antonette T.; Ramma, Wenda; Abdel-Razeq, Sonya S.; Zhao, Guomao; Ahmad, Shakil; Ahmed, Asif; Buhimschi, Catalin S.

In: Circulation, Vol. 124, No. 23, 06.12.2011, p. 2543-2553.

Research output: Contribution to journalArticle

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T1 - Heparin elevates circulating soluble fms-like tyrosine kinase-1 immunoreactivity in pregnant women receiving anticoagulation therapy

AU - Rosenberg, Victor A.

AU - Buhimschi, Irina A.

AU - Lockwood, Charles J.

AU - Paidas, Michael J.

AU - Dulay, Antonette T.

AU - Ramma, Wenda

AU - Abdel-Razeq, Sonya S.

AU - Zhao, Guomao

AU - Ahmad, Shakil

AU - Ahmed, Asif

AU - Buhimschi, Catalin S.

PY - 2011/12/6

Y1 - 2011/12/6

N2 - 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. Methods and 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.

AB - 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. Methods and 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.

KW - anticoagulation

KW - angiogenesis

KW - sFlt-1

KW - heparin

KW - pregnancy

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