Low-molecular weight heparin increases circulating sFlt-1 levels and enhances urinary elimination

PLoS One. 2014 Jan 21;9(1):e85258. doi: 10.1371/journal.pone.0085258. eCollection 2014.

Abstract

Rationale: Preeclampsia is a devastating medical complication of pregnancy which leads to maternal and fetal morbidity and mortality. While the etiology of preeclampsia is unclear, human and animal studies suggest that excessive circulating levels of soluble fms-like tyrosine-kinase-1 (sFlt-1), an alternatively spliced variant of VEGF-receptor1, contribute to the signs and symptoms of preeclampsia. Since sFlt-1 binds to heparin and heparan sulfate proteoglycans, we hypothesized that the anticoagulant heparin, which is often used in pregnancy, may interfere with the levels, distribution and elimination of sFlt-1 in vivo.

Objective: We systematically determined serum and urine levels of angiogenic factors in preeclamptic women before and after administration of low molecular weight heparin and further characterized the interaction with heparin in biochemical studies.

Methods and results: Serum and urine samples were used to measure sFlt-1 levels before and after heparin administration. Serum levels of sFlt-1 increased by 25% after heparin administration in pregnant women. The magnitude of the increase in circulating sFlt-1 correlated with initial sFlt-1 serum levels. Urinary sFlt-1 levels were also elevated following heparin administration and levels of elimination were dependent on the underlying integrity of the glomerular filtration barrier. Biochemical binding studies employing cation exchange chromatography revealed that heparin bound sFlt-1 had decreased affinity to negatively charged surfaces when compared to sFlt-1 alone.

Conclusion: Low molecular weight heparin administration increased circulating sFlt1 levels and enhanced renal elimination. We provide evidence that both effects may be due to heparin binding to sFlt1 and masking the positive charges on sFlt1 protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Female
  • Fibrinolytic Agents / metabolism
  • Fibrinolytic Agents / therapeutic use*
  • Glomerular Filtration Rate / drug effects
  • Heparin, Low-Molecular-Weight / metabolism
  • Heparin, Low-Molecular-Weight / therapeutic use*
  • Humans
  • Pre-Eclampsia / blood
  • Pre-Eclampsia / drug therapy*
  • Pre-Eclampsia / urine
  • Pregnancy
  • Protein Binding
  • Vascular Endothelial Growth Factor Receptor-1* / blood
  • Vascular Endothelial Growth Factor Receptor-1* / urine
  • Venous Thrombosis / blood
  • Venous Thrombosis / drug therapy*
  • Venous Thrombosis / urine

Substances

  • Fibrinolytic Agents
  • Heparin, Low-Molecular-Weight
  • FLT1 protein, human
  • Vascular Endothelial Growth Factor Receptor-1

Grant support

This work was supported by Forschungspool “Klinische Studien”, Faculty of Medicine, University of Cologne and by the DFG (SFB 635 to T.B. and BR2955 to P.T.B.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.