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


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.


CONCLUSIONS
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.
Division of Nephrology, Department of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany.
Henning
H
Hagmann
Department of Obstetrics and Gynecology, University of Cologne, Cologne, Germany.
Verena
V
Bossung
Department of Biochemistry, University of Cologne, Cologne, Germany.
Abdel Ali
AA
Belaidi
Department of Obstetrics and Gynecology, University of Cologne, Cologne, Germany.
Alexander
A
Fridman
Howard Hughes Medical Institute and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
S Ananth
SA
Karumanchi
Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Ravi
R
Thadhani
Division of Nephrology, Department of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany.
Bernhard
B
Schermer
Department of Obstetrics and Gynecology, University of Cologne, Cologne, Germany.
Peter
P
Mallmann
Department of Biochemistry, University of Cologne, Cologne, Germany.
Guenter
G
Schwarz
Division of Nephrology, Department of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany.
Thomas
T
Benzing
Division of Nephrology, Department of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany.
Paul T
PT
Brinkkoetter
D000328:Adult; D005260:Female; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000627:therapeutic use*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006495:Heparin, Low-Molecular-Weight / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D011225:Pre-Eclampsia / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D011247:Pregnancy; D011485:Protein Binding; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood / Q000652:urine; D020246:Venous Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000652:urine
D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1