title: Distinct effects of unfractionated heparin versus bivalirudin on circulating angiogenic peptides.
abstract: BACKGROUND
  Human studies of therapeutic angiogenesis, stem-cell, and progenitor-cell therapy have failed to demonstrate consistent clinical benefit. Recent studies have shown that heparin increases circulating levels of anti-angiogenic peptides. Given the widely prevalent use of heparin in percutaneous and surgical procedures including those performed as part of studies examining the benefit of therapeutic angiogenesis and cell-based therapy, we compared the effects of unfractionated heparin (UFH) on angiogenic peptides with those of bivalirudin, a relatively newer anticoagulant whose effects on angiogenic peptides have not been studied.
  
  
  RESULTS
  We measured soluble fms-like tyrosine kinase-1 (sFLT1), placental growth factor (PlGF), vascular endothelial growth factor (VEGF), and soluble Endoglin (sEng) serum levels by enzyme linked immunosorbent assays (ELISA) in 16 patients undergoing elective percutaneous coronary intervention. Compared to baseline values, sFLT1 and PlGF levels increased by 2629±313% and 253±54%, respectively, within 30 minutes of UFH therapy (p<0.01 for both; n = 8). VEGF levels decreased by 93.2±5% in patients treated with UFH (p<0.01 versus baseline). No change in sEng levels were observed after UFH therapy. No changes in sFLT1, PlGF, VEGF, or sEng levels were observed in any patients receiving bivalirudin (n = 8). To further explore the direct effect of anticoagulation on circulating angiogenic peptides, adult, male wild-type mice received venous injections of clinically dosed UFH or bivalirudin. Compared to saline controls, sFLT1 and PlGF levels increased by >500% (p<0.01, for both) and VEGF levels increased by 221±101% (p<0.05) 30 minutes after UFH treatment. Bivalirudin had no effect on peptide levels. To study the cellular origin of peptides after anticoagulant therapy, human coronary endothelial cells were treated with UFH and demonstrated increased sFLT1 and PlGF levels (ANOVA p<0.01 for both) with reduced VEGF levels (ANOVA p<0.05). Bivalirudin had no effect on peptide levels in vitro.
  
  
  CONCLUSIONS
  Circulating levels of sFLT1, PlGF, and VEGF are significantly altered by UFH, while bivalirudin therapy has no effect. These findings may have significant implications for clinical studies of therapeutic angiogenesis, stem-cell and progenitor-cell therapy.
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America. nkapur@tuftsmedicalcenter.org
authors.forename: Navin K
authors.initials: NK
authors.lastname: Kapur
authors.forename: Chetan
authors.initials: C
authors.lastname: Shenoy
authors.forename: Adil A
authors.initials: AA
authors.lastname: Yunis
authors.forename: Najwa N
authors.initials: NN
authors.lastname: Mohammad
authors.forename: Szuhuei
authors.initials: S
authors.lastname: Wilson
authors.forename: Vikram
authors.initials: V
authors.lastname: Paruchuri
authors.forename: Emily E
authors.initials: EE
authors.lastname: Mackey
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Qiao
authors.forename: Ameer
authors.initials: A
authors.lastname: Shah
authors.forename: Michele L
authors.initials: ML
authors.lastname: Esposito
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
mesh_terms: D042501:Angiogenic Proteins / Q000097:blood* / Q000378:metabolism; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D003331:Coronary Vessels / Q000166:cytology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006493:Heparin / Q000737:chemistry* / Q000494:pharmacology*; D006629:Hirudins / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors
chemical_list: D042501:Angiogenic Proteins; D000925:Anticoagulants; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D006493:Heparin; C074619:bivalirudin