PMID- 14576044
OWN - NLM
STAT- MEDLINE
DCOM- 20040318
LR  - 20210206
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 103
IP  - 4
DP  - 2004 Feb 15
TI  - Novel concatameric heparin-binding peptides reverse heparin and 
      low-molecular-weight heparin anticoagulant activities in patient plasma in vitro 
      and in rats in vivo.
PG  - 1356-63
AB  - Patients given unfractionated heparin (UFH) or low-molecular-weight heparin 
      (LMWH) for prophylaxis or treatment of thrombosis sometimes suffer serious 
      bleeding. We showed previously that peptides containing 3 or more tandem repeats 
      of heparin-binding consensus sequences have high affinity for LMWH and neutralize 
      LMWH (enoxaparin) in vivo in rats and in vitro in citrate. We have now modified 
      the (ARKKAAKA)(n) tandem repeat peptides by cyclization or by inclusion of 
      hydrophobic tails or cysteines to promote multimerization. These peptides exhibit 
      high-affinity binding to LMWH (dissociation constant [K(d)], approximately 50 
      nM), similar potencies in neutralizing anti-Factor Xa activity of UFH and 
      enoxaparin added to normal plasma in vitro, and efficacy equivalent to or greater 
      than protamine. Peptide (ARKKAAKA)(3)VLVLVLVL was most effective in all plasmas 
      from enoxaparin-treated patients, and was 4- to 20-fold more effective than 
      protamine. Several other peptide structures were effective in some patients' 
      plasmas. All high-affinity peptides reversed inhibition of thrombin-induced clot 
      formation by UFH. These peptides (1 mg/300 g rat) neutralized 1 U/mL anti-Factor 
      Xa activity of enoxaparin in rats within 1 to 2 minutes. Direct blood pressure 
      and heart rate measurements showed little or no hemodynamic effect. These 
      heparin-binding peptides, singly or in combination, are potential candidates for 
      clinical reversal of UFH and LMWH in humans.
FAU - Schick, Barbara P
AU  - Schick BP
AD  - Cardeza Foundation for Hematologic Research, Thomas Jefferson University, 1015 
      Walnut St, Philadelphia, PA 19107, USA. barbara.schick@jefferson.edu
FAU - Maslow, David
AU  - Maslow D
FAU - Moshinski, Adrianna
AU  - Moshinski A
FAU - San Antonio, James D
AU  - San Antonio JD
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20031023
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Anticoagulants)
RN  - 0 (Enoxaparin)
RN  - 0 (Factor Xa Inhibitors)
RN  - 0 (Heparin Antagonists)
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 0 (Peptide Fragments)
RN  - 0 (Polysaccharides)
RN  - EC 3.4.21.6 (Factor Xa)
RN  - J177FOW5JL (Fondaparinux)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Anticoagulants/chemistry/metabolism/*pharmacology
MH  - Blood Pressure/drug effects
MH  - Enoxaparin/chemistry/metabolism/pharmacology
MH  - Factor Xa/metabolism
MH  - Factor Xa Inhibitors
MH  - Fondaparinux
MH  - Heart Rate/drug effects
MH  - Heparin Antagonists/chemistry/metabolism/*pharmacology
MH  - Heparin, Low-Molecular-Weight/chemistry/metabolism/*pharmacology
MH  - Humans
MH  - In Vitro Techniques
MH  - Molecular Sequence Data
MH  - Peptide Fragments/chemistry/metabolism/*pharmacology
MH  - Platelet Aggregation/drug effects
MH  - Polysaccharides/metabolism/pharmacology
MH  - Rats
MH  - Repetitive Sequences, Nucleic Acid
EDAT- 2003/10/25 05:00
MHDA- 2004/03/19 05:00
CRDT- 2003/10/25 05:00
PHST- 2003/10/25 05:00 [pubmed]
PHST- 2004/03/19 05:00 [medline]
PHST- 2003/10/25 05:00 [entrez]
AID - S0006-4971(20)50160-2 [pii]
AID - 10.1182/blood-2003-07-2334 [doi]
PST - ppublish
SO  - Blood. 2004 Feb 15;103(4):1356-63. doi: 10.1182/blood-2003-07-2334. Epub 2003 Oct 
      23.