PMID- 17169412
OWN - NLM
STAT- MEDLINE
DCOM- 20071018
LR  - 20070730
IS  - 0049-3848 (Print)
IS  - 0049-3848 (Linking)
VI  - 120
IP  - 4
DP  - 2007
TI  - Antithrombotic and anticoagulant effects of wild type and Gla-domain mutated 
      human activated protein C in rats.
PG  - 531-9
AB  - The antithrombotic and anticoagulant effects of recombinant wild type (WT) and 
      mutated human activated protein C (hAPC) were investigated using a rat model of 
      arterial thrombosis. Recent in vitro studies using human plasma have shown 
      enhanced anticoagulant effects of hAPC by mutagenesis of either loop 148 in the 
      serine protease domain or of the Gla domain. The Gla-domain mutant QGNSEDY-hAPC 
      (= H10Q/S11G/S12N/D23S/Q32E/N33D/H44Y) was found to be particularly active as an 
      anticoagulant. We now combined the two mutations to create the variant 
      QGNSEDY-hAPC:B148 and investigated the in vivo effects of this variant as well as 
      of QGNSEDY-hAPC and WT hAPC using a rat model of arterial thrombosis. In vitro 
      clotting experiments using rat plasma demonstrated WT hAPC to be inefficient, 
      whereas both mutant hAPC variants yielded distinct dose dependent anticoagulant 
      effects. In the arterial injury model, a segment of the left common carotid 
      artery was opened longitudinally. An endarterectomy was performed and the 
      arteriotomy was closed, whereafter the vessel was reperfused and the patency rate 
      determined after 31 min. Three treatment groups each containing 10 rats and a 
      control group of 20 animals were in a blind random fashion given intravenous 
      bolus injections of 0.8 mg/kg WT or mutant hAPC or vehicle only. The ex vivo 
      clotting times of plasma drawn 3 min after the injections, as compared to 
      baseline clotting times, were approximately doubled by QGNSEDY-hAPC and tripled 
      by QGNSEDY-hAPC:B148 infusions, while WT APC had little effect. Compared to the 
      control group, none of the hAPC preparations had significant antithrombotic 
      effect or increased arteriotomy bleeding.
FAU - Malm, Karl
AU  - Malm K
AD  - Department of Clinical Sciences, Division of Reconstructive Surgery, University 
      Hospital, Malmo, Sweden. karl.malm@med.lu.se
FAU - Arnljots, Bjorn
AU  - Arnljots B
FAU - Persson, Ing-Marie
AU  - Persson IM
FAU - Dahlback, Bjorn
AU  - Dahlback B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20061212
PL  - United States
TA  - Thromb Res
JT  - Thrombosis research
JID - 0326377
RN  - 0 (Anticoagulants)
RN  - 0 (Fibrinolytic Agents)
RN  - 0 (Protein C)
RN  - 0 (Recombinant Proteins)
SB  - IM
MH  - Animals
MH  - Anticoagulants/administration & dosage/*pharmacology
MH  - Carotid Artery Thrombosis
MH  - Disease Models, Animal
MH  - Drug Evaluation, Preclinical
MH  - Fibrinolytic Agents/administration & dosage/*pharmacology
MH  - Humans
MH  - *Mutation
MH  - Protein C/administration & dosage/*genetics/*pharmacology
MH  - Protein Structure, Tertiary
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Recombinant Proteins
EDAT- 2006/12/16 09:00
MHDA- 2007/10/19 09:00
CRDT- 2006/12/16 09:00
PHST- 2006/06/12 00:00 [received]
PHST- 2006/06/12 00:00 [revised]
PHST- 2006/11/01 00:00 [accepted]
PHST- 2006/12/16 09:00 [pubmed]
PHST- 2007/10/19 09:00 [medline]
PHST- 2006/12/16 09:00 [entrez]
AID - S0049-3848(06)00443-9 [pii]
AID - 10.1016/j.thromres.2006.11.004 [doi]
PST - ppublish
SO  - Thromb Res. 2007;120(4):531-9. doi: 10.1016/j.thromres.2006.11.004. Epub 2006 Dec 
      12.