PMID- 32153221
OWN - NLM
STAT- MEDLINE
DCOM- 20210312
LR  - 20210312
IS  - 1092-874X (Electronic)
IS  - 1091-5818 (Linking)
VI  - 39
IP  - 3
DP  - 2020 May/Jun
TI  - Monitoring Compound-Related Effects on Coagulability in Rats and Cynomolgus and 
      Rhesus Monkeys by Thrombin Generation Kinetic Measurement.
PG  - 207-217
LID - 10.1177/1091581820907324 [doi]
AB  - Thrombin generation assay (TGA) is a sensitive method for the assessment of the 
      global clotting potential of plasma. This kinetic assay can detect both 
      hypocoagulable and hypercoagulable conditions: delayed or reduced thrombin 
      generation leading to a prolonged clotting time, or induced thrombin activity, 
      shifting the coagulation cascade toward thrombosis. The purpose of this study is 
      to qualify the TGA in nonhuman primates (NHP) and rats for its use during 
      nonclinical in vivo and in vitro studies. Blood was drawn from nonanesthetized 
      animals, and platelet-poor plasma was obtained after double centrifugation; 
      coefficients of variation were <10% for all derived parameters of thrombin 
      generation assessed with 5 pM of tissue factor. Thrombin generation was evaluated 
      in vitro in rat and NHP plasmas with ascending doses of unfractionated heparin 
      (UFH), recombinant tissue factor, and anticoagulant compounds. Thrombin 
      generation was decreased with UFH and anticoagulant compounds, but was increased 
      in the presence of tissue factor, in a dose-dependent manner. In a rat model of 
      inflammation, animals were administered a low dose of lipopolysaccharides. 
      Thrombin generation measurements were decreased 3 hours post-LPS administration 
      with a nadir at 24 hours, while thrombin-antithrombin complexes reached a peak at 
      8 hours, supporting an earlier production of thrombin. In conclusion, these data 
      demonstrated that TGA can be performed in vitro for screening of compounds 
      expected to have effects on coagulation cascade, and thrombin generation can be 
      measured at interim time points during nonclinical in vivo studies in rats and 
      NHP.
FAU - Poitout-Belissent, F
AU  - Poitout-Belissent F
AUID- ORCID: 0000-0001-9681-7952
AD  - Charles River Laboratories, ULC, Senneville, Canada.
FAU - Culang, D
AU  - Culang D
AD  - Pathology and Microbiology Department, St.-Hyacinthe Veterinary School, 
      University of Montreal, Canada.
FAU - Poulin, D
AU  - Poulin D
AD  - Charles River Laboratories, ULC, Senneville, Canada.
FAU - Samadfan, R
AU  - Samadfan R
AD  - Charles River Laboratories, ULC, Senneville, Canada.
FAU - Cotton, S
AU  - Cotton S
AD  - Charles River Laboratories, ULC, Senneville, Canada.
FAU - Bedard, C
AU  - Bedard C
AD  - Pathology and Microbiology Department, St.-Hyacinthe Veterinary School, 
      University of Montreal, Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200310
PL  - United States
TA  - Int J Toxicol
JT  - International journal of toxicology
JID - 9708436
RN  - 0 (Coagulants)
RN  - 0 (Lipopolysaccharides)
RN  - EC 3.4.21.5 (Thrombin)
SB  - IM
MH  - Animals
MH  - Blood Coagulation/drug effects
MH  - *Blood Coagulation Tests
MH  - Coagulants/toxicity
MH  - Female
MH  - Kinetics
MH  - Lipopolysaccharides/toxicity
MH  - Macaca fascicularis
MH  - Macaca mulatta
MH  - Male
MH  - Rats, Sprague-Dawley
MH  - Thrombin/*biosynthesis
OTO - NOTNLM
OT  - anticoagulant
OT  - heparin
OT  - lipopolysaccharides
OT  - nonhuman primate
OT  - rat
OT  - thrombin generation assay
OT  - tissue factor
EDAT- 2020/03/11 06:00
MHDA- 2021/03/13 06:00
CRDT- 2020/03/11 06:00
PHST- 2020/03/11 06:00 [pubmed]
PHST- 2021/03/13 06:00 [medline]
PHST- 2020/03/11 06:00 [entrez]
AID - 10.1177/1091581820907324 [doi]
PST - ppublish
SO  - Int J Toxicol. 2020 May/Jun;39(3):207-217. doi: 10.1177/1091581820907324. Epub 
      2020 Mar 10.