PMID- 25700433
OWN - NLM
STAT- MEDLINE
DCOM- 20150805
LR  - 20210202
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 125
IP  - 20
DP  - 2015 May 14
TI  - Cellular fibronectin containing extra domain A promotes arterial thrombosis in 
      mice through platelet Toll-like receptor 4.
PG  - 3164-72
LID - 10.1182/blood-2014-10-608653 [doi]
AB  - Cellular fibronectin containing extra domain A (Fn-EDA+), which is produced in 
      response to tissue injury in several disease states, has prothrombotic activity 
      and is known to interact with Toll-like-receptor 4 (TLR4). The underlying 
      mechanism and cell types involved in mediating the prothrombotic effect of 
      Fn-EDA+ still remain unknown. Using intravital microscopy, we evaluated 
      susceptibility to carotid artery thrombosis after FeCl3-induced injury in mice 
      expressing Fn lacking EDA (Fn-EDA(-/-) mice) or Fn containing EDA (Fn-EDA(+/+) 
      mice). Fn-EDA(-/-) mice exhibited prolonged times to first thrombus formation and 
      complete occlusion and a significant decrease in the rate of thrombus growth (P < 
      .05 vs Fn-EDA(+/+) mice). Genetic deletion of TLR4 reversed the accelerated 
      thrombosis in Fn-EDA(+/+) mice (P < .05) but had no effect in Fn-EDA(-/-) mice. 
      Bone marrow transplantation experiments revealed that TLR4 expressed on 
      hematopoietic cells contributes to accelerated thrombosis in Fn-EDA(+/+) mice. In 
      vitro studies showed that cellular Fn-EDA+ interacts with platelet TLR4 and 
      promotes agonist-induced platelet aggregation. Finally, Fn-EDA(+/+) mice 
      specifically lacking platelet TLR4 exhibited prolonged times to first thrombus 
      formation and complete occlusion (P < .05 vs Fn-EDA(+/+) mice containing platelet 
      TLR4). We conclude that platelet TLR4 contributes to the prothrombotic effect of 
      cellular Fn-EDA+, suggesting another link between thrombosis and innate immunity.
CI  - (c) 2015 by The American Society of Hematology.
FAU - Prakash, Prem
AU  - Prakash P
AUID- ORCID: 0000-0001-9501-0065
AD  - Department of Internal Medicine, University of Iowa, Iowa City, IA.
FAU - Kulkarni, Paresh P
AU  - Kulkarni PP
AD  - Department of Internal Medicine, University of Iowa, Iowa City, IA.
FAU - Lentz, Steven R
AU  - Lentz SR
AD  - Department of Internal Medicine, University of Iowa, Iowa City, IA.
FAU - Chauhan, Anil K
AU  - Chauhan AK
AUID- ORCID: 0000-0001-8554-0898
AD  - Department of Internal Medicine, University of Iowa, Iowa City, IA.
LA  - eng
GR  - P01 HL062984/HL/NHLBI NIH HHS/United States
GR  - R01 HL118246/HL/NHLBI NIH HHS/United States
GR  - R01 HL118742/HL/NHLBI NIH HHS/United States
GR  - HL062984/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150219
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Fibronectins)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (extra domain A fibronectin, human)
SB  - IM
CIN - Blood. 2015 May 14;125(20):3043-4. PMID: 25977580
MH  - Animals
MH  - Blood Platelets/*metabolism
MH  - Carotid Artery, Common/metabolism/pathology
MH  - Disease Models, Animal
MH  - Female
MH  - Fibronectins/genetics/*metabolism
MH  - Immunity, Innate
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Platelet Aggregation
MH  - Thrombosis/genetics/immunology/*metabolism
MH  - Toll-Like Receptor 4/*metabolism
PMC - PMC4432011
EDAT- 2015/02/24 06:00
MHDA- 2015/08/06 06:00
PMCR- 2016/05/14
CRDT- 2015/02/21 06:00
PHST- 2014/10/27 00:00 [received]
PHST- 2015/02/11 00:00 [accepted]
PHST- 2015/02/21 06:00 [entrez]
PHST- 2015/02/24 06:00 [pubmed]
PHST- 2015/08/06 06:00 [medline]
PHST- 2016/05/14 00:00 [pmc-release]
AID - S0006-4971(20)31694-3 [pii]
AID - 2014/608653 [pii]
AID - 10.1182/blood-2014-10-608653 [doi]
PST - ppublish
SO  - Blood. 2015 May 14;125(20):3164-72. doi: 10.1182/blood-2014-10-608653. Epub 2015 
      Feb 19.