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Imaging analyses of coagulation-dependent initiation of fibrinolysis on activated platelets and its modification by thrombin-activatable fibrinolysis inhibitor
- Source :
- Thrombosis and Haemostasis. 117:682-690
- Publication Year :
- 2017
- Publisher :
- Georg Thieme Verlag KG, 2017.
-
Abstract
- SummaryUsing intravital confocal microscopy, we observed previously that the process of platelet phosphatidylserine (PS) exposure, fibrin formation and lysine binding site-dependent plasminogen (plg) accumulation took place only in the centre of thrombi, not at their periphery. These findings prompted us to analyse the spatiotemporal regulatory mechanisms underlying coagulation and fibrinolysis. We analysed the fibrin network formation and the subsequent lysis in an in vitro experiment using diluted platelet-rich plasma supplemented with fluorescently labelled coagulation and fibrinolytic factors, using confocal laser scanning microscopy. The structure of the fibrin network formed by supplemented tissue factor was uneven and denser at the sites of coagulation initiation regions (CIRs) on PS-exposed platelets. When tissue type plasminogen activator (tPA; 7.5 nM) was supplemented, labelled plg (50 nM) as well as tPA accumulated at CIRs, from where fibrinolysis started and gradually expanded to the peripheries. The lysis time at CIRs and their peripheries (50 µm from the CIR) were 27.9 ± 6.6 and 44.4 ± 9.7 minutes (mean ± SD, n=50 from five independent experiments) after the addition of tissue factor, respectively. Recombinant human soluble thrombomodulin (TMα; 2.0 nM) attenuated the CIR-dependent plg accumulation and strongly delayed fibrinolysis at CIRs. A carboxypeptidase inhibitor dose-dependently enhanced the CIR-de- pendent fibrinolysis initiation, and at 20 µM it completely abrogated the TMα-induced delay of fibrinolysis. Our findings are the first to directly present crosstalk between coagulation and fibrinolysis, which takes place on activated platelets’ surface and is further controlled by thrombin-activatable fibrinolysis inhibitor (TAFI).Supplementary Material to this article is available online at www.thrombosis-online.com.
- Subjects :
- Blood Platelets
0301 basic medicine
Carboxypeptidase B2
Time Factors
Intravital Microscopy
Thrombomodulin
medicine.medical_treatment
Phosphatidylserines
030204 cardiovascular system & hematology
Fibrin
03 medical and health sciences
Tissue factor
0302 clinical medicine
Fibrinolysis
medicine
Humans
Protease Inhibitors
Platelet
Platelet activation
Blood Coagulation
Microscopy, Confocal
Dose-Response Relationship, Drug
biology
Platelet-Rich Plasma
Chemistry
Hematology
Platelet Activation
Molecular biology
030104 developmental biology
Coagulation
Immunology
biology.protein
Plasminogen activator
Subjects
Details
- ISSN :
- 2567689X and 03406245
- Volume :
- 117
- Database :
- OpenAIRE
- Journal :
- Thrombosis and Haemostasis
- Accession number :
- edsair.doi.dedup.....20d00311f384732fae1e0329a26baf43
- Full Text :
- https://doi.org/10.1160/th16-09-0722