PB0398 - Platelet β1 and β3 integrins play a key role in hemostasis, arterial thrombosis and tumor metastasis

Sunday, June 25, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Alexandra A. Yakusheva, PhD

Post Doc
Etablissement Français du Sang GRAND EST
Strasbourg, Alsace, France

Co-Author(s)

Emily Janus-Bell, PhD (she/her/hers)

Post-doc
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France
CM

Clarisse Mouriaux

Technician
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France
CB

Catherine Bourdon

Technician
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France
MG

Maria Garcia-Leon

Post Doc
INSERM UMR_S1109, Tumor Biomechanics Lab, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS)
Illkirch-Graffenstaden, Alsace, France
OL

Olivier Lefebvre

Researcher
INSERM UMR_S1109, Tumor Biomechanics Lab, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS)
Strasbourg, Alsace, France
JG

Jacky Goetz

Research Director
INSERM UMR_S1109, Tumor Biomechanics Lab, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS)
Strasbourg, Alsace, France
PM

Pierre Mangin

Research Director
Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
Strasbourg, Alsace, France

Background: Platelets play a central role in hemostasis, arterial thrombosis and contribute to non-hemostatic functions such as tumor metastasis. Integrin α2β1, α5β1, α6β1, αvβ3 and αIIbβ3 mediate stable platelet adhesion, and the latter also ensures aggregation. To date, the consequence of the combined absence of all integrins on platelet function, hemostasis, arterial thrombosis and tumor metastasis has never been studied.

Aims: To characterize platelet function, hemostasis, thrombosis and tumor metastasis in the absence of platelet integrins.

Methods: We generated a mouse strain which does not expressed platelet integrins using the PF4Cre/lox recombination system (PF4Cre-β1-/-/β3-/-). In vitro flow based-assay was used to monitor platelet adhesion and thrombus formation. Ferric chloride- and pinching-injury models were used for arterial thrombosis evaluation and tail-bleeding time assay for hemostasis evaluation. Experimental metastasis models were used to assess tumor metastasis.

Results: In PF4Cre-β1-/-/β3-/- mice, the expression of the main platelet surface receptors (GPIbα, GPV, GPIX, GPVI) was normal, except for integrin α2β1, α5β1, α6β1, αvβ3 and αIIbβ3, which were markedly reduced. Fibrinogen binding was completely inhibited and annexin V binding was reduced in response to a series of soluble agonists including ADP, PAR-4 and convulxin. PF4Cre-β1-/-/β3-/- platelet adhesion under flow was normal on vWF but completely inhibited on fibrinogen and fibrillar fibronectin. PF4Cre-β1-/-/β3-/- mice presented an increased tail-bleeding time. Thrombus formation was severely impaired in an in vitro flow based-assay over collagen and in two experimental models of arterial thrombosis. Experimental lung metastasis of breast carcinoma AT3 cells was significantly reduced in PF4Cre-β1-/-/β3-/- mice.

Conclusion(s): These results highlight the central role of integrins in platelet hemostatic functions, experimental thrombosis, and show their major role in tumor metastasis.