Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis.
The growth arrest-specific gene 6 product (Gas6) is a secreted protein related to the anticoagulant protein S but its role in hemostasis is unknown. Here we show that inactivation of the Gas6 gene prevented venous and arterial thrombosis in mice, and protected against fatal collagen/epinephrine-induced thrombo embolism. Gas6-/- mice did not, however, suffer spontaneous bleeding and had normal bleeding after tail clipping. In addition, we found that Gas6 antibodies inhibited platelet aggregation in vitro and protected mice against fatal thrombo embolism without causing bleeding in vivo. Gas6 amplified platelet aggregation and secretion in response to known agonists. Platelet dysfunction in Gas6-/- mice resembled that of patients with platelet signaling transduction defects. Thus, Gas6 is a platelet-response amplifier that plays a significant role in thrombosis. These findings warrant further evaluation of the possible therapeutic use of Gas6 inhibition for prevention of thrombosis.
Angelillo-Scherrer
A
A
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.
de Frutos
P
P
Aparicio
C
C
Melis
E
E
Savi
P
P
Lupu
F
F
Arnout
J
J
Dewerchin
M
M
Hoylaerts
M
M
Herbert
J
J
Collen
D
D
Dahlbäck
B
B
Carmeliet
P
P
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006487:Hemostasis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010974:Platelet Aggregation; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D000099255:Growth Arrest-Specific Protein 6