Identification of a fibrin-independent platelet contractile mechanism regulating primary hemostasis and thrombus growth.
A fundamental property of platelets is their ability to transmit cytoskeletal contractile forces to extracellular matrices. While the importance of the platelet contractile mechanism in regulating fibrin clot retraction is well established, its role in regulating the primary hemostatic response, independent of blood coagulation, remains ill defined. Real-time analysis of platelet adhesion and aggregation on a collagen substrate revealed a prominent contractile phase during thrombus development, associated with a 30% to 40% reduction in thrombus volume. Thrombus contraction developed independent of thrombin and fibrin and resulted in the tight packing of aggregated platelets. Inhibition of the platelet contractile mechanism, with the myosin IIA inhibitor blebbistatin or through Rho kinase antagonism, markedly inhibited thrombus contraction, preventing the tight packing of aggregated platelets and undermining thrombus stability in vitro. Using a new intravital hemostatic model, we demonstrate that the platelet contractile mechanism is critical for maintaining the integrity of the primary hemostatic plug, independent of thrombin and fibrin generation. These studies demonstrate an important role for the platelet contractile mechanism in regulating primary hemostasis and thrombus growth. Furthermore, they provide new insight into the underlying bleeding diathesis associated with platelet contractility defects.
Ono
Akiko
A
Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
Westein
Erik
E
Hsiao
Sarah
S
Nesbitt
Warwick S
WS
Hamilton
Justin R
JR
Schoenwaelder
Simone M
SM
Jackson
Shaun P
SP
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D003018:Clot Retraction / Q000502:physiology; D005337:Fibrin / Q000502:physiology*; D006487:Hemostasis / Q000502:physiology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020409:Molecular Motor Proteins / Q000502:physiology; D024507:Nonmuscle Myosin Type IIA / Q000037:antagonists & inhibitors / Q000502:physiology; D010973:Platelet Adhesiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044462:Receptors, Proteinase-Activated / Q000097:blood / Q000172:deficiency / Q000235:genetics; D013927:Thrombosis / Q000097:blood* / Q000209:etiology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000097:blood
C459092:2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine; D006576:Heterocyclic Compounds, 4 or More Rings; D020409:Molecular Motor Proteins; D047428:Protein Kinase Inhibitors; D044462:Receptors, Proteinase-Activated; C481942:protease-activated receptor 4, mouse; C472645:blebbistatin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D005337:Fibrin; D054460:rho-Associated Kinases; D024507:Nonmuscle Myosin Type IIA