Platelets of Female Mice Are Intrinsically More Sensitive to Agonists Than Are Platelets of Males

Abstract

Objective-It has been reported that women fare worse after ischemic coronary events, but the mechanisms remain unclear.Because platelets play a central role in the formation of occlusive thrombi at sites of ruptured atherosclerotic plaques, we studied male/female paired mouse littermates for sex differences in platelet function. Methods and Results-We compared platelet reactivity in male/female mouse littermates by monitoring agonist-induced fibrinogen (FGN) binding and platelet aggregation. Compared with the platelets from males, platelets from females bound more FGN in response to low concentrations of thrombin and collagen-related peptide. Female platelets also demonstrated greater aggregation in response to adenosine diphosphate and collagen-related peptide. Platelet protein tyrosine phosphorylation on activation also showed small differences between sexes. These differences are independent of platelet size and surface expression of ␣ IIb ␤ 3 and GPIb-IX-V, and they were not blocked by apyrase or aspirin. The sex differences we observed were intrinsic to platelets, because they were observed in washed platelets, but not when platelets were in plasma. Conclusions-The platelets of female mice were more reactive than those of males in a manner independent of COX-1 and secreted ADP.

The Modifier of hemostasis (Mh) locus on chromosome 4 controls in vivo hemostasis of Gp6−/− mice

“…Platelets from female mice are more resistant to inhibitors of platelet function than platelets from male mice, regardless of strain. 18 Because of this sex difference, we used only male mice for our in vitro functional studies, unless otherwise specified.…”

“…Platelets from female mice are more resistant to inhibitors of platelet function than platelets from male mice, regardless of strain. 18 Because of this sex difference, we used only male mice for our in vitro functional studies, unless otherwise specified.All Gp6 Ϫ/Ϫ mice exhibit a single 6.2-kb amplicon, the increased size of which results from the insertion of the neomycin-resistance cassette (neo) into exon 1 8 ; the amplicon from wild-type littermates is 4.5 kb, the anticipated length of the native Gp6 genomic sequence. …”

Interrelation between inflammation, thrombosis, and neuroprotection in cerebral ischemia

“…There also seem to be sex-related differences in platelet function. It is known that isolated female platelets bind more fi brinogen and have a greater maximal aggregation extent than male platelet isolates, and this platelet reactivity is altered in ovariectomized females (Leng et al , 2004 ;Bailey et al , 2009 ). Males have been shown to have higher platelet counts and faster clotting times than their female counterparts, thus making them more susceptible to thrombosis -possibly due to the differences in growth hormone secretion between the sexes (pulsatile in males, sustained in females), which in turn infl uence protein production of coagulation and thrombosis regulators (Wong et al , 2008 ;Bailey et al , 2009 ).…”

“…Coagulation factors and proteins are lowered by the presence of estrogen, though some factors (i.e., fi brinogen) are inherently higher in females than in males (Mendelsohn and Karas , 1999 ;Bailey et al , 2009 ); in addition, there are cyclic patterns in these coagulation proteins that correspond to the menstrual cycle in females (Kadir et al , 1999 ;Bailey et al , 2009 ). Functionally, female platelet isolates, though capable of binding more fi brinogen and displaying a greater maximal aggregation extent than male platelet isolates (Leng et al , 2004 ;Bailey et al , 2009 ), actually do not aggregate as quickly as the larger number of male platelets do, thus to some degree rendering females less susceptible to thrombosis. In the absence of estradiol in acyclicity, female platelets are again more susceptible to thrombosis (Wong et al , 2008 ;Bailey et al , 2009 ).…”

“…Sex hormones not only alter procoagulant protein expression (Lowe et al , 2004 ) and the function of blood and vascular cells (Kadir et al , 1999 ;Butenas and Mann , 2002 ;Leng et al , 2004 ), but differences in platelet function (Liao et al , 2001 ;Suzuki et al , 2009 ) and in thrombosis activity (Bailey et al , 2009 ) have also been noted. Estrogen is to a degree neuroprotective (Liao et al , 2001 ;Suzuki et al , 2009 ;Selvamani and Sohrabji , 2010 ) in certain cases of induced cerebral ischemia, as females appear to suffer less severe consequences of stroke, including lesser neural tissue loss, than their male counterparts (McCullough and Hurn , 2003 ;Suzuki et al , 2009 ).…”