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The polymorphism responsible for the PlA2alloantigen on the β3-component of β3-containing integrins is reported to be a risk factor for coronary thrombosis. This study examined the effect of PlA2on the function of β3-integrins using platelets from subjects homozygous and heterozygous for PlA1and PlA2. There was overlap in the distribution of the dissociation constant (Kd) and maximum fibrinogen binding (Bmax) values for fibrinogen binding to αIIbβ3on platelets from PlA1and PlA2homozygotes and PlA1/PlA2heterozygotes. However, whereas there was no statistical difference in these values for the PlA1homozygotes and PlA2heterozygotes, the Kdfor the PlA2homozygotes was significantly lower than that for the PlA1/PlA2heterozygotes, but was not statistically different from that for the PlA1homozygotes. No differences were detected in ADP sensitivity between platelets from PlA1homozygotes and PlA1/PlA2heterozygotes, in the IC50for RGDS inhibition of fibrinogen binding to αIIbβ3, in the αvβ3-mediated adhesion of platelets to osteopontin and vitronectin, and in the phorbol ester-stimulated adhesion to fibrinogen of B lymphocytes expressing αIIbβ3containing either the PlA1or the PlA2polymorphism. Finally, no differential effects of PlA2on turbidometric platelet aggregation, platelet secretion, or platelet thrombus formation were found as measured in the PFA-100. Because no differences were detected in the ability of β3-integrins to interact with ligands based on the presence or absence of the PlA2polymorphism, the results suggest that factors unrelated to β3-integrin function may account for the reported association of the PlA2allele with coronary thrombosis.

Thromboxane A2 is a potent vasoconstrictor and platelet agonist; prostacyclin is a potent platelet inhibitor and vasodilator. Altered biosynthesis of these eicosanoids is a feature of human hypercholesterolemia and atherosclerosis. This study examined whether in 2 murine models of atherosclerosis their levels are increased and correlated with the evolution of the disease. Urinary 2,3-dinor thromboxane B2 and 2,3-dinor-6-keto prostaglandin F1a, metabolites of thromboxane and prostacyclin, respectively, were assayed in apoliprotein E (apoE)-deficient mice on chow and low-density lipoprotein receptor (LDLR)-deficient mice on chow and a Western-type diet. Atherosclerosis lesion area was measured by en face method. Both eicosanoids increased in apoE-deficient mice on chow and in LDLR-deficient mice on a high-fat diet, but not in LDLR-deficient mice on chow by the end of the study. Aspirin suppressed ex vivo platelet aggregation, serum thromboxane B2, and 2,3-dinor thromboxane B2, and significantly reduced the excretion of 2,3-dinor-6-keto prostaglandin F1a in these animals. This study demonstrates that thromboxane as well as prostacyclin biosynthesis is increased in 2 murine models of atherogenesis and is secondary to increased in vivo platelet activation. Assessment of their generation in these models may afford the basis for future studies on the functional role of these eicosanoids in the evolution and progression of atherosclerosis.

The capacity of platelets to generate thromboxane A2'reflected by measurement of serum thromboxane B2(TxB2), greatly exceeds the systemic production of throm boxane in vivo. Thus, it is possible that substantial but incomplete inhibition of thromboxane formation ex vivo would still allow marked augmentation of thromboxane production in vivo. To address this hypothesis, we adminis tered aspirin 120 mg, a selective inhibitor of thromboxane synthase (TxSI). 3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indole-1-propanoic acid (UK-38, 485) 200 mg, and a com bination of both drugs to 12 healthy volunteers and measured the effects on serum TxB2and urinary 2,3-dinor-thromboxane B2(Tx-M), an index of endogenous thromboxane biosynthesis. Although serum TxB2was maximally inhibited by 94 ± 1 % after aspirin and 96 ± 2% after the TxSI, maximal depression of Tx-M was only 28 ± 8% and 37 ± 9%, respectively. Combination of aspirin with the TxSI resulted in a small but significant increase in inhibition of thromboxane generation ex vivo (98 ± 1 % v94 ± 1%; P < 0.05), but a disproportionately greater fall in thromboxane synthesis in vivo (58 ± 7%; P <0.01). Consistent with further inhibition of platelet thromboxane synthesis, addition of the TxSI abolished the transient decline in prostacyclin formation after aspirin alone. Administration of a lower dose of aspirin (20 mg) to 6 healthy subjects caused a small reduction in Tx-M (12 ± 4%; P <0.05) and inhibited serum TxB2by 48 ± 2%. The relationship between inhibition of platelet capacity to form thromboxane ex vivo (serum TxB2) and synthesis in vivo (Tx-M) departed markedly from the line of identity. When total blockade of the capacity of platelets to generate thromboxane is approached, minor decrements in capacity result in a disproportionate depression of actual thrombox ane biosynthesis. These results imply that pharmacologic inhibition of serum TxB2must be virtually complete before thromboxane-dependent platelet activation is influenced in vivo.