Pl(A2) polymorphism of beta(3) integrins is associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury.

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Undas A, Brummel K, Musial J, Mann KG, Szczeklik A

Pl(A2) polymorphism of beta(3) integrins is associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury.

Circulation. 2001 Nov 27;104(22):2666-72.

PubMed ID

11723016 [ View in PubMed

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Abstract

BACKGROUND: Mechanisms by which the Pl(A2) (Leu33Pro) polymorphism of beta(3) integrins could lead to an increased risk for coronary events are unclear. This study was designed to examine the effect of this polymorphism on blood coagulation. METHODS AND RESULTS: In normal subjects (12 with Pl(A1A1), 9 with Pl(A1A2), and 3 with Pl(A2A2)), we evaluated the activation of prothrombin, factor V, and factor XIII and fibrinogen removal by quantitative immunoblotting; thrombin-antithrombin III complex generation using ELISA; and levels of fibrinopeptide A and B by high-performance liquid chromatography in blood collected every 30 seconds at sites of standardized microvascular injury before and after 7 days of aspirin ingestion (75 mg/d). Compared with the Pl(A1A1) subjects, the Pl(A2) carriers exhibited higher maximum rates of thrombin B-chain generation (by 31.6%; P=0.005), thrombin-antithrombin III complex generation (by 30.7%; P=0.003), fibrinogen consumption (by 31.3%; P=0.002), prothrombin consumption (by 26.1%; P=0.011), and activation of factor V (by 14.1%; P=0.033) and factor XIII (by 27.0%; P=0.012). In the Pl(A1A1) homozygotes, aspirin ingestion resulted in reductions in the velocity of thrombin B-chain formation (by 32.1%; P=0.007), prothrombin consumption (by 30.4%; P=0.018), factor Va generation (by 28.9%; P=0.014), fibrinogen removal (by 41.2%; P=0.001), and factor XIII activation (by 22.6%; P=0.026). In the Pl(A2) carriers, aspirin did not alter the velocity of all these processes. After aspirin ingestion, fibrinopeptide A and B concentrations in the last 30-second interval were significantly reduced, but only in the Pl(A1A1) subjects. CONCLUSIONS: The presence of the Pl(A2) allele is associated with enhanced thrombin formation and an impaired antithrombotic action of aspirin, which might favor coronary thrombosis in the Pl(A2) carriers.

DrugBank Data that Cites this Article

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Acetylsalicylic acid	Integrin beta-3 Gene symbol: ITGB3 UniProt: P05106	GPIIIa PlA2	(C;C) / (C;T)	T > C (rs5918)	Effect Directly Studied	Patients with this genotype have increased resistance to the anti-thrombotic effects of aspirin.	Details