Polymorphism of Platelet Membrane Glycoprotein IIIa: Human Platelet Antigen 1b (HPA-1b/PlA2) Is an Inherited Risk Factor for Premature Myocardial Infarction in Coronary Artery Disease

Zotz, Rainer B.; Winkelmann, Bernhard R.; Nauck, Markus; Giers, G.; Maruhn-Debowski, Beate; März, Winfried; Scharf, Rüdiger E.

doi:10.1055/s-0037-1615054

Cited by 79 publications

(68 citation statements)

References 32 publications

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“…Increased PIA2-prevalence in CAD and in patients after myocardial infarction was reported [31,32,33,34,35]. In a prospective nested case control trial within the Physician's Health Study no association was found of the PIA2-prevalence with any thrombotic endpoint at all and this was confirmed by the ECTIM and ARIC studies and by some smaller studies [36,37,38,39,40].…”

Section: Discussionmentioning

confidence: 86%

“…In a prospective nested case control trial within the Physician's Health Study no association was found of the PIA2-prevalence with any thrombotic endpoint at all and this was confirmed by the ECTIM and ARIC studies and by some smaller studies [36,37,38,39,40]. Others seem to resolve these striking differences by their suggestion that PIA2-prevalence does not act as a risk factor per se, but strongly determines the thrombogenic reactivity of the circulating platelets [32]. This concept is attractive, since it addresses platelet hyperreactivity super-imposed to coronary atherosclerosis to act as the final mechanism which translates risk factor-dependent vessel wall morphology into blood-dependent thrombotic infarction.…”

Section: Discussionmentioning

confidence: 96%

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Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

et al. 2003

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Aims/hypothesis. The gene encoding the β 3 -subunit (GPIIIa) of the platelet α 2 β 3 -integrin (fibrinogen receptor) shows a polymorphism PlA1/A2 with the A2 allele putatively associated with an increased risk of acute ischaemic events. This study investigated whether Type 2 diabetes as a particular macrovascular risk factor associates with the thrombogenic PIA2 genotype. Methods. The PlA genotype was determined in 112 consecutive Type 2 diabetic patients additionally classified according to the presence of macrovascular disease. Forty-four non-diabetic patients with angiografically documented cardiovascular disease (CAD/ AMI) and a further 59 non-diabetic subjects with no angiografical signs of CAD were investigated as genomic background control (n=103). PIA-genotyping was carried out by standard restriction fragment length analysis (RFLA) of PCR amplified lymphocyte template DNA. Results. The overall allelic PlA2-prevalence accounted to 34.8% (39/112) in diabetic patients as compared to 14.6% (15/103) in non-diabetic patients [OR 3.1 (1.6-6.1), p<0.01].This odds ratio increased to 7.0 (2.5-19.7), (p<0.01) in subjects free of criteria of macrovascular disease. In non-diabetic control subjects without CAD there was an allelic PIA2 frequency of 10.2% (6/59) as compared to 20.5% (9/44) in patients with CAD and a history of AMI being less than either diabetes subgroup. The PIA2 prevalence in the subgroup of diabetes patients with macrovascular complications did not differ from the respective value in patients without macrovascular disease. [29.0% (20/69) vs. 44.2% (19/43)]. Conclusion/interpretation. This study confirms a trendwise association of PlA2 with severe coronary artery disease, but rather suggests an even stronger, highly significant association with the metabolic condition of Type 2 diabetes mellitus. This justifies the speculation that pathways dependent on the platelet α 2 β 3 integrin physiology could be implicated in the pathogenesis of Type 2 diabetes which lends further support to the "common soil" hypothesis of diabetes and vascular disease. [Diabetologia (2003) Abbreviations: AMI, acute myocardial infarction; CAD, coronary artery disease; GPIIIa, β 3 subunit of the platelet surface α 2 β 3 -integrin (GPIIb-IIIa, fibrinogen-receptor); PIA, platelet antigen; RGD, aminoacidsequence Arg-Gly-Asp; SNP, single nucleotide polymorphism. Diabetologia (2003) 46:984-989

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 96%

Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

et al. 2003

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“…The PL A2 polymorphism has been identi®ed in 10À21% of the Caucasian population [38À41]. The presence of the PL A2 allele has been associated with increasing platelet sensitivity to platelet agonists [42] and has been proposed as a hemostatic risk factor associated with arterial thrombotic disease [38,43] and neurological damage [39,44,45]. The reported allele frequency is similar to the frequency of donors exhibiting HIPA, and a DNA analysis was performed using a previously published protocol [41] to determine if a correlation between the PL A2 allele and HIPA exists.…”

Section: Pl A2 Allelementioning

confidence: 99%

Hypothermia‐induced platelet aggregation in heparinized flowing human blood: Identification of a high responder subpopulation

Hall¹,

Goodman²,

Alston³

et al. 2001

American J Hematol

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Cold-induced platelet aggregation (CIPA) in PRP has previously been documented in connection with platelet preservation (4±15°C). This report describes hypothermia-induced platelet aggregation (HIPA) in whole blood and at temperatures used in open-heart surgery (24±32°C). HIPA (speci®cally, the formation of occlusive aggregates) was studied in human whole blood. Fresh heparinized (1.5 U/ml) human blood was cooled and maintained at target temperatures (15, 20, 24, 28, 32, or 37°C) as it¯owed (1 ml/min) through 75-cm long 1/32" internal diameter polymer conduit. The formation of aggregates in the tubing was veri®ed using optical video microscopy and was quanti®ed by a lightscattering method and a constant-pressure ®ltration method. Donors were tested at least twice at each target temperature and were classi®ed into three separate response regimes (Low, Medium, and High) on the basis of the number of aggregates and the duration of their appearance. The screening of 121 donors (average age 22.3 4.3 years) for HIPA at 24°C (the temperature of maximum response) indicated 14% High Responders, 18% Medium Responders, and 68% Low Responders. HIPA was inhibited by EDTA, citrate, PGE 1 , and Tiro®ban, but not by aspirin, and it was enhanced by elevated heparin levels. HIPA was consistently noted in the blood of a subpopulation of donors, and the associated platelet aggregates in the blood of High Responders were rigid and occlusive. It is postulated that such aggregates may contribute to cognitive dysfunction noted in patients undergoing hypothermic open-heart surgery, and that postulus is being investigated. Am.

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“…Specifically, the domain is believed to have a biomechanical role in the allosteric signal transmission across the structure (21). The human platelet antigen-1 (HPA-1) polymorphism of the β 3 gene of α IIb β 3 arises from a LeuPro exchange at residue 33 of the mature β3 subunit (22,24), resulting in Leu33 (HPA-1a) or Pro33 (HPA-1b) platelets. This amino acid exchange, located within the PSI domain, leads to an inherited dimorphism that can be of clinical relevance (22).…”

mentioning

confidence: 99%

“…For example, the HPA-1b allele was significantly more frequent among young patients with acute coronary syndrome than among agematched healthy subjects (23). In the LURIC trial, an association study including more than 4,000 individuals, we documented that patients with coronary artery disease (CAD) 1 , who are carriers of the HPA-1b allele, experience their myocardial infarction five years earlier in life than CAD patients who are HPA-1b negative (22,24). In a prospective study on CAD patients undergoing saphenous-vein coronary-artery bypass grafting, we demonstrated that HPA-1b is a hereditary risk factor for bypass occlusion, myocardial infarction, or death after coronary-artery bypass surgery (25).…”

mentioning

confidence: 99%

The human platelet antigen-1b (Pro33) variant of αIIbβ3 allosterically shifts the dynamic conformational equilibrium of this integrin toward the active state

Pagani¹,

Pereira

Stoldt

et al. 2018

Journal of Biological Chemistry

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Integrins are heterodimeric cell-adhesion receptors comprising α and β subunits that transmit signals allosterically in both directions across the membrane by binding to intra-and extracellular components. The human platelet antigen-1 (HPA-1) polymorphism in α IIb β 3 arises from a Leu→Pro exchange at residue 33 in the genu of the β3 subunit, resulting in or Pro-33 (HPA1b) isoforms. Although clinical investigations have provided conflicting results, some studies have suggested that Pro-33 platelets exhibit increased thrombogenicity. Under flow-dynamic conditions, the Pro-33 variant displays prothrombotic properties, characterized by increased platelet adhesion, aggregate/thrombus formation, and outside-in signaling. However, the molecular events underlying this prothrombotic phenotype have remained elusive. As residue 33 is located > 80 Å away from extracellular binding sites or transmembrane domains, we hypothesized that the Leu→Pro exchange allosterically shifts the dynamic conformational equilibrium of αIIbβ3 toward an active state. Multiple microsecond-long, allatom molecular dynamics simulations of the ectodomain of the Leu-33 and Pro-33 isoforms provided evidence that the Leu→Pro exchange weakens interdomain interactions at the genu and alters the structural dynamics of the integrin to a more unbent and splayed state. Using FRET analysis of fluorescent proteins fused with αIIbβ3 in transfected HEK293 cells, we found that the Pro-33 variant in its resting state displays a lower energy transfer http://www.jbc.org/cgi

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Polymorphism of Platelet Membrane Glycoprotein IIIa: Human Platelet Antigen 1b (HPA-1b/PlA2) Is an Inherited Risk Factor for Premature Myocardial Infarction in Coronary Artery Disease

Cited by 79 publications

References 32 publications

Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

Hypothermia‐induced platelet aggregation in heparinized flowing human blood: Identification of a high responder subpopulation

The human platelet antigen-1b (Pro33) variant of αIIbβ3 allosterically shifts the dynamic conformational equilibrium of this integrin toward the active state

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