Glycoprotein Ib polymorphisms influence platelet plug formation under high shear rates

Jilma‐Stohlawetz, Petra; Homoncik, Monika; Jilma, Bernd; Knechtelsdorfer, Maarten; Unger, Petra; Mannhalter, Christine; Panzer, Simon

doi:10.1046/j.1365-2141.2003.04083.x

Cited by 29 publications

(28 citation statements)

References 14 publications

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“…In yet another study of healthy young adults in Vienna, who were either HPA-2a (Thr,Thr) or HPA-2b (Thr, Met/Met,Met), platelet function testing indicated no significant difference in collagen/ epinephrine closure times, as measured by the PFA-100 TM assay. They also had similar expression of platelet surface GP Ib as measured by flow cytometric expression, indicating no platelet functional differences [21]. In our study that consisted of 22% African Americans, we found no significant differences in mean collagen/ADP closure times and comparable results with collagen/epinephrine closure when we compared results from those with Ko a (HPA-2b) and those with Ko b (HPA-2a).…”

Section: Discussionsupporting

confidence: 53%

“…Furthermore, the presence of the C allele did not confer increased platelet aggregation in the entire group. Investigators have found that homozygotes with the -5TT Kozak genotype have shortened collagen-adrenaline-induced closure time when compared to those individuals who are -5CT [21]. However, others have not found an association between shortening of the PFA Collagen-epinephrine closure time and Kozak status [28].…”

Section: Kozak Polymorphismmentioning

confidence: 99%

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Platelet functional implications of glycoprotein Ibα polymorphisms in African Americans

Williams¹,

Ng’alla²,

Vaidya³

2006

American J Hematol

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The platelet glycoprotein Iba is crucial in the binding of platelets to Von Willebrand Factor within areas of high stress. A single nucleotide polymorphism of GP Iba gives rise to the Ko a (HPA-2b) and the -5C Kozak polymorphism. The presence of these polymorphisms has been associated with an increased risk for atherothrombotic disease. The Ko a polymorphism has been shown to have a higher prevalence in African Americans compared to American Caucasians. However, very little is known regarding any functional consequences of these platelet polymorphisms in African Americans. We assessed the prevalence of the Ko and -5C Kozak polymorphisms in a population of both African American and American Caucasian patients with and without CAD and determined whether there were platelet functional consequences in both groups. We studied 99 patients of which 22 were African American and 77 were American Caucasian. Aggregations were performed and shear induced platelet plug formation was tested using a platelet function analyzer. The HPA-2b allele was significantly higher in African Americans when compared to Caucasians (P ¼ 0.001). Genotype frequencies of the -5C Kozak polymorphism were not significantly different between the two groups. We found no differences in platelet aggregation in African Americans who were either heterozygous or homozygous for the HPA-2b allele or the -5C Kozak allele when compared to American Caucasians of the same category. We found no significant differences in PFA-100 testing. We conclude from our study that these polymorphisms do not lead to altered platelet function in African Americans. Am. J. Hematol. 82:15-22, 2007. V V C 2006 Wiley-Liss, Inc.

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Section: Discussionsupporting

confidence: 53%

Section: Kozak Polymorphismmentioning

confidence: 99%

Platelet functional implications of glycoprotein Ibα polymorphisms in African Americans

Williams¹,

Ng’alla²,

Vaidya³

2006

American J Hematol

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“…As in population studies, results of platelet function studies for T145M variants are mixed (31)(32)(33)(34)(35)(36)(37)(38). No differences for variants were reported for ADP-induced platelet aggregation and von Willebrand factor binding (31), von Willebrand factor binding to truncated GPIb␣ T and M variant proteins (32), and collagen-epinephrine closure time (33).…”

Section: Discussionmentioning

confidence: 99%

“…No differences for variants were reported for ADP-induced platelet aggregation and von Willebrand factor binding (31), von Willebrand factor binding to truncated GPIb␣ T and M variant proteins (32), and collagen-epinephrine closure time (33). However, other studies do report differences, including greater inhibition of von Willebrand factormediated platelet agglutination by aurintricarboxylic acid (a von Willebrand factor antagonist) for M allele carriers, but no difference in prolongation of collagen-ADP closure time (34); increased ristocetin-induced and shear stressinduced agglutination and shortened collagen-epinephrine closure time for homozygous T subjects (35); greater binding of von Willebrand factor to T variant NH 2 -terminal fragments of GPIb␣-transfected Chinese hamster ovary (CHO) cells (36); mildly shortened collagen-ADP closure time for CAD patients homozygous for T (37); and, in CHO cell transfectants of T145M and a second GPIb␣ polymorphism (variable number tandem repeats) variants, stronger interaction of von Willebrand factor with the M variant of T145M (38).…”

Section: Discussionmentioning

confidence: 99%

Glycoprotein Ibα Polymorphism T145M, Elevated Lipoprotein-Associated Phospholipase A2, and Hypertriglyceridemia Predict Risk for Recurrent Coronary Events in Diabetic Postinfarction Patients

et al. 2007

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To explore altered platelet function in recurrent coronary event risk among diabetic postinfarction patients, we investigated a function-altering genetic polymorphism (T145M) in the von Willebrand factor binding region of the platelet glycoprotein Ib␣ (GPIb␣) subunit. The study comprised diabetic and nondiabetic patients of the Thrombogenic Factors and Recurrent Coronary Events postinfarction study. Cox proportional hazards multivariable modeling, adjusted for significant clinical covariates, was performed using the polymorphism and metabolic, inflammatory, and thrombogenic blood markers. Nondiabetic patients demonstrated risk for elevated lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ). In contrast, diabetic patients demonstrated significant and independent risk for the M allele of the T145M polymorphism (MT plus MM versus TT, hazard ratio [HR] 3.73, 95% CI 1.90 -7.33, P < 0.001), hypertriglyceridemia (2.91, 1.52-5.56, P ‫؍‬ 0.001), and elevated Lp-PLA 2 (2.78, 1.45-5.35, P ‫؍‬ 0.002). Joint risk (one, two, or three risk factors) expressed as relative outcome rates (compared with no risk factors) were 2.4, 4.0, and 8.2, respectively. We conclude that the M allele of the T145M polymorphism of the GPIb␣ subunit predicts risk for recurrent coronary events in diabetic postinfarction patients, but not in nondiabetic postinfarction patients, supportive of an important role for platelet hyperactivation in diabetic coronary heart disease.

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“…All three characterized polymorphisms are located either in the promoter or in the coding region, which influence the amount of the receptor expression and/or its function [5,6,15,16]. Moreover, it is known that the distribution of the distinct alleles is heterogeneous among subjects of distinct ethnic backgrounds [8,12,14].…”

Section: Discussionmentioning

confidence: 99%

Genetic variability of platelet glycoprotein Ibα gene

et al. 2004

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Platelet membrane glycoprotein (GP) Ibα is a critical component of platelet adhesion complex to subendothelium structures following tissue injury or pathological surfaces, such as atherosclerotic plaques. Polymorphisms of the GPIbα gene have been associated with a high risk for occlusive vascular disease, and its distribution varies considerably among distinct populations. These polymorphisms comprise the human platelet antigen (HPA)‐2 system, the −5C/T dimorphism of the Kozak sequence, and the variable number of tandem 39‐bp repeats (VNTR). Here we report the prevalence of the GPIbα gene polymorphisms among Brazilians, a highly ethnically diverse population. We analyzed 492 subjects of European, African, or Indigenous origin. It was possible to determine ten distinct haplotypes. The most common (∽40%) haplotype was the Kozak‐TT/HPA‐2aa/VNTR‐CC for both Caucasian and African descent. However, among Indigenous, Kozak‐TT/HPA‐2aa/VNTR‐CC and Kozak‐TC/HPA‐2aa/VNTR‐CC were equally present. Although a strong linkage disequilibrium between VNTR and HPA‐2 polymorphism had also been observed, here we determined incomplete linkage disequilibrium in 10% of subjects from all ethnic groups. VNTR‐E, a rare variant lacking the 39‐bp repeat, was identified in two unrelated subjects, and functional platelet studies revealed no abnormalities. The VNTR‐A allele, the largest variant containing four copies of the repeats, was not identified in this population. However, homozygosity for the VNTR‐A allele (Kozak‐TT/HPA‐2aa/VNTR‐AA) was determined in two distinct species of nonhuman primates. These results suggest a greater complex evolutionary mechanism in the macroglycoprotein region of the GPIbα gene and may be useful in the design of gene–disease association studies for vascular disease. Am. J. Hematol. 77:107–116, 2004. © 2004 Wiley‐Liss, Inc.

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Glycoprotein Ib polymorphisms influence platelet plug formation under high shear rates

Cited by 29 publications

References 14 publications

Platelet functional implications of glycoprotein Ibα polymorphisms in African Americans

Platelet functional implications of glycoprotein Ibα polymorphisms in African Americans

Glycoprotein Ibα Polymorphism T145M, Elevated Lipoprotein-Associated Phospholipase A2, and Hypertriglyceridemia Predict Risk for Recurrent Coronary Events in Diabetic Postinfarction Patients

Genetic variability of platelet glycoprotein Ibα gene

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