Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute ischaemic stroke is characterised by reductions in local cerebral blood flow (CBF) and activation of circulating platelets and leucocytes. Nitric oxide is a vasodilator and can inhibit these circulating cells. The aim of this study was to assess the effect of nitric oxide on platelet function and regional CBF in patients with acute ischaemic stroke. Sodium nitroprusside (SNP), a spontaneous nitric oxide donor, was administered at a dose which caused a 10 mm Hg fall in mean arterial blood pressure (MABP) in a pathophysiological study to 22 patients with acute ischaemic stroke and 12 matched control subjects. Platelet function (whole blood aggregation and flow cytometry) was assessed before and during SNP administration. Changes in regional CBF were measured using single photon emission computerised tomography (SPECT) scanning. SNP significantly reduced platelet aggregation in both the patient and control subject groups. Equally, the expression of platelet adhesion molecules P-selectin (CD62) and glycoprotein (GP) GP IIIa (CD61) were significantly reduced in both groups. GP Ia (CDw49b) expression was significantly attenuated in the patient but not in the control group. Four patients underwent SPECT scanning and improvements in local CBF corresponding to the penumbral area of the clinical stroke site were seen in 3 of these patients. A total of 24 regions of asymmetrical perfusion were examined, pre-SNP (median (SQR)), 0.68 (0.14) vs. peri-SNP 0.78 (0.17), 2p = 0.065. SNP, given at a dose which reduced MABP by 10 mm Hg, significantly inhibited platelet aggregation and adhesion molecule expression. Improved regional CBF was seen in some patients. SNP is a candidate therapeutic agent for patients with acute ischaemic stroke and warrants further study.
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PMID:Pathophysiological assessment of nitric oxide (given as sodium nitroprusside) in acute ischaemic stroke. 961 99

A number of polymorphisms of the platelet glycoprotein (GP) Ib-V-IX and IIb/IIIa complexes have been described, and the PlA polymorphism of GP IIIa has been associated with coronary thrombosis. We determined the levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) and the genotype distributions of PlA and a variable number tandem repeat (VNTR) polymorphism of GP 1b in subjects with acute stroke (n=609) and healthy control subjects (n=435). Levels of beta-TG were higher in patients both initially (47.4 [44.7 to 50.2] ng/mL, P<0.0001) and after 3 months (42.9 [40.3 to 45.7] ng/mL, P=0.03) compared with control subjects (39.4 [37.7 to 41.2] ng/mL). Initial levels of beta-TG were significantly higher in those who subsequently died (58.7 [52.3 to 65.8] ng/mL) compared with those still alive (42.7 [40.1 to 45.5] ng/mL, P<0.0001). In a logistic regression model, beta-TG remained an independent predictor of poststroke mortality, with an odds ratio for an increase in 10 ng/mL of 1.12 (1.03 to 1.21, P=0.006). In subjects who had never smoked, there was a significant difference in the genotype distributions of patients with atherothrombotic stroke (A1/A1=147, A1/A2=70, and A2/A2=2) compared with controls (A1/A1=165, A1/A2=47, and A2/A2=5, P=0.03). The PlA distribution of subjects with atherothrombotic stroke before the age of 50 years (A1/A1=19 and A1/A2+A2/A2=18) was also significantly different from age- and sex-matched controls (A1/A1=54 and A1/A2+A2/A2=20, P=0.02). We found no association of VNTR with stroke or poststroke mortality. These data indicate that there is a persistent state of enhanced platelet activation in subjects with acute stroke, which is associated with poststroke mortality. The increased frequency of the PlA2 allele in young subjects with atherothrombotic stroke lends further support for a role of the PlA polymorphism in acute thrombosis.
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PMID:Platelet GP IIIa PlA and GP Ib variable number tandem repeat polymorphisms and markers of platelet activation in acute stroke. 967 73

Thrombosis may play an important role in the pathophysiology of certain complications of sickle cell disease (SCD), including stroke and avascular necrosis (AVN). Currently there is no laboratory or clinical parameter that can identify patients who are at highest risk of developing these thrombotic complications. We hypothesized that some patients with SCD have an inherited hypercoagulable state that results in an increased risk of developing stroke or AVN. We examined the role of two common inherited thrombophilic mutations that, in other populations, have been associated with arterial and venous thrombosis and are amenable to screening with DNA restriction enzyme analysis. The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and the C1565T mutation in the platelet glycoprotein IIIa (GPIIIa) gene were evaluated. We analyzed genomic DNA from 86 children and adults with SCD, including 16 patients with a history of a clinical stroke and 14 patients with AVN, for the presence of these mutations. The C677T MTHFR mutation was found in 19% of patients with stroke, 14% of patients with AVN, and 14% of patients with neither complication (P = NS). The C1565T GPIIIa mutation was found in 25% of patients with stroke, 14% of patients with AVN, and 18% of patients with neither complication (P = NS). Although each of these mutations is relatively common in patients with SCD, neither is independently associated with an increased risk of developing stroke or AVN.
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PMID:Inherited DNA mutations contributing to thrombotic complications in patients with sickle cell disease. 984 Sep 6

Platelets are formed from, and their function determined by, bone marrow megakaryocytes (MK). Previous studies have found that hypertension is associated with accentuated platelet function and that some antihypertensive drug classes have antiplatelet activity. We measured MK ploidy (DNA content), size, granularity, and expression of the adhesion molecule glycoprotein (GP) IIIa, using flow cytometry and measures of platelet function, in 12 untreated hypertensive patients and 14 normotensive subjects. Eight hypertensive patients were then treated with losartan (50 mg daily), an angiotensin receptor antagonist that lowers blood pressure, and MK and platelet parameters re-measured after 6 weeks. Hypertensive patients had, as compared with matched normotensive subjects: increased MK ploidy (mean +/- SD) 22.9 +/- 2.2 N versus 20.8 +/- 1.6 N (2P = 0.009); increased platelet size, 10.67 +/- 1.03fl versus 9.26 +/- 0.72fl (2P < 0.001); increased platelet expression of GP IIIa, 108.6 +/- 22.5 versus 92.0 +/- 12.3 (2P = 0.036); and reduced platelet count, (207 +/- 52) x 10(9)/l versus (257 +/- 55) x 10(9)/l (2P = 0.026). Losartan significantly reduced MK ploidy, 22.6 +/- 2.2 N versus 21.4 +/- 1.9 N (2P = 0.006); MK size, 607 +/- 22 versus 579 +/- 16 (2P = 0.003); and lengthened cutaneous bleeding time, 424 +/- 86s versus 563 +/- 164s (2P = 0.011), in hypertensive patients. Losartan did not alter MK granularity or GP IIIa expression, or platelet count, size, mass, GP IIIa expression, or aggregation. The data suggest that platelet changes in hypertension may be secondary to changes in MKs, and that anti-hypertensive treatment can alter MKs and the function of platelets they produce. Since antihypertensive therapy reduces the risk of stroke and myocardial infarction, MKs are a novel therapeutic target for the prevention of vascular events.
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PMID:Prothrombotic megakaryocyte and platelet changes in hypertension are reversed following treatment: a pilot study. 1130 15

Currently, the established risk factors for cardiovascular disease (CVD) are largely environmental in nature. Conflicting studies have suggested that mutations in specific coagulation genes may also provide a genetic basis for CVD risk. We reviewed clinical studies that examined the role of single nucleotide polymorphisms in coagulation and platelet factors, and a biochemical factor to determine if specific genotypes are correlated with patients with a history of arterial thrombotic diseases (acute coronary syndromes or stroke). A meta-analysis was performed on studies for factors II (G20210A variant), V Leiden (G1691A), VII (R353Q), glycoprotein (GP) IIIa receptor (PI(A1/A2)), and methylenetetrahydrofolate reductase (MTHFR, C677T). There was no correlation for factor II or factor V polymorphisms to coronary artery disease (CAD) in 5,607 and 5,431 patients studied, respectively. There was also no correlation for factor II variants and stroke in 3,451 patients studied. For factor V, statistical significance was achieved for the G1691A variant on 3,399 patients with stroke (odds ratio [OR] 1.43, 95% confidence intervals [CI] 1.03 to 1.97). The GP IIIa PI(A1/A2) genotype was associated with increased risk for CAD in 7,920 patients (OR 1.12, 95% CI 1.01 to 1.24), but not for 1,855 patients who had a stroke (OR 0.80, 95% CI 0.62 to 1.04). The combined RQ and RR genotypes of factor VII R353Q were correlated to a reduced risk for CVD in 2,574 patients (OR 0.78, 95% CI 0.65 to 0.93), whereas the QQ genotype had offered more protection (OR 0.53, 95% CI 0.27 to 1.03). The TT homozygous variant of MTHFR was associated with CAD risk in 5,644 patients studied (OR 1.30, 95% CI 1.11 to 1.52) but not for 3,075 patients with stroke. This study shows that for some genes, further studies are unnecessary, whereas for others, no more enrollments are needed. The impact of certain genotypes must be examined in relation to other established risk factors and potentially new therapeutic strategies.
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PMID:Correlation of polymorphisms to coagulation and biochemical risk factors for cardiovascular diseases. 1139 54

Over the past several years, platelet glycoprotein gene polymorphisms have received increasing attention as possible inherited determinants of prothrombotic tendency. However, their role in genetic susceptibility to thrombotic disease remains controversial. The glycoprotein IIIa Leu33Pro amino acid substitution appears to be associated with a subtle effect on platelet thrombogenicity in vitro, but is not a major risk factor for arterial thrombotic disease among the general population. Evidence suggests that the glycoprotein IIIa Pro33 allele may be associated with increased risk of thrombotic events following coronary re-vascularization and possibly among younger subjects with atherosclerosis. The nucleotide 807T variant of glycoprotein Ia is associated with increased platelet glycoprotein Ia/IIa receptor density, collagen-induced platelet adhesion and an increased risk of early onset myocardial infarction and stroke. Evaluation of the roles of the glycoprotein Ibalpha Thr145Met and variable number of tandem repeat polymorphisms has been complicated by their lack of well-defined effects on platelet adhesive function and the strong linkage disequilibrium between the two sites. Future epidemiologic studies of platelet glycoprotein gene polymorphisms will require larger sample sizes and family based approaches to further elucidate clinically important associations with thrombotic disease, including gene-environment and gene-gene interactions. Other polymorphisms of potential functional significance within genes encoding platelet membrane proteins will undoubtedly be discovered. The challenge will be to integrate advances in platelet biology with molecular and genetic epidemiology to enhance our understanding of the genetic determinants of common, but etiologically complex thrombotic diseases.
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PMID:Platelet glycoprotein gene polymorphisms and risk of thrombosis: facts and fancies. 1170 18

This study examined the influence of the Pl(A) polymorphism of glycoprotein IIIa (GPIIIa) in determining the response to an oral GPIIb/IIIa antagonist, orbofiban, in patients with unstable coronary syndromes. Genotyping for the Pl(A) polymorphism was performed in 1014 patients recruited into the OPUS-TIMI-16 (orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction 16) trial, in which patients were randomized to low- or high-dose orbofiban or placebo for 1 year. The primary end point (n = 165) was a composite of death, myocardial infarction (MI), recurrent ischemia requiring rehospitalization, urgent revascularization, and stroke. Overall, orbofiban failed to reduce ischemic events when compared with placebo, but increased the rate of bleeding. In the whole population, Pl(A2) carriers had a significant increase in MI (n = 33) during follow up, with a relative risk (RR) of 2.71 (95% CI, 1.37 to 5.38; P =.004). There was a significant interaction between treatment (placebo and orbofiban) and the Pl(A) polymorphism for bleeding (n = 187; P =.05). Thus, while orbofiban increased bleeding in noncarriers (RR = 1.87, 1.29 to 2.71; P <.001) in a dose-dependent fashion, it did not increase bleeding events in Pl(A2) carriers (RR = 0.87, 0.46 to 1.64). There was no interaction between treatment (placebo and orbofiban) and the Pl(A) polymorphism for the primary end point (P =.10). However, in the patients receiving orbifiban there was a higher risk of a primary event (RR = 1.55, 1.03 to 2.34; P =.04) and MI (RR 4.27, 1.82 to 10.03; P <.001) in Pl(A2) carriers compared with noncarriers. In contrast, there was no evidence that Pl(A2) influenced the rate of recurrent events in placebo-treated patients. In patients presenting with an acute coronary syndrome, the Pl(A) polymorphism of GPIIb/IIIa may explain some of the variance in the response to an oral GPIIb/IIIa antagonist.
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PMID:Genetic variation in glycoprotein IIb/IIIa (GPIIb/IIIa) as a determinant of the responses to an oral GPIIb/IIIa antagonist in patients with unstable coronary syndromes. 1171 62

Platelet glycoprotein receptors play a role in the pathogenesis of chronic diabetic complications. Genetic polymorphisms of the alpha2beta1 integrin and glycoprotein IIIa (GPIIIa) have been associated with myocardial infarction, stroke, and diabetic retinopathy. To identify risk factors for their development in a cohort of patients with type 2 diabetes, we evaluated clinical variables and genetic polymorphisms in the alpha2beta1 integrin and GPIIIa genes. Two hundred thirty-four subjects with type 2 diabetes (126 patients with and 108 patients without diabetic nephropathy), as well as 217 nondiabetic healthy subjects, were recruited for this study. Clinical factors for investigation included sex, age at diagnosis, duration of diabetes, body mass index (BMI), and fasting plasma glucose, hemoglobin A(1c) (HbA(1c)), total cholesterol, and triglyceride levels. Genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism analyses. No difference in the Bgl II polymorphism of the alpha2beta1 integrin gene was found between patients with type 2 diabetes with or without nephropathy (11 [8.7%], 47 [37.3%], and 68 patients [54.0%] versus 10 [9.3%], 32 [29.6%], and 66 patients [61.1%] for Bgl II+/+, Bgl II+/-, and Bgl II-/-, respectively; P = 0.271). Multiple logistic regression analyses showed that duration of diabetes, BMI, hypertension, and poor glycemic control were four independent predictors for the development of diabetic nephropathy. No contribution of the Bgl II+ allele of the alpha2beta1 integrin was found for the risk for nephropathy (odds ratio, 1.258; 95% confidence interval, 0.655 to 2.418; P = 0.490). The Pl(A2) allele genotype was not found among our studied subjects. In conclusion, age, duration of diabetes, BMI, and HbA(1c) level are strong predictors for nephropathy in patients with type 2 diabetes. However, the Bgl II polymorphism of the alpha2beta1 integrin gene and the Apa I polymorphism of the platelet GPIIIa gene do not have a major role in the development of diabetic nephropathy in our population.
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PMID:Platelet collagen receptor alpha2beta1 integrin and glycoprotein IIIa Pl(A1/A2) polymorphisms are not associated with nephropathy in type 2 diabetes. 1172 49

Platelet function is accentuated in acute ischaemic stroke (IS) and may also be altered in haemorrhagic stroke. Whether these changes are a direct reaction to the stroke or are secondary to changes in megakaryocytes (MKs) is unknown. To determine whether MKs are altered in acute stroke we studied 24 patients (18 with ischaemic stroke, six with haemorrhagic stroke) within 3 days of symptom onset, and 14 matched controls. MK ploidy (DNA content, N), size (forward scatter, FSC, arbitrary units), granularity (side scatter, SSC, arbitrary units) and glycoprotein (GP) IIIa expression (arbitrary units) were assessed by flow cytometry. Platelet size (MPV, fl), platelet count (PC, x109/l), circulating reticulated platelets (%), and cutaneous bleeding time (s) were also measured. MK ploidy 22.5 (2.7) vs. 20.6 (1.7) (2p = 0.014); FSC 629 (51) vs. 594 (41) (2p = 0.025); and SSC 843 (88) vs. 776 (76) (2p = 0.020) were each increased, whereas bleeding time 318 (102) vs. 401 (94) (2p = 0.050) was decreased in patients with acute stroke as compared with controls. Trends to increased MK GP IIIa expression and reticulated platelets were also apparent. In a post hoc analysis, the increase in MK ploidy was most prominent in patients with a prior history of hypertension. Ischaemic stroke was associated with non-significant increases in MK ploidy, size, and granularity. However, MK parameters were different in acute haemorrhagic stroke as compared with controls: MK ploidy 23.0 (1.8) vs. 20.6 (1.7) (2p = 0.018); MK FSC 637 (21) vs. 594 (41) (2p = 0.050); MK SSC 872 (41) vs. 776 (76) (2p = 0.020), changes which could be related to the high prevalence of hypertension (83%) in this group. These results demonstrate that pro-thrombotic changes in the megakaryocyte-platelet-haemostatic axis (MPHA) are present in acute stroke. Although megakaryocyte changes are likely, in part, to be secondary to the stroke, they could also precede the stroke and therefore explain some of the increased platelet function observed in acute stroke.
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PMID:Altered megakaryocyte-platelet-haemostatic axis in patients with acute stroke. 1189 47

Platelet plays a pivotal role in the pathogenesis of thrombotic cardiovascular diseases. Recently, the polymorphism of platelet glycoprotein (GP) genes has been reported to be associated with an increased risk for ischemic stroke. The purpose of this study is to evaluate the association between platelet GP genetic variants and ischemic stroke in young Taiwanese. We conducted a case-control study in 157 young ischemic stroke patients recruited between September 2001 and March 2003 and 157 age- and sex-matched controls. The genotypes of platelet GP Ia C807T, GP Ib C3550T, and GP IIIa Pl(A1/A2) polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Student's t-test, chi-square test, and logistic regression modeling were used for data analyses. The GP Ia C807T CC, CT and TT genotype frequencies were similar between patients (50.3%, 43.9%, 5.7%) and controls (53.5%, 38.9%, 7.6%; p=0.58). There were no significant differences in GP Ib C3550T CC and CT genotype distributions between patients (91.1%, 8.9%) and controls (91.7%, 8.3%; p=0.84). Of all subjects, none carries GP IIIa Pl(A2) mutation. In conclusion, platelet GP Ia C807T and GP Ib C3550T polymorphisms in our population are less common compared with Caucasians, and GP IIIa Pl(A1/A2) genetic mutation is not found, and all of them are not associated with ischemic stroke in young Taiwanese.
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PMID:Platelet glycoprotein Ia C807T, Ib C3550T, and IIIa Pl(A1/A2) polymorphisms and ischemic stroke in young Taiwanese. 1554 85


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