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)

Glycocalicin (GC) is the soluble portion of platelet membrane protein GP1b, and may be cleaved from the platelet surface during platelet activation. Previous study has indicated that plasma glycocalicin/platelet (GC/plt) levels are elevated in patients presenting with acute stroke. The present study was undertaken to determine the GC/plt levels in patients being treated for transient ischaemic episodes, to assess whether the elevated GC/plt level in acute stroke is due to a detectable, constitutive premorbid state of platelet activation. In sixteen consecutive patients attending a vascular surgery clinic, GC levels were measured on a citrated plasma sample, and corrected for circulating platelet count. Since 15 of 16 patients were taking aspirin when seen at clinic, a control study was undertaken to assess the effect of aspirin on sequential plasma GC/plt levels measured over 10 days--5 pre and post daily aspirin for 5 days, 4 acting as non-aspirinated controls. Plasma GC/plt levels in normal plasma were 21.6 +/- 8.0 fg; mean +/- SD. In the 16 patients the GC/plt levels were 13.1 fg/plt; SD 5.4, range 2.9-24.3. All platelet counts were in the normal range in all patients involved. While a masking effect due to aspirin cannot be completely ruled out, these studies indicate that plasma GC/plt level is not useful as a predictor of acute stroke in the premorbid population.
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PMID:Plasma glycocalicin levels are not elevated in patients with a history of transient ischaemic event and are normal in aspirinated normal volunteers. 892 91

Several platelet membrane glycoprotein polymorphisms have been identified as potential risk factors for cardiovascular disease. Recently a nucleotide -5T/C dimorphism in the translation initiation site (Kozak sequence) of the platelet glycoprotein Ibalpha (GPIbalpha) gene was associated with increased platelet surface levels of the GPIb-IX-V receptor complex. The role of this GPIbalpha Kozak sequence polymorphism in the occurrence of arterial thrombotic disease is unknown. We performed genotype analysis of the Kozak sequence polymorphism of GPIbalpha in a population-based study of 18- to 44-year-old women with nonfatal myocardial infarction (MI) (n = 78), nonfatal stroke (n = 106), and 384 demographically similar female control subjects. Analysis of -5T/C genotypes revealed that at least one copy of the C allele was present in 14.1% of MI cases, 23.6% of stroke cases, and 23.7% of controls. The age-adjusted odds ratio for MI in women carrying at least one copy of the C allele was 0.53 (95% confidence interval [CI] 0.27-1.05). The age-adjusted odds ratio for stroke in women carrying at least one copy of the C allele was 0.99 (95% CI 0.59-1.65). Analyses stratified by stroke type (ischemic, hemorrhagic) yielded similar results. In conclusion, young women carrying the C allele of the Kozak sequence polymorphism of GPIbalpha are not at increased risk of MI or stroke. Paradoxically, the C allele may even be associated with a reduced risk of MI in this population. This finding requires further study.
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PMID:The Kozak sequence polymorphism of platelet glycoprotein Ibalpha and risk of nonfatal myocardial infarction and nonfatal stroke in young women. 1115 11

Depression is a significant risk factor for and consequence of both cardiovascular disease and stroke. The pathophysiological processes underlying this association are poorly understood. This study utilised a technique for measurement of whole blood platelet surface glycoproteins involved in early adhesion and aggregation in sample populations of patients with depression and stroke, and healthy controls. We analysed the platelet surface glycoproteins GPIb and GPIIbIIIa using flow cytometry in eight depressed subjects (Hamilton depression score >17), 14 post-stroke subjects (seven depressed and seven non-depressed), and in eight healthy control subjects. The number of GPIb receptors was significantly increased in subjects with depression and in post-stroke subjects compared to control subjects. The number of GPIb receptors from post-stroke subjects was not significantly different from that of depressed subjects. There were no differences between any groups in measures of GPIIbIIIa receptor numbers. No additive effect of co-morbid depression on the surface expression level of either marker could be detected in the post-stroke subjects. Platelet dysfunction may be involved in the pathophysiological process underlying the association between depression and cerebrovascular disease.
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PMID:Platelet surface glycoprotein expression in post-stroke depression: a preliminary study. 1279 82

Excessive coagulation and impaired fibrinolysis lead to many hemostatic disorders, which enhance the risk of development of life-threatening cardiovascular diseases such as myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism, belonging to the most important factors influencing morbidity and mortality in civilized societies. The adverse events induced by currently used drugs, the need for regular monitoring of coagulation parameters, inconvenient, in some cases, route of administration stimulate further search for novel, effective and safe methods of therapies of these disorders. In this paper, we describe those new agents which are now under experimental and clinical study, such us prostanoids, nitroaspirin, GP IIb/IIIa receptor antagonists, thienopyridine derivatives, collagen-GPVI and von Willebrand factor-GPIb-IX contact blockers, direct thrombin inhibitors, inhibitors of thrombin-platelet interactions, factor VII inhibitors and tissue factor-factor VII contact blockers. Based on the available literature, we discuss the possible role of these agents in the future prevention and treatment of thromboembolic diseases.
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PMID:Progress in pharmacotherapy of thrombosis. 1458 10

Patho/physiological platelet aggregate (thrombus) formation is initiated by engagement of platelet surface receptors, glycoprotein (GP)Ib-IX-V and GPVI that bind von Willebrand factor or collagen. Although beneficial in response to vascular injury by preventing blood loss (haemostasis), platelet aggregation in a sclerotic coronary artery or other diseased blood vessel (thrombosis) can cause thrombotic diseases like heart attack and stroke. At the molecular level, ligand interactions with GPIb-IX-V or GPVI trigger signalling responses, including elevation of cytosolic Ca2+, dissociation of calmodulin from their cytoplasmic domains, cytoskeletal actin-filament rearrangements, activation of src-family kinases or PI 3-kinase, and 'inside-out' activation of the integrin, alphaIIbbeta3 (GPIIb-llla), that binds von Willebrand factor or fibrinogen and mediates platelet aggregation. Furthermore, emerging evidence supports a topographical co-association of these receptors of the leucine-rich repeat family (GPIb-IX-V) and immunoglobulin superfamily (GPVI) in an adhesive cluster or 'adhesosome'. This arrangement may underlie common mechanisms of initiating thrombus formation in haemostasis or thrombotic disease.
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PMID:Platelet interactions in thrombosis. 1499 75

The European Stroke Prevention Study showed greater stroke prevention for Aggrenox than either for aspirin or dipyridamole alone. To test whether Aggrenox has superior antiplatelet properties to aspirin alone we conducted the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial. Forty patients with prior ischemic stroke not taking aspirin for at least 30 days were randomized to Aggrenox (2 pills/daily) or aspirin (81 mg plus matching placebo/daily) for 30 days. Platelet function was assessed at baseline, 24 h, and days 3, 7, 15, and 30 by aggregometry, flow cytometry and cartridge-based analyzers. Both Aggrenox and aspirin provided fast and sustained platelet inhibition. Aggrenox(R), however, especially after 15 days, showed significant prolongation of the closure time (P=0.04), diminished expression of platelet/endothelial cell adhesion molecule-1 (PECAM-1) (P=0.01), glycoprotein IIb (GPIIb) antigen (P=0.02), and GPIIb/IIIa activity (P=0.01) by PAC-1 C antibody, CD63 (P=0.03), as well as inhibition of Protease Activated Receptors (PAR-1) associated with intact (SPAN12, P=0.01) and cleaved (WEDE15, P=0.01) thrombin receptors as compared with aspirin. Surprisingly, GPIb expression increased, especially after aspirin. In the randomized trial of small sample size, aspirin and Aggrenox produced fast and sustained platelet inhibition. In 25 of 90 direct comparisons, Aggrenox was superior to aspirin, whereas in 4 of 90, aspirin was superior to Aggrenox. In 61 of 90 direct comparisons, aspirin and Aggrenox were equivalent. Aggrenox was associated with a profound reduction of PAR-1 receptors, an observation that may be related to the greater clinical benefit of Aggrenox compared with Aspirin in preventing recurrent stroke.
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PMID:Magnitude and time course of platelet inhibition with Aggrenox and Aspirin in patients after ischemic stroke: the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial. 1538 Oct 54

Platelet glycoprotein (GP)Ib-IX-V and GPVI are unique platelet receptors that bind von Willebrand factor or collagen, respectively, and control the initial interaction of circulating platelets with the blood vessel wall in physiology (hemostasis) or pathology (heart attack or stroke). Engagement of GPIbalpha (the major ligand-binding subunit of GPIb-IX-V) by von Willebrand factor or GPVI by collagen, leads to mobilization of cytosolic Ca2+, secretion of platelet agonists such as ADP, cytoskeletal changes, and activation of the platelet integrin alphaIIbbeta3 that mediates von Willebrand factor- or fibrinogen-dependent platelet aggregation. Recent evidence suggests the cytosolic regulatory protein, calmodulin, plays a central role in regulating GPVI or GPIb-IX-V: first, calmodulin directly binds to conserved, juxtamembrane motifs within cytoplasmic domains of both GPVI and GPIb-IX-V (GPIbbeta and GPV subunits) on resting platelets, interactions that dissociate upon platelet activation; second, an intact calmodulin-binding site within GPVI in transfected cells is required for CaCa2+ signaling, but not for GPVI-dependent pathways involving Src family kinases or co-associated FcRgamma-chain; and third, calmodulin regulates metalloproteinase-dependent ectodomain shedding of GPVI and GPV from human platelets. Other vascular cell adhesion receptors, i.e. leukocyte L-selectin, or PECAM-1 (platelet-endothelial cell adhesion molecule-1), also bind calmodulin within the juxtamembrane region of their cytoplasmic tails, an interaction involved in their proteolytic regulation. Further studies should define the precise functional role of calmodulin in thrombus formation initiated by GPIb-IX-V or GPVI.
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PMID:Role of calmodulin in platelet receptor function. 1625 Aug 59

The functional nexus involving the platelet adhesion receptor, the glycoprotein (GP)Ib-IX-V complex, and the signaling protein, 14-3-3zeta, is emerging as a new drug target for control of GPIb-IX-V-dependent thrombotic diseases such as heart attack and stroke. Together, advances in understanding mechanisms of regulation and functional consequences of the GPIb-IX-V/14-3-3zeta interaction, and the growing potential of 14-3-3-targeting therapeutic approaches used for 14-3-3-dependent processes in other cells--principally involving cell cycling and cancer--point to 14-3-3zeta as a promising antithrombotic target. The unique recognition sequences and arrangement of functional 14-3-3zeta-binding sites found within the cytoplasmic domain of GPIb-IX-V increase the likelihood of selective targeting of this interaction.
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PMID:The 14-3-3zeta-GPIb-IX-V complex as an antiplatelet target. 1787 56

Polymorphisms in human platelet alloantigen (HPA)-1 and HPA-3 (GPIIb/IIIa), HPA-2 (GPIb/IX), HPA-4 (GPIIIa) and HPA-5 (GPIa/IIa) were investigated in 216 stroke patients and 318 matched control subjects. HPA genotyping was done by the polymerase chain reaction method using sequence-specific primers. Higher frequencies of the HPA-1 a/b (p < 0.001) and HPA-5 a/b (p < 0.001) allele, together with HPA-1 b/b, HPA-5 a/b and HPA-5 b/b genotypes were seen in patients, which was confirmed by regression analysis after controlling for a number of confounding variables. Furthermore, HPA-1 b/b and HPA-5 b/b were significantly associated with the extent of neurological symptoms, and with the recurrence of stroke. Both susceptible (1a/ b -2a/a-3a/ b -4a/a-5a/ b ) and protective (1a/a-2a/a-3a/a-4a/a-5a/a; 1a/a-2a/a-3a/ b -4a/a-5a/a; 1a/ b -2a/a-3a/a-4a/a-5a/a; 1a/ b -2a/a-3a/ b -4a/a-5a/a) HPA genotypes were identified. This is the first evidence demonstrating differential association of the common 5 HPA gene variants with stroke, with HPA-1b and HPA-5b representing strong genetic risk factors.
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PMID:Association of human platelet alloantigen 1 through 5 polymorphisms with ischemic stroke. 1805 77

Beside their main physiological function in hemostasis, platelets are also highly involved in pathological processes, such as atherothrombosis and inflammation. During hemostasis, binding of adhesive substrates to tyrosine-kinase-linked adhesion receptors and/or soluble agonists to G-protein coupled receptors leads to a cascade of intracellular signaling processes based on substrate (de)phosphorylation. The same mechanisms are involved in platelet activation at sites of atherosclerotic plaque rupture, contributing to vessel occlusion and consequently to pathologic states, such as myocardial infarction, stroke, or peripheral artery disease. To gain a deeper insight into platelet function, we analyzed the phosphoproteome of resting platelets and identified 564 phosphorylation sites from more than 270 proteins, of which many have not been described in platelets before. Among those were several unknown potential protein kinase A (PKA) and protein kinase G (PKG) substrates. Because platelet inhibition is tightly regulated especially by PKA and PKG activity, these proteins may represent important new targets for cardiovascular research. Thus, our finding that GPIbalpha is phosphorylated at Ser603 in resting platelets may represent a novel mechanism for the regulation of one of the most important platelet receptor (GPIb-IX-V) mediated signaling pathways by PKA/PKG.
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PMID:Phosphoproteome of resting human platelets. 1808 87


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