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PubMedDate not supplied

Effect of clopidogrel on platelet aggregation and intimal hyperplasia following carotid endarterectomy in the rat.

Intimal hyperplasia results in significant morbidity and mortality following vascular intervention. Both platelets and elevated homocysteine have been implicated in the development of intimal hyperplasia. We previously demonstrated that a locally applied antiplatelet agent decreases the development of intimal hyperplasia. We were therefore interested in a systemic antiplatelet agent, clopidogrel. We hypothesized that clopidogrel would decrease platelet aggregation and activity and intimal hyperplasia. Male Sprague-Dawley rats underwent carotid endarterectomy (CEA) and treatment with either placebo or varying regimens of clopidogrel, including chronic, pre-CEA bolus, chronic plus pre-CEA bolus, and chronic plus post-CEA bolus; a homocystine diet was used to elevate both plasma homocysteine and the degree of intimal hyperplasia. Platelet aggregation, platelet activity, and intimal hyperplasia were then assessed. Platelet aggregation was not decreased with chronic clopidogrel; however, it was decreased with pre-CEA bolus clopidogrel. Similarly, platelet activity was not inhibited by chronic clopidogrel but was inhibited by pre-CEA and chronic plus pre-CEA bolus clopidogrel. Neither chronic, pre-CEA bolus, chronic plus pre-CEA bolus, nor chronic plus post-CEA bolus clopidogrel resulted in a decrease in intimal hyperplasia. Although pre-CEA bolus clopidogrel resulted in a decrease in both platelet aggregation and activity, it was unable to decrease the development of intimal hyperplasia at any dose. Additional factors must therefore contribute to the pathologic development of intimal hyperplasia.

Animals↗
PubMed2003

Inhibition of baboon platelet aggregation in vitro and in vivo by the garlic derivative, ajoene.

BACKGROUND: The infusion of pig growth factor-mobilized peripheral blood leukocytes (containing 1 to 2% progenitor cells) (pPBPC) into baboons is associated with a thrombotic microangiopathy, which results from a direct effect of these pig cells on platelet aggregation. Ajoene is a synthetic derivative of garlic that inhibits aggregation of human platelets induced by all known agents. To assess its potential use in models of xenotransplantation, this agent was tested for its effect on baboon platelet aggregation in vitro and in vivo. METHODS IN VITRO STUDIES: Baboon platelet aggregation assays, using adenosine diphosphate (ADP) (20 or 40 microm) or collagen (12.5 microg/ml), were performed after incubation with ajoene (0 to 150 microg/ml) or dipyridamole (0 to 200 microg/ml). Platelets were also incubated with pPBPC (5 x 10(6) cells) without or with ajoene in the absence of a known agonist. In vivo studies: Baboons received either a single intravenous dose of ajoene (10 to 25 mg/kg) or dipyridamole (0.8 mg/kg), or repeated doses of both agents at 2 to 3 h intervals. Platelet-rich plasma was obtained for platelet aggregation assays at time points up to 4 h post-drug administration. RESULTS: In vitro, platelet aggregation was inhibited by 95% (ADP assay) and 89% (collagen assay) by ajoene at concentrations of > or =75 microg/ml. Dipyridamole had no effect at concentrations of <100 microg/ml, but inhibited aggregation almost completely at higher concentrations. Ajoene inhibited the aggregation caused by pPBPC by 33 to 50%. In vivo, platelet aggregation was completely inhibited for 2 h by ajoene at 25 mg/kg. Dipyridamole at 0.8 mg/kg reduced aggregation by 20% for 15 min, but the effect was lost by 60 min. In combination, the two agents prolonged inhibition marginally. Repeated doses of both agents at 2 h intervals maintained complete inhibition of aggregation, but did not do so when the interval between doses was extended to 2.5 or 3 h. Combined therapy was not associated with any bleeding complications. CONCLUSIONS: Although ajoene is a powerful inhibitor of platelet aggregation, the need for repeated administration and its partial effect on pPBPC-induced platelet aggregation would suggest that it may be of only limited value in preventing the thrombotic microangiopathy that develops when pPBPC are infused into baboons. However, it would seem worthy of further investigation when used in combination with other agents.

Animals↗
PubMed1987

[Synthesis and platelet aggregating activity of structural analogs of platelet-activating factor with a heterocyclic head group].

Structural analogues of platelet-activating factor (PAF, 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine) containing an imidazole or thiazole residue as polar head group have been prepared and tested for platelet aggregating properties. Compared with PAF all analogues exert considerably lower platelet-stimulating activities. The agonistic behaviour is shown to depend primary on the presence of a positively charged polar head group.

Animals↗
PubMed1986

Platelet aggregation and thromboxane release induced by arachidonic acid, collagen, ADP and platelet-activating factor following low dose acetylsalicylic acid in man.

The present study was undertaken in order to characterize the dose-dependent nature of acetylsalicylic acid (ASA) on platelet aggregation and plasma thromboxane B2 (TXB2) release in healthy volunteers. Volunteers received either 25, 50, 100 or 500 mg daily for five consecutive days. At the end of the five day period, all dosages of ASA were capable of completely suppressing TXB2 production and arachidonic acid-induced platelet aggregation. At that time, the second phase of ADP-induced aggregation was also blocked. However, while the inhibition following 500 mg ASA was complete after 24 hours, total inhibition with 100, 50 and 25 mg was attained only after two, three and four days, respectively, indicating the cumulative effect of ASA on platelets. Aggregation induced by collagen was also inhibited dose-dependently- yet slower and at no time complete. ASA had no inhibitory effect on aggregation by platelet-activating factor (PAF). It is concluded that a daily dose of 50 mg ASA would suffice in blocking platelet TXA2 production and aggregation induced by most physiological agents.

Adenosine Diphosphate↗
PubMedDate not supplied

Leukocyte count and leukocyte ecto-nucleotidase are major determinants of the effects of adenosine triphosphate and adenosine diphosphate on platelet aggregation in human blood.

ADP induces platelet aggregation in human whole blood and platelet-rich plasma (PRP). ATP induces aggregation in whole blood only; this involves leukocytes and is mediated by ADP. Here we studied ATP- and ADP-induced aggregation in patients with raised leukocyte counts (mean 46.2x10(3) leukocytes/microl). Platelet aggregation was measured by platelet counting. ATP, ADP and metabolites were measured by HPLC. Aggregation to ADP (1-10 microM) and ATP (10-100 microM) was markedly reduced, but to ATP (1000 microM) was enhanced (all p<0.001). Aggregation to ADP in PRP was normal. Increasing the leukocyte count in normal blood reproduced the findings in the patients. Adding leukocytes (either MNLs or PMNLs) to normal PRP enabled a response to ATP and caused marked inhibition of ADP-induced aggregation. Breakdown of ATP or ADP to AMP and adenosine in leukocyte-rich plasma was rapid (t1/2=4 min) and far higher than in cell-free plasma or PRP. With ATP there was also formation of ADP, maximal at 4 min. The presence of the ectonucleotidase NTPDase1 (CD39) was demonstrated on MNLs (all of the monocytes and a proportion of the lymphocytes) and all PMNLs by flow cytometry. We conclude that leukocytes provide a means of dephosphorylating ATP which enables ATP-induced aggregation via conversion to ADP, but also convert ADP to AMP and adenosine. Platelet aggregation extent is a balance between these activities, and high white cell counts influence this balance.

Adenosine Diphosphate↗
PubMed1988

Identity of saturable calcium-binding sites on blood platelets and their involvement in platelet aggregation.

Extracellular Ca2+ ions are required for platelet aggregation and we show that they enter two platelet pools. One pool is rapidly filled and easily displaced by EGTA. The second is filled more slowly and is not displaced by EGTA. The EGTA-displaceable pool is believed to be surface-located and was found to contain at least one class of saturable binding sites as well as a class of non-saturable binding sites. The saturable sites were found to be highly selective for Ca2+ (dissociation constant, 3.5 X 10(-7) M) even in the presence of 1 mM Mg2+ ions, and they took up between 261,000 and 307,000 Ca2+ ions/platelet. Full occupancy of the saturable binding sites appeared to be necessary for platelet aggregation to proceed. We also studied platelets that were unable to aggregate normally, either due to the congenital bleeding disorder Glanzmann's thrombastenia or due to experimental manipulation. In both cases we found decreased Ca2+ uptake specifically by the saturable Ca2+ binding sites, and that this was associated with decreased number of GP IIb/IIIa molecules expressed on these platelets. We suggest that the Ca2+ binding sites involved in platelet aggregation are located on the GP IIb/IIIa complexes and may be involved in holding the glycoproteins in the complex together, and that the binding sites need to be fully occupied before aggregation can proceed.

Binding Sites↗
PubMed1994

The effect of serum amyloid protein A fragment-SAA25-76 on blood platelet aggregation.

The effect of the major acute phase protein serum amyloid A (SAA) on collagen induced platelet aggregation was investigated. A truncated version of SAA, SAA25-76 was tested for inhibitory capacity of collagen induced platelet aggregation in platelet-rich plasma (PRP) and whole blood (WB). The tetrapeptide RGDV, a known inhibitor of platelet aggregation, was included as a reference compound. SAA25-76 at a concentration of 390 micrograms/ml inhibited platelet aggregation induced by 1 microgram/ml of collagen in PRP. This corresponds to the plasma concentration of SAA during an acute phase response. However, the inhibitory effect of the SAA25-76 fragment was lost at higher collagen concentrations (> or = 2.0 micrograms/ml). The SAA fragment at 390 micrograms/ml had no significant effect on platelet aggregation in WB. In contrast, RGDV blocked collagen induced platelet aggregation in both PRP and WB.

Amino Acid Sequence↗
PubMed1986

Functional involvement of thrombospondin in platelet aggregation induced by low versus high concentrations of thrombin.

Thrombospondin (TSP) is a major platelet secretory glycoprotein. Earlier studies of various investigators demonstrated that TSP is the endogenous platelet lectin and is responsible for the hemagglutinating activity expressed on formaldehyde-fixed thrombin-treated platelets. The direct effect of highly purified TSP on thrombin-induced platelet aggregation was studied. It was observed that aggregation of gel-filtered platelets induced by low concentrations of thrombin (less than or equal to 0.05 U/ml) was progressively inhibited by increasing concentrations of exogenous TSP (greater than or equal to 60 micrograms/ml). However, inhibition of platelet aggregation by TSP was not observed when higher than 0.1 U/ml thrombin was used to activate platelets. To exclude the possibility that TSP inhibits platelet aggregation by affecting thrombin activation of platelets, three different approaches were utilized. First, by using a chromogenic substrate assay it was shown that TSP does not inhibit the proteolytic activity of thrombin. Second, thromboxane B2 synthesis by thrombin-stimulated platelets was not affected by exogenous TSP. Finally, electron microscopy of thrombin-induced platelet aggregates showed that platelets were activated by thrombin regardless of the presence or absence of exogenous TSP. The results indicate that high concentrations of exogenous TSP (greater than or equal to 60 micrograms/ml) directly interfere with interplatelet recognition among thrombin-activated platelets. This inhibitory effect of TSP can be neutralized by anti-TSP Fab. In addition, anti-TSP Fab directly inhibits platelet aggregation induced by a low (0.02 U/ml) but not by a high (0.1 U/ml) concentration of thrombin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease.

OBJECTIVES: We sought to examine whether patients with stable coronary artery disease (CAD) have increased platelet reactivity and an enhanced propensity to form monocyte-platelet aggregates. BACKGROUND: Platelet-dependent thrombosis and leukocyte infiltration into the vessel wall are characteristic cellular events seen in atherosclerosis. METHODS: Anticoagulated peripheral venous blood from 19 patients with stable CAD and 19 normal control subjects was incubated with or without various platelet agonists and analyzed by whole blood flow cytometry. RESULTS: Circulating degranulated platelets were increased in patients with CAD compared with control subjects (mean [+/- SEM] percent P-selectin-positive platelets: 2.1 +/- 0.2 vs. 1.5 +/- 0.2, p < 0.01) and were more reactive to stimulation with 1 micromol/liter of adenosine diphosphate (ADP) (28.7 +/- 3.9 vs. 16.1 +/- 2.2, p < 0.01), 1 micromol/liter of ADP/epinephrine (51.4 +/- 4.6 vs. 37.5 +/- 3.8, p < 0.05) or 5 micromol/liter of thrombin receptor agonist peptide (TRAP) (65.7 +/- 6.8 vs. 20.2 +/- 5.1, p < 0.01). Patients with stable CAD also had increased circulating monocyte-platelet aggregates compared with control subjects (percent platelet-positive monocytes: 15.3 +/- 3.0 vs. 6.3 +/- 0.9, p < 0.01). Furthermore, patients with stable CAD formed more monocyte-platelet aggregates than did control subjects when their whole blood was stimulated with 1 micromol/liter of ADP (50.4 +/- 4.5 vs. 28.1 +/- 5.3, p < 0.01), 1 micromol/liter of ADP/epinephrine (60.7 +/- 4.3 vs. 48.0 +/- 4.8, p < 0.05) or 5 micromol/liter of TRAP (67.6 +/- 5.7 vs. 34.3 +/- 7.0, p < 0.01). CONCLUSIONS: Patients with stable CAD have circulating activated platelets, circulating monocyte-platelet aggregates, increased platelet reactivity and an increased propensity to form monocyte-platelet aggregates.

Adenosine Diphosphate↗
PubMed1988

Shear-induced platelet aggregation can be mediated by vWF released from platelets, as well as by exogenous large or unusually large vWF multimers, requires adenosine diphosphate, and is resistant to aspirin.

Fluid shear stress in arteries and arterioles partially obstructed by atherosclerosis or spasm may exceed the normal time-average level of 20 dyne/cm2. In vitro, at fluid shear stresses of 30 to 60 dyne/cm2 applied for 30 seconds, platelet aggregation occurs. At these shear stresses, either large or unusually large von Willebrand factor (vWF) multimers in the suspending fluid exogenous to the platelets mediates aggregation. Adenosine diphosphate (ADP) is also required and, in these experiments, was released from the platelets subjected to shear stress. At 120 dyne/cm2, the release of endogenous platelet vWF multimers can substitute for exogenous large or unusually large vWF forms in mediating aggregation. Endogenous released platelet vWF forms, as well as exogenous large or unusually large vWF multimers, must bind to both glycoproteins Ib and the IIb/IIIa complex to produce aggregation. Shear-induced aggregation is the result of shear stress alteration of platelet surfaces, rather than of shear effects on vWF multimers. It is mediated by either large plasma-type vWF multimers, endogenous released platelet vWF forms, or unusually large vWF multimers derived from endothelial cells, requires ADP, and is not inhibited significantly by aspirin. This type of aggregation may be important in platelet thrombus formation within narrowed arterial vessels, and may explain the limited therapeutic utility of aspirin in arterial thrombosis.

Adenosine Diphosphate↗
PubMed1976

Prostaglandin E2 potentiation of platelet aggregation induced by LASS endoperoxide: absent in storage pool disease, normal after aspirin ingestion.

Patients with storage pool disease and normal subjects who ingest aspirin show diminished collagen-induced platelet aggregation and an absent second wave of aggregation with ADP or adrenaline. These 'second-phase' aggregation responses are thought to be mediated by cyclic endoperoxide ('labile aggregation stimulating substance', LASS) that is derived from arachidonic acid and is the precursor of prostaglandin E2 (PGE2) and PGE2alpha. Furthermore, although PGE2 does not directly aggregate platelets, it markedly potentiates LASS-induced aggregation. The platelets of six patients with storage pool disease were capable of converting arachidonic acid to LASS, but the potentiation of LASS-induced aggregation by PGE2 was markedly diminished. In contrast, PGE2-potentiation of LASS aggregation was not reduced after aspirin ingestion. The effects of aspirin can be attributed entirely to its ability to block the enzymatic conversion of arachidonic acid to LASS and PGE2. These findings explain why a mutual correction of the aggregation defects is often seen when aspirin-treated platelets are mixed with storage pool-deficient platelets. This is because 'aspirin platelets' aggregate to the mixture of LASS and PGE2 produced by the storage pool-deficient platelets, which are themselves unresponsive. The findings in storage pool disease support previous conclusions that prostaglandin sensitization of platelets to the pro-aggregatory effects of LASS is an important factor in irreversible aggregation, and could be clinically important.

Adenosine Diphosphate↗
PubMed1997

The role of immunoglobulin G and fibrinogen in platelet aggregation by Streptococcus sanguis.

Previous work has shown that the type strain of Streptococcus sanguis, NCTC 7863, induces aggregation of normal platelets by a complement-dependent mechanism. We investigated the roles of IgG and fibrinogen in the aggregation process. Plasma depleted of IgG by passage through protein A-sepharose failed to support platelet aggregation, as did plasma absorbed at 0 degrees C with whole bacteria. However, absorption of plasma with a non-aggregating strain of S. sanguis, SK96, did not remove aggregating activity for NCTC 7863. Supplementing 0 degrees C-absorbed plasma with purified IgG restored the aggregation supporting activity. A monoclonal antibody to the Fc gammaRII receptor inhibited platelet aggregation by the bacteria, indicating a requirement for bacteria-IgG complexes interacting with the Fc receptor in platelet aggregation. There was a lag time to the onset of platelet aggregation of 7-19 min depending upon the platelet donor, but the length of this lag did not correlate with either total IgG concentration recognizing NCTC 7863 in subjects' plasma, or the concentration any of the four IgG subclasses or with IgG avidity levels. Fibrinogen was shown to bind rapidly to the bacterial cell surface. Monoclonal antibody to GPIIb/IIIa, RGDS peptide, and a specific antagonist for the platelet fibrinogen receptor, GPIIb/IIIa, FK633, inhibited platelet aggregation by NCTC 7863, indicating that platelet aggregation is fibrinogen dependent. These data suggest that platelet aggregation by some strains of S. sanguis requires multiple stimuli/agonists, including IgG-Fc receptor interaction, complement and fibrinogen.

Complement System Proteins↗
PubMed1980

Relative effects of aspirin on platelet aggregation and prostaglandin-mediated coronary vasodilatation in the dog.

Aspirin, as an inhibitor of platelet aggregation, may be of benefit in ischemic heart disease. However, aspirin blocks not only platelet aggregation but also synthesis of prostacyclin, a vasodilator and platelet deaggregator. The relative sensitivity of prostaglandin-mediated coronary vasodilatation and platelet aggregation to inhibition by aspirin remains uncertain. We therefore investigated the relative dose-response relationship of aspirin on arachidonic acid-induced increments in coronary blood flow and on ADP-induced aggregation of platelets. In 11 open-chest dogs, intracoronary arachidonic acid, 0.1-3.0 mg, produced dose-related increases in coronary blood flow that were inhibited progressively by i.v. aspirin over the dose range 0.3-3.0 mg/kg. Aspirin at 3 mg/kg almost completely obliterated the response to 3 mg of arachidonic acid. Similarly, aspirin doses of 0.3-3.0 mg/kg progressively raised the minimal concentration of ADP necessary for platelet aggregation. The threshold concentration of ADP that produced aggregation of platelets from 10 control dogs ranged from 2.3 x 10(-6) M to 1.2 x 10(-5) M. Aspirin at 3 mg/kg completely inhibited aggregation of platelets from 11 of 12 dogs, even with ADP at 2.3 x 10(-4) M concentration, the maximum tested. Aspirin at 0.1 mg/kg failed to inhibit either ADP-induced platelet aggregation or arachidonic acid-induced increments in coronary blood flow. Thus, the two test systems showed similar sensitivity to inhibition by aspirin with respect to threshold dose and maximal effect. These results show that very low doses of aspirin inhibit arachidonic acid-induced coronary vasodilatation and that aspirin at low doses does not appear to selectively inhibit platelet activity relative to coronary vasodilatation.

Adenosine Diphosphate↗
PubMed2006

Expression of phosphorylcholine by Histophilus somni induces bovine platelet aggregation.

Histophilus somni-induced platelet aggregation was inhibited by antagonists of the platelet-activating factor (PAF) receptor but not inhibitors of PAF synthesis. In addition, H. somni cells expressing phosphorylcholine (ChoP) induced aggregation, while ChoP(-) H. somni cells did not. This suggests that H. somni ChoP may induce platelet aggregation via interactions with the PAF receptor.

Animals↗
PubMed1978

Platelet aggregation in chronic idiopathic thrombocytopenic purpura.

A method for washing platelets by albumin density gradient separation has been modified to prepare platelet rich plasma of thrombocytopenic patients for platelet aggregation studies. The concentration procedure, consisting of centrifuging platelets into a specific gravity gradient between plasma and 40-45% aqueous solution of bovine albumin, does not affect platelet aggregation adversely. Platelet aggregation in eight patients with chronic idiopathic thrombocytopenic purpura was determined by this method. On the basis of the results the patients could clearly be divided into two groups: four patients with normal aggregation and four with a qualitative platelet defect. In contrast to the other patients, the group with an in vitro platelet functional defect all had more prolonged bleeding times and the presence of a serum antiplatelet antibody.

Blood Cell Count↗
PubMed2003

Platelet aggregation profiles in cluster headache.

BACKGROUND: Platelets are activated in patients with cluster headache, during both the remission period and the active cycles. OBJECTIVE: To delineate more clearly the origin of platelet activation in cluster headache. Methods.-Platelet aggregation induced by collagen (0.5 micro g/mL and 2 micro g/mL), adenosine diphosphate (10-5 M and 10-6 M), and platelet-activating factor (10-6 M and 10-7 M) was determined by the Born's method in 26 patients with cluster headache and 24 sex- and age-matched controls. RESULTS: The platelets of patients with cluster headache aggregated significantly less to collagen at a concentration of 0.5 micro g/mL compared to those of controls (P =.04). The extent of platelet aggregation obtained with a higher dose of collagen (2 micro g/mL) was in the same range in both groups. Platelet aggregation obtained via adenosine diphosphate at a concentration of 10-6 M was significantly reduced in patients with cluster headache in comparison to controls (P =.002), but no differences were found at a concentration of 10-5 M. In contrast, the platelets of patients with cluster headache aggregated significantly more to platelet-activating factor at both the concentrations of 10-6 M (P =.001) and 10-7 M (P =.00001) compared to those of controls. CONCLUSIONS: This study suggests that platelet aggregation is impaired in patients with cluster headache during the active phase of the disease. We found hypoaggregation in response to low doses of collagen and adenosine diphosphate, and hyperaggregation when platelets were stimulated with platelet-activating factor. Any interpretation of these results can only be speculative. It may be that impairment of platelet aggregation with collagen and adenosine diphosphate may indicate a derangement of nitric oxide function, while the hypersensitivity to platelet-activating factor may be due to fluctuations in its plasma levels.

Adenosine Diphosphate↗
PubMed1999

Real-time analysis of mural thrombus formation in various platelet aggregation disorders: distinct shear-dependent roles of platelet receptors and adhesive proteins under flow.

We evaluated real-time processes of platelet thrombus formation on a collagen surface in a flow chamber with whole blood from patients with various platelet aggregation disorders, such as Bernard-Soulier syndrome (BSS), Glanzmann's thrombasthenia (GTA), type 3 von Willebrand disease (vWD), and congenital afibrinogenemia (Af), who lack platelet glycoprotein (GP) Ib-IX complex, GP IIb-IIIa, von Willebrand factor (vWF), and fibrinogen, respectively. Blood from GTA patients showed impaired thrombus growth but significant initial platelet-surface interaction under all shear conditions tested (50 to 1,500 s(-1)). By contrast, blood from patients with BSS or type 3 vWD showed no platelet-surface interaction under high shear (>/=1, 210 s(-1)) but normal thrombus formation under low shear (</=340 s(-1)). When shear rate was increased stepwise to 1,500 s(-1) during perfusion, the thrombus growth observed in type 3 vWD or BSS under low shear was arrested, whereas that in control blood was sharply accelerated as a function of shear rate. Overall thrombus formation in Af appeared indistinguishable from that of a control under shear rates between 50 and 1,500 s(-1). However, Af thrombi formed under such conditions collapsed immediately when shear rate was further increased to 4,500 s(-1), whereas thrombi of type 3 vWD or BSS formed under low shear were stable even when shear rate was elevated to 9,000 s(-1) during perfusion. These findings suggest that distinct molecular mechanisms underlie the pathologic bleeding in these diseases and point to the distinct roles of two major adhesive proteins, vWF and fibrinogen. In mural thrombus formation under flow conditions, vWF, perhaps mainly through its interaction with GP Ib-IX, acts as an "initiator and promoter," whereas fibrinogen, via its binding to GP IIb-IIIa, acts as a "stabilizer" against heightened shear forces that could lead to peeling off of platelets from the surface.

Blood Coagulation Disorders↗
PubMed2001

Platelet glycoprotein IIIa Pl(a) polymorphism, fibrinogen, and platelet aggregability: The Framingham Heart Study.

BACKGROUND: Recent data suggest that the Pl(A2) allele of the platelet glycoprotein IIIa receptor may be a genetic risk factor for cardiovascular disease. We previously reported that the Pl(A2) allele was associated with increased platelet aggregability, as indicated by lower epinephrine threshold concentrations. Paradoxically, however, it has been reported that Pl(A2)-positive platelets have reduced fibrinogen binding. Because fibrinogen mediates platelet aggregability, we hypothesized that plasma fibrinogen levels may interact with Pl(A) genotype in modulating platelet aggregability. Methods and Results-- Glycoprotein IIIa Pl(A) genotype, fibrinogen level, and platelet aggregability were ascertained in 1340 subjects enrolled into the Framingham Offspring Study. Platelet aggregability was evaluated by the Born method. Higher fibrinogen levels were associated with increased epinephrine-induced aggregation (P=0.002) and a trend for ADP-induced aggregation (P=0.07). The fibrinogen effect was genotype specific, however, in that the increase in platelet aggregability with higher fibrinogen was present for the Pl(A1/A1) genotype (P=0.0005 and P=0.03 for epinephrine- and ADP-induced aggregation, respectively) but not for the Pl(A2)-positive genotype (P>0.90). CONCLUSION: Higher fibrinogen levels were associated with increased platelet aggregability. However, the association between fibrinogen and platelet aggregability was genotype specific. This interaction may be responsible for the conflicting findings regarding Pl(A) genotype and platelet aggregability. Further study of this gene-environment interaction may provide insight into cardiovascular disease risk.

Adenosine Diphosphate↗