Ex vivo?in vitro interaction between aspirin, clopidogrel, and the glycoprotein IIb/IIIa inhibitors abciximab and SR121566A

Klinkhardt, Ute; Kirchmaier, C. M.; Westrup, Dagmar; Graff, Jochen; Mahnel, R.; Breddin, H. K.; Harder, Sebastian

doi:10.1067/mcp.2000.104613

Cited by 38 publications

(34 citation statements)

References 30 publications

(47 reference statements)

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“…It was reported in a study that there is a significant decrease in fibrinogen binding to GpIIb/IIIa by an aspirin and clopidogrel combination and a reduction in platelet P-selectin expression by clopidogrel alone [49]. Similarly, in our study, in the presence of ADP, clopidogrel reduced the fibrinogen expression on the platelet surface, and thereby, presumably decreased the platelet activation in both groups.…”

Section: Discussionsupporting

confidence: 60%

New in vitro effects of clopidogrel on platelets in hyperlipidemic and healthy subjects

Özsavcı¹,

Şener²,

Oba³

et al. 2010

Turk J Hematol

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Objective: We aimed to detect novel in vitro effects of clopidogrel on platelets by assessment of the following parameters: malondialdehyde, glutathione, nitrite, aggregation response, and expressions of P-selectin, fibrinogen, apolipoprotein A1, apolipoprotein B, and phosphatidylserine. Materials and Methods: Platelets were obtained from healthy (n: 9) and hyperlipidemic (n: 9) volunteers. Expressions of P-selectin, fibrinogen, apolipoproteins A1/B and phosphatidylserine with and without clopidogrel were assayed by flow cytometry. Malondialdehyde, glutathione, aggregation and nitrite levels were also assayed. Results: Without clopidogrel, the baseline values of platelet aggregation, malondialdehyde, and expressions of P-selectin, fibrinogen and phosphatidylserine were significantly higher, whereas nitrite and expression of apolipoproteins A1/B were significantly lower in hyperlipidemics than in the healthy group. In both groups, clopidogrel significantly reduced aggregation and expression of fibrinogen, but it elevated nitrite levels. Clopidogrel significantly decreased P-selectin and phosphatidylserine expression and malondialdehyde but increased expressions of apolipoproteins A1/B only in hyperlipidemics. Conclusion: It seems that clopidogrel has some new in vitro antiplatelet effects. The present study is a basic in vitro study to suggest new insights into the effects of clopidogrel on platelet functions. Özet Amaç: Klopidogrelin trombositler üzerinde yeni in vitro etkilerini tayin etmek: Malondialdehit, glutatyon, nitrit, aggregasyon cevabı, P-selektin, fibrinojen, apolipoprotein A1, apolipoprotein B ve fosfatidilserin ekspresyonları. Yöntem ve Gereçler: Sağlıklı (n: 9) ve hiperlipidemik (n: 9) olgulardan trombositler elde edildi. Klopidogrelli ve klopidogrelsiz trombositlerde P-selektin, fibrinojen, apolipoprotein A1, apolipoprotein B ve fosfatidilserin ekspresyonları flow sitometre ile tayin edildi. Malondialdehit, glutatyon, aggregasyon ve nitrit seviyeleri de tayin edildi. Bulgular: Klopidogrel yokluğunda, hiperlipidemililerde kontrollere göre trombosit agregasyonu, malondialdehit, P-Selektin, fibrinojen ve fosfatidilserin ekspresyonunun başlangıç değerleri yüksek; bununla birlikte nitrit, apolipoprotein A1 ve apolipoprotein B ekspresyonlarınınki ise daha düşüktü. Her iki grupta, klopidogrel anlamlı düzeyde aggregasyonu ve fibrinojen ekspresyonunu azalttı, fakat nitrit seviyelerini artırdı. Klopidogrel sadece hiperlipidemililerde P-selektin ve fosfatidilserin ekspresyonunu ve malondialdehiti azalttı ancak apolipoprotein A1 ve apolipoprotein B ekspresyonlarını artırdı.

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Section: Discussionsupporting

confidence: 60%

New in vitro effects of clopidogrel on platelets in hyperlipidemic and healthy subjects

Özsavcı¹,

Şener²,

Oba³

et al. 2010

Turk J Hematol

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“…The thienopyridine P2Y 12 receptor antagonists are the only antiplatelet drugs that are known to reduce CD62 expression (Rupprecht et al, 1998;Klinkhardt et al, 2000), whereas treatment with GPIIb/IIIa inhibitors (Fredrickson et al, 2000;Klinkhardt et al, 2000), or aspirin (Rinder et al, 1993;Fredrickson et al, 2000;Klinkhardt et al, 2000) did not. We could demonstrate a significant decrease in the platelet activation marker CD62 and the secretion product PDGF after 6 …”

Section: Discussionmentioning

confidence: 99%

“…Blood was drawn from healthy subjects (n ϭ 6, age 22-38 years) as indicated above and spiked with abciximab (5 g/ml final concentration). This concentration of abciximab has been proven to confer Ͼ80% inhibition of platelet aggregation and GPIIb/ IIIa-receptor activation (Klinkhardt et al, 2000).…”

Section: Experimental Protocolsmentioning

confidence: 99%

“…Moreover, it remains to be determined whether changes in CD62 expression induced by either drugs or diseases are paralleled by changes in the secretion of granule-derived products. Therefore, the aim of the present study was to characterize the relationship between platelet activation status (translocation of CD62) and PDGF secretion from ␣-granules in response to different concentrations of thrombin-receptor activating peptide (TRAP), and to determine whether such a relationship is maintained under antiplatelet drugs for which it is known that they either reduce CD62 expression (namely, the thienopyridine clopidogrel) (Rupprecht et al, 1998;Klinkhardt et al, 2000) or do not influence CD62 expression (namely the GPIIb/IIIa-inhibitor abciximab) (Fredrickson et al, 2000;Graff et al, 2001), or in clinical conditions that are associated with platelet hyper-reactivity (e.g., diabetes).…”

mentioning

confidence: 99%

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Close Relationship between the Platelet Activation Marker CD62 and the Granular Release of Platelet-Derived Growth Factor

Graff

Klinkhardt²,

Schini‐Kerth³

et al. 2002

J Pharmacol Exp Ther

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The expression of CD62 on the surface of platelets is considered to be an indicator of platelet degranulation and secretion. We characterized the relationship between CD62 expression and platelet-derived growth factor (PDGF) AB and PDGF BB secretion in response to thrombin-receptor activating peptide (TRAP). The principal findings were 1) expression of CD62 as a constituent of platelet ␣-granule membrane and secretion of PDGF, an important ingredient of ␣-granules, can be stimulated by TRAP-induced activation in a dose-dependent fashion; 2) the activation marker and secretion product are closely correlated with each other; and 3) changes in the CD62 expression induced by a drug, namely clopidogrel, or by a disease, namely diabetes, are paralleled by changes in PDGF secretion. Although CD62 is perceived as an activation marker of platelets indicating enhanced aggregability and secretion of ␣-granular content, the proof that the CD62 status and its modifications reflect directly the actual secretion of the most important platelet mitogen, PDGF, has so far not been given. This ex vivo-in vitro study shows that at least for the activation pathway provided by the PAR-1 receptor for which TRAP is the selective agonist, CD62 expression on platelets could be a surrogate for their secretory activity.

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“…We would like to compare their recent 2 studies 1,2 with previous ones including our study, 3 their previous study 4 and others. [5][6][7][8][9][10] Platelet activation in patients with chronic phase of stroke has been observed using CD62p expression as a marker of platelet activation. [3][4][5] In the previous study by Grau et al, 4 the proportion of platelets expressing activation-dependent antigens (CD62p and CD63) was higher in patients with both acute and previous cerebrovascular ischemia as compared with age-and sex-matched control subjects.…”

mentioning

confidence: 99%

Platelet Function Under Aspirin, Clopidogrel, and Both After Ischemic Stroke: A Case-Crossover Study

Yamazaki

Uchiyama

2003

Stroke

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We read with great interest the articles by Grau et al 1 and Marquardt et al, 2 which were from the same institute, concerning the platelet function under antiplatelet therapy and the course of platelet activation markers after acute ischemic stroke. Many studies have shown that activated platelets can be detected in the systemic circulation in patients with stroke, undergoing cardiopulmonary bypass surgery, peripheral artery occlusive disease, acute myocardial infarction, and other thrombotic disorders. However, which marker for activated platelets can most precisely reflect in vivo platelet activation remains uncertain. Besides, it is of great importance whether the marker is useful to predict the recurrence of vascular event and to monitor the antiplatelet therapy. We would like to compare their recent 2 studies 1,2 with previous ones including our study, 3 their previous study 4 and others. [5][6][7][8][9][10] Platelet activation in patients with chronic phase of stroke has been observed using CD62p expression as a marker of platelet activation. [3][4][5] In the previous study by Grau et al, 4 the proportion of platelets expressing activation-dependent antigens (CD62p and CD63) was higher in patients with both acute and previous cerebrovascular ischemia as compared with age-and sex-matched control subjects. In addition, relatively more platelets expressed CD62p than CD63 in most patients in that study. They explained it was because the secretion of lysosomes usually require stronger stimulation than the release of ␣-granules. On the contrary, in the recent study by Marquardt et al, 2 CD62p expression was not significantly different on days 14 and 90 after stroke compared with control groups. We wonder why platelet activation detected by CD62p expression was not observed when compared serially. On the other hand, increased CD63 expression was observed on days 14 and 90 after stroke, which indicates continuously ongoing platelet activation. They explained that in the subacute stage after ischemic stroke, CD63 is a more sensitive marker of platelet activation than CD62p, most likely because of shedding of CD62p. 2 If so, it may be possible to detect the elevation of soluble p-selectin. Then, we would like to know if soluble p-selectin in plasma rather than CD62p on the platelet surface can be a marker of platelet activation in the subacute stage after stroke. Another question is about the course of platelet activation markers in their study. 2 It is considered that platelets are activated more strongly in the acute phase of stroke than in the chronic phase of stroke. 2,5 In the study by Marquardt et al, 2 CD62p expression declined over time after stroke, and 60% of patients showed a decrease in CD62p. However, the percentage of CD63-expressing platelets did not change between days 1 and 90 after stroke, and only 36% of patients showed a decrease in CD63 over time. Moreover, 30% of patients showed an increase in CD63, and in 34% of patients, CD63 expression did not change. If CD63 is a more sensitive marker of ...

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Ex vivo?in vitro interaction between aspirin, clopidogrel, and the glycoprotein IIb/IIIa inhibitors abciximab and SR121566A

Abstract: The augmentation of the antiaggregatory effects of GPIIb/IIIa inhibitors by aspirin and clopidogrel and the lack of antisecretory effects of GPIIb/IIIa inhibitors may favor their combination with clopidogrel.

Cited by 38 publications

References 30 publications

New in vitro effects of clopidogrel on platelets in hyperlipidemic and healthy subjects

New in vitro effects of clopidogrel on platelets in hyperlipidemic and healthy subjects

Close Relationship between the Platelet Activation Marker CD62 and the Granular Release of Platelet-Derived Growth Factor

Platelet Function Under Aspirin, Clopidogrel, and Both After Ischemic Stroke: A Case-Crossover Study

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