Glycoprotein (GP) IIb-IIIa (αIIbβ3-integrin) is the central receptor of platelet aggregation. Activated GP IIb-IIIa binds fibrinogen or von Willebrand factor, which forms molecular bridges between aggregating platelets. This review summarizes data on the relationship between GP IIb-IIIa expression on the platelet surface and platelet aggregating activity. GP IIb-IIIa number, measured as maximal binding of complex-specific monoclonal antibody, varied by approximately two fold in both healthy volunteers (n = 35) and patients with acute coronary syndrome (ACS) (n = 65). In healthy volunteers positive associations were observed between GP IIb-IIIa number and the level of ADP-induced aggregation when this relationship was analysed in untreated platelet-rich plasma (PRP) as well as upon in vitro addition of aspirin or non-saturating concentrations of GP IIb-IIIa blockers. In the same group of volunteers almost no differences in aggregating activity were detected between donors carrying the GP IIIa Pro33 allele (n = 15) and those with the GP IIIa Leu33Leu33 genotype (n = 20). No significant relationships were revealed between platelet aggregability and variations of plasma fibrinogen concentration. Positive correlation of the level of ADP-induced aggregation and GP IIb-IIIa content was detected in patients with ACS within the first hour upon admission to the hospital when they had already received aspirin, but not clopidogrel. However, there were no correlations between these parameters at days 3-5 and days 8-12 (before discharge). At these time points patients were treated not only with aspirin but were saturated with clopidogrel as well. In ACS patients we also evaluated the expression of another platelet adhesive receptor, GP Ib, and found a significant positive correlation between GP IIb-IIIa and GP Ib content. A strong association was also revealed between the number of both receptors and mean platelet volume. The latter observation indicated that individual variations of the number of glycoprotein molecules are mainly affected by platelet size but not the density of their expression on the platelet membrane. Possible usefulness of measuring GP IIb-IIIa content as a marker of increased platelet reactivity is discussed.
Quantity of platelet adhesion molecules significantly varies in normal donors and cardiovascular patients and might be affected by platelet size and genetic variations. In this study, we assessed relationships of the content of glycoprotein (GP) IIb-IIIa and GPIb with mean platelet volume (MPV) and their genetic polymorphisms. MPV and GPIIb-IIIa and GPIb numbers were measured in 116 patients with acute coronary syndrome (ACS) at days 1, 3-5 and 8-12 after disease onset and in 32 healthy volunteers. GPIIb-IIIa and GPIb allelic variants were determined in ACS patients. Strong interactions of GPIIb-IIIa and GPIb numbers and MPV were observed in ACS patients and healthy volunteers. In patients, coefficients of correlation (r) were 0.642 and 0.510 (analysis of individual mean values) and in volunteers - 0.594 and 0.508 for GPIIb-IIIa and GPIb, respectively (everywhere P < 0.005). In ACS patients, correlations were highly significant at each tested time point. GPIIb-IIIa and GPIb genetic polymorphisms [GPIIIa Leu33Pro, GPIbα Thr145Met and GPIbα (-5)T/C (Kozak)] determined in ACS patients had no significant impact on their expression. Modest correlation was revealed between MPV and plasma thrombopoietin (TPO) measured at the first day of ACS (r = 0.279, P = 0.005). The data obtained indicated that GPIIb-IIIa and GPIb levels are mainly affected by platelet size (MPV) but not by their genetic variations. In some ACS patients, production of large platelets with high GPIIb-IIIa and GPIb contents might be stimulated by elevated TPO.
2 ФГБУ "Петербургский институт ядерной физики им. Б.П. Константинова", Гатчина, Ленинградская область 3 ГБОУ ВПО "Северо-Западный государственный медицинский университет им. И.И. Мечникова" Минздрава России, Санкт-Петербург.Повышенный средний объём тромбоцитов (СОТ) является независимым фактором риска тромботических событий у больных с сердечно-сосудистыми патологиями. В настоящей работе изучали взаимосвязи СОТ с агрегационной активностью тромбоцитов и содержанием гликопротеина (ГП) IIb-IIIa (aIIb/b3 интегрин, рецептор фибриногена) и ГП Ib (рецептор фактора Виллебранда). Исследования проводили в группе здоровых добровольцев (n=38) и группе больных с острым коронарным синдромом (ОКС, n=116). У больных кровь собирали в 1, 3-5 и 8-12 сутки после развития ОКС. Все больные получали в качестве антиагрегантной терапии ацетилсалициловую кислоту (АСК, ингибитор синтеза тромбоксана А2) и большинство -клопидогрел (антагонист рецептора ADP), за исключением части больных (n=44) в 1 сутки, которые до первого сбора крови не принимали клопидогрел. Агрегацию тромбоцитов у добровольцев стимулировали 1,25, 2,5, 5, и 20 мкМ ADP, а у больных -5 и 20 мкМ ADP. Количество ГП IIb-IIIa и ГП Ib на поверхности тромбоцитов измеряли с помощью 125 I-меченных моноклональных антител. Генетические полиморфизмы ГП IIb-IIIa и ГП Ib определяли у больных с ОКС. Достоверные корреляции между СОТ и уровнем агрегации тромбоцитов были выявлены у здоровых доноров при дозах ADP 1,25 и 2,5 мкМ (коэффициенты корреляции (r) -0,396 и 0,373, р<0,05), а при дозах 5 и 20 мкМ эти взаимосвязи не достигали достоверного уровня (r -0,279 и 0,205, p>0,05). Корреляции между СОТ и уровнем агрегации наблюдали в 1 сутки ОКС в подгруппе больных, которые получили АСК, но еще не начали прием кропидогрела (r -0,526, p<0,001 и 0,368, p<0,05 для 5 и 20 мкМ ADP соответственно). Взаимосвязей между этими параметрами не было отмечено на фоне совместного приема АСК и клопидогрела. Сильные прямые корреляции между СОТ и количеством ГП IIb-IIIa и ГП Ib были зарегистрированы как у здоровых доноров, так и у больных с ОКС (во всех временных точках), -r от 0,439 до 0,647 (для всех корреляций p£0,001). Генетические полиморфизмы ГП IIb-IIIa (ГП IIIa Leu33Pro) и ГП Ib ((-5)T/C (Kozak) и Thr145Met), определяемые у больных с ОКС, не влияли на содержание соответствующих гликопротеинов. Полученные данные указывают на то, что высокие показатели СОТ коррелируют с увеличенной агрегационной активностью тромбоцитов и повышенной экспрессией ГП IIb-IIIa и ГП Ib.Ключевые слова: средний объём тромбоцитов, агрегация тромбоцитов, гликопротеин IIb-IIIа, гликопротеин Ib, острый коронарный синдром. 94* -адресат для переписки
Spontaneous platelet aggregation was evaluated in patients with acute coronary syndrome on days 1, 3-5, and 8-12 of the disease. On day 1, aggregation was analyzed after aspirin, but before clopidogrel administration; during other periods after both antiaggregants. The mean levels of spontaneous aggregation after antithrombotic therapy did not change during different periods after the onset of acute coronary syndrome, in contrast to ADP-induced aggregation that decreased after the development of clopidogrel effects (days 3-5 and 8-12). Spontaneous aggregation during different periods directly correlated (r>0.4, p<0.01) with spontaneous and ADP-induced aggregation during different periods (r=0.372, r=0.447, and r=0.543 on days 1, 3-5, and 8-12, respectively; p<0.01). No relationship between spontaneous aggregation and plasma concentration of von Willebrand's factor was detected. Spontaneous aggregation was completely suppressed after in vitro addition of prostaglandin E1 (platelet activation inhibitor), slightly (by ≈20%) decreased in the presence of antibodies to glycoprotein Ib, blocking its reactions with von Willebrand's factor, and did not change in the presence of aptamer inhibiting thrombin activity.
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