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- Ингибиторы фибринолиза (антифибринолитики)
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- Свертывание крови и фибринолиз
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Вторичные антикоагулянты
Первичные антикоагулянты
Противосвертывающая система крови
Антикоагулянты (блокируют разные фазы свертывания крови).
Первичные антикоагулянты имеются в крови до начала свертывания:
• антитромбин III (в основном образуется в эндотелии и в печени) — плазменный кофактор гепарина. При отсутствии гепарина его активность уменьшается в 700 раз. В активной форме составляет 90 % всей антитромбиновой и 70 % антикоагулянтной активности крови. Ингибирует тромбин (фактор Па), а также факторы Ха, IXa, XIa (специфическим ингибитором тромбина является пептид гирудин, образуемый пиявками);
• гепарин (сульфатированные полисахариды, образуются тучными клетками особенно печени и легких) образует комплекс с антитромбином III, превращая его в активный антикоагулянт. В малых концентрациях ингибирует образование протромбиназы (фазу I), в высоких концентрациях тормозит все три фазы коагуляции, активирует фибринолиз. Комплекс «гепарин + антитромбин III» может фиксироваться на мембране эндотелиальных клеток, обеспечивая тромборезистентность сосудистой стенки;
• a1-антитрипсин ингибирует тромбин (Па), факторы ХПа, IXa, XIa;
• протеин С (сериновая протеаза, образуется в печени с участием витамина К) инактивирует факторы Va, VIII, ускоряет фибринолиз. Сам активируется тромбином, протеином S, тромбомодулином;
• тромбомодулин (образуется в эндотелии) блокирует рецепторы для тромбина на эндотелиоцитах, активирует протеин С;
• антитромбопластины ингибируют факторы III и VIIa.
Вторичные антикоагулянты образуются в процессе свертывания крови и фибринолиза:
• атитромбин I — это фибрин, который адсорбирует и инактивирует тромбин, факторы Va, Ха;
• антитромбин VI — это продукты фибринолиза, которые блокируют фибриноген и фибрин-мономер, тромбин и фактор XIa.
Фибринолиз (препятствует образованию и осуществляет лизис фибрина тромба, образующегося в процессе постоянного локального гемостаза, может осуществляться по двум вариантам: с участием плазмина и без участия плазмина).
Плазминовый вариант фибринолиза:
• осуществляется в две фазы (рис. 3.3):
♦ в первой фазе плазменный профермент плазминоген превращается в активную сериновую протеазу — плазмин. Плазминоген — одноцепочечный гликопротеин, образуемый в печени, костном мозге, почках и других органах; концентрация в плазме 0,2 г/л. Он имеет лизинсвязывающие участки, через которые присоединяется к фибрину (высокое сродство) и фибриногену (низкое сродство), поэтому в норме всегда входит в состав образующегося фибринового тромба. В его активации участвуют:
■ тканевые активаторы плазминогена: сериновые протеазы из клеток разных тканей (например, урокиназа почек, фактор Р8 тромбоцитов, протеазы нейтрофилов) и эндотелия их сосудов;
■ плазменные активаторы плазминогена: фактор ХПа, калликреин (XlVa), факторы комплемента С8 и СЗ, протеин С и др.;
■ экзогенные вещества: стрептокиназа стрептококков, лекарства;
♦ во второй фазе образовавшийся плазмин расщепляет фибрин тромба (по пептидным связям Лиз—-Apr и Лиз—Лиз) до пептидов и аминокислот (продукты деградации фибрина);
♦ сс2-антиплазмин (гликопротеин, синтезируется в печени) — самый активный ингибитор фибринолиза, образует прочные комплексы с плазмином, лишая его ферментативной активности, и с фибрином, делая его нечувствительным к плазмину;
♦ a2-макроглобулин (гликопротеин) оказывает более медленное, но длительное ингибирующее действие на плаз-мин, образуя с ним ковалентный комплекс;
♦ a1-антитрипсин (синтезируется в печени) оказывает медленное ингибирующее действие на плазмин (быстрое — на трипсин).
Неплазминовый вариант фибринолиза
Неплазминовый вариант фибринолиза осуществляется фибринолитическими протеазами лейкоцитов, тромбоцитов, эритроцитов и антитромбином III в комплексе с гепарином, которые могут непосредственно расщеплять фибрин.
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Фибринолиз (от Фибрин и греч. lýsis – разложение, растворение) — процесс растворения тромбов и сгустков крови, неотъемлемая часть системы гемостаза, всегда сопровождающая процесс свертывания крови и культивирующаяся факторами, принимающими участие в данном процессе. Является важной защитной реакцией организма и предотвращает закупорку кровеносных сосудов сгустками фибрина. Также фибринолиз способствует реканализации сосудов после прекращения кровотечения.
Включает в себя расщепление фибрина под воздействием плазмина, присутствующего в плазме крови в виде неактивного предшественника — плазминогена. Последний активируется одновременно с началом процесса свертывания крови.
Содержание
Внутренний и внешний путь активизации [ править | править код ]
Фибринолиз, как и процесс свертывания крови, протекает по внешнему или внутреннему механизму. Внешний путь активации осуществляется при неотъемлемом участии тканевых активаторов, синтезирующихся преимущественно в эндотелии сосудов. К данным активаторам относят тканевый активатор плазминогена (ТАП) и урокиназу.
Внутренний механизм активации осуществляется благодаря плазменным активаторам и активаторами форменных элементов крови — лейкоцитов, тромбоцитов и эритроцитов. Внутренний механизм активации разделяют на Хагеман-зависимый и Хагеман-независимый. Хагеман-зависимый фибринолиз происходит под влиянием фактора XIIа свертывания крови, калликреина, которые вызывают превращение плазминогена в плазмин. Хагеман-зависимый фибринолиз происходит наиболее быстро и носит срочный характер. Его основным назначением является очищение сосудистого русла от нестабилизированного фибрина, который образуется в процессе внутрисосудистого свертывания крови.
Хагеман-независимый — осуществляется под влиянием протеинов C и S
Ингибирование фибринолиза [ править | править код ]
Фибринолитическая активность крови во многом определяется именно соотношением ингибиторов и активаторов процесса фибринолиза.
В плазме крови находятся также ингибиторы фибринолиза, подавляющие его. Одним из важнейших таких ингибиторов являются α2-антиплазмин, который вызывает связывание плазмина, трипсина, калликреина, урокиназы, тканевой активатор плазминогена. Таким образом препятствуя процессу фибринолиза на его ранних и на поздних стадиях. Сильным ингибитором плазмина является также α1-протеазный ингибитор. Также фибринолиз тормозится альфа2-макроглобулином, C1-протеазным ингибитором,и целым рядом ингибиторов активатора плазминогена, вырабатываемых в эндотелии, а также фибробластами, макрофагами и моноцитами.
Регуляция фибринолиза [ править | править код ]
Между процессами свертывания крови и фибринолизом в организме поддерживается равновесие.
Усиление фибринолиза обусловлено повышением тонуса симпатической нервной системы и поступлением в кровь адреналина и норадреналина. Это вызывает активацию фактора Хагемана, что запускает внешний и внутренний механизмы продукции протромбиназы, а также стимулирует Хагеман-зависимый фибринолиз. Из эндотелия также происходит выделение тканевого активатора плазминогена и урокиназы, стимулирующих процесс фибринолиза.
При повышении тонуса парасимпатической нервной системы наблюдаются также ускорение свертывания крови и стимуляция процесса фибринолиза.
Основным эфферентным регулятором процессов свертывания крови и фибринолиза является сосудистая стенка.
Литература [ править | править код ]
Физиология человека. Под ред. Покровского В.М., Коротько Г.Ф М.: Медицина, 1997; Т1 — 448 с., Т2 — 368с
См. также [ править | править код ]
Физиология человека. Учебник/Под ред. В. М. Смирнова.- М.: Медицина, 2002. — 608 с.: ил.(Учеб. лит. Для студентов мед. вузов). ISBN 5-225-04175-2 (стр. 231)
Фибринолиз — это процесс расщепления фибринового сгустка, в результате которого происходит восстановление просвета закупоренного тромбом сосуда. Фибринолиз начинается одновременно с ретракцией сгустка, но идет медленнее. Это тоже ферментативный процесс, который осуществляется под влиянием протеолитического фермента — плазмина (фибринолизина).
Плазмин находится в плазме крови в неактивном состоянии в виде плазминогена. Плазминоген синтезируется в печени, костном мозге, почках и других органах. Под влиянием кровяных и тканевых активаторов осуществляется его активация — переход в плазмин. Плазмин расщепляет фибрин на отдельные полипептидные цепи, в результате чего происходит лизис (растворение) фибринового сгустка (рис.4)
Рис.4. Фибринолиз
Активация плазминогена, как и образование протрамбиназы, может протекать по внешнему и внутреннему путям. Внешний путь активации плазминогена осуществляется с помощью тканевых активаторов. К ним относятся в первую очередь тканевой активатор плазминогена (t -РА), который продуцируется эндотелиальными клетками разных тканей и находится главным образом в стенках кровеносных сосудов (преимущественно в венах и венулах), и урокиназа (и — РА), синтезируемая преимущественно почками и фибробластами. Тканевой активатор плазминогена принимает участие в растворении фибрина, находящегося в плазме. Урокиназа участвует в растворении фибрина, расположенного на поверхности клеток, в том числе эндотелиальных. Во внутреннем пути активации плазминогена участвуют кровяные активаторы, например, активированный фактор Хагемана, каллликреин, протеины С и S. Способностью активировать плазминоген обладают и некоторые экзогенные вещества, например, стрептокиназа стрептококков, некоторые лекарства.
В плазме крови находятся и физиологические ингибиторы фибринолиза. Одни ингибиторы (активаторы) нейтрализуют действие активаторов плазминогена, другие (антиплазмины) угнетают сам плазмин. Среди антиактиваторов выделено 3 типа ингибиторов. Антиплазминовым действием обладают б2— антиплазмин (б2-глобулин) и б2-макроглобулин. В первую очередь плазмин инактивируется б2— антиплазмином, способным нейтрализовать 2/3 всего плазмина, который может образоваться в крови из имеющегося плазминогена. Поэтому он быстро исчезает из кровотока и оказывает свое влияние местно в сгустке крови. При чрезмерном образовании плазмина может произойти истощение б2— антиплазмина. Тогда в ингибирование включается б2-макроглобулин, который является менее специфичным ингибитором плазмина. К ингибитором плазминогена относится и б1— антитрипсин.
Существует и неплазминовый вариант фибринолиза, который осуществляется фибриеолитическими протеазами лейкоцитов, тромбоцитов, эритроцитов и антитромбином III в комплексе с гепарином, которые могут непосредственно расщеплять фибрин. Все вещества, принимающие участие в процессе фибринолиза, объединены фибринолитическую систему. Кроме растворения сгустков крови и удаления отложений фибрина компоненты фибринолитической системы принимают участие и в других физиологических процессах: заживлении ран, регуляции роста, деления и миграции клеток, регенерации мышц, росте аксонов нейронов, процессах овуляции, оплодотворения и др. Процесс фибринолиза длится несколько суток и его результатом является реканализация сосуда, т.е. восстановление его проходимости. Ретракцию кровяного сгустка и фибринолиз выделяют как дополнительные фазы свертывания крови. Подчеркнем, что существующие два вида свертывания приводят к образованию двух видов тромбов — тромбоцитарного и плазменного.
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