Antikoagulandid, nende toimemehhanismid ja määramine TIIT SALUM
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1 Antikoagulandid, nende toimemehhanismid ja määramine TIIT SALUM
2 Figure. Classification of established anticoagulants and new anticoagulants that were recently licensed for use or are in advanced stages of clinical development. fixa indicates factor IXa. *Indirectly inhibit coagulation by interacting with antithrombin.... Eikelboom J, Weitz J. Circulation 2010;121: Copyright American Heart Association
3 Hüübimismehhanism Antikoagulantide toime hüübimisele Määramismeetodid
4 HÜPERKOAGULATSIOON Kasvajad, sepsis, trombofiilia VERESOONE SEINA KAHJUSTUS Trauma, ateroskleroos STAAS Südame töö häired, liikumatus, rasedus, rasvtõbi
5 TF M. Dashty, V. Akbarkhanzadeh, C. J. Zeebregts, C. A. Spek, E. J. Sijbrands, M. P. Peppelenbosch, F. Rezaee Characterization of coagulation factor synthesis in nine human primary cell types
6 HÜPERKOAGULATSIOON - Trombofiilia: Kaasasündinud: Factor V Leiden (apcr) Füsioloogiliste antikoagulantide häired AT III, PC, PS, FXIII mutats., düsfibrinogeneemia Omandatud: Antifosfolipiid sündroom PC inhib., FIIa teke Hüperlipideemia (oxldl) PLT aktivatsioon Homotsüsteiini tõus (metab. häire, B6, foolhappe, B12 defitsiit) endoteeli kahjustus, oxldl teke, trombomoduliini aktiivsuse langus, TF laadne toime hüübimisele Suitsetamine oxldl teke, NO langus, veresoonte ahenemine ATEROSKLEROOS naastu makrofaagid on olulised TF allikad
7 HÜÜBIMISMEHHANISM 1. Kaskaad 2. Cell based
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9 Trombiini tähtsus hüübimise regulatsioonis: 1. Fibrinogeen fibriin 2. FV ja FVIII aktivatsioon 3. FXIII aktivatsioon 4. PLT aktivatsioon 5. Trombomoduliiniga koos PC aktivatsioon
10 Füsioloogilised antikoagulandid Seriinproteaaside inhibiitorid 1.Serpin C1 (ATIII) (VIIa+TF; IXa; Xa; XIa; XIIa; trombiin; kallikreiin) 2.Heparin (basofiilid, nuumrakud) koos ATIII Aktiveeritud koagulatsioonifaktorite neutraliseerijad: 1.Trombomoduliin (trombiin) 2.PC (serpin A5); PS Va; VIIIa 3.TFPI (TF inhib)
11 FIBRINOLÜÜS E1 Lp(a)
12 Venoosne tromb Arteriaalne tromb
13 Antikoagulantide toime hüübimisele ANTIKOAGULANDID 1.Varfariin 2.Hepariinid 3.Otsesed FXa inhibiitorid (xabans) 4.Otsesed trombiini inhibiitorid 5.FIXa inhibiitorid
14 Figure. Classification of established anticoagulants and new anticoagulants that were recently licensed for use or are in advanced stages of clinical development. fixa indicates factor IXa. *Indirectly inhibit coagulation by interacting with antithrombin.... Eikelboom J, Weitz J. Circulation 2010;121: Copyright American Heart Association
15 Varfariin toimib vitamiin K-st sõltuvatele hüübefaktoritele (II, VII, IX,X); PC; PS Vitamiin K on kofaktoriks Glu karboksüülimisel. Tekkinud Gla + Ca 2+ on vajalik koagulatsiooni faktorite seostumiseks PLT fosfolipiididega PT aja pikenemine Toimemehhanism
16 Glu karboksüülimine Ca seostumine Ca seostumine PLT fosfolipiididega Protrombiin trombiin II, VII, IX, X, PC, PS
17 HEPARIINID kaudse Xa toimega (ATIII); FIIa 1. UFH 2. LMWH 3. Hepariini derivaadid
18 1/3 hepariinist seostub ATIII-ga (Serpin C1) Suurte dooside puhul toimub seostumine ka HCII-ga (Serpin D1) Hepariin/AT kompleks inhibeerib: F IIa (ka Va;VIIIa); Xa ; IXa; XIa; XIIa; TF (LMWH mitte) Võrreldes LMWH-ga, UFH seostub rohkem plasmavalkudega, endoteeliga, makrofaagidega, seega biosaadavus väheneb ja doosi variaabelsus on suur.
19 NB! Seostudes trombiiniga inhibeeritakse fibriini teket aga ka trombiini poolt FV ja FVIII aktivatsiooni
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24 Otsesed FXa toimega (xabans)
25 Trombiini vastased ained
26 Trombiinile otseselt toimivad ravimid: Bivalentsed Hirudin (lepirudin) bivalirudin Univalentsed argatroban dabigatran, NB! Pidurdub fibriini moodustumine ja faktorite XIII, V ja VIII aktivatsioon (V ja VIII kiirendavad trombiini moodustumist)
27 C J Lee, JE Ansell Direct thrombin inhibitors Br J Clin Pharmacol. 2011,72(4):
28 Rationale for Targeting Factor IXa FVIIIa/FIXa activation of FX is the rate limiting step in thrombin generation FIX knockout mice lack occlusive clot formation following vascular injury due to insufficient generation of thrombin to form platelet aggregates. FIXa concentration is lower than Xa and thrombin, making high levels of target inhibition more readily achievable High Factor IX levels are associated with increase in ACS and venous thromboembolism Transgenic mice overexpressing FIXa have a shorter lifespan and develop arterial thrombosis and myocardial fibrosis with vascular distribution patterns similar to those of ischemic cardiomyopathy in humans Hemophilia B Carriers-Reduced CHD Mortality Foreign materials (eg. catheters and guidewires) lead directly to FIX activation
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31 Määramismeetodid
32 PT test Välise tee ja ühise tee test (tromboplastiin - TF, fosfolipiid, Ca 2+ Varfariinravi kontrolliks (II, VII, X, fibrinogeen, TF) Varfariin toimib vitamiin K-st sõltuvatele hüübefaktoritele (II, VII, IX,X); PC; PS
33 aptt test sisemise ja ühise tee test (osaline tromboplastiin - Fosfolipiid (kefaliin) PLT fosfolip. asendaja, pinna-aktivaator (kaoliin, silica) FXII aktiveerimine, Ca 2+ HMWK, Kallikreiin, XII, XI, IX, VIII, X, V, II, fibrinogeen UFH määramiseks Kui FVIII; fibrinogeen tõusnud, vajalik anti-xa määramine (ka ACT) Activated Clotting Time [ACT] point-of-care testimiseks Kontaktaktivats (FXII) UFH
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35 LMWH määramine Kromogeenne FXa uuring, (4h peale sc injektsiooni) aptt ei sobi (LMWH ei toimi FII ja FIX) Ei ole mõjutatud teistest koagulatsioonifaktoritest, vit.k mõjutavatest antikoagulantidest, NB! Used to monitor warfarin in the presence of a lupus anticoagulant, hirudin or argatroban (which prolong the PT and increase the INR), because warfarin decreases factor X (also factors II, VII, IX), and the chromogenic assay has no interference from lupus anticoagulant, hirudin or argatroban
36 Figure 3. Factor Xa heparin assay. Bates S M, and Weitz J I Circulation 2005;112:e53-e60 Copyright American Heart Association
37 Otsesed trombiini inhibiitorid Testimine: 1. Hemoclot (diluted thrombin time) 2. Ecarin clotting time, chromogenic assay, ROTEM 3. aptt (lineaarsus, erinevad ravimid, reagendid) 4. TT on tundlik kuid ei ole korrelatsiooni doosiga
38 Ecarin (prothrombin activator) clotting time involves the addition of small amounts to Ecarin to plasma and measuring the time to clot formation i.e. the conversion of fibrinogen to fibrin. Meizothrombin is generated by the Ecarin and cleavage at the Arg323 bond is the rate-limiting step in its formation. In the presence of hirudin, meizothrombin is inhibited and so clot formation is prolonged.
Coagulation Cascade. TF-VIIa. Tissue Factor + VII. XIIa. Prothrombin. XIa. IXa. VIIIa. Thrombin. XL- Fibrin. XIII Monomer. Fibrinogen.
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