Recomendados
Más contenido relacionado
La actualidad más candente
La actualidad más candente (20)
Destacado
Destacado (20)
Similar a Terapia anticoagulante
Similar a Terapia anticoagulante (20)
Más de evidenciaterapeutica
Más de evidenciaterapeutica (20)
Último
Último (20)
Terapia anticoagulante
- 1. FARMACOTERAPIA DE LA ANTICOAGULACION CESAR GARCIA CASALLAS QF MD Msc MEDICINA INTERNA FARMACOLOGIA CLINICA
- 2. Tromboembolismo Venoso TEP Embolo, originado en vena femoral, presente en arteria pulmonar TV Gran trombo en vena femoral
- 3. Warfarin-induced Venous Limb Gangrene in HIT Patients Warkentin et al., Ann Intern Med 1997; 127: 804 Microvascular thrombosis (venules) Arterial pulses detectable Occurred in 8 of 158 patients with HIT Associated with warfarin treatment while the patients were still thrombocytopenic May be caused by depletion of protein C in the setting of ongoing platelet activation and thrombin generation
- 5. COAGULACION
- 6. MODELO ACTUAL DE COAGULACION
- 7. Eight ACCP Consensus Conference On Antithrombotic Therapy 2008
- 8. Efectos HNF y HBPM
- 14. Heparina - Estructura PM promedio 12,000 daltons (40 unidades de glucosa) con la siguiente estructura:
- 18. Antithrombin-binding Heparin Pentasaccharide Petitou and van Boeckel, Angew Chem Int Ed 2004; 43: 3118 = contributory = essential
- 19. Efecto Alosterico de la Heparina Jin et al., Proc Natl Acad Sci USA 1997; 94: 14683 Sufficient for inhibition of factor Xa Binding of heparin pentasaccharide Reactive site arginine becomes accessible to Xa Conformational change in antithrombin Activated antithrombin (inhibits factor Xa) Antithrombin
- 20. Efecto de la Heparina Heparin ( > 18 monosaccharide units) Antithrombin Thrombin Petitou and van Boeckel, Angew Chem Int Ed 2004; 43: 3118 Required for inhibition of thrombin
- 21. AT Heparina Inactivacion de la Trombina Thrombin H F S C
- 22. Trombina resistente a la inactivacion de la Heparina Heparina Fibrina AT Thrombin H F S C
- 30. HBPM Nadroparin - Fraxiparine Enoxaparin - Clexane O NHSO 3 Ca CaO 3 SO OR 1 Saccharide chain O OH OSO 2 ONa Saccharide chain O O H R 2 CHOR 2 CH 2 OH OH OR 1 HO Saccharide chain Dalteparin - Fragmin R 1 = H or SO 3 Na R 2 = COONa O COONa
- 33. AT HNF HNF vs HBPM AT HBPM Thrombin (IIa) H F S C Thrombin (IIa) H F S C
- 39. Factores de la Coagulación Vitamina K-Dependientes Vitamina K VII IX X II J. CESAR GARCIA C. QF MD Msc
- 40. Mecanismo de Acción Vitamina K J. CESAR GARCIA C. QF MD Msc
- 41. Mecanismo de Acción de la Warfarina J. CESAR GARCIA C. QF MD Msc
- 44. INR ( ) Patient’s PT in Seconds Mean Normal PT in Seconds INR = ISI INR = International Normalized Ratio ISI = International Sensitivity Index J. CESAR GARCIA C. QF MD Msc
- 48. Nuevos Anticoagulantes TFPI (tifacogin) Fondaparinux Idraparinux Rivaroxaban Apixaban LY517717 YM150 DU-176b PRT-054021 Ximelagatran Dabigatran ORAL PARENTERAL DX-9065a Otamixaban Xa IIa TF/VIIa X IX IXa VIIIa Va II Fibrin Fibrinogen AT APC (drotrecogin alfa) sTM (ART-123) Adapted from Weitz & Bates, J Thromb Haemost 2005 TTP889
- 52. Fondaparinux: Mecanismo de Accion IIa II Fibrinogen Coagulo Coagulacion AT Xa AT AT Fondaparinux Xa Antithrombin Turpie AGG et al. N Engl J Med . 2001;344:619.
- 53. Overall Efficacy Fondaparinux vs Enoxaparin Ephesus N = 1817 Pentathlon 2000 N = 1584 Penthifra N = 1250 Pentamaks N = 724 Overall Odds Reduction % odds reduction Fondaparinux better Enoxaparin better -100 -80 -60 -40 -20 20 0 40 60 80 100 58.5% 28.1% 61.6% 63.1% 55.3% [72.9; 37.5] [52.2; 7.6] [73.4; 45.0] [75.5; 44.8] [63.2; 45.8] Exact 95% CI P = 10 -17 Overall odds reduction for proximal DVT = 57.4% [CI: 72.3 - 35.6]; p = 10 x -6 Turpie AGG, et al. Arch Intern Med . 2002;162:1833-1840.
- 57. Inhibidores Directos Factor Xa
- 59. Inhibicion Directa Factor Xa VIIa Xa IXa XIa XIIa Factor Tisular Fibrinogen Coagulo Factor II (prothrombin) Rivaroxaban Apixaban DU-176b YM150 LY517717 PRT-054021 ×
- 66. 終 於 結 束 了
Notas del editor
- The four Vitamin K dependent clotting factors are synthesized in the liver.
- The Vitamin K dependent clotting factors are carboxylated in a reaction that is linked to the oxidation of the reduced form of the vitamin . The non carboxylated forms of these clotting factors are inactive because they cannot bind calcium. When Vitamin K is deficient, non-carboxylated prothrombin is secreted and this protein is non functional. Carboxylation of terminal glutamic acid side chains (known as the Glu to Gla conversion) allows the clotting factors to bind calcium which in turn bridges the clotting factors to phospholipid surfaces, a necessary requirement for their activity.
- Warfarin works by interfering with internal recycling of oxidized Vitamin K to the reduced form. When warfarin is given, the oxidized form of Vitamin K builds up in the blood leading to a deficiency of reduced Vitamin K and a decrease in carboxylation of prothrombin. Warfarin interferes with –carboxylation of terminal glutamic acids on the procoagulant proteins, Factors II, VII, IX, and X. –carboxylation from the Glu to the Gla form of these proteins in a critical step in the biosynthesis of these proteins that is required their normal function in coagulation. – carboxylation is a post-translational step that is Vitamin K dependent and linked to the oxidation of hydroquinone (the active cloting form of Vitamin K) to the Vitamin K epoxide. The reaction uses molecular oxygen for the conversion of hydroquinone to the epoxide, and CO 2 , for the –carboxylation of the glutamic acid residues on the Vitamin K dependent proteins from the inactive carboxylation of the glutamic acid residues on the Vitamin K dependent proteins from the inactive Glu to the active Gla form. Under normal physiologic circumstances, Vitamin K is absorbed as the quinone form (Vitamin K 1 ). The quinone is reduced to the hydroquinone (the reduced form), which in turn is oxidized to Vitamin K epoxide (the oxidized form). The active cofactor form of Vitamin K (hydroquinone) is then regenerated through two reduction steps. First the 2–3 epoxide is reduced to the quinone (the dietary source of Vitamin K 1 ). This is then reduced to the hydroquinone which, when recycled to the epoxide, acts as the cofactor for the Glu to Gla conversion of the Vitamin K dependent coagulation factors by blocking both reduction steps, thereby depleting the stores of the hydroquinone form of Vitamin K.
- The INR is calculated by the formula shown on this slide. The ISI is the International Sensitivity Index. Each thromboplastin is assigned an ISI which reflects the sensitivity of the thromboplastin to Warfarin-mediated reduction of the Vitamin K dependent clotting factors. By convention, the ISI of the reference thromboplastin is 1.0. The higher the ISI, the less sensitive the thromboplastin is to Warfarin-mediated reduction of the Vitamin K dependent clotting factors. The next two slides provide an example of how the ISI (sensitivity) of the thromboplastin influences the PT ratio (PTR) and how the resulting variability is corrected by expressing the results as an INR.
- This slide provides guidelines for safe and effective warfarin use. The dose of warfarin should be monitored daily until the INR is in the therapeutic range and then less frequently when a stable dose-response relationship is achieved. Regardless of the degree of stability in warfarin dosing and INR value in the hospital, it is important to monitor the INR frequently post hospital discharge (i.e., at least 1–3 days after discharge) and to spread out the interval of monitoring thereafter depending on INR response. Monitoring is necessary in all patients, but can be reduced to four weekly intervals in the low risk (for bleeding) patient who shows a stable dose-response.
- The relative contraindications for warfarin are listed on this slide. Warfarin crosses the placenta and is teratogenic in the first trimester, producing warfarin embryopathy in about 5% of exposed neonates. It is also fetopathic when used after the first trimester in an unknown (but much smaller) percentage of fetuses. Warfarin is contraindicated (relative or absolute) in patients with an increased risk of serious bleeding. The indication for warfarin should be reviewed carefully in patients with relative contraindications.
- The signs of warfarin overdosage are listed on this slide. Hemorrhagic complications from warfarin therapy are more likely to occur with excessive degrees of anticoagulation, but even with an INR in the therapeutic range, bleeding can occur. Because of the likelihood of finding an underlying lesion in an individual who has gastrointestinal bleeding or significant genito-urinary bleeding in the face of therapeutic levels of anticoagulation, one is advised to consider and evaluate for underlying abnormalities predisposing to the bleeding. The return on such evaluations in the face of an excessive degree of anticoagulation diminishes, and one must use judgement whether or not to pursue an evaluation.
- There are many targets for novel anticoagulants in the coagulation pathway: Tissue factor pathway inhibitor (TFPI) bound to Factor Xa inactivates the tissue factor (TF)–Factor VIIa complex, preventing initiation of coagulation Activated protein C (APC) degrades Factors Va and VIIIa, and thrombomodulin (soluble; sTM) converts thrombin (Factor IIa) from a procoagulant to a potent activator of protein C Fondaparinux and idraparinux indirectly inhibit Factor Xa, requiring antithrombin (AT) as a cofactor Direct (AT-independent) inhibitors of Factor Xa include rivaroxaban (BAY 597939), LY517717, YM150 and DU-176b (all orally available), and DX-9065a (intravenous) Oral, direct thrombin inhibitors include ximelagatran (now withdrawn) and dabigatran Weitz JI & Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843–1853
- This slide shows the X-ray crystal structure of rivaroxaban in complex with human Factor Xa, demonstrating the direct binding of rivaroxaban to human Factor Xa Supported by two hydrogen bonds, the ( S )-oxazolidinone core of rivaroxaban provides the L-shape needed for binding to Factor Xa. It serves as a central template for directing the substituents into the S1 and S4 subsites Perzborn E et al . In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514–521 Roehrig S et al . Discovery of the novel antithrombotic agent 5-chloro-N-({(5 S )-2-oxo-3-[4-(3- oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (BAY 59-7939): An oral, direct Factor Xa inhibitor. J Med Chem 2005;48:5900–5908