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Pacientes hemofílicos con inhibidor
- 1. Pacientes Hemofílicos con Inhibidor. Tratamiento. XVII Curso de Farmacoterapia con Hemoderivados Barcelona, abril del 2013 Joan M Tusell Pediatra y Hematólogo Asesor Externo de Biotest
- 2. Anticuerpos Inhibidores en Hemofilia A. Un reto a la Hemostasia. ● La presencia de anticuerpos anti-factor VIII/IX representa una grave complicación del tratamiento de la hemofilia. ● Constituye un auténtico reto para los centros de tratamiento, en su intento de disminuir la alta morbilidad e incluso mortalidad que presentan estos pacientes. 25/04/13 2Joan M Tusell
- 3. Inhibidores: Complicación Grave. • Incidencia: 30 % en Hemofilia A. 5% en hemofilia B. • No sangran más, pero presentan una peor evolución por una peor respuesta al tratamiento. • Gran incremento de morbilidad y mortalidad. 25/04/13 Slide No 3Joan M Tusell
- 4. Anticuerpos Inhibidores. • IgG; Generalmente subclase 4 ó mezcla 1 and 4. • Se presentan en: – Hemofilia congénita tras el tratamiento = aloinmune. – Personas previamente normales = autoinmune. Hemofilia adquirida. IgG= Inmunoglobulina G 25/04/13 4Joan M Tusell
- 5. Inhibidores en Hemofilia Congénita. • Incidencia: – Inhibidores del F VIII:~ 30 % (10–45 %) – Inhibidores del F IX: ~ 5% • Medida: – Unidades Bethesda = UB. – 1 UB = candidad de inhibidor que neutraliza el 50% de la actividad del factor VIII; 2 horas, 37°C. • Aparición: Antes de las 20-30 primeras infusiones. • Rara desaparición espontánea 25/04/13 5Joan M Tusell
- 6. Hemophilia Inhibitors Low Responding 10 Time 100 BU 10 Time 100 BU 10 Time 100 BU Transient 10 Time 100 BU *ISTH definition of high titer is >5 BU High RespondingHigh Responding High RespondingHigh Responding 25/04/13 6 Joan M Tusell
- 7. Desarrolo de Inhibidores. Factores Genéticos. • Alto riesgo: – Grandes delecciones. – Mutaciones sin sentido (cadena ligera). – Inversión del intron 22. • Bajo riesgo: – Pequeñas delecciones. – Mutaciones con sentido perdido. – Mutaciones sin sentido (cadena pesada). – Mínimos errores. 25/04/13 7Joan M Tusell
- 8. Desarrollo de Inhibidores. Otros Factores. • No todos los miembros de una misma familia afecta desarrollan inhibidores. • No todos los hermanos. • No todos los gemelos. Implicación de otros factores de riesgo no genético. 25/04/13 8Joan M Tusell
- 9. Desarrollo de Inhibidores. Factores de Riesgo no Genético. • Edad al inicio del tratamiento (< 2 años). • Intensidad del tratamiento. (En la fase inicial del tratamiento) • Asociación con retos inmunológicos (infecciones, vacunaciones, actos quirúrgicos, hemorragias del sistema nervioso central). • Modelo de tratamiento (profilaxis vs demanda). • Tipo de producto (recombinante vs plasmático). Papel del Factor vonWillebrand. 25/04/13 9Joan M Tusell
- 10. Incidence rate of inhibitors in PUPs with haemophilia A A systematic review Iorio A et al; JTH, 2010 Included studies n=24 2094 patients 887 with severe Haemophilia 14 % 27 %A. Iorio et al. 2010, Journal of Thrombosis and Haemostasis 04/25/13 En PUPs
- 11. Issued on June 7th 2011 Inhibitor Development in Parallel Cohort Studies Iorio A et al; JTH, 2010 High responding inhibitors Riesgo 1.67 veces superior para el rFVIII rFV III 04/25/13 A. Iorio et al. 2010, Journal of Thrombosis and Haemostasis Alta Respuesta
- 12. Inhibitor development in PUPs with hemophilia A treatedInhibitor development in PUPs with hemophilia A treated with plasma derived or recombinant factor VIII concentrateswith plasma derived or recombinant factor VIII concentrates Prospective studies • GTH-PUP-Study Yes (1,59) • RODIN-Study No • Canal Study No • SIPPET-Study Ongoing
- 13. 25/04/13 13Joan M Tusell
- 14. Tratamiento de la hemorragia aguda. • Agentes de bypass. – PCCs plasmático – aPCCs plasmático – FVIIa Recombinante. (Único en inhibidores en hemofilia B). • Factor VIII – Humano (solamente para títulos bajos de inhibidor). – Porcino. (No disponible). • Desmopresina (solamente para títulos bajos de inhibidor). • Factor IX en inhibidores en hemofilia B ??? 25/04/13 14Joan M Tusell
- 15. Modelo clásico de la coagulación 25/04/13
- 16. Potencial Trombogénico de los Concentrados de Complejo Protrombina • Concentrados de factor II, VII, IX y X. • Potencial trombogénico por la presencia de factores. activados en su composición. • Factores IIa, VIIa, IXa y Xa. • Efecto bypass en la cascada de la coagulación. • Eficacia en el tratamiento de pacientes hemofílicos con inhibidor. 25/04/13 16Joan M Tusell
- 17. 17 FEIBA: Sites of Action FEIBA FIX, FIXa FEIBA FVII, FVIIa FEIBA FX, FXa FEIBA FIIa FEIBA FII FEIBA FXa/FII Turecek PL et al. Vox Sang 1999; 77 (suppl 1): 72-79. PL = Phospholipids FV FVIIa FVII TF Extrinsic Pathway TF = Tissue Factor Common Pathway Leading to Clot FII FIIa (Thrombin) FVa Fibrinogen Fibrin CLOT Fibrin Polymer FXIIIa FXIII FXa FXIntrinsic Pathway FXII FXIIa FXI FXIa FIX FIXa Ca++ -PL FVIII FVIIIa FXa 25/04/13 17Joan M Tusell
- 18. Modelo clásico de la coagulación 25/04/13
- 19. Subendothelial Cell New Model of Haemostasis 3 25/04/13 19Joan M Tusell
- 20. Vision • Dr Ulla Hedner is a haematologist. • In 1972, driven by the belief that there was a better way to help people with haemophilia and inhibitors, she started work on factor VIIa. • Her discovery would go on to change the lives of people with haemophilia and inhibitors the world over. • Dr Hedner was inspired to join Novo Nordisk and is now a Senior Vice President for Research and Development. 25/04/13 20Joan M Tusell
- 21. 25/04/13 21Joan M Tusell
- 22. rVIIa. Primera experiencia. • Uso de recombinante en 1988. • Successful use of recombinant factor VIIa in a patient with severe haemophilia A during synovectomy. U Hedner. The Lancet 1988; ii: 1193 25/04/13 22Joan M Tusell
- 23. Inhibitors. Past 3,1 4,7 3,1 4,4 4 3,7 1,1 1 1,6 0,3 22,9 5,8 0,7 1,2 0,3 31,8 2,7 2 2,2 1,4 0,1 1,6 0 2,9* 7,3*7,7* 6,2*6,4*6,2* 8* 1,6*1,1* 2,7* 0 5 10 15 20 25 30 35 Knee R Knee L Ankle R Ankle L Elbow R Elbow L Shoulder R Shoulder L Hip R Hip L 6 main joints pettersson'sscore Group A Group B Group C ESOS Study: Inhibitors 15-35 y: an average of two joints severely affected. Morfini. Haemophilia 2007 25/04/13 23Joan M Tusell
- 24. Effectiveness and safety of secondary prophylaxis with rFVIIa in haemophilia patients with inhibitors: results from the pro-pact observational study. Blanchette V , Santagostino E, Morfini M, Auerswald GK, Lambert T, Jimenez-Yuste V and Young G. Journal of Thrombosis and Haemostasis a 2011 International Society on Thrombosis and Haemostasis 9 (Suppl. 2) (2011) 1–970. Page 511 Inhibitors. Secondary prophylaxis Bleeding reduction during secondary prophylaxis with bypassing agents in inhibitor patients. (FEIBA). Bruce M. Ewenstein, Wing-Yen Wong Thrombosis Research 127 (2011) 174–175 25/04/13 24Joan M Tusell
- 25. 25/04/13 25Joan M Tusell
- 26. Protocol Background Bonn •Developed in Germany in the late 1970s •Original protocol recommended very high daily doses of FVIII/FIX •Modified versions of the protocol developed for different patient groups Malmö • Intensive inpatient regimen that includes immune absorption and close medical observation developed in Sweden (Malmö University Hospital) in 1980s •Has since undergone many modifications ITI Protocol 25/04/13 26Joan M Tusell
- 27. Tratamiento de Inducción de la Inmunotolerancia. FVIII • Consiste en la administración de dosis altas y repetidas (diarias) para conseguir la depleción de la memoria de las células B. • Es un tratamiento muy costoso y muy intenso, con importante afectación de la calidad de vida de paciente y familia . • Se puede conseguir en una mayoría de los casos (65-90%) erradicar el inhibidor en un corto espacio de tiempo si se lleva a cabo precozmente (3-6-12 m). • Puede convertir de nuevo al paciente en un hemofílico candidato al tratamiento profiláctico con factor VIII. • Es considerada ampliamente como la mejor opción y es preciso llevarla a cabo lo más pronto posible para optimizar los resultados. 25/04/13 27Joan M Tusell
- 28. ITI. Estado del Arte. • Iniciar el tratamiento lo antes posible. Título < 10UB. (?) • Duración: ~6 m (3-24 m). • Eficacia: global ~75 %; casos seleccionados :~ 90 %. • Recaídas: no frecuentes, 5-10 %. • Tratamiento de elección para pacientes jóvenes en recomendaciones europeas y americanas. • Intenso debate sobre la dosis a utilizar; dosis altas diarias, dosis bajas tres veces por semana y tipo de concentrado autilizar (recombinante frente a plasmático). 25/04/13 28Joan M Tusell
- 29. Inhibitors. ITI Study. • International ITI Study. High vs low doses. • ITI success rates did not differ between treatment arms: 76% of pts reaching a study end-point became tolerant. • International prospective randomised immune tolerance (ITI) study: interinanalysis of therapeutic efficacy and safety. • C. HAY,* I . GOLDBERG,_ M. FOULKES* and D. DIMICHELE. 25/04/13 29Joan M Tusell
- 30. Success rates of Immune tolerance induction therapySuccess rates of Immune tolerance induction therapy - Hemophilia Centers Bonn and Bremen -- Hemophilia Centers Bonn and Bremen - [Auerswald G, Spranger Th, Brackmann HH; Haematologica, 2003] <1990 n=51 >1990-7/2001 n=42 Plasma-derived FVIII Recombinant FVIII (n=14) Plasma-derived FVIII (n=28) Overall success rate 87% 54% 82% Success rate (high responder >5BU) 86% 43% 78% Success rate (low responder >0,6-5BU) 93% 72% 91%
- 31. ITI at the Frankfurt Haemophilia Centre (1979-2000)ITI at the Frankfurt Haemophilia Centre (1979-2000) 88%14/16total 80%8/10Changed to pd FVIII-vWFn=10 29%4/14hp FVIII 100%2/2pd (FVIII-vWF)Patients n=16 Since 1993 91%19/21pd (FVIII-vWF)Patients [%][n/n] Success rateComplete ITIType of concentrate [Kreuz et al.; Haematologica, 2001] 1979-93
- 32. Use of FVIII/VWF for ITIUse of FVIII/VWF for ITI in inhibitor patients with poor prognostic factors*in inhibitor patients with poor prognostic factors* Author Pts [n] HR [n] Therapy regimen Product Duration [months] Outcome Gringeri et al., 2007 17 17 50IU 3x/week up to 200 IU/kg/d vWF-FVIII 24 (median) 4-30 9/17 complete success (53%) 7 partial success 1 failure / drop out Orsini et al., 2005 8 8 50-230 IU/kg BW vWF-FVIII 8 (median) 7/8 complete Suc. 1 partial success Portuguese experience 2006 7 6 200 IU/kg BW vWF-FVIII 7 (mean) 3-22 6/7 complete success Kurth et al., 2008 25 25 100-200 IU/kg BW vWF-FVIII n.a. 32% complete S 40% partial S. 8% Failure Greninger et al., 2008 11 11 200 IU/kg BW vWF-FVIII 22.75 (mdian) 7/11 complete success
- 33. ITI Study Current studies on ITI RESIST ObsITI Good prognosis patients High vs low dose regimen Poor prognostic patients (randomized rFVIII vs pdVWF/FVIII) Failures (pd VWF/FVIII) All inhibitor patients (good and poor prognosis, Bonn protocol) Study Stopped
- 34. Inhibitors: “The Problem” in Haemophilia • Since the prophylaxis, the development of inhibitors remains as the must important problem in haemophilia • Eradication: the “obsession” of haemophilia treaters – ITI. 1st attempt: Recombinant ???? 60% – ITI. 2nd attempt: Plasma derivate (50% of 40%) 20 % – 3st attempt: Immune suppression (50% of 20%) 10 % Global prevalence: 10%. Total eradicated: 90% 25/04/13 34Joan M Tusell
- 35. Futuro Esperanzador • Aparecen menos inhibidores y mejor porcentaje de erradicación por ITI. • Mejores y nuevos productos que faciliten mejores modelos de tratamiento (tratamiento agudo y profilaxis). • Persistir en la mejoría en la calidad de vida. • Reducir costes. 25/04/13 35Joan M Tusell
- 36. Presente 25/04/13 36Joan M Tusell
Notas del editor
- Inhibitors Inhibitors in persons with hemophilia A or hemophilia B are alloantibodies of the IgG class, usually subtypes IgG1 and IgG4. Inhibitors occur either in patients with congenital factor deficiencies, in which case they are alloimmune antibodies, or in previously unaffected individuals, in which case they are termed autoimmune antibodies, or acquired hemophilia.
- Inhibitors Congenital Deficiency States The prevalence of inhibitors for persons with severe FVIII deficiency has been estimated to be approximately 30% with a reported range of 10 to 50%. In individuals with severe FIX deficiency, inhibitors are mush less common with a prevalence of approximately 3 to 5%. The presence of an inhibitor is measured in the Bethesda assay and is reported in Bethesda units (BU). One BU is the amount of inhibitor that will result in a loss of 50% of factor activity when the patient’s plasma is incubated with normal plasma for 2 hours at 37 C.
- Inhibitors generally can be classified into the 3 types illustrated graphically on this slide. Patients with inhibitor assays that increase to >10 BU after some exposure to factor concentrate or who have inhibitor assays >10 BU at baseline are considered to have high-titer or high-responding inhibitors. Patients who have inhibitor assays of <10 BU that despite repeated exposure do not significantly increase when treated with factor concentrate are defined as low-titer or low-responding inhibitors. Infrequently, patients may develop transient inhibitors that spontaneously disappear and generally are of short duration. Of the hemophilia patients who develop clinically significant inhibitors, 20% to 25% have the low-responding type. Bleeding in these patients may be treated successfully with larger doses of factor concentrate, whereas treatment of bleeding episodes in patients with high-titer inhibitors poses a greater challenge.
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- Persons with low-titer inhibitors often can be treated with FVIII concentrates, either human or porcine derived. However, bypassing products typically are used as first-line treatment for bleeding episodes. These include PCCs (either “standard” or activated), APCCs, and now rFVIIa. There currently are several options available for treatment of acute hemorrhage in patients with high-responding inhibitors. Acutely, patients experiencing a limb- or life-threatening bleeding episode may be treated with FVIII concentrates, either human or porcine, if the respective human or porcine factor VIII inhibitor titer is <10 BU. However, bypassing products typically are used as first-line treatment for bleeding episodes in routine hemorrhagic episodes regardless of present inhibitor titer, or in those patients who experience limb- or life-threatening bleeding with a present human or porcine titer greater than 10 BU. These bypassing products include PCCs or their activated counterparts, APCCs (such as FEIBA ® or Autoplex ® ), and now rFVIIa (NovoSeven ® ).
- Previous models of coagulation as you can see in the slide were useful for explainig the coagulation tests, but it is known nowadays that they do not represent the phisyological process of clotting.
- FEIBA: Sites of Action Based on FEIBA components there are several sites of action along the coagulation cascade: FVIIa is not the major active component of FEIBA. FXa and FII (prothrombin) are crucial to FEIBA’s Factor VIII inhibitor bypassing activity. The complex FXa/FII binds to FVa and catalyses the conversion of prothrombin to thrombin. Thrombin formation is the keystone of clot formation. Turecek PL et al. Vox Sang 1999; 77 (suppl 1): 72-79.
- Previous models of coagulation as you can see in the slide were useful for explainig the coagulation tests, but it is known nowadays that they do not represent the phisyological process of clotting.
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- Un grupo de pacientes con inhibidor, en el campo de verano de La Charca del año 2009.