Hemofilia consideraii practice i opiuni actuale de management

Hemofilia consideraii practice i opiuni actuale de managementDr. Adriana DiaconuClinica de Pediatrie, Institutul Clinic Fundeni, Bucureti1

PERETE VASCULAR INTEGRU

PERETE VASCULAR LEZAT

HEMOSTAZA PRIMARA FORMAREA CHEAGULUI

HEMOSTAZA SECUNDARA STABILIZAREA CHEAGULUI RETEAUA DE FIBRINA

DefiniieHemofilia:- afeciune hemoragic congenital X-linkat- Hemofilie A: deficit de factor VIII- Hemofilie B: deficit de factor IX

Prevalena:- hemofilie A: 1 caz la 5 000 de biei nscui- hemofilie B: 1 caz la 30 000 de biei nscui

Hemofilia A este mai frecvent dect Hemofilia B, reprezentnd 80-85% din totalul cazurilor de hemofilie. 1. Franchini and Mannucci ,Orphanet Journal of Rare Diseases 2012: 7-24; 2. WFH Guidelines for the management of hemophilia 2012, 2nd Edition, available at http://www.wfh.org, accesat la 07 Iulie 2014 8FIZIOPATOLOGIE (1)Hemofilii congenitale

Ambele gene pentru F VIII si F IX sunt localizate pe bratul lung al cr X (coagulopatii X-linkate )Gena pentru F VIII (F8C): regiunea Xq28~ 186 kb din cr XAlcatuita din 26 exoni si 25 introniF VIII matur contine 2332 aa40% din formele severe: inversie 50-60% : deletii, insertii, mutatii punctiforme

FIZIOPATOLOGIE (2)

Gena pentru F IX: localizata in regiunea X q27 ~ 34 kb din cr X Alcatuita din 8 exoni si 7 secvente F IX matur contine 415 aa mutatii frecvente: deletii si mutatii punctiforme

Expresia clinic

Expresia clinic complet a bolii este ntalnit exclusiv la biei, care dispun de 1 singur cr X

Un tat hemofilic are bieii sntoi i toate fetele purttoare

Fetele heterozigote pot transmite boala la descendenii de sex M (risc de 50% la fiecare sarcin)

CLINICA: Generaliti

Debutul depinde de concentraia factorului incriminat formele severe:

postnatal, niciodat la secionarea CO (foarte bogat n tromboplastin tisular)cderea COvaccinriprimele cderi (copilul ncepe s mearg)erupie / schimbarea dentiiei

CLINICACaracteristicile hemoragiilor, indiferent de localizare:

Sunt provocate (uneori la traumatisme mici, nesesizate, puncii, injecii)Nu se nsoesc niciodat de purpurSunt profundeApar tardiv dup traumatism sau postoperator i sunt prelungiteSunt greu de controlatAu tendina la recidiv

LOCALIZARE HEMORAGIIMANIFESTARIcutanate / subcutanateEchimoze, hematoame mucoaseEpistaxis, gingivoragii, hemoragii alveolare musculareHematomul m.psoas sau retroperitoneal este caracteristic (10-15%)

spaiile celularePlaneul bucal, hemoragii retroorbitare, hematoame cervicale, perineale

visceraleHematurie macroscopic, hemoragii intestinale, peritoneale,hematemez, hemotorax, hemoptiziiHemoragii retiniene/choroidiene/labirinticeLa niv.SNC (meningeale, cerebrale): = adesea cauz de deces a hemofilicilor

seroase articulare hemartroze 90%CLINICA

6. Hemoragiile la nivelul seroaselor articulare = hemartrozele 90%

Afecteaz predominant articulaiile mari (genunchi, coate, maleol, pumn, old)Pot fi provocate de un traumatism uor (un drum lung / efort simplu)Caracteristic: tendina la recidivEvoluie: hemartroza pur artropatia hemofilic anchiloza articularManifestri clinice hemoragice Episoade hemoragice severe: HemartrozeHemoragii musculare sau la nivelul membranelor mucoaseEpisoade hemoragice amenintoare de via: Hemoragii cerebrale (Incidena hemoragiei intracraniene a fost de 5 ori mai mare la pacienii cu hemofilie comparativ cu populaia fr hemofilie )Hemoragii cu localizare la nivelul gtului, laringe Hemoragii gastrointestinaleLocalizarea hemoragiilorFrecvena (%)Hemartroze70-80Hemoragii musculare10-20Alte hemoragii majore5-10Hemoragii SNC 5 UB = titru ( >10 UB neutralizeaza eficacitatea terapiei substitutive cu F)

Inhibitori = Anticorpi Anti Factor de coagulare VIII / IXAnticorpi tip IgG (la 36% din pacientii cu HA)

1 UB neutralizeaz 50% activitate F

Low responder: I < 5UB, fr rspuns anamnestic la expuneri repetate F ( = 25-50% din totalul pac cu inhibitori, 10% fiind tranzitorii)

High responder:I > 5 UBI < 5UB, dar cu rspuns anamnestic la exp.repetate F ( titrul I)!In absena expunerii la F VIII, titrul inhibitorilor poate nedetectabil: la reexpunerea de F VIII, titrul in 4-7 zile = rspuns anamnestic Cand dozam inhibitorii?In perioada primelor 50 de administrari

Screening regulat inainte de proceduri invazive

Pt pacientii care au primit 150 zile terapie, riscul de aparitie a inhibitorilor semnificativ: screening anual

Tratamentul episoadelor hemoragice :Creterea dozei de FVIII Ageni de by-passing

ITI (inducerea toleranei imune) cu scopul de eliminare a inhibitorilor Optiuni terapeutice la pacienii cu inhibitori anti-FVIII1.DiMichele D. Haemophilia. 2002;8:280-287. 2.DiMichele D, et al. Haemophilia. 2004;10(suppl 4):140-145.

FVIII InhibitorsNeutralizing alloantibodies (inhibitors) directed at FVIII develop in approximately 20% to 30% of patients with severe hemophilia, and in 10% to 15% of all patients regardless of severity who are exposed to exogenous FVIII replacement therapy. Inhibitors are typically detectable within the first 30 FVIII replacement exposure days.Most FVIII inhibitors belong to the IgG4 subclass.In approximately 60% of patients, there are 2 or 3 major inhibitor binding sites on the FVIII molecule.Antibody titers are measured in Bethesda units (BU), and inhibitor responses are classified as low (5 BU) based upon the peak titer achieved which often characterizes their anamnestic response upon re-exposure.Low responding: 5 BU at anytime, regardless of present titerScandella D. Human anti-factor VIII antibodies: epitope localization and inhibitory function. Vox Sang. 1996;70(suppl 1):9-14.Scandella DH. Properties of anti-factor VIII inhibitor antibodies in hemophilia A patients. Semin ThrombHemost. 2000;26:137-142.Algoritm terapeutic in Hemofilia cu inhibitoriTitru InhibitoriSeveritatea sangerariiTratament recomandatLow responder (5 UB)

Minora / Majora

F rVIIa, CCP sau CCPa

Inducerea imunotolerantei (ITI)ProtocolF VIIIAsociere medicatieDoza mare (High dose)Bonn

100-150 UI/kg x 2/zi, zilnic

+ CCPaDoza intermediaraKasper/ Ewing50-100 UI/kg/zi, zilnic+ PDN p.o.Unuvar50-100 UI/kg/zi, apoi25 UI/kg/zi, zilnicDoza mica (Low Dose)Dutch25 UI/kg/zi, alternativImplicaii ale dezvoltrii inhibitorilorPrezena inhibitorilor poate:Ricul hemoragiilor incontrolabile1Riscurile de invaliditate (ex. artropatie)1,2, nevoia de dispozitive pentru mobilitate asistat i chirurgie ortopedicCosturile de tratament2,3

calitatea vieii4,51.Ingerslev J et al. Haemostasis. 1996;26(suppl 1):118-123; 2. Dimichele D. Haemophilia. 2004; 10(suppl 4):140-145; 3. Nerich V, et al. Pharm World Sci 2008;30: 287-92; 4. Colowick AB et al. Blood. 2000;96:1698-1702; 5. Leissinger CA. Haemophilia. 1999; 5(suppl 3):25-32.53ConcluziiHemofilia este o afeciune hemoragic congenital X-linkat datorat deficitului de factor VIII (Hemofilia A) sau factor IX (Hemofilia B) de coagulare.

Hemartrozele recurente la nivelul aceleiai articulaii pot cauza distrugerea articular

Tratamentul profilactic scade numrul episoadelor hemoragice, reduce afectarea articular i mbuntete calitatea vieii pacienilor

1. Franchini and Mannucci ,Orphanet Journal of Rare Diseases 2012: 7-24; 2. WFH Guidelines for the management of hemophilia 2012, 2nd Edition, available at http://www.wfh.org, accesat la 07 Iulie 2014 ; 3. Pergantou H et al. Haemophilia. 2006;12(3):241-247; 4. Dhillon S Drugs 2012; 72(7):987-1007

ReferencesManco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe haemophilia. N Engl J Med. 2007;357(6):535-544.Gringeri A, Lundin B, von Mackensen S, Mantovani L, Mannucci PM. A randomized clinical trial of prophylaxis in children with haemophilia A (the ESPRIT Study). J Thromb Haemost. 2011;9(4):700-710.Manco-Johnson MJ, Kempton CL, Reding MT, et al. Randomized, Controlled, Parallel-Group Trial of Routine Prophylaxis Versus On-Demand Treatment With rFVIII-FS in Adults With Severe Haemophilia A (SPINART). J Thromb Haemost. 2013.US National Hemophilia Foundation. MASAC [Medical and Scientific Advisory Council] Recommendation 179. MASAC recommendation concerning prophylaxis (regular administration of clotting factor concentrate to prevent bleeding). Adopted November 4, 2007. Available at: http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=57&contentid=1007; accessed June 1, 2013.Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of haemophilia. Haemophilia. 2013;19(1):e1-47.Berntorp E, Boulyjenkov V, Brettler D. Modern treatment of haemophilia. Bull World Health Organ.1995;73:691-701.Kasper CK. Diagnosis and management of inhibitors to factors VIII and IX. An introductory discussion for physicians. Treatment of Hemophilia Monograph Series, no. 34. Published September 2004. Available at: www.wfh.org/2/docs/.../Inhibitors/TOH-34_English_Inhibitors.pdf.Leissinger CA. Use of prothrombin complex concentrates and activated prothrombin complex concentrates as prophylactic therapy in haemophilia patients with inhibitors. Haemophilia. 1999;5(suppl 3):25-32.Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors.N Engl J Med. 2011;365(18):1684-92. Gringeri A, Leissinger C, Cortesi PA, et al. Health-related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: results from the Pro-FEIBA study. Haemophilia. Published online April 14, 2013; DOI:10.1111/hae.12178.Antunes SV, Tangada S, Stasyshyn O, et al. Randomised comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia. Published online August 1, 2013; DOI:10.1111/hae.12246.54