avanos em anemia falciforme_lucia silla

ESTA PALESTRA NÃO PODERÁ
SER REPRODUZIDA SEM A
REFERÊNCIA DO AUTOR.
Lucia Mariano da Rocha Silla
Faculdade de Medicina
UFRGS
Doenças Falciformes
Genotipo
Abreviatura
Características
βA/βs
HbAS
Heterozigoto – Traço Falciforme
βs/βs
HbSS
Anemia Falciforme
Fenótipo Severo
βs/βc
HbSC
Heterozigoto para HbS e HbC
Fenótipo de Gravidade Intermediária/leve
βs /β0
HbS/β0-talassemia
Heterozigoto para HbS e talassemia
Fenótipo Severo semelhante à AF
βs /β+
HbS/β+-talassemia
Fenótipo intermediário/leve
Distribuição étnica do gene S
● Aproximadamente 200,000 a
300,000 casos novos/ano de
DF na África
● Devido à migração, a
frequencia aumentou em
outras regiões
– Nos USA, 70.000 a 100.000
pessoas com DF
– Na França, 12.000-15.000
pessoas com DF e 400
RN/ano
– No Brasil 20.000-50.000
Etnia
Frequencia de traço
Asiatico
1/1336
Asia-Indiano
1/725
Afro-Americano
1/12
Hispanico
1/183
Meio Oriente
1/360
Americano
Nativo
1/176
Caucasiano
1/625
World Health Organization; Weatherall DJ & Clegg JB. The Thalassaemia Syndromes. 4th ed. Oxford, UK Blackwell Science
2001; Ashley-Koch A et al. Am J Epidemiol 2000;151:839–845; Gluckman E. Hematology 2013. ASH
Prevalência da DF no Brasil
Dados da Triagem neonatal para Doença Falciforme. 2011 e 2012
2011
UF
2012
nº Casos
DF
5
17
253
6
22
28
47
60
229
17
19
19
41
56
123
10
0
23
3
Total triados
12.408
AC
44.447
AL
190.648
BA
105.710
CE
42.323
DF
47.757
ES
75.569
GO
96.256
MA
236.512
MG
36.363
MS
36.351
MT
109.174
PA
98.580
PE
168.671
PR
156.382
RJ
26.765
RO
6.202
RR
103.734
RS
73.977
SC
27.791
SE
482.468
240
SP
Fonte: PNTN - CGSH/DAHU/SAS/MS
1 para
cada
2.500
2.500
800
17.500
2.000
1.500
1.500
1.500
1.000
2.000
2.000
5.500
2.500
3.000
1.200
2.500
4.500
25.000
2.000
Total triados
12.331
41.438
181.145
103.206
43.897
46.255
73.385
97.618
232.934
35.750
37.186
104.971
97.731
169.715
168.156
25.351
6.374
102.448
73.592
28.123
533.028
nº Casos
DF
5
13
210
26
17
18
34
55
131
8
21
31
25
211
124
5
4
12
2
29
209
1 para
cada
2.500
3.000
800
4.000
2.500
2.500
2.000
1.500
1.500
4.500
1.500
3.000
4.000
800
1.500
5.000
1.500
8.500
36.500
900
2.500
21 estados
BA
Cortesia Dra Ana Stela Goldbeck
Pathophysiology of SCD
HbS
(α2βS2)
+O2
-O2
Low oxygen tension
Polymerization of
deoxygenated HbS
Hemolysis,
anemia
Irreversibly
sickled cells
Vaso-occlusion
Micro-vascular obstruction
Acute painful ischemic episodes
Chronic progressive organ damage
Sequestration of
erythrocytes in
capillaries
Courtesy of Professor SL Thein, King's College Hospital, King's College London, London
Nitric oxide
consumption
RBC dehydration
HbS polymerization
Clustering /
alterations of
membrane proteins
Cytokine storm
(CXCL1)
ATP
Release of
haem
Adenosine
Inflamação
Sequestration of
erythrocytes in
capillaries
Exp Biol Med
Hibbert JM et al, 2005
Clinical expression of SCD
according to basal Hb level
Endothelial
dysfunction
70%
PHT, priapism, leg ulcer,
stroke
Steady-state Hb
Hyperviscosity
VOC, ACS,
ON
8 g/dL
ACS, acute chest syndrome; ON, osteonecrosis; PHT, pulmonary hypertension; VOC, vaso-occlusive crisis
Figure used with the permission of M de Montalembert
MANIFESTOES CLÍNICAS

Complicações Neurológicas









Complicações oftalmológicas





Glaucoma
Retionpatia proliferative
Hemorragia vítreo
Descolamento de retina

Cardiomegalia
Cardiomiopatia
Insuficiencia cardiaca congestive
Prolapso de válvula mitral
Hipertensao arterial


Infarto esplenico agudo
Asplenia funcional
Hiperesplenismo
Sequestro esplenico aguda
Insuficiencia renal aguda
Insuficiencia renal cronica
Hematúria
Priapismo
Síndrome Nefrótica/proteinúria
Pielonefrite
Complicações Musculoesqueléticas/pele







Colecistite
Colelitíase
Sequestro hepático
Colestase intrahepática
Hepatite viral
Complicações renais e genito-urinárias







Síndrome toráciaca aguda
Hipertensao pulmonary
Complicações hepatobiliares





Complicações esplenicas




Complicações Pulmonares


Complicações Cardíacas






Acidente Vascular Cerebral Isquemico
Acidente Vascular Cerebral hemorrágico
Aneurismas
Síndrome Moyamoya
Infarto cerebral silencioso
Isquemia cerebral transitória
Velocidade elevada no Doppler transcraniano
Crises epiléticas
Necrose avascular
Dactilite
Ulceras de pernas
Miosite/mionecrose/fasceite
Osteomielite
Osteopenia/osteoporose
Distúrbios de
crescimento/desenvolvimento

Retardo crescimento
Clinical outcomes in children with
SCD
A neonatal cohort in East London
Proportion without events
1.0
0.8
Death
Stroke
0.6
Splenic
sequestration
0.4
Dactylitis
Chest crisis
0.2
Pain
0
0
5
10
15
20
Age (years)
Kaplan-Meier curves indicating time to first event for patients with HbSS
Telfer P et al. Haematologica 2007;92:905–912
Survival of Patients in the Cooperative Study
of Sickle Cell Disease
HbF > 8,5%
SS x
Controles
SC
HbF < 8,5%
Platt O et al. N Engl J Med 1994;330:1639-1644
Causa de Morte na DF
306 autopsias
•
Morte frequentemente súbita e
inesperada (40.8%) ou
aconteceu dentro das primeiras
24hs do atendimento (28.4%)
•
Mortes usualmente associadas a
eventos agudos(63.3%)
• As primeiras 24hs
são críticas o
tratamento deve ser
agressivo com
monitoramento
contínuo.
60
50
Patients (%)
•
33–48%
40
30
20
9.8%
10
7.0%
6.6%
Therapy
complications
Splenic
sequestration
0
Adapted from Manci EA et al. Br J Haematol 2003;123:359–365
Infection
Stroke
MANEJO CLÍNICO
HU for the treatment of SCD
3.2%
2.5
2.0
1.5
P=0.002
1.0
0.5
0
Placebo
•
•
Fetal Hb (HbF) and painful crises in adult
patients with SCD after 2 years treatment with
HU
10
HU
Percentage change from baseline
Yearly hospitalization rate
3.0
Yearly hospitalization rate during
treatment with HU compared with
placebo
0
–10
–20
–30
–40
–50
–44%
%HbF
Median number of
painful crises
Adverse events associated with HU treatment include neutropenia, skin
rashes and nail changes
Barriers to the use of HU include patients’ (or parents’) perceptions of HU
efficacy and safety
Segal JB et al. Evid Rep Technol Assess (Full Rep) 2008;(165):1–95. AHRQ Publication No. 08-E007. Rockville, MD. Agency
for Healthcare Research and Quality. February 2008
NIHState-of-the-Science Conference Statement on
Hydroxyurea Treatment for Sickle Cell Disease
NIHConsensus and State-of-the-Science Statements
Volume 25, Number 1
February 25–27, 2008
Other treatment options in
development
Therapeutic approach
HU and arginine
therapy
5-deoxyazacytidine
(decitabine)
Clinical effect
Increased production of nitric oxide, a potent vasodilator1
Increase of Hb F
Low doses can elevate HbF with acceptable toxicity
Butyric acid
compounds
Increases HbF production in erythroid cells and inhibits the
proliferation of other cell types, including erythroid cells
Clotrimazole
Inhibits cation transport channels in erythrocyte membranes,
thereby reducing cellular dehydration.
May have value as an adjunct to HU therapy2
Gene therapy
Early promise demonstrated in a transgenic mouse model,
but no clinical evidence available3,4
1Morris
CR et al. J Pediatr Hematol Oncol 2003;25:629–634; 2Brugnara C. Blood Cells Mol Dis 2001;27:71–80;
3Pawliuk R et al. Science 2001;294:2368–2371; 4Wu L-C et al. Blood 2006;108:1183–1188
TCD acoustic windows
•
•
Examination of an artery by TCD is called ‘insonation’
TCD probe is placed over different ‘acoustic windows’ –
specific areas of skull where cranial bone is thin
A. Transtemporal (temporal) window
•
MCA
•
Anterior cerebral artery
•
Posterior cerebral artery
•
Terminal portion of internal carotid artery, before its
bifurcation
B. Transorbital window
•
Ophthalmic artery
•
Internal carotid artery at siphon level
C. Transforaminal (occipital) window
•
Distal vertebral arteries
•
Basilar artery
D. Submandibular window
•
More distal portions of the extracranial internal
carotid artery
Kassab MY et al. J Am Board Fam Med 2007;20:65–71; Image from: http://www.gehealthcare.com/usen/ultrasound/
products/cmetcd.html (Taken from: Katz ML. Intracranial Cerebrovascular Evaluation. In: Textbook of Diagnostic
Ultrasonography. Mosby, St. Louis, 2001)
Probability of remaining stroke
stroke-free
Stroke risk increases with TCD
ultrasound flow rate
1.0
0.9
P=0.0001
0.8
0.7
0.6
<170 cm/s
170–199 cm/s
200 cm/s
0.5
0.4
0
5
10 15 20 25
Time (months)
Adams RJ et al. Control Clin Trials 1998;19:110–129
30
35
TCD testing and transfusion
therapy: Stroke Prevention Trial in
Sickle Cell Anemia (STOP)
1934 children aged 2–16 years with SCD screened with TCD
(identical equipment in all cases)
130 with abnormal TCD (mean flow velocity in
MCA or ICA ≥200 cm/s) + no prior history of
stroke
RANDOMIZED
Ongoing transfusions to reduce HbS
concentration to <30% total Hb
(n=63)
Adams RJ et al. N Engl J Med 1998;339:5–11
Standard care
(n=67)
TCD testing and transfusion
therapy
in SCD: STOP findings
● Regular transfusions (every 3–4
weeks) reduced stroke risk in
children identified as high risk
using TCD
Children with stroke
35
30
Percentage
● After a mean follow-up of 19.6
months, there was a 92%
reduction in stroke risk in the
transfusion group compared with
the standard care group (P<0.001)
40
25
92%
difference
(P<0.001)
20
10/67 (14.9%)
15
10
5
1/63 (1.6%)
0
Transfusion
(n=63)
Adams RJ et al. N Engl J Med 1998;339:5–11
Standard care
(n=67)
TCD testing and transfusion therapy
in SCD: STOP II
Prospective, randomized, controlled, multicenter treatment trial
38 continued
chronic transfusion
therapy
79 children with SCD aged 2–
16 years:
No neurological
event
 At high risk for stroke
based on TCD findings
and had received
transfusions for ≥30
months
 TCD had normalized and
patients had no severe
MRA lesions at the start
of STOP II
41 discontinued
chronic transfusion
therapy
14 (34%) reverted
to high-risk TCD;
2 developed stroke
STOP II trial terminated 2 years early. It is not recommended to stop blood
transfusions in patients with SCD at high risk of stroke based on TCD findings
MRA, MR angiography
Adams RJ et al. N Engl J Med 2005;353:2769–2778
Hydroxyurea is less effective than transfusion
therapy at preventing secondary stroke
Incidence of secondary stroke
Percentage of patients with
secondary stroke
12
10
8
6
4
2
0
Transfusion + chelationHydroxyurea + phlebotomy
(n=66)
(n=67)
Treatment arm
Ware & Helms. Presented at ASH 2010 [Blood 2010;116(21):abst 844]
Guidelines for treatment of iron
overload in patients with SCD
NIH guidelines on ‘The management of sickle cell disease’ (2002)1 recommend that
chelation therapy (with DFO) is considered when:
• Patients have received cumulative transfusions of 120 cc packed red blood cells/kg
• Steady state serum ferritin level >1000 ng/mL
• LIC ≥7 mg Fe/g dw
UK guidelines on ‘Standards for the Clinical Care of Adults with Sickle Cell Disease’
(2008)2 recommend that chelation therapy (with DFO or deferasirox) is considered
when:
• Patients have received at least 20 top-up transfusions
• LIC ≥7 mg Fe/g dw
1NIH
Publication No 02-2117. NIH, Bethesda, MD, USA, http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf;
Cell Society, UK 2008. Available at: http://www.sicklecellsociety.org/pdf/CareBook.pdf
2Sickle
Tipos de Tranplante de Células Tronco
Hematopoéticas
Autólogo
Singênico
aparentado
Alogênico
não aparentado
Haploidêntico
Identidade HLA
Cromossoma 6
D
B
C
A
– 1/4 irmãos
– 1/10.000 familiares
– 1/100.000 não familiares
Pitombeira B, 2010
Fontes de células tronco
?
Pitombeira B, 2010
6.9%
1 sepsis, 1 hemorragia SNC, 4 GVHD
c/ATG – 2.90%
7
s/ATG – 22.6%
Epoca do TCTH
86.1%
95.3%
76.7%
● 20% de DECHa
● DECHa predominou nos maiores de 15 anos (P
.003).
● cGVHD em 12.6%.
• Leve a moderada em 9 pacientes (11%)
• Grave em 2 pacientes (2.4%)
TMO em DF: França
•
N= 144 pacientes
– 84M; 60F
•
•
Mediana de Idade: 9 anos
Indicações
–
–
–
–
–
–
•
Vasculopatia cerebral (89)
CVO frequentes (41)
Osteonecrose (7)
Aloimunização (4)
Hipertensão Pulmonar (1)
Leucemia (2)
Condicionamento: BuCy ATG
Fonte CTH
–
–
–
–
MO (121)
CB (21)
CTHP (1)
MO+CB (1)
Mediana Tempo Seguimento
3.1 anos (0.2-15.5)
F. Bernaudin et al, EBMT 2011 #396
TMO em DF: França
144 pacientes
F. Bernaudin et al, EBMT 2011 #396
E. Gluckman
Hematology 2013 - ASH
TCTH de intensidade reduzida
série de casos menores
risco elevado de rejeição
EXPERIMENTAL
Celula tronco do sangue
periférico de individuos AS
DOADOR IRMÃO
Abboud M, Laver J, Blau CA. Granulocytosis causing sicklesickle-cell crisis [letter].
Lancet. 1998; 351(9107):959.
Adler BK, Salzman DE, Carabasi MH, Vaughan WP, Reddy VV, Prchal JT. Fatal
sickle cell crisis after granulocyte colonycolony-stimulating factor
administration. Blood. 2001;97(10):3313-3314.
Grigg AP. Granulocyte colonycolony-stimulating factor induced sickle cell crisis and
multiorgan dysfunction in a patient with compound heterozygous sickle
cell/beta thalassemia.
thalassemia Blood. 2001;97(12):3998-3999.
Fitzhugh CD, Hsieh MM, Bolan CD, Saenz C, Tisdale JF. Granulocyte colonycolonystimulating factor (G(G-CSF) administration in individuals with sickle cell
disease: time for a moratorium? Cytotherapy.2009;11(4):464-471.
Célula tronco de cordão ubilical
aparentado e não aparentado
TMO com CTH de cordão
Cordão Relacionado
N=44 pacientes
11 doenças falciformes
Mediana Idade 5 anos
Mediana Seguimento 24 meses
Perda do Enxerto
1 paciente com DF
7 pacientes com Talassemia
SLE: 79% Talassemia
90% Doenças Falciformes
Locatelli F et al, Blood 2003
TMO com CTH de cordão
Cordão Não Relacionado
N=51 pacientes
16 doenças falciformes
Mediana Idade 6 anos
Mediana Seguimento 24 meses
SLD: 21% Talassemia
50% Doenças Falciformes
SG: 62% Talassemia
94% Doenças Falciformes
MRT 1p
Ruggeri A et al, Blood 2011
Indicações TMO
Protocolo Brasileiro
Órgão
Algum dos achados abaixo
Idade
Qualquer Idade
Crises Vasoclusivas
a.
b.
Duas STA nos 2 anos antes de entrar no estudo
> 3episódios de dor intensa/ano nos 2 anos antes de entrar no estudo
SNC
a.
b.
c.
Evento neurológico significativo (AVC ou déficit neurológico> 24hs)
Achado neurológico
DTC > 200 cm/seg (2x)
Dano orgânico
a.
b.
c.
d.
e.
Pneumopatia falciforme graus I ou II
Hipertensão Pulmonar
TFG 30 a 50% do esperado
Osteonecrose de múltiplas articulações
Retinopatia proliferativa
Aloimunização
> 2 anticorpos em esquema transfusão crônica
Hidroxiurea
Redução < 50% das crises álgicas com HU ou intolerância à HU
TMO em DF no Brasil
•
N=16 pacientes
– 17 transplantes
•
Idade mediana 15,5 anos (7 a 39 anos)
– Idade mediana casos Ribeirão Preto : 20 anos
•
•
Tempo seguimento mediana 23 meses (25 dias a 12 anos)
Indicações Principais
–
–
–
–
–
•
AVC
Priapismo
Crises Vasoclusivas
Alosensibilização
DTC alterado
Condicionamento
– Fludarabina e Bussulfan 12 mg/kg (Ribeirão Preto)
– Fludarabina e Ciclofosfamida (2 casos)
– Bussulfan e Ciclofosfamida
TMO em DF no Brasil
Controle Populacional
•
•
•
•
•
Doença hereditária
Identificação do heterozigoto
Aconselhamento genético
Diagnóstico pré-natal
Seleção de embriões
[email protected]
Obrigada!