Transcript Diapositiva 1

Aplastic Anemia
Fanconi Anemia
NPH
Severe Aplastic Anemia (SAA)
• Pancytopenia caused by hypoplasia of the
marrow
• May be congenital or acquired
• Incidence: 2 new cases / million population /
year
• In 50% of acquired forms no cause can be
found
• The response to IS therapy (ATG, CSA)
suggests an immune mechanism may be
involved
Drugs & Chemicals associated with SAA
• Agents that regularly produce marrow depression as
major toxicity in commonly used doses or normal
exposures
• Cytotoxic drugs used in cancer chemotherapy
• Benzene
• Agents probably associated with SAA but with a low
probability relative to their use
• Chloramphenicol, insecticides
• Non steroidal antiinflammatory drugs
• Anticonvulsants, Gold salts, sulfonamides, estrogens
• Agents more rarely associated with SAA
• Antibiotics (streptomycin, tetracycline, bactrim)
• Antihistamines, sedatives, allopurinol, lithium
Ionizing radiation
• SAA has been reported after exposure io
radiation due to:
• Nuclear bomb explosion
• Radioactive fallout
• Medical or occupational exposure
• SAA is observed at total body exposures
between 1.0 and 2.5 Gy
• LD50 is observed at 4.5 Gy
• 100% mortality in the range of 10 Gy
Viruses
• Antecedent Acute hepatitis has been noted in 2-5%
of SAA. Aplasia occurs 2 months after the acute
episode
• EBV, CMV, HIV
• Viruses may be directly cytotoxic to bone marrow
cells or alternatively, may stimulate an immune
response against those cells
• Infection of BM stromal cells has also been
postulated to compromise the BM microenvironment
Pathophysiology (I)
• Quantitative stem cell defect
– LTIC and CD34+ cells are reduced
– 50% of matched BMT works without conditioning
• Qualitative stem cell defect
– increased incidence of late clonal dosorders
(MDS, Acute Leukemia)
• BM Stroma defect
– Abnormal adipocyte proliferation
– However, after BMT, most stromal cells remain of
host origin and adequately support the donor’s
stem cells
Pathophysiology (II)
• Immune suppression of hematopoiesis
– AA responds to ATG, CSA treatment
– Patient’s BM cells inhibit normal BM
colony formation (serum??)
– Lymphocyte infiltration of aplastic BM
Clinical Features
• Anemia
• Fatigue, lack of energy, shortness of breath,
angina secondary to anemia, excessive sleep
• Bleeding is an alarming symptom
• Gum oozing, hepistaxis, easy bruising
• Heavy menstrual flow or menorrhagia
• Serious Infections is unusual early in
the course of disease
Classification of Aplastic
Anemia by counts
SAA. Hemorrhages
• Petechiae are usually
located over
dependent surfaces,
oropharynx, palate.
• Petechiae of the
mucosa are the most
common oral
manifestations
SAA. Hemorrhages
• Retinal hemorrhages in
a patients with SAA and
profound
thrombocytopenia
(1 x 109/l)
• Spontaneous mucosal
hemorrhages in a 10-y
old boy with Fanconi
anemia (PLT <5x109/l)
• Spontaneous facial
ecchymoses in pt with
undetectable platelets
in PB
SAA. Infections
• Ulceration of the buccal
mucosa associated with
severe neutropenia
(<500 x 109/l)
• Raised, erythematous
skin nodule from
infection with candida
albicans, which was
also present in the
bloodstream
Diagnosis
•
•
•
•
•
Anemia (Hb<7 gr/dl, MCV 95-110 fl)
Granulocyte count below 0.5 x 109/L
Platelet count below 20 x 109/L
Absolute reticulocyte count ≤ 40 x 109/L
BM biopsy must contain <25% of the
normal cellularity
• BM Cytogenetics are normal
• EPO levels are usually increased
• Iron and ferritinemia are increased
Normal bone marrow
Aplastic bone marrow
Bone marrow
• Bone marrow biopsy
shows the
characteristic
hypocellularity.
• The few cellular
elements are
comprised primarly of
lymphocytes
Differential Diagnosis
Differential Diagnosis
SAA and Thymoma
• SAA may appear in
conjunction with thymoma
• Upper mediastinal CT scan
shows a thymoma as
retrosternal mass of
irregular outline in a 62-yr
old man with myastenia and
PRCA.
• Section of thymoma
showing spindle cells and
epithelial cells
Terapia
• Generica:
– Terapia anti-infettiva (contro batteri e funghi)
– Ricovero in camera a pressione positiva
• Specifica:
– Se secondaria: rimozione patologia di base
– Se idiopatica : dipende dall’età
Algoritmo Terapeutico
< 50
> 50
Tipizzazione HLA immediata
Donatore HLA
identico
SI
CSA, ATG
NO
Risposta
HSCT +/condizionamento
NO
HSCT da
Donatore
alternativo
SI
Overall Survival
Age > 20
N > 200
Age < 20
N < 200
Fanconi Anemia
•
•
•
•
•
•
Autosomal recessive disease
The mean age at Dx is 7 to 9 yrs
75% diagnosed between 4 and 14 yrs
Similar frequencies in both genders
No ethnic restriction
Is genetically heterogeneous with 8
different complementation groups
• 10% develop acute myeloid leukemia
Anemia di Fanconi:
gruppi e geni identificati
Gruppo
Gene
identificato
Frequenza
(%)
Localizzazione
cromosomica
FA-A
FA-C
FANCA
FANCC
66
12
16q24.3
9q22.3
FA-D1
FA-D2
BRCA2
FANCD2
<1
<1
13q12-13
3p25.3
FA-E
FA-F
FA-G
FANCE
FANCF
FANCG
4
4
12
6p21.3
11p15
9p13
FA-L
FANCL
<1
2p16
malformazioni congenite più frequenti
Tipo di malformazione
Pigmentazione cutanea (macchie caffè-latte, iper- e ipo-pigmentazione)
Frequenza
(%)
60-70
Ritardo di crescita (bassa statura)
65
Alterazioni del radio e del pollice
60-70
Anomalie apparato genito-urinario
50-57
Anomalie oculari (microftalmia)
35-45
Alterazioni gastrointestinali (atresia esofago, duodeno o ano)
10-15
Diagnosis
• The underlying problem seems to be
defective DNA repair
• Cells from FA have an high frequency of
spontaneous chromosomal breakage
• Increased chromosomal fragility is
enhanced in the presence of DNA
clastogenic agents :
– Mitomycin C (MMC)
– Diepoxybutane (DEB)
Emoglobinuria Parossistica Notturna. EPN
• Anemia emolitica acquisita da difetto intrinseco
– Coesistono GR monoclonali patologici e GR policlonali normali
• Rara (1/100.000 abitanti), colipsce adulti (40 a)
• Clinicamente caratterizzata da:
– Emolisi cronica con tipiche crisi notturne di emoglobinuria
macroscopica
– Tendenza alla trombosi venosa
– Associazione con aplasia midollare severa
• Patogenesi:
– Malattia della cellula staminale determinata dalla mutazione del
gene PIG-A coinvolto nella sintesi del legame fosfatidil-inositolo,
attraverso il quale proteine di superficie si ancorano alla
membrana eritrocitaria.
Complement regulatory proteins on
normal erythrocytes
GPI-anchored proteins
Transmembrane protein
DAF
MIRL
CR1
Membrane
Lipid
Bilayer
CR1: complement receptor 1 (CD35)
DAF: decay accelerating factor (CD55)
MIRL: membrane inhibitor of reactive lysis (CD59)
GPI: glycosylphosphatidylinositol
Ethanolamine
Glucosamine
Mannose
20% to 50% dei
pazienti con SAA
hanno il fenotipo
della EPN al
citofluorimetro
DAF: decay-activating factor (CD55)
MIRL: membrane inhibitor reactive lysis (CD59)