bone marrow failure/ aplastic anemia dr. mervat a.hesham 2008
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Bone Marrow Failure/ Bone Marrow Failure/ Aplastic AnemiaAplastic Anemia
Bone Marrow Failure/ Bone Marrow Failure/ Aplastic AnemiaAplastic Anemia
Dr. MERVAT A.HESHAMDr. MERVAT A.HESHAM
20082008
What is Aplastic Anemia?
Aplastic Anemia is a bone marrow failure disease.
Bone marrow is a Factory of Blood Cells
Red Blood Cell
White Blood Cell
Platelets
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Aplastic Anemia patients
•Aplastic Anemia patients have decreased amounts of:- Red Blood Cells
-White Blood Cells -Platelets
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Functions of Blood Cells
Red Blood CellsCarry oxygen to all body organsWhite Blood CellsFight infection and keep you healthyPlateletsHelp control bleeding
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Symptoms
Low Red Blood CellFatigue, Headache, Inability to ConcentrateLow White Blood CellViral Infections, Bacterial InfectionsLow PlateletsEasy Bruising, Nosebleeds, Petichiae
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DEFINITIONA disorder of the hemtopoietic system characterized by:Bone marrow - marked reduction of all 3 cell lines
Peripheral blood - pancytopenia
PATHOGENESISStem cell failure resulting from:
1-An acquired intrinsic stem cell defect
2-An environmental cause Immune mechanisms
Growth factor deficiency
Defects in the microenvironment
EpidemiologyIncidence: 5-10:106 per year
Age: 15 –30 years > 60 years
Sex: M = F
Etiology
Hereditary
1-Schwacman – Diamond
2-Fanconi’s anemia syndrome
3-Dyskeratosis congenita
Acquired1-Idiopathic
2 -Drugs: dose relatedidiosyncratic
3-Radiation 4-Chemicals
5-Viruses6-Pregnancy
7-PNH8-Disorders of immune
system
Clinical manifestations
Insidious onsetManifestations caused by pancytopeniaAnemia - weakness, fatigueThrombocytopenia – bleedingNeutropenia - infections
Diagnosis
Peripheral blood*Pancytopenia
*Normocytic-normochromic anemia
*Low reticulocyte index
Bone marrow biopsy
*Empty fatty spaces
*Few hematopoietic cells
*Lymphocytes and plasma cells
Bone Marrow FailureCongenital/ SyndromicAcquired
Acquired Aplastic Acquired Aplastic AnemiaAnemia
Acquired Aplastic Acquired Aplastic AnemiaAnemia
Acquired Aplastic Anemia
**Secondary
**Idiopathic
Secondary AA1-Meds/ toxins
Chemo Chloramphenicol, benzene,
carbamazapine, indomethacin, cimetidine, sulfas, acetazolamide, lithium
2 -Radiation3-Viruses - EBV, HIV, parvo, hepatitis
4-Paroxysmal Nocturnal Hemoglobinurea
5-Malnutrition6-Myelodysplastic syndromes
7-Thymoma
PATHOPHYSIOLOGYDirect toxic injury to hematopoietic stem cells can be induced by exposure toionizing radiation, cytotoxic chemotherapy, or benzene. These agents can crosslinkDNA and induce DNA strand breaks leading to inhibition of DNA and RNA synthesis.
2-Immune-mediated destruction of hematopoietic stem cells
--Direct killing of the stem cells has been hypothesized to occur via interations between Fas ligand expressed on the T-cells and Fas (CD95) present on the stem cells, which triggers programmed cell death (apoptosis) .
--T-lymphocytes also may suppress stem cell proliferation by elaborating soluble factors including interferon-γ.
-T cells from aplastic anemia patients secrete IFN-ã and tumor necrosis factor (TNF).
-IFN-ã and TNF are potent inhibitors of both early and late hematopoietic progenitor cells.
-Both of these cytokines suppress hematopoiesis by their effects on the mitotic cycle and, more importantly, by the mechanism of cell killing .
-Activation of the Fas receptor on the hematopoietic stem cell by the Fas ligand present on the lymphocytes leads to apoptosis of the targeted hematopoietic progenitor
cells.
*Cytotoxic T cells also secrete interleukin-2 (IL-2), which causes polyclonal expansion of the T cells.
*IFN-ã also induces the production of the toxic gas nitric oxide, diffusion of which causes additional toxic effects on the
hematopoietic progenitor cells .
Young NEJM 1997
Suppress proliferation
with ligand, signals apoptosis
Idiopathic AA*70% or more of cases
Higher in SE AsiaM = F
AA - Clinical **Symptoms are due to pancytopenia:
pallor, mucosal bleeding, ecchymoses, or petechiae and bacterial or fungal
infections.. **Hepatosplenomegaly and
lymphadenopathy do not occur; their presence suggestsan underlying leukemia.
**Hyperplastic gingivitis is also a symptom of aplastic anemia.
AA - LabsNo RBC = pale, tachycardicNo plt = bruising, bleedingNo WBC = infectionRetic < 1%Plt < 20,000ANC < 500
AA - LabsMarrow : < 25% cellularity
AA - Evaluation*CBC w/ diff and retic
*Bone marrow
*Send DEB (Fanconi’s test)*Send Hep A, B, C, D titers HIV
*Test for PNH (CD55, CD59)*HLA typing
*Fetal hemoglobin*Liver and renal function chemistries
*Quantitative immunoglobulins, C3,
C4, and complement. *Autoimmune disease evaluation:
Antinuclear antibody (ANA), total hemolytic complement (CH50), Coombs’ test.
*HLA typing: Patient and family done at the time of diagnosis of severe aplastic anemia to ensure a timely transplant.
CLASSIFICATIONDesignationDesignationCriteriaCriteria
Peripheral bloodBM biopsy
Severe aplastic anemia
-2 / 3 values-Neutrophils > 500/L
-Platelets > 20,000/ ul--Reticulocyte index >
1%
-Marked hypocellular > 25% cellularity
-Moderate hypocellular >25-50%
-normal cellularity with >30% of remaining cell hematopoietic
Very severe aplastic anemia
As above but neutrophils > 200/LInfection present
Treatment Options
Bone Marrow Transplant
GrowthHormones
Immune SuppressiveTherapy
Supportive Care
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TREATMENT1-Withdrawal of the etiologic agent
2-Supportive treatmentBlood and platelet transfusion used with caution- sensitization (filtered)
3-Allogeneic BMT- Preferably from sibling
- Curative in 60-90% of patients- Applicable only for a third of patients
*Immunosuppression Cyclosporin + ATG
Corticosteroids High dose cyclophosphamide
*G-CSF/ GM-CSF/ EPO - maybe** Response rate 50-70% Occurs 2-3 months
post Rx.
AANewer
*Mycophenolate mofetil (MMF) - cytotoxic to T cells
*Monoclonal Ab against IL-2 receptor which is present on activated lymphocytes
AA - Outcomes
Age, Younger is betterBMT
<20 yr with a sib… 75%20 - 40 yr with a sib…60%
<20 yr unrelated BMT… 40%20 - 40 yr unrelated BMT…35%
Immunosuppression - 60 - 80%But for how long and consequences…
Fanconi AnemiaFanconi AnemiaFanconi AnemiaFanconi Anemia
History: Guido FanconiFanconi Anemia (Fanconi pancytopenia syndrome): 1927 - 3 brothers with pancytopenia and physical abnormalities, “perniziosiforme”
Fanconi Syndrome (renal Fanconi syndrome): 1936 – Ricketts, growth retardation, proteinuria, glucosuria, and proximal renal tubular acidosis
Alter, FA101 (2006)
Fanconi Anemia (FA)Rare (< 1/ 100,000 births)Autosomal recessiveMany physical featuresBut up to 20-25% will have no physical findings
Mean age at dx 7.8 yrs
Autosomal Recessive Autosomal Recessive InheritanceInheritance
FA- Clinical
Abnormality %of FA Patients
Skin60%
Short Stature57%
Upper Limb Abnl48%
Head/ Microcephaly27%
Renal23%
Dev. Delay13%
None Reported20%
Short Stature Only1%
Skin Only3%
Progressive bone marrow failure Most common etiology of inherited bone marrow failureOthers include dykeratosis congenita, amegakaryocytic thrombocytopenia, Schwachman-Diamond syndrome
Increased risk of MDS and AML (15,000x)Many have monosomy 7, or duplication of 1q (Auerbach et al., Cancer Genet Cytogenet 1991)
Clinical Features
Clinical FeaturesIncreased risk of solid tumor formation (hepatic, esophageal, oropharyngeal, vulvar)Average age at diagnosis is 23*
Cumulative incidence ~30% by age 45**
*Shimamura et al., Gene Reviews 2002 (genetests.org)**Alter et al. Blood 2003
FA - geneticsIdentification of subtypes (compliment groups)A, B, C, D1, D2, E, F, GIdentical clinicallySub-units of a common protein/ common pathway
Protein modifies FANCD2FANCD2 interacts with BRCA1 and 2BRCA1 and 2 needed for DNA repair
PATHOPHYSIOLOGYDNA damage activates a complex consisting of Fanconi proteins A, C, G, and F. This in turn leads to the modification of the FANCD2 protein. This protein interacts, for example, with the breast cancer susceptibility gene BRCA1.
*Fanconi anemia cells are characterized by hypersensitivity to chromosomal breakage as well as hypersensitivity to G2/M cell cycle arrest induced by DNA cross-linking agents.
* In addition there is sensitivity to oxygen-free radicals and to ionizingradiation.
Diagnosis*-Pts. with congenital abnormalities are
often diagnosed as neonates/infants*Others may be diagnosed when
hematological problems occur*Median age of onset of pancytopenia is 7
Usually normal CBC at birth*First develop macrocytosis, then
thrombocytopenia, and eventually neutropenia
DiagnosisBased on chromosomal hypersensitivity to cross-linking agentsChromosome fragility test: Mitomycin C (MMC) or diepoxybutane (DEB) added to lymphoctyes – increases the number of chromosome breaks and radial structuresVery specific for FA, regardless of severity of diseaseCan do chromosome breakage analysis on amniotic cells, chorionic villus cells or fetal blood
FA cells were treated with mitomycin C and harvested in metaphase. Typical abnormalities include radial formation (green circle) and chromosome breaks (red arrows).
Initial managementRefer for genetic counselingTesting of siblingsRenal ultrasound, hearing test, eye examEndocrine evaluation if evidence of growth failure (check growth hormone levels, TSH)Referral to hand surgeon for radial ray defects Bone marrow biopsy
Management•Bone marrow failure
–Transfusions–Androgens (e.g. oral oxymethalone) – can improve
blood counts in 50% of pts.•Side effects: Masculinization, acne, hyperactivity,
premature closure of epiphyses, liver toxicity, hepatic adenomas
–Growth factors (G-CSF, CM-CSF) – should not be used in patients with clonal cytogenetic abnormalities
–Bone marrow transplantation•FA cells are very sensitive to radiation and alkylating
agents – can use greatly reduced doses •2-yr. survival 70% for allo;* 20-40% for MUD**
*Guardiola et al. Bone Marrow Transplant 1998;**MacMillan et al., Br J Haematol 2000
Management - Gene therapy
*Goal is to permanently correct hematological manifestations by transducing hematopoietic progenitor cells with a vector containing the deficient gene
*Knockout mice with FANCC using retroviral vectors - phenotypic correction (Gush et al., Blood 2000)
*Knockout mice with FANCA and FANCC using lentiviral vectors – more promising (integrates into the genome) (Galimi et al. Blood 2002)
Other Congenital Marrow Failures
Dystkeratosis CongenitaRareDifferent modes of inheritanceEctodermal dysplasia
50% develop aplastic anemia in midteens
Schwachman-DiamondCartilage-Hair HypoplasiaFamilial Marrow Dysfunction
Marrow Failure
Pearson’s syndromeSeckel’s syndromeAmegakaryocytic ThrombocytopeniaNoonan’s syndrome
Marrow FailureSingle Cytopenias
-Pure Red Cell Aplasia (Diamond-Backfan)
-Congenital Neutropenia (Kostmann’s) -Thrombocytopenia with Absent
Radii
Definition
A syndrome characterized by
Normocytic normochromic anemia
Reticulocytopenia <1%
BM erythroblasts < 0.5%
Aplasia selective to erythroid cell line
only!
EpidemiologyRelatively uncommonMay affect any age group but predominantly ofinfancy and childhood
M=F
No ethnic predisposition
Of autosomal dominant inheritance
Etiology & Pathogenesis
Congenital hypoplastic
anemia
)Diamond-Blackfan syndrome(
Acquired PRCA
Primary
Secondary
PrimaryPrimaryAutoimmunePreleukemicIdiopathic
SecondarySecondaryThymoma
Hematologic malignanciesSolid tumors
InfectionsChronic hemolytic anemiasCollagen vascular diseases
PregnancySevere renal failure
Severe nutritional deficienciesDrugs & chemicals
Miscellaneous
Acquired PRCA
Mechanisms of Immunologic Inhibition
Antibodies directed againstErythropoietin
Erythroblasts?
Cellular inhibitionInhibitory T cellsNK cells
Pure red cell aplasia
IgG inhibitors T cell inhibition Parvovirus
Erythropoietin Epo Responsive cells
Clinical Manifestations
Symptoms of anemia*The median age at presentation of anemia
is 2 months and the median age at diagnosis of DBA is 3 months.
*Physical anomalies, excluding short stature*No hepatosplenomegaly.
*Malignant potential
In patients with long-standing PRCA – transfusional hemosiderosis
Laboratory Evaluation
Diagnostic criteria:
--Normochromic, usually macrocytic anemia, relative to patient’s age and occasionally
normocytic anemia developing in early childhood
--Reticulocytopenia
--Normal or only slightly decreased granulocyte count
--Normal or slightly increased platelet count
Supportive criteria:
-Typical physical abnormalities
-Increased fetal hemoglobin
-Increased erythrocyte adenosine deaminase (eADA) activity
BM*Absence of erythroblasts <1% on BM
)absence of normoblasts, in some cases with relative increase in proerythroblasts or normal number of proerythroblasts with a
maturation arrest .(
*normal myeloid and megakaryocytic series.
* Usually – normal karyotype, except for preleukemic cases
TreatmentCongenital Hypoplastic
Anemia
Corticosteroids
AlloBMT
IL-3 –experimental
Patients refractory to all treatments – regular transfusions & desferioxamine
Treatment Acquired PRCA
-Discontinuation of all drugs-R/O infections
-If parvovirus suspected – high dose IgG-In the presence of thymoma – thymectomy
-In 30-40% erythropoiesis remits within 4-8 weeks
-Non-responding pts. – should be treated as primary acquired PRCA
-Thymectomy in the absence of thymoma is not recommended
-If an underlying disease – treat the disease
Treatment Acquired PRCA
For primary or secondary PRCA not responding to treatment of underlying
disease:PrednisoneCyclophosphamide / azathioprineCyclosporineATGHigh dose IgGPlasmapheresisSplenectomyRituximab
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