pancytopenia and aplastic anemia. pancytopenia : definition the simultaneous presence of –anemia...
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Pancytopenia and
Aplastic Anemia
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Pancytopenia : Definition
• The simultaneous presence of – Anemia– Leukopenia– Thrombocytopenia
• Hb< 11.5 g/dL (adult females),< 13.5 g/dL (adult males)
• WBC < 4x10^9/L (4000/mm3)• Plt. < 150 x10^9/L (150.000/mm3 )
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Causes of Pancytopenia1. Aplastic anemia2. Bone marrow
infiltration by– Hematologic
malignancies– Non-hematologic Tm
met.– Storage cell
disorders– Osteopetrosis– Myelofibrosis
3. Paroxysmal nocturnal hemoglobinuria (PNH)
4. Myelodysplastic syndrome5. Hypersplenism6. Vit B12 or folate
deficiencies7. S. Lupus erythematosus8. Cytotoxic agents and
antimetabolites9. Radiotherapy10.Overwhelming infections11.other
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Clinical features
• Related to– PancytopeniaOr– Underlying condition/disease
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Symptoms/Findings•Related to pancytopenia
– The presenting symptoms are related to anemia or thrombocytopenia
– Leukopenia may sometimes be life threatining (eg: late in the course of AA, severe neutropenia)
– Anemia develops slowly ( long life span of RBC’s) •symptoms of gradual onset.
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Symptoms/Findings•Related to pancytopenia
– Thrombocytopenic type bleeding may occur and
– severity depends on the plt. number.
eg: spontaneous bleeding indicates plt<20.000/mm3
– Infections are related to neutropenia , with severity depending on the decrease in neutrophyl counts.
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Symptoms/Findings
• Related to the cause of pancytopeniaeg:– Splenomegaly: Hypersplenism,
lymphoma, leukemia, myelofibrosis etc– Lymphadenomegaly:Lymphoma ,
leukemia,SLE etc– Atrophic glossitis: Megaloblastic anemia– Others
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Investigation of Pancytopenia
(Outline) • History:
– Age , sex, occupation, diet– Chemical or drug or radiation exposure– Bone pain– Fever, night sweats , malaise, weight
loss– Symptoms related to diseases that
cause splenomegaly
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Investigation of Pancytopenia (Outline)• Physical exam:
– Splenomegaly– Bone tenderness– Hepatomegaly – Lymph node enlargement– Gingival hypertrophy– Signs of liver failure or portal
hypertension– Evidence of malignancy
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Investigation of Pancytopenia (Outline)
– Lab.•Essential tests
– CBC:Pancytopenia– Reticulocyte count– MCV– Peripheral blood smear
» Anizocytosis, poikilocytosis, » leuko-erythroblastosis » neutrophyl granules,» neutrophyl segments,» rouleaux formation,» atypical cells
– Bone marrow exam. (aspiration + biopsy)
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Investigation of Pancytopenia (Outline)• Lab:
– Further investigations when required• X-Rays: Bone, chest etc• Alk. Phosp, acid. Phosp• Serum protein electrophoresis• Anti-DNA, FANA, etc• Urinary proteins (Bence-Jones)• Lymph node or other biopsies
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Aplastic Anemia (AA)
• The term AA is first used by Ehrlich in 1888
• Describes a disorder of unknown etiology characterized by– pancytopenia with – hypo or acellular bone marrow.
• It is one of the stem cell disorders.
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Classification of AA
– Fanconi’s anemia: • Autosomal. recessive
inheritance• Skeletal and renal defects• Hyperpigmentation• Small stature• Hypogonadism• Chromosomal changes
– Familial AA (non-Fanconi)• Familial but without features
of Fanconi’s anemia
– Dyskeratosis congenita
• Skin, nail and hair abnormalities
• Telangiectasia• Alopecia• Abnormal sweating• Mental retardation• Growth failure and
hypogonadism– Shwachman–Diamond
syndrome
I-Inherited AA
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FAOccurrence of Pancytopenia: Age 7(med) 90% up to age 40
Leukemia & other malignancy hepatic squamous cell carcinomas of the
vulva, oesophagus,head and neck
Important: Chromosomal breakage and hypersensitivity to the clastogenic effect of DNA cross-linking agents diepoxybutane (DEB) and mitomycin C (MMC)
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Dyskeratosis congenitaAbnormal skin pigmentation Nail dystrophy
Bone marrow failure
> 80-90 % up to age 30Leucoplakia Learning difficultiesDevelopmental delaymental retardationPulmonary diseaseShort statureExtensive dental caries/lossOesophageal stricturePremature hair loss
MalignancyIntrauterine growth
retardation Liver disease/peptic
ulceration/enteropathyAtaxia/cerebellar hypoplasiaHypogonadism/
undescended testes MicrocephalyUrethral stricture/phimosis Osteoporosis/aseptic
necrosis/scoliosisDeafness
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DC genetic subtypes
• X-linked recessive 40% (Xq2)• Autosomal dominant 5% (3q21–
3q28)
• Autosomal recessive 50 %
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Shwachman–Diamond syndrome
• Exocrine pancreatic insufficiency (100%),
• Bone marrow dysfunction (100%) and• Other somatic abnormalities
(particularly involving the skeletal system)
• SDS gene (SBDS) on 7q11– important role in RNA metabolism and/or
ribosome biogenesis.
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Shwachman–Diamond syndrome
• Short stature (~70%), • Ichthyotic skin rash (~60%). • Metaphyseal dysostosis ~75% • Other abnormalities include
– hepatomegaly, – rib/thoracic cage abnormalities,– syndactyly, cleft palate, dental dysplasia,– ptosis and skin pigmentation.
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Classification of AAII-Acquired AA
1. Idiopathic2. Radiation3. Drugs/chemicals
• Chloramphenicol• NSAID:
(phenylbutasone,indomethacin,gold etc)
• Oral hypoglycemic drugs (chlorpropamide,tolbutamide)
• Antithyroid drugs, phenothiazines, antimalarials, diuretics,antiepileptics
• Antineoplastic and cytotoxic drugs
• Pesticides• Solvents and glues:
benzene,toluene,xylene,naphtalene
• Dyes and industrial toxins
• Others
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Classification of AA (continued)
4. Infections– Hepatitis – E.Barr virus– Rubella– CMV– HIV– Parvovirus– Brucellosis– Tbc– Toxoplasmosis
5. Paroxysmal nocturnal hemoglobinuria(PNH)
6. Immunologic disorders– SLE, eosinophilic fasciitis– Graft- versus- Host Disease– Hypoimmunoglobulinemia– Thymoma
7. Pregnancy8. Pancreatic
insufficiency
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Epidemiology of AA
• A disease of the young– Median age: about 25 y
• 1.5 – 2 /1.000.000-year• Equal sex ratio
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Pathophysiology
• Defective stroma• Stem cell damage
– Damage to stem cell DNA: Radiation, drugs etc
– Later progenitor cell damage: Viruses– Immune mediated
• Inadequate production of growth factors?
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Immune mediated injury• Blood and bone marrow of AA patients
supress normal progenitor cell cultures
• Cultured AA marrow recovers colony formation after removal of T-cells
• Immunosupressive therapy is effective in about half of AA patients
• Viruses may cause an infection of the stem cell further leading to an immune response to permanent stem cell failure
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Clinical Features of AA
• History:– Bleeding– Symptoms of anemia– Infections– Drugs, chemicals or other etiologically
important exposures have to be questioned.
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Clinical Features of AA
• Physical exam:– Petechiae, ecchymosis– Retinal bleeding– Pallor– Fever and other signs of infection– Presence of lymphadenomegaly
and /or splenomegaly are unusual (indicate other diagnoses).
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Clinical Features of AA•LAB:
– Pancytopenia– Reticulocytes: Low or absent– RBC: normochrome-normocytic,or slight
macrocytosis– Neutropenia and relative lymphocytosis– Red and white cell precursors are
almost never seen in the peripheral smear
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Clinical Features of AALAB:
– PNH tests may be positive (Ham’s or sucrose lysis tests,others)
– Serum iron is increased– Bone marrow :
• Aspiration; Dry tap • Biopsy; all three cell lines are reduced or
absent, raplaced by fatty tissue, residual lymphocytes, increased iron stores,rarely hot spots of hematopoesis
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Course and prognosis of AA
• Definition of severe aplastic anaemia: hypocellular bone marrow
2-neutrophils <500/mm3 3-platelets<20.000/mm3
reticulocytes<20.000/mm3 (<%1)• Survival in severe disease is about 1 year
if it is treated with transfusions only.
• Very severe AA: Severe AA criteria + Neutrophils:< 200/mm3
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Treatment of AA(1)
Treatment alternatives:• Allogeneic bone marrow/stem cell
transplantation• Immunosupressive treatment• Androgens• Hematopoietic growth factors• Supportive therapy
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Treatment of AA (2)
• Stem cell transplantation:– Young patients with severe AA and a
HLA matched donor should undergo a stem cell transplantation(minimally transfused patients have a chance of > 80% survival )
– Risks: GVHD, engraftment failure, other
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Treatment of AA (3)
•Immunosupressive treatment– ATG or ALG (antithymosit or antilymphocytic
globulin )– Cyclosporin A– Prednisolone(50% chance of recovery )– Risks:
• Early:infections• Late: MDS, PNH, leukemia, other malignancies, relapse
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Treatment of AA (4)Supportive treatment• Hemopoetic Growth Factors: GM-CSF, G-CSF: efficiency ? (limited or not)
• Transfusions:– Only when indicated– Exclude family members as transfusion donors– Cellular blood products must be irradiated before
transfusions – May cause:Iron overload (Repeated RBC’s),
alloimmunization, infection transmission (eg : HIV,HCV,HBV,CMVetc),
• Infections: Preventive care, early diagnosis and treatment
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Pure Red Cell Aplasia• Anemia + Erythropoetic hypoplasia/aplasia occuring in
a normocellular bone marrow
Classification• Congenital (Diamond-Blackfan Syndrome)• Acquired
– During chronic hemolytic anemia (aplastic crisis)– Infections(eg: Parvovirus B19)– Malnutrition– Drugs (Alpha Methyl Dopa, Azathioprine, Carbamazepine,Gold,
NSAID,RMP ,Chloramphenicol etc)
– Thymoma– Malignancy– Idiopathic