Pancytopenia and Aplastic Anemia Ok

8/10/2019 Pancytopenia and Aplastic Anemia Ok

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PancytopeniaandAplastic 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 nocturnalhemoglobinuria (PNH)

4. Myelodysplastic syndrome5. Hypersplenism6. Vit B12 or folate

deficiencies7. S. Lupus erythematosus8. Cytotoxic agents and

antimetabolites

9. 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 relatedto anemia or thrombocytopenia

Leukopenia may sometimes be lifethreatining (eg: late in the course ofAA, severe neutropenia)

Anemia develops slowly ( long life spanof RBCs) symptoms of gradual onset.


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Symptoms/Findings

Related to pancytopenia Thrombocytopenic type bleeding mayoccur and

severity depends on the plt. number.eg: spontaneous bleeding indicatesplt


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Symptoms/Findings

Related to the cause ofpancytopeniaeg: 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 thatcause 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 Ehrlichin 1888

Describes a disorder of unknownetiology characterized by pancytopenia with hypo or acellular bone marrow.

It is one of the stem cell disorders.


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Classification of AA

Fanconis anemia: Autosomal. recessive

inheritance Skeletal and renal defects Hyperpigmentation Small stature Hypogonadism Chromosomal changes

Familial AA (non-Fanconi) Familial but without features

of Fanconis anemia

Dyskeratosiscongenita

Skin, nail and hairabnormalities

Telangiectasia Alopecia Abnormal sweating

Mental retardation Growth failure and

hypogonadism ShwachmanDiamond

syndrome

I-Inherited AA


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FAOccurrence of Pancytopenia: Age 7(med) 90% up to age 40

Leukemia & other malignancyhepaticsquamous cell carcinomas of the

vulva, oesophagus,head and neck

Important:Chromosomal breakage and hypersensitivity to the

clastogenic effect of DNA cross-linking agentsdiepoxybutane (DEB) and mitomycin C (MMC)


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Dyskeratosis congenitaAbnormal skin pigmentationNail dystrophyBone marrow failure > 80-90 % up to age 30 LeucoplakiaLearning difficultiesDevelopmental delaymental retardationPulmonary diseaseShort statureExtensive dental caries/lossOesophageal stricturePremature hair loss

MalignancyIntrauterine growth

retardationLiver disease/peptic

ulceration/enteropathyAtaxia/cerebellar hypoplasiaHypogonadism/undescended

testesMicrocephaly

Urethral stricture/phimosisOsteoporosis/asepticnecrosis/scoliosis

Deafness


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DC genetic subtypes

X-linked recessive 40% (Xq2) Autosomal dominant 5% (3q213q28) Autosomal recessive 50 %


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ShwachmanDiamond syndrome

Exocrine pancreatic insufficiency (100%), Bone marrow dysfunction (100%) and

Other somatic abnormalities (particularlyinvolving the skeletal system)

SDS gene ( SBDS ) on 7q11

important role in RNA metabolism and/orribosome biogenesis.


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ShwachmanDiamond 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 andcytotoxic drugs

Pesticides Solvents and glues:

benzene,toluene,xylene,naphtalene

Dyes and industrialtoxins

Others


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Classification of AA (continued)

4. Infections Hepatitis E.Barr virus

Rubella CMV HIV Parvovirus Brucellosis Tbc Toxoplasmosis

5. Paroxysmal nocturnalhemoglobinuria(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 patientssupress normal progenitor cell cultures

Cultured AA marrow recovers colonyformation after removal of T-cells

Immunosupressive therapy is effective inabout half of AA patients

Viruses may cause an infection of the stemcell further leading to an immune responseto 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 bequestioned.


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Physical exam: Petechiae, ecchymosis Retinal bleeding Pallor Fever and other signs of infection

Presence of lymphadenomegaly and /orsplenomegaly are unusual (indicate otherdiagnoses).


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LAB: Pancytopenia Reticulocytes : Low or absent

RBC: normochrome-normocytic,orslight macrocytosis Neutropenia and relative

lymphocytosis Red and white cell precursors are

almost never seen in the peripheralsmear


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LAB: PNH tests may be positive (Hams 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, residuallymphocytes, increased iron stores,rarelyhot spots of hematopoesis


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Course and prognosis of AA

Definition of severe aplastic anaemia: 1- hypocellular bone marrow2-neutrophils


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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 astem cell transplantation(minimally transfused patients have achance 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 RBCs), 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 marrowClassification 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

Idi thi

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Pancytopenia and Aplastic Anemia Ok