Aplastic Anemia Aplastic Anemia

Failure of the bone marrow percursors to produce Failure of the bone marrow percursors to produce maturemature

cells. Characterized by hypocellular marrow and cells. Characterized by hypocellular marrow and pancytopenia.pancytopenia.

Etiology:Etiology: Acquired: More commonAcquired: More common Inherited: Fanconi anemiaInherited: Fanconi anemia

Acquired:Acquired:1.1. Drugs Drugs

- Cytotoxic drugs- Cytotoxic drugs - Antibiotics- Antibiotics- Chloramphenicol- Chloramphenicol - Anti-inflammatory- Anti-inflammatory- Anti-convulsant- Anti-convulsant - Sulphonamides- Sulphonamides- 2-3 months usually between exposure and the development of - 2-3 months usually between exposure and the development of

aplastic anemia.aplastic anemia.

Aplastic Anemia: Aplastic Anemia: (Cont.)(Cont.)

Acquired:Acquired: RadiationsRadiations Chemicals e.g., Benzene and pesticidesChemicals e.g., Benzene and pesticides Viruses:Viruses:

– Hepatitis A, Non-A and Non-BHepatitis A, Non-A and Non-B– Herpes simplexHerpes simplex– E-B virusE-B virus– Parvovirus: TransientParvovirus: Transient

Important clinically in patients with hemolytic anemiasImportant clinically in patients with hemolytic anemias 5-10% of cases of AA in the West and 10-20% in the Far East. 5-10% of cases of AA in the West and 10-20% in the Far East. 2-3 months between exposure to the virus and the development of 2-3 months between exposure to the virus and the development of

AA.AA. Immune: SLE, RA (rheumatoid arthritis)Immune: SLE, RA (rheumatoid arthritis) PregnancyPregnancy Idiopathic: 75%Idiopathic: 75% PNHPNH

Pathogenesis Pathogenesis

Potential mechanisms:Potential mechanisms:

– Absent or defective stem cells (stem cell failure).Absent or defective stem cells (stem cell failure).– Abnormal marrow micro-environment.Abnormal marrow micro-environment.– Inhibition by an abnormal clone of hemopoietic cells.Inhibition by an abnormal clone of hemopoietic cells.– Abnormal regulatory cells or factors.Abnormal regulatory cells or factors.– Immune mediated suppression of hematopoiesis. Immune mediated suppression of hematopoiesis.

It is believed that genetic factors play a role. It is believed that genetic factors play a role. ThereThere

is a higher incidence with HLA (11) histo comp. is a higher incidence with HLA (11) histo comp. Antigen. Immune mechanism is involved.Antigen. Immune mechanism is involved.

Pathogenesis Pathogenesis (Cont…)(Cont…) The latest theory is: there is an intrinsic derangement The latest theory is: there is an intrinsic derangement of hemopoietic proliferative capacity, which is consistentof hemopoietic proliferative capacity, which is consistentwith life. The immune mechanism attempt to destroy with life. The immune mechanism attempt to destroy the abnormal cells (self cure) and the clinical course and the abnormal cells (self cure) and the clinical course and complications depend on the balance. If the immune complications depend on the balance. If the immune mechanism is strong, there will be severe pancytopenia.mechanism is strong, there will be severe pancytopenia.If not, there will be myelodysplasia.If not, there will be myelodysplasia.

Forms of disease:Forms of disease: Inevitable: dose related e.g. cytotoxic drugs, ionizing radiation. The Inevitable: dose related e.g. cytotoxic drugs, ionizing radiation. The

timing, duration of aplasia and recovery depend on the dose. timing, duration of aplasia and recovery depend on the dose. Recovery is usual except with whole body irradiation.Recovery is usual except with whole body irradiation.

Idiosyncratic: unpredictable to drugs e.g., anti-inflammatory Idiosyncratic: unpredictable to drugs e.g., anti-inflammatory antibiotics, anti-epileptic, these agents usually do not produce antibiotics, anti-epileptic, these agents usually do not produce marrow failure in the majority of persons exposed to these agents. marrow failure in the majority of persons exposed to these agents.

Common Traits To All Various Common Traits To All Various CausesCauses

Aplasia due to any cause may recover Aplasia due to any cause may recover after immunosuppressive therapy after immunosuppressive therapy indicating that immune mechanisms are indicating that immune mechanisms are involved.involved.

Transition to a clonal disorder of Transition to a clonal disorder of hemopoiesis can occur in any patient who hemopoiesis can occur in any patient who has recovered bone marrow function, has recovered bone marrow function, suggesting that fragility of the hemopoietic suggesting that fragility of the hemopoietic system is common to all forms of aplasia.system is common to all forms of aplasia.

Clinical FeaturesClinical Features Non-specific:Non-specific:

– Bruising, petechiaeBruising, petechiae– Manifestations of anemiaManifestations of anemia– InfectionsInfections

Hematological findings:Hematological findings:Peripheral blood:Peripheral blood:– Pancytopenia: initially only 1 or 2 parameters. WBC Pancytopenia: initially only 1 or 2 parameters. WBC

< 2.0, Hb < 10. Plat. < 100. No gross morphological < 2.0, Hb < 10. Plat. < 100. No gross morphological abnormalities.abnormalities.

– Anemia is usually NCNC.Anemia is usually NCNC.– Reticulocytopenia.Reticulocytopenia.– 10% Ham’s test is + (complement mediated lysis)10% Ham’s test is + (complement mediated lysis)

Clinical FeaturesClinical Features

Hematological findings: (Cont…)Hematological findings: (Cont…)

Bone Marrow:Bone Marrow:– Hypocellular:Hypocellular:

<50% of normal cellularity Trephine <50% of normal cellularity Trephine biopsy is the most important for biopsy is the most important for diagnosis.diagnosis.

– Most of the cells present are lymphocytes, Most of the cells present are lymphocytes, plasma cells and stromal cells.plasma cells and stromal cells.

– Iron stores: increasedIron stores: increased

TreatmentTreatment

Withdrawal of etiological agents.Withdrawal of etiological agents. Supportive.Supportive. Restoration of marrow activity:Restoration of marrow activity:

– Bone marrow transplantBone marrow transplant– Immunosuppressive treatmentImmunosuppressive treatment

- Prednisolone- Prednisolone - Antilymphocyte glob.- Antilymphocyte glob.- Cyclosporin- Cyclosporin - Anti T cells abs.- Anti T cells abs.- Splenectomy- Splenectomy

– AndrogensAndrogens– Growth factorsGrowth factors

Clinical Course Clinical Course

Usually fatal in constitutional type.Usually fatal in constitutional type.

In the acquired type depends on In the acquired type depends on severity: defined by retic count, months severity: defined by retic count, months or years depending on the severity.or years depending on the severity.

Stable course: constant over a long Stable course: constant over a long period.period.

Progressive, fluctuating. Progressive, fluctuating. Unstable: Associated with abnormal Unstable: Associated with abnormal

clones.clones.

Inherited Anemia Inherited Anemia Fanconi’s Anemia:Fanconi’s Anemia: The most common type of inherited aplastic anemias.The most common type of inherited aplastic anemias. Associated with anomalies e.g., skeletal, skin.Associated with anomalies e.g., skeletal, skin. Autosomal recessive.Autosomal recessive. Marrow failure is at the level of CFU-GM.Marrow failure is at the level of CFU-GM.

Genetics:Genetics: Increased sensitivity of the cells to chromosomal Increased sensitivity of the cells to chromosomal

damage by DNA cross linking agents.damage by DNA cross linking agents. 5 genes are responsible A5 genes are responsible A E. E. IV54 mutation, is associated with multiple dysmorphism, IV54 mutation, is associated with multiple dysmorphism,

severe pancytopenia, higher incidence of AML.severe pancytopenia, higher incidence of AML.

Inherited AnemiaInherited Anemia

Clinical Features:Clinical Features: Skeletal and skin anomalies seen at Skeletal and skin anomalies seen at

birth e.g., microcephally.birth e.g., microcephally. Manifestations of marrow failure, Manifestations of marrow failure,

usually later at age 5-10 yrs. Present usually later at age 5-10 yrs. Present as anemia, mucusal bleeding e.g. as anemia, mucusal bleeding e.g. nasal.nasal.

Chromosomal breaks. Chromosomal breaks.

Clinical Features of Fanconi’s Clinical Features of Fanconi’s AnemiaAnemia

Common Findings:Common Findings: Low birth weightLow birth weight Short statureShort stature MicrocephalyMicrocephaly MicrophthalmiaMicrophthalmia MicrostomiaMicrostomia Skeletal abnormalities, particularly of thumbs and radiiSkeletal abnormalities, particularly of thumbs and radii Hypoplastic hypothenar eminencesHypoplastic hypothenar eminences Generalized increased pigmentation of skinGeneralized increased pigmentation of skin Patches of hypopigmentationPatches of hypopigmentation CryptorchismCryptorchism Abnormalities of renal anatomyAbnormalities of renal anatomy

- Horseshoe kidneysHorseshoe kidneys - Pelvic kidney- Pelvic kidney StrabismusStrabismus Hyper-reflexiaHyper-reflexiaUncommon associations:Uncommon associations: Mental retardationMental retardation Vascular malformationsVascular malformations Growth hormone deficiencyGrowth hormone deficiency

Thank You For Thank You For Your Attention!Your Attention!