APLASTIC ANAEMIA UNDER GUIDANCE OF DR. S.R.TALWELKAR APLASTIC ANEMIA Aplastic anemia is a severe, life threatening syndrome in which production of erythrocytes, WBCs, and platlets has failed. Aplastic anemia may occur in all age groups and both genders. The disease is characterized by peripheral pancytopenia and accompanied by a hypocellular bone marrow. HISTORY OF APLASTIC ANAEMIA. Paul Ehrlich (1854-1915) described the first case of aplastic anaemia in a pregnant woman who died of marrow failure in1888. The term “aplastic anaemia” first used by Anatole Chauffard in 1904. AETIOLOGY. INHERITED(20%) ACQUIRED(80%) Idiopathic secondary cause AETIOLOGY. INHERITED(20%) o Fanconi Anaemia o Dyskeratosis congenita o Shwachman-Diamond syndrome o Congenital megakaryocytic thrombocytopenia anaemia. ACQUIRED(80%) o Idiopathic o Secondary cause: Drug induced 1)Drug which produce marrow depression Alkylating agent: Cyclophosphomide,melphalan and chlorambucil Anti metabolites: Mtx, 5FU, Azathioprine Anti-mitotic: Vincristine, Vinblastine 2) Drug causing idiosyncratic marrow injury Chloramphenicol, nitrufurontoin, cotrimoxazole, Phenylbutazone, indomethazine, diclofenac Gold 3) Chemical associated with AA Benzene, Arsenic, Alcohol ACQUIRED Viral (Hepatitis,EBV,HIV,parvoB19) o Ionising radiation(>1.5 gy dose) o Toxins (pesticides, benzene, arsenic) o Pregnancy o PNH INHERITED BONE MARROW FAILURE SYNDROME Disease Inheritance Additional Lab Associated tumour finding Fanconi anaemia AR Chromosome AML ,MDS ,SCC,brain XR breakage and wilms tumor Dyskeratosis AR Telomere length AML ,MDS ,SCC congenita XR AD Schwamann AR Serum AML Diamond trypsinogen syndrome Pancreatic isomylase rise Congenital AR AML Amegakaryocytic thrombocytopenia FANCONI’S ANEMIA. This common congenital form of aplastic anemia is an autosomal recessive inherited condition . Age : 7 to 9 yr ,also in adult. Sex : M=F Typical physical stigmata include short stature, skin hyperpigmentation, microcephaly, thumb or radius hypoplasia, urogenital abnormalities, and mental retardation. Lab.inv : mild macrocytosis,mild anisocytosis & anaemia > thrombocytopenia> Leucopenia. and increased HBF BM aspiration & biopsy :norm cellular to frank aplastic with dysplastic changes Fanconi’s anemia is confirmed by cytogenetic analysis of peripheral blood lymphocytes, which show chromosome breaks by mitomycin, diepoxybutane . Fanconi’s anemia associate with AML,MDS,SCC Curative Rx is stem cell transplantation Nearly 50% of patient may be controlled with androgen therapy. DYSKERATOSIS CONGENITA Autosomal recessive, autosomal dominant,X-link recessive. Age : 5 to 10 yr ,also in adult. Sex : M>F C/F: Clasical triad inclued skin pigmentation , nail dystrophy & leukoplakia. Also associate with pulmonary fibrosis. Lab.inv :Cytopenia and macrocytosis. Curative Rx is stem cell transplantation Androgen therapy,G-CSF SHWACHMAN-DIAMOND SYNDROME Autosomal recessive. C/F: pancreatic insufficiency and BM failure. Lab.inv :Cytopenia (mainly neutropenia) and macrocytosis. BM aspiration & biopsy :normocellular to frank aplastic with dysplastic changes and cytogenetic abnormality include monosomy 7,isochromosome 7,del 7q) CONGENITAL MEGAKARYOCYTIC THROMBOCYTOPENIC ANAEMIA. Autosomal recessive Age : 3 to 7 yr C/F: Increased bleeding tendency may progress to severe aplastic anemia Lab.inv :severe thrombocytopenia (<20,000/mm3),normal size and morphology.RBCs norm chronic normocytic & reduce. WBCs reduce. BM aspiration & biopsy :Normocellular or hypocllular with decrease megakaryocyte. ACQUIRED APLASTIC ANAEMIA(80%) Incidence: 2-5/million per year Incidence is higher in East. Male to female incidence = equal Disease of young adults, 2nd peak in 4th -5th decade of life. Idiopathic(75%) PATHOPHYSIOLOGY The pancytopenia in aplastic anemia reflects failure of the hematopoietic process manifested as a severe decrease in the numbers of all hematopoietic progenitor cells. Two mechanisms have been suggested for bone marrow failure. The first mechanism is direct hematopoietic injury by chemicals (eg, benzene), drugs, or radiation to both proliferating and quiescent hematopoietic cells. The second mechanism, supported by clinical observations and laboratory studies, is immune- mediated suppression of marrow cell, Cytotoxic T cells are thought to mediate the suppressive effect on hematopoietic cells through the production of hematopoiesis-inhibiting cytokines such as interferon-γ and tumor necrosis factor-α. The mechanism for idiopathic, pregnancy associated, and some cases of drug-associated aplastic anemia is not clear but may involve immunologic processes as well. HAEMATOPOIETIC STEM CELL. CLINICAL PRESENTATION Fatigue, Shortness of breath& weakness(reduce RBCs) Gingival bleeding; petechiae, oral blood blisters; hematuria; heavy menses(reduce platelets) Recurrent bacterial infections(reduce WBCs) Sepsis, pneumonia, UTI Invasive fungal infections PHYSICAL EXAMINATION Physical examination may show signs of Anemia, such as pallor and tachycardia, Thrombocytopenia: such as petechiae, purpura, or ecchymoses. Leukopenia:Overt signs of infection are usually not apparent at time of diagnosis. A subset of patients with aplastic anemia present with jaundice and evidence of clinical hepatitis. Findings of Lymphadenopathy or organomegaly should suggest an alternative diagnosis (eg, hepatosplenomegaly and supraclavicular Lymphadenopathy are observed more frequently in cases of leukemia and lymphoma than in cases of aplastic anemia). LABORATORY STUDIES Determination of complete blood cell (CBC) count and peripheral smears: Severe pancytopenia with relative lymphocytosis (lymphocytes live a long time) Normochromic, normocytic RBCs (may be slightly macrocytic) Mild to moderate anisocytosis and poikilocytosis LABORATORY STUDIES The corrected reticulocyte count is uniformly low in aplastic anemia. The peripheral blood smear is often helpful in distinguishing aplasia from infiltrative and dysplastic causes. Teardrop poikilocytes and leukoerythroblastic changes suggest an infiltrative process. LABORATORY STUDIES Patients with MDS often have certain characteristic abnormalities such as dyserythropoietic RBCs and neutrophils with hypogranulation, hypolobulation, or apoptotic nuclei. A leukemic process may result in evidence of blasts (myeloblasts) on the peripheral smear. LABORATORY STUDIES Biochemical profile is useful in evaluating the etiology and in the differential diagnosis. The profile includes ; an analysis of kidney function; and liver function test and lactic dehydrogenase(LDH) levels. Serologic testing for hepatitis and other viral entities, such as EBV, CMV, and HIV may be useful. The Ham test, or the sucrose hemolysis test, is frequently performed to diagnose PNH. However, at present, the fluorescence-activated cell sorter (FACS) profile of PIGA anchor proteins, such as CD55 and CD59, may be more accurate than the Ham test for excluding PNH. BONE MARROW ASPIRATION AND BIOPSY BM aspiration : to assess cell morphology BM biopsy : to assess cellularity and architecture. Aspiration is dry tap or samples may appear hypo cellular because of technical reasons (eg,dilution with peripheral blood), or they may appear hypercellular because of areas of focal residual hematopoiesis. Bone marrow biopsy is performed in addition to aspiration to assess cellularity both qualitatively and quantitatively. In aplastic anemia, the specimens are hypocellular. The specimen is considered hypocellular if it is <30% cellular in individuals aged <60 years or if it is <20% in those aged >60 years. A relative or absolute increase in mast cells, plasma cells may be observed around the hypoplastic spicules. A proportion of marrow lymphocytes >70% is correlated with poor prognosis in aplastic anemia. Some dyserythropoiesis with megaloblastosis may be observed in aplastic anemia. NORMAL APLASTIC ANAEMIA HYPOCELLULAR BONE MARROW IN APLASTIC ANEMIA FAT SPACES RESIDUAL MARROW Iron deposition in marrow. HISTOLOGIC FINDINGS Histologic findings of aplastic anemia include hypocellular bone marrow with fatty replacement and relatively increased nonhematopoietic elements, such as plasma cells and mast cells. Careful examination to exclude metastatic tumor foci on biopsy STAGING Staging of aplastic anemia is based on the criteria of the International Aplastic Anemia Study Group: 1) Severe aplastic anaemia(SAA) Bone marrow cellularity <25% Two of three peripheral blood criteria; a)Absolute neutrophils (ANC)– < 500/mm3 . b)Platelets – < 20,000mm3 c)Reticulocytes – Less than 60,000mm3 or<1% corrected 2)Very Severe aplastic anaemia(VSAA) Same as SAA with ANC Less than 200/mm3 3)Nonsevere (moderate)aplastic anaemia Bone marrow cellularity <25% Peripheral cytopenia do not fulfill criteria for SAA DIFFERENTIAL DIAGNOSIS HYPOCELLULAR MARROW Aplastic Anaemia Hypoplastic MDS Post chemotherapy Aplastic crisis in hemoloytic anaemia Congenital marrow failure syndrome CELLULAR MARROW WITH DEFICIENCY / SYSTEMIC DISEASE Deficiency of B12 or folic acid Hypersplenism Kala azar SLE Sjogren Sarcoidosis Metastatic solid tumour Alcoholism Storage disease PRIMARY MARROW DISEASE WITH CELLULAR MARROW Aleukemic leukemia Hairy cell leukemia MDS Marrow fibrosis PNH D/D One or more of the following signs in patient with pancytopenia suggest diagnosis other than aplastic anemia. Splenomegaly Hepatomegaly Lymphadenopathy Bone tenderness Immature RBC and WBC precursors in blood. PNH ASSOCIATION WITH APLASTIC ANEMIA PNH patients have a 10-20% chance of developing Aplastic Anemia, and 5% of AA patients eventually develop PNH. In upto 70% of patients with acquired Aplastic Anemia, mutated PNH clones are found in their blood Pathophysiological link between the two disorders. AA ASSOCIATION WITH HEPATITIS Hematopoietic failure developing within 6 months (usually several weeks) of episode of hepatitis Accounts for 5-10% off aplastic anemia cases Most often in previously healthy adolescent boys and young men Infectious cause is unknown(non A non B non C non G), – Serology negative for known hepatitis viruses TREATMENT : APLASTIC ANEMIA Remove Offending Agents Supportive care Selective transfusion therapy to avoid sensitization Definitive therapy Immunosuppressive therapy Allogeneic bone marrow transplantation DEFINITIVE THERAPY: IMMUNOSUPPRESSION Immunosuppression is NOT curative Goal is sustained remission 20-36% have recurrent aplastic anemia 20-36% develop clonal disorder, PNH, MDS or acute leukemia Combination therapy is best Antithymocyte globulin (ATG) Toxic side effect is serum sickness, tx with steroid Can lower platelet counts, transfuse plt. Cyclosporine High dose corticosteroids DEFINITIVE THERAPY: BMT Therapy choice influenced by age and disease severity <20 years old Allogeneic BMT if matched sibling available 50-80% cure rate, with low incidence clonal disorders unrelated donor, but survival only half then matched sib 20-45 years old Allogeneic BMT >45 years old ?Immunosuppression only ?BMT PROGNOSIS The natural history of aplastic anemia suggests that one fifth of patients may spontaneously recover with supportive care; Prognosis depends upon severity of marrow damage. 25% patient die within 4 month of onset of syndrome. 50% patient die within 12 month of onset of syndrome. 71% patient die within 5 year of onset of syndrome. POOR PROGNOSTIC FACTORS Low retic. Count Low neutrophil count Very Low platelet count Lower % of myeloid cell in marrow Shorter interval between onset of symptom and visit to physician Male gender Age and etiology do not affect the prognosis Acute and fulminating clinical course associated with rapid progression to death Thank you INVESTIGATIONS. FBC Reticulocyte count Blood film. B12/folate. Liver function tests Virology Bone marrow aspirate & trephine PNH screen. APLASTIC ANEMIA Pathophysiology: The primary defect is a reduction in or depletion of hematopoietic precursor stem cells with decreased production of all cell lines. This is what leads to the peripheral pancytopenia. This may be due to quantitative or qualitative damage to the pluripotential stem cell. In rare instances it is the result of abnormal hormonal stimulation of stem cell proliferation or the result of a defective bone marrow microenvironment or from cellular or humoral immunosuppression of hematopoiesis. Pathophysiology of aplastic anemia APLASTIC ANEMIA Etiology Acquired Most cases of aplastic anemia are idiopathic and there is no history of exposure to substances known to be causative agents of the disease Exposure to ionizing radiation – hematopoietic cells are especially susceptible to ionizing radiation. Whole body radiation of 300-500 rads can completely wipe out the bone marrow. With sublethal doses, the bone marrow eventually recovers. Chemical agents – include chemical agents with a benzene ring, chemotherapeutic agents, and certain insecticides. Idiosyncratic reactions to some commonly used drugs such as chloramphenicol or quinacrine. APLASTIC ANEMIA Infections – viral and bacterial infections such as infectious mononucleosis, infectious hepatitis, cytomegalovirus infections, and miliary tuberculosis occasionally lead to aplastic anemia Pregnancy (rare) Paroxysmal nocturnal hemoglobinuria – this is a stem cell disease in which the membranes of RBCs, WBCs and platlets have an abnormality making them susceptible to complement mediated lysis. Other diseases – preleukemia and carcinoma APLASTIC ANEMIA Congenital disorders Fanconi’s anemia – the disorder usually becomes symptomatic ~ 5 years of age and is associated with progressive bone marrow hypoplasia. Congenital defects such as skin hyperpigmentation and small stature are also seen in affected individuals. Familial aplastic anemia – a subset of Fanconi’s anemia in which the congenital defects are absent. Clinical manifestations Fatigue Heart palpitations Pallor Infections Petechiae Mucosal bleeding APLASTIC ANEMIA Lab findings Severe pancytopenia with relative lymphocytosis (lymphocytes live a long time) Normochromic, normocytic RBCs (may be slightly macrocytic) Mild to moderate anisocytosis and poikilocytosis Decreased reticulocyte count Hypocellular bone marrow with > 70% yellow marrow Treatment – in untreated cases the prognosis is poor Remove causative agent, if known Multiple transfusions Bone marrow transplant RELATED DISORDERS Disorders in which there is peripheral pancytopenia, but the bone marrow is normocellular, hypercellular, or infiltrated with abnormal cellular elements Myelopthesic anemia – replacement of bone marrow by fibrotic, granulomatous, or neoplastic cells BONE MARROW ASPIRATE IN APLASTIC ANAEMIA Hypocellular Abnormal cytogenetics in 12% patients Trisomy 6, 8, or 15 most common, similar outcome to no clone. Monosomy 7 may have poor outcome, suggests possible hypoplastic MDS. MARROW TREPHINE RELATED DISORDERS Myelodysplastic syndromes – are primary, neoplastic stem cell disorders that tend to terminate in acute leukemia. The bone marrow is usually normocellular, or hypercellular with evidence of qualitative abnormalities in one or more cell lines resulting in ineffective erythropoiesis and/or granulopoiesis and/or megakaryopoiesis. The peripheral smear shows dysplastic (abnormality in development) cells including nucleated RBCs, oval macrocytes, pseudo-Pelger-Huet PMNs (hyposegmented neutrophils) with hyperchromatin clumping, hypogranulated neutrophils, and giant bizarre platlets. Hypersplenism – why can this lead to pancytopenia? PURE RED CELL APLASIA Pure red cell aplasia is characterized by a selective decrease in erythroid precursor cells in the bone marrow. WBCs and platlets are unaffected. Acquired Transitory with viral or bacterial infections Patients with hemolytic anemias may suddenly halt erythropoiesis Patients with thymoma – T-cell mediated responses against bone marrow erythroblasts or erythropoietin are sometimes produced. PURE RED CELL APLASIA Congenital Diamond-Blackfan syndrome – occurs in young children and is progressive. It is probably due to an intrinsic or regulatory defect in the committed erythroid stem cell. OTHER HYPOPROLIFERATIVE ANEMIAS Renal disease – due to decreased erythropoietin Endocrine deficiencies – may lead to decreased erythropoietin production. For example: hypothyroidism leads to decreased demand for oxygen from tissues; decreased androgens in males; decreased pituitary function PATTHOPHYSIIOLLOGY – IIMMUNE SYSTTEM 1Support for immune destruction off stem cells.. Patients respond to immunosuppressive therapy 2.. See increased number off activated CD8 lymphocytes in bone marrow 3.. T-lymphocytes from patients inhibit hematopoiesis when cultured within marrow Depleting these cells restores cell production 4.. IFN-gamma,, TNF,, and IL-2 elevatted in pattients Known to suppress proliferation and induce apoptosis of stem cells With immunosuppression cytokine levels drop 5.. HLA-DR2 in 58% vs.. 28% off normal population B.M IN APLASTIC ANEMIA For diagnosis of aplastic anemia...... at least TWO of following - granulocytes < 500 cells / cumm - platelets < 20,000 cells / cumm - absolute reticulocyte count.< 1% in addition to bone marrow cellularity < 25% of normal is required. BM aspiration : to assess cell morphology BM biopsy : to assess cellularity and architecture. - IN APLASTIC / HYPOPLASTIC PARTICLES Mainly fat cells, plasma cells, reticulum cells and lymphocytes present -IN CELLULAR AREAS Redused fat cells, increased haemopoetic cells, dyserythropoesis, decreased megakaryocytes are BM BX OF AA. TREATMENT TREATMENT Alleviate the underlying disorder or prevent further exposure to the causal agent If platelet count is less than 10,000 cells/μl, platelet transfusions are used to increase the number of platelets in circulation. Packed RBC’s should be administered to increase the Hb level Administering broadspectrum antibiotics Bone marrow transplant or immunosuppressive therapy Antithymocyte globulin (ATG) but slightly less effective Androgen therapy INTRODUCTION Aplastic anemia is a rare, non-contagious and often life-threatening disorder that results from the unexplained failure of the bone marrow to produce red blood cells, white blood cells and platelets. A decrease in the production of blood cells means that patients are more susceptible to bleeding, fatigue and infections.
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