BONE MARROW FAILURE: APLASTIC ANAEMIA (AA)

DR ODE. I.C

INTRODUCTION

• Bone marrow failure is defined as decreased production of one or more of the haemopoietic lineages
• It can be inherited or acquired

INTRODUCTION

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• Bone marrow failure could affect one cell lineage (monolineage) causing monolineage cytopenia or more cell lineages (multilineage) causing multilineage cytopenias

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INTRODUCTION

• Examples of multlineage cytopenias include:
• Aplastic anaemia
• Fanconi anaemia
• Shwachman – Diamond syndrome (SDS) e.t.c.
• Dyskeratosis congenita

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INTRODUCTION

• Examples of monolineage cytopenias include:
• Congenital dyserythropoietic anaemia (CDA)
• Diamond-Blackfan anaemia (DBA)
• Kostmann syndrome/congenital neutropenia

APLASTIC ANAEMIA

• Aplastic anaemia is a model of bone marrow failure syndromes (BMFs)
• It is defined as a hypocellular marrow with peripheral pancytopenia that results from bone marrow failure

APLASTIC ANAEMIA

• It is a syndrome in which there is decreased production of red cells, neutrophils, monocytes and platelets without morphologic evidence of another marrow disorder
• Diagnosis of aplastic anaemia is made when other causes of marrow failure that could manifest as a hypocellular marrow with peripheral pancytopenia are excluded

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APLASTIC ANAEMIA

• Aplastic anaemia is characterized by decreased production of all the cell lines including the erythroid, myeloid and lymphoid lineages
• It is classified into primary (constitutional or congenital) and secondary (acquired)

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APLASTIC ANAEMIA

• Here, ‘constitutional’ is used interchangeably with the term ‘inherited’ to imply that a genetic disorder causes the BMF especially when it occurs in two or more members of the same family
• Note that ‘congenital’ can be inherited or acquired

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APLASTIC ANAEMIA

• Primary (inherited) cause of aplastic anaemia include:
• Fanconi anaemia (FA)
• Other causes of inherited bone marrow failure include:
• Dyskeratosis congenita (DC)
• Schwachman-Diamond syndrome (SDS
• Diamond-Blackfan anaemia(DBA)

APLASTIC ANAEMIA

• secondary causes of aplastic anaemia include:
• Idiopathic (it is acquired but the aetiology is unknown
• Ionizing radiation which could be from radiotherapy, radioactive isotopes or nuclear powers e.g Bombs

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APLASTIC ANAEMIA

• Drugs like busulfan, melphalan, cyclophosphamide, anthracyclines and nitrosoureas are associated with regular bone marrow suppression
• Drugs that occassionally cause marrow suppression include chloramphenicol, sulphonamide, gold, phenytoin, carbamazepine, NSAID etc

APLASTIC ANAEMIA

• Note that bone marrow failure from injury caused by drugs may or may not depend on the dose of the drug
• Marrow failure that is drug dose dependent may revert after cessation of the drug
• While drug-induced bone marrow failure that is dose independent (idiosyncratic) may not revert with cessation of the drug e.g chloramphenicol

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APLASTIC ANAEMIA

• Chemicals like benzene, organophosphates, pesticides e.g DDT, organochlorines and recreational drugs are associated with marrow suppression
• Viruses e.g Epstein Barr virus (EBV), hepatitis, HIV, parvovirus*

APLASTIC ANAEMIA

• Graft versus host disease (GvHD)
• Thymoma (thymic cancer)*
• Paroxysmal nocturnal haemoglobinuria (PNH)*
• Note that those with * may only cause single lineage cytopenias or more

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PATHOPHYSIOLOGY OF APLASTIC ANAEMIA

• The various mechanisms by which various agents cause aplastic anaemia are not known
• However studies have shown that damage to the haemopoietic microenvironment that affects the stem cells, the progenitor cell compartment as well as factors that stimulate haemopoiesis may be responsible

PATHOPHYSIOLOGY OF APLASTIC ANAEMIA

• And that direct and indirect assault to the haemopoietic microenvironment, the stem cells and the progenitor compartment by mechanisms unknown may culminate in bone marrow failure

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PATHOPHYSIOLOGY OF APLASTIC ANAEMIA

• Immune mechanisms are also thought to play a role in aplastic anaemia
• And that cytotoxic drugs, radiations, chemicals and viruses could directly cause damage to the stem cell or the progenitor cell compartment leading to aplastic anaemia

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PATHOPHYSIOLOGY OF APLASTIC ANAEMIA

• Radiation, drugs, chemicals and viruses could also stimulate an immune response that could also cause assault to the stem cells and the progenitor cell compartment resulting in aplastic anaemia (indirect)

PATHOPHYSIOLOGY OF APLASTIC ANAEMIA

• Failure of haemopoiesis could be from various mechanisms such as:
• Defect in haemopoietic stem cells and reduction in their numbers such that the ability of the stem cell to self-renew, proliferate and differentiate to various cell lines is not sustained
• Defect in haemopoietic microenvironment and the deficient haemopoietic stimulating factors impair haemopoiesis

PATHOPHYSIOLOGY OF APLASTIC ANAEMIA

• Immunologic mechanism supported by response to immunosuppressive therapy in patients with aplastic anaemia is evidential in the role played by immune mechanism
• Studies have shown that cytokines like interferon and tumour necrosis factor produced by activated T lymphocytes suppress haemopoietic stem cell growth

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CLINICAL FEATURES OF APLASTIC ANAEMIA

• The clinical presentation of patients with aplastic anaemia is related to the decrease in bone marrow production of haematopoietic cells
• Anaemia: patient may present with body weakness, easy fatiguability, dyspnoea on exertion and other symptoms of anaemia
• Bleeding from thrombocytopenia
• Mucosal and gingival bleeding or petechiae

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CLINICAL FEATURES OF APLASTIC ANAEMIA

• Infections from neutropenia
• Organomegaly is not a finding in aplastic anaemia
• Presence of enlarged lymph node, liver or spleen should prompt a search for alternate diagnosis to aplastic anaemia

INVESTIGATION OF APLASTIC ANAEMIA

• Aim of investigation is to:
• Confirm diagnosis
• Exclude other causes of pancytopenia
• Determine possible cause of aplastic anaemia
• Determine severity/prognosticate

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INVESTIGATION OF APLASTIC ANAEMIA

• Full blood count shows pancytopenia:
• Packed cell volume (PCV) is low
• Leucopenia with relative lymphocytosis
• Thrombocytopenia

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INVESTIGATION OF APLASTIC ANAEMIA

• Smear morphology should not show any abnormality such as blast or dysplastic cells, except the aplastic anaemia has transformed to AML, or the Aplastic anaemia evolved from myelodysplastic syndrome in which case the diagnosis of aplastic anaemia will no longer apply

INVESTIGATION OF APLASTIC ANAEMIA

• Smear morphology shows normocytic normochromic red cells with mild macrocytic red cells
• Reticulocyte count is low in comparison to the degree of anaemia

INVESTIGATION OF APLASTIC ANAEMIA

• Bone marrow aspiration/biopsy shows a hypocellular marrow with fat replacement but if aspirate is obtained from focal area of residual haemopoiesis it will be hypercellular
• Marrow biopsy cellularity of <30% in age below 60years is considered hypocellular while cellularity of less than 20% in patients older than 60years is hypocellularity

INVESTIGATION OF APLASTIC ANAEMIA

• Note that marrow cellularity decreases with age as red marrow is replaced with fatty marrow hence the reason for reduced % cellularity in patients greater than 60years compared to younger age groups

INVESTIGATION OF APLASTIC ANAEMIA

• Viral serology for hepatitis, EBV, cytomegalovirus (CMV) and HIV
• Liver function test with deranged reference ranges and a positive hepatitis virus may suggest a post hepatitis aplastic anaemia
• Baseline renal function test should also be performed

INVESTIGATION OF APLASTIC ANAEMIA

• Anti-nuclear antibody screening for autoimmune diseases
• Coombs test to rule out autoimmune disease
• Flow cytometry for CD55 and CD59 to exclude PNH
• Ham test is also done to exclude PNH (not as specific as Flow cytometry)

INVESTIGATION OF APLASTIC ANAEMIA

• Cytogenetic studies to rule out Fanconi anaemia and myelodysplastic syndrome
• Diepoxybutane to assess chromosomal breakage for Fanconi anaemia
• Sepsis screening; chest xray, urine culture, blood culture in cases of infection

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APLASTIC ANAEMIA STAGING

• Peripheral blood and marrow findings are used for staging of aplastic anaemia
• Peripheral blood criteria include:
• Neutrophils less than 0.5 x 10⁹/L
• Platelet less than 20 x10⁹/L
• Reticulocyte count less than 1%

APLASTIC ANAEMIA STAGING

• Bone marrow criteria include:
• Severe marrow hypocellularity
• Moderate hypocellularity with haemopoietic cells less than 30%

APLASTIC ANAEMIA STAGING

• severe aplastic anaemia (SAA)
• Neutrophils less than 0.5 x 10⁹/L
• Platelet less than 20 x10⁹/L
• Reticulocyte count less than 1%
• Plus any one of the marrow criterion
• This means 3 pheripheral blood criteria plus one marrow criterion

• very severe aplastic anaemia (VSAA)
• Neutrophils less than 0.2 x 10⁹/L
• Platelet less than 20 x10⁹/L
• Reticulocyte count less than 1%
• Plus any one of the marrow
• The only difference between SAA and VSAA is the neutrophil count

DIAGNOSIS OF APLASTIC ANAEMIA

• Diagnosis of aplastic anaemia require excluding other causes of pancytopenia
• Detailed history taking including exposure to chemicals, drugs, radiation infections is essential
• Detailed examination looking for features of Fanconi anaemia like short stature, skin hyperpigmentation, upper limb abnormality

TREATMENT OF APLASTIC ANAEMIA

• Aim of treatment is to improve quality of life
• To reduce transfusion dependency
• To avoid infection risk
• To prevent bleeding

TREATMENT OF APLASTIC ANAEMIA

• Treatment is grouped into supportive and specific
• Supportive treatment include:
• Transfusional Support
• Red Blood Cell and Platelets
• Give prophylactic platelet support when platelet count is <10 x 10⁹/L or <20 x 10⁹/L
• Give irradiated granulocyte transfusion to patients with life-threatening neutropaenic fever and blood products should be leuco-depleted to avoid alloimmunization and irradiated to prevent GvHD in BMT eligible patients

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TREATMENT OF APLASTIC ANAEMIA

• In patients with aplastic anaemia who may receive bone marrow transplantation, transfusion from family members should be avoided because of possible sensitization by antigens of the donors

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TREATMENT OF APLASTIC ANAEMIA

• Broad spectrum antibiotics should be incases of infections and prophylactically to prevent infection
• Give antifungals
• Iron chelating agents to avoid iron overload from repeated blood transfusion when serum ferritin is greater than 1000mg/L

SPECIFIC TREATMENT OF APLASTIC ANAEMIA

• Choice of specific treatment depends on:
• Age of the patient
• Disease severity
• Availability of HLA identical donor
• Allogeneic stem cell transplantation (SCT) is the treatment of choice in younger patients with SAA who have an HLA- matched sibling donor
• Stem cell transplant of an HLA matched donor that is not related to the patients is an option in situations where a related donor is unavailable

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SPECIFIC TREATMENT OF APLASTIC ANAEMIA

• Immunosuppressives like antithymocyte globulin (ATG) and cyclosporin are other forms of treatment option in aplastic anaemia patients that are old and may not be able to withstand SCT.
• Either of the drug can be given alone or in combination
• Androgens are also given

PROGNOSIS OF APLASTIC ANAEMIA

• The prognosis is poor in most cases
• Complete or partial remission is acheivable
• Stem cell transplant may offer a cure
• GvHD, infections and graft rejections are complications
• The disease can transform to acute myeloblastic leukaemia (AML), myelodysplastic syndrome (MDS) or Paroxysmal nocturnal haemoglobinuria (PNH)

FANCONI ANAEMIA

• First described by Dr Guido Fanconi in 1927 in three brothers with pancytopenia combined with physical anomalies
• It is inherited in autosomal recessive pattern
• It may be transmitted in X – linked recessive mode, caused by a mutant FANCB gene

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FANCONI ANAEMIA

• It is a cause of bone marrow failure (aplastic anaemia)
• Thirteen genes have been identified in this disease: Fanconi anaemia genes A,B,C,D1,D2,E,F,G,H,I,J,L,M and N
• They present with physical and haematological anomalies in combination or singlely

CLINICAL FEATURES OF FANCONI ANAEMIA

• They present with features of bone marrow failure
• Short stature
• skin hyperpigmentation

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CLINICAL FEATURES OF FANCONI ANAEMIA

• Upper limb anomalies involving radii, ulna, hands and thumb
• Hypogonadal and genitalia changes especially males e.g micropenis, undescended or atrophic or absent testes e.t.c

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CLINICAL FEATURES OF FANCONI ANAEMIA

• Renal anomalies e.g ectopic, horseshoe kidneys, as well as duplicated, hypoplastic, dysplastic or absent kidney, hydronephrosis and hydroureters
• Microcephaly, small eyes, epicanthal folds, abnormally shaped and positioned ears – Fanconi facies

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LAB FEATURES IN FANCONI ANAEMIA

• Blood counts and marrow cellularity are often normal until 5 to 10 years of age, when pancytopaenia develops gradually over an extended interval
• Thrombocytopaenia may precede the development of granulocytopaenia and anaemia�

LAB FEATURES IN FANCONI ANAEMIA

• Bone marrow aspiration shows normal cellularity with progressive erythroid hyperplasia and dyserythropoiesis at the early stage of the disease
• There is hypocelluarity of the marrow at the latter stage with complete bone marrow failure as in aplastic anaemia
• Relative lymphocytosis is a feature just as in aplastic anaemia

LAB FEATURES IN FANCONI ANAEMIA

• Chromosomal breakage is observed using diepoxybutane
• Treatment is supportive and specific
• Support patients with blood component transfusions
• Give androgens like oxymethalone and danazol , SCT may be curative