Bone marrow failure syndromes

Definition
1. Failure of the bone marrow to provide sufficient cells to support a normal blood count
  1. May be due to inefficient production or inadequate production
  2. Usually all cell lines affected (but may be limited to one)
Clinical features of bone marrow failure
1. Red cell effects
  1. Anaemia
    1. Pallor
    2. Lethargy
    3. Dypnoea
      1. = difficulty breathing
2. White cell effects
  1. Infections
    1. Fever
    2. Malaise
    3. Local infections: often of skin, perianal, chest, throat and mouth ulcers
    4. Septicaemia
3. Platelet effects
  1. Spontaneous bruising
  2. Purpura
  3. Bleeding gums
  4. Rarely a severe haemorrhage
4. Supportive management
  1. Anaemia
    1. Transfuse red cells
    2. Iron chelation
  2. Bleeding
    1. Prophylactic with platelet transfusions
    2. Treatment of bleeding episodes
      1. Packing, cautery, make sure not on 'blood thinners' (aspirin and NSAIDs)
  3. Infection
    1. Prophylactic antibiotics/antifungals/antivirals/PCP (protozoan)
    2. Protective isolation
    3. Life threatening events usually G-ve sepsis
    4. Promt treatment of infections
      1. Emergency antibiotics
        Rapid admission to hospital
  4. Other issues
    1. Venous access
    2. Growth factors
      1. Granulocyte colony stimulating factor (G-CSF)
      2. Erythropoietin (EPO)
Causes
1. Ineffective production
  1. Myelodysplasia (MDS)
    1. What is it?
      1. Group of disorders
        Characteristic morphological abnormalities
        Impaired BM function
        Peripheral cytopenias
        Cytopenia = reduction in blood cells
        Tendency to evolve into acute leukaemia
      2. Usually occurs in the elderly (80-85yrs, with >75% >70yrs)
    2. Aetiology (cause)
      1. Primary
        Most common
        Unknown cause
        Low dose radiation?
        Organic chemicals?
      2. Secondary
        Following previous chemotherapy
        Usually 4-10 years after treatment
        Most common with alkylating agents (nitrogen mustards - e.g. cyclophosphamide)
        Other drugs include; azathrioprine (immunosuppressant)
    3. Presentation
      1. Bone marrow failure
        Obvious symptoms (see AA)
      2. Splenomegaly (in 10%)
      3. Incidental asymptomatic finding
        Macrocytosis (large RBCs)
        Cyopenias
        Monocytosis
        Increase in peripheral monocytes
    4. Diagnosis
      1. Full blood count
      2. Morphology
        Often tri-lineage abnormalities
        In peripheral blood...
        Oval macrocytes
        Basophilic stippling
        Hypogranulated/lobulated neutrophils
        Agranular/giant platelets
      3. Bone marrow
        Hypercellular
        Erythroid
        Nuclear/cytoplasmic abnormalities
        Ring sideroblasts
        Small megakaryocytes (micromegakaryocytes) with abnormal nuclei
        Myeloid
        Hypogranular
        Increased immature cells
      4. Cytogenetics
        30-50% primary MDS
        80% is therpay related
        Prognostic significance
        Common genetic abnormalities
        5q-
        Primary (10-20%)
        Secondary (20%)
        Monosomy 7
        Primary (10-15%)
        Secondary (30-50%)
        Trisomy 8
        17p-
        Secondary (10%)>primary(3%)
    5. Prognosis
      1. Apporx. 66% die from bone marrow failure
      2. 50% progress to acute leukaemia
        Depends on number of blast cells in BM
      3. International prognostic scoring system
        Based on: % BM blasts, karyotype and number of cytopenias
        Survival
        Low risk = 36 months
        Medium risk = 18 months
        High risk = 8 months
        Other prognostic factors
        Age
        Subtypes
    6. Treatment
      1. Observation
      2. Supportive care
      3. Chemotherapy
        Reduction in abnormal cells and hypomethylating agents
      4. Anti-lymphocyte globulin
      5. Bone marrow transplantation
        Especially in younger patients
2. Insufficient production
  1. Aplastic anaemia (AA)
    1. What is it?
      1. Pancytopaenia (reduction in all red, white and platelet blood cells)
        Results from an aplasia (reduction/destruction of the tissue) of the bone marrow
        Cause is probably autoimmune
        Microscopically appears as hypocellular bone marrow
      2. No evidence of marrow fibrosis or malignancy
    2. Classification
      1. Constitutional / inherited
        Causes 25% of childhood AA
        Rarely adult AA
        Inherited?
        Family history
        Somatic abnormailities
        Forms
        Fanconi anaemia
        Dykeratosis congenita
        Schwachmann-diamond syndrome
        Reticular dysgenesis
      2. Acquired
        In most cases, no cause is identified (= idiopathic)
        Causes can include
        Direct bone marrow toxicity
        Ionising radiation
        Chemicals (e.g. benzene; organic solvents; insecticides)
        Drugs
        Anti-rheumatics
        Anti-inflammatory
        Anti-convulsants
        Anti-thyroids
        Anti-depressants
        Anti-diabetics
        Anti-malarials
        Immune-mediated
        Pregnancy
        Idiosyncratic drug reaction (individual's react to drugs differerntly)
        Viruses (EBV, parvovirus (causes fifth's disease in children), HIV)
        Transfusion-associated Graft versus host disease (TA-GVHD)
        T-lymphocytes in donor blood start an immune reaction against the recipient
        Eosinophilic fasciitis
        Eosinophil-mediated inflammation of the fascias (connective tissue around; muscles, nerves, blood vessels)
    3. Diagnosis
      1. Full blood count (FBC)
        Hb <10g/dL
        Platelets <50
        Neutrophils <1.5
        Everything is LOW
      2. Reticulocyte count (= low)
      3. Blood film
        Normal looking cells, but reduced in number / absent
      4. Bone marrow aspirate and trephine (and cytogenetics)
        Trephine = cyclindrical core biopsy of bone+marrow
      5. Exclude other causes of pancytopaenia
        Vit. B12 and folate levels
        Liver function tests
        BM and cytogenetics - exclude myelodysplasia (MDS)
        Exclude drug causes
        Liver function and virology
        Test for paroxysmal nocturnal haemoglobinuria
    4. Treatment
      1. Supportive care
        Blood product replacement
        Bone marrow transplant
        Avoid HLA sensitisation and cytomegalo virus (CMV) exposure
        Antimicrobials
        Growth factors
      2. Specific therapy for AA
        Aimed at functional peripheral blood count recovery
        Depends on: type of AA, age and donor availability
        Immunosupression
        Bone marrow transplant
        Up to 80% patients are cured
        Typically reserved with sibling matches (HLA matching)
        G-CSF
        May cause monosomy 7 in children
        Oxymethalone
        Androgenic steroid hormone -> increases erythropoiesis and BM recovery
        Splenectomy
        Reduces transfusion requirements, increases thrombocyte count and progressive haemopoiesis
  2. Bone marrow infiltration with malignancy (lymphoma, leukaemia, carcinoma etc.)

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Bone marrow failure syndromes

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