Bone marrow failure syndromes

Bone marrow failure syndromes

1. Definition

   • Failure of the bone marrow to provide sufficient cells to support a normal blood count
     • May be due to inefficient production or inadequate production
     • Usually all cell lines affected (but may be limited to one)

2. Clinical features of bone marrow failure

   • Red cell effects
     • Anaemia
       • Pallor
       • Lethargy
       • Dypnoea
         • = difficulty breathing
   • White cell effects
     • Infections
       • Fever
       • Malaise
       • Local infections: often of skin, perianal, chest, throat and mouth ulcers
       • Septicaemia
   • Platelet effects
     • Spontaneous bruising
     • Purpura
     • Bleeding gums
     • Rarely a severe haemorrhage
   • Supportive management
     • Anaemia
       • Transfuse red cells
       • Iron chelation
     • Bleeding
       • Prophylactic with platelet transfusions
       • Treatment of bleeding episodes
         • Packing, cautery, make sure not on 'blood thinners' (aspirin and NSAIDs)
     • Infection
       • Prophylactic antibiotics/antifungals/antivirals/PCP (protozoan)
       • Protective isolation
       • Life threatening events usually G-ve sepsis
       • Promt treatment of infections
         • Emergency antibiotics
           • Rapid admission to hospital
     • Other issues
       • Venous access
       • Growth factors
         • Granulocyte colony stimulating factor (G-CSF)
         • Erythropoietin (EPO)

3. Causes

   • Ineffective production
     • Myelodysplasia (MDS)
       • What is it?
         • Group of disorders
           • Characteristic morphological abnormalities
           • Impaired BM function
           • Peripheral cytopenias
             • Cytopenia = reduction in blood cells
           • Tendency to evolve into acute leukaemia
         • Usually occurs in the elderly (80-85yrs, with >75% >70yrs)
       • Aetiology (cause)
         • Primary
           • Most common
           • Unknown cause
             • Low dose radiation?
             • Organic chemicals?
         • 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)
       • Presentation
         • Bone marrow failure
           • Obvious symptoms (see AA)
         • Splenomegaly (in 10%)
         • Incidental asymptomatic finding
           • Macrocytosis (large RBCs)
           • Cyopenias
           • Monocytosis
             • Increase in peripheral monocytes
       • Diagnosis
         • Full blood count
         • Morphology
           • Often tri-lineage abnormalities
             • In peripheral blood...
               • Oval macrocytes
               • Basophilic stippling
               • Hypogranulated/lobulated neutrophils
               • Agranular/giant platelets
         • Bone marrow
           • Hypercellular
           • Erythroid
             • Nuclear/cytoplasmic abnormalities
             • Ring sideroblasts
           • Small megakaryocytes (micromegakaryocytes) with abnormal nuclei
           • Myeloid
             • Hypogranular
             • Increased immature cells
         • 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%)
       • Prognosis
         • Apporx. 66% die from bone marrow failure
         • 50% progress to acute leukaemia
           • Depends on number of blast cells in BM
         • 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
       • Treatment
         • Observation
         • Supportive care
         • Chemotherapy
           • Reduction in abnormal cells and hypomethylating agents
         • Anti-lymphocyte globulin
         • Bone marrow transplantation
           • Especially in younger patients
   • Insufficient production
     • Aplastic anaemia (AA)
       • What is it?
         • 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
         • No evidence of marrow fibrosis or malignancy
       • Classification
         • 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
         • 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)
       • Diagnosis
         • Full blood count (FBC)
           • Hb <10g/dL
           • Platelets <50
           • Neutrophils <1.5
           • Everything is LOW
         • Reticulocyte count (= low)
         • Blood film
           • Normal looking cells, but reduced in number / absent
         • Bone marrow aspirate and trephine (and cytogenetics)
           • Trephine = cyclindrical core biopsy of bone+marrow
         • 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
       • Treatment
         • Supportive care
           • Blood product replacement
             • Bone marrow transplant
               • Avoid HLA sensitisation and cytomegalo virus (CMV) exposure
           • Antimicrobials
           • Growth factors
         • 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
     • Bone marrow infiltration with malignancy (lymphoma, leukaemia, carcinoma etc.)