BM FAILURE

• Pancytopenia


  Decreased numbers of circulating red blood cells (RBCs), white blood cells (WBCs), and platelets
• Bone marrow failure


  Reduction or cessation of blood cell production affecting one or more cell lines
• Pathophysiology of bone marrow failure

  1. Destruction of hematopoietic stem cells

  2. Premature senescence and apoptosis of hematopoietic stem cells

  3. Ineffective hematopoiesis

  4. Disruption of the bone marrow microenvironment

  5. Decreased production of hematopoietic growth factors

  6. Loss of normal hematopoietic tissue
• Clinical consequences of bone marrow failure

  • Severe pancytopenia can be rapidly fatal if untreated
  • Thrombocytopenia can result in bleeding and increased bruising
  • Decreased RBCs and hemoglobin can result in fatigue, pallor, and cardiovascular complications
  • Sustained neutropenia increases the risk of life-threatening bacterial or fungal infections
• Aplastic anemia


  A rare but potentially fatal bone marrow failure syndrome
• Characteristic features of aplastic anemia

  • Pancytopenia
  • Reticulocytopenia
  • Bone marrow hypocellularity
  • Depletion of hematopoietic stem cells
• Etiologic classification of bone marrow failure

  • Acquired aplastic anemia (idiopathic, secondary)
  • Inherited/congenital bone marrow failure syndromes
• Idiopathic acquired aplastic anemia


  No known cause
• Secondary acquired aplastic anemia

  Associated with an identified cause
• Approximately 70% of all aplastic anemia cases are idiopathic, whereas 10% to 15% are secondary
• Idiopathic and secondary acquired aplastic anemia have similar clinical and laboratory findings
• In North America and Europe the annual incidence of aplastic anemia is approximately 1 in 500,000
• In Asia and East Asia the incidence of aplastic anemia is two to three times higher than in North America or Europe
• Aplastic anemia can occur at any age, with peak incidence at 15 to 25 years and the second highest frequency at older than 60 years
• There is no gender predisposition for aplastic anemia
• Causes of secondary acquired aplastic anemia

  • Cytotoxic drugs
  • Radiation
  • Benzenes (predictable, dose-dependent)
  • Idiosyncratic reactions to drugs or chemicals
• Approximately 70% of cases of secondary aplastic anemia occur as a result of idiosyncratic reactions to drugs or chemicals
• Selected drugs reported to have a rare association with idiosyncratic secondary aplastic anemia

  • Antiarthritics
  • Antibiotics
  • Anticonvulsants
  • Antidepressants
  • Antidiabetic agents
  • Anti-inflammatories
  • Antiprotozoals
  • Antithyroidals
  • Carbonic anhydrase inhibitors
  • Mesalazine
• Genetic variations in immune response pathways or metabolic enzymes may play a role in idiosyncratic secondary aplastic anemia
• Acquired aplastic anemia can occur as a complication of infection with Epstein-Barr virus, HIV, hepatitis virus, and human parvovirus B19
• Approximately 10% of individuals with acquired aplastic anemia have a concomitant autoimmune disease
• Approximately 10% of individuals with acquired aplastic anemia develop hemolytic or thrombotic manifestations of paroxysmal nocturnal hemoglobinuria (PNH)
• Primary lesion in acquired aplastic anemia

  Quantitative and qualitative deficiency of hematopoietic stem cells
• Hematopoietic stem and progenitor cells in acquired aplastic anemia


  • Diminished colony formation in methylcellulose cultures
  • Decreased CD34+ cell population in the bone marrow
  • Increased expression of Fas receptors and apoptosis-related genes
• Bone marrow stromal cells are functionally normal in acquired aplastic anemia
• Individuals with aplastic anemia have elevated serum levels of erythropoietin, thrombopoietin, G-CSF, GM-CSF, and FLT3 ligand
• Possible causes of stem cell depletion in acquired aplastic anemia

  • Direct damage to stem cells
  • Immune damage to stem cells
• Evidence supporting an autoimmune pathophysiology in acquired aplastic anemia

  • Elevated blood and bone marrow cytotoxic T lymphocytes
  • Increased T cell production of IFN-γ and TNF-α
  • Upregulation of T-bet transcription factor
  • Increased TNF-α receptors on CD34+ cells
  • Improvement in cytopenias after immunosuppressive therapy
• Approximately two-thirds of patients with acquired aplastic anemia respond to immunosuppressive therapy
• Possible autoimmune mechanisms in acquired aplastic anemia include mutation of stem cell antigens and disruption of immune regulation
• Approximately one-third of patients with acquired aplastic anemia have shortened telomeres in their peripheral blood granulocytes
• Patients with aplastic anemia

  • Have single nucleotide polymorphisms in IFN-y/+874 TT, TNF-α/-308 AA, transforming growth factor-ẞ1/-509 TT, and interleukin-6/-174 GG
  • These polymorphisms result in cytokine overproduction and may contribute to genetic susceptibility and severity of aplastic anemia
• The specific antigens responsible for triggering and sustaining the autoimmune attack on stem cells in aplastic anemia are unknown
• Candidate antigens identified from aplastic anemia patient sera include kinectin, diazepam-binding inhibitor-related protein 1, and moesin
• These proteins are expressed in hematopoietic progenitor cells, but their role in the pathogenesis of aplastic anemia requires further investigation
• Approximately one-third of patients with acquired aplastic anemia

  • Have shortened telomeres in their peripheral blood granulocytes compared with age-matched controls
  • Telomeres protect the ends of chromosomes from damage and erosion, and cells with abnormally short telomeres undergo proliferation arrest and premature apoptosis
• Telomerase


  Enzyme complex that repairs and maintains telomeres
• Approximately 10% of patients with acquired aplastic anemia and shortened telomeres have a mutation in the telomerase complex gene for either the ribonucleic acid (RNA) template (TERC) or the reverse transcriptase (TERT)
• The cause for shortened telomeres in the other 90% of patients may be due to stress hematopoiesis or other yet unidentified mutations
• Approximately 4% of patients with acquired aplastic anemia and shortened telomeres have mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene