19:Understanding Bone Marrow Failure

• Bone marrow failure involves reduced or ceased blood cell production, impacting one or more cell lines.
• Pancytopenia, a decrease in red blood cells (RBCs), white blood cells (WBCs), and platelets, is common, particularly in severe cases.

Pathophysiology of Bone Marrow Failure:

• Destruction of hematopoietic stem cells from drugs, chemicals, radiation, viruses, or autoimmune issues.
• Premature senescence and apoptosis of hematopoietic stem cells due to genetic mutations.
• Ineffective hematopoiesis from stem cell mutations or vitamin B12/folate deficiency.
• Disruption of the bone marrow microenvironment.
• Decreased production of hematopoietic growth factors or related hormones.
• Loss of normal hematopoietic tissue due to infiltration by abnormal cells.

Aplastic Anemia

• Aplastic anemia is characterized by pancytopenia, reticulocytopenia, bone marrow hypocellularity, and depletion of hematopoietic stem cells
• Aplastic anemia typically presents as normocytic, normochromic anemia but can be macrocytic, especially in hereditary forms.
• Acquired aplastic anemia is categorized as either idiopathic (unknown cause) or secondary (associated with a known cause).

Pathophysiologic Mechanisms of Acquired Aplastic Anemia

• Functionally Normal Bone Marrow Stromal Cells
  • In acquired aplastic anemia (AAA), the bone marrow stromal cells remain functionally normal; the problem lies within the hematopoietic stem and progenitor cells (HSPCs).
• Elevated Growth Factors
  • To compensate for the depletion of HSPCs, the body upregulates these cells resulting in elevated levels of growth factors such as erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), and thrombopoietin (TPO).
• Severe Depletion of Hematopoietic Stem and Progenitor Cells (10% of Normal or Less)
  • A hallmark of AAA is the severe depletion of HSPCs, often reduced to 10% of their normal levels or even less.
• Direct Damage
  • Exposure to toxic chemicals (e.g., benzene), certain medications (e.g., chloramphenicol), and radiation can cause direct damage to the bone marrow, leading to the depletion of HSPCs.
• Immune Damage
  • Immune-mediated destruction is a significant mechanism in AAA, dysregulated immune responses, particularly involving CD8+ cytotoxic T cells and CD4+ T cells, lead to the destruction of HSPCs. Cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β) play a role in inducing apoptosis of these cells.
• Other Factors
  • Other factors contributing to AAA include viral infections (e.g., hepatitis) and genetic predispositions that may make individuals more susceptible to bone marrow failure.
• Shortened Peripheral Blood Granulocyte Telomeres
  • In AAA, shortened telomeres in peripheral blood granulocytes indicate a deficiency in telomere repair mechanisms, contributing to the premature aging and depletion of HSPCs.

Pathophysiologic Mechanisms of Inherited/ Congenital Bone Marrow Failure Syndromes

• Functionally Normal Bone Marrow Stromal Cells
  • Similar to AAA, the stromal cells in congenital bone marrow failure syndromes (IBMFS) are functionally normal, and the defects primarily lie within the HSPCs.
• Elevated Growth Factors
  • In response to bone marrow failure, the body upregulates HSCs, leading to elevated growth factors such as EPO, G-CSF, and TPO.
• Severe Depletion of Hematopoietic Stem and Progenitor Cells (10% of Normal or Less)
  • IBMFS also presents with severe depletion of HSPCs, often due to genetic mutations affecting various cellular pathways.
• Direct Damage
  • While direct damage is less common in IBMFS compared to AAA, genetic mutations can cause cellular dysfunctions that mimic direct damage effects.
• Immune Damage
  • Immune dysregulation can also play a role in inherited syndromes, though it is less prominent than in AAA. The immune system may contribute to the depletion of HSPCs through abnormal cytokine production.
• Other Factors
  • Genetic mutations are the primary drivers in IBMFS. For example:
• Shortened Peripheral Blood Granulocyte Telomeres
  • Similar to AAA, shortened telomeres are observed in IBMFS, contributing to hematopoietic failure. Genetic mutations affecting telomere maintenance are a common feature in these syndromes.
  • DNA Repair Defects: Syndromes like Fanconi anemia (FA) involve defects in DNA repair pathways, leading to chromosomal instability and increased susceptibility to bone marrow failure.
  • Telomere Biology: Dyskeratosis congenita (DC) is associated with mutations in genes involved in telomere maintenance, resulting in shortened telomeres and premature cellular aging.
  • Ribosome Biogenesis: Diamond Blackfan anemia (DBA) and Shwachman Diamond syndrome (SDS) involve defects in ribosome biogenesis, leading to impaired protein synthesis and hematopoietic failure.
  • Hematopoietic Stem Cell Defects: These syndromes present with severe depletion of HSPCs due to genetic mutations affecting various cellular processes.

Peripheral Blood Features in Aplastic Anemia:

• Hemoglobin:
  • Typically less than 10 g/dL -Anemia is present due to the decreased production of red blood cells (RBCs).
• Mean Cell Volume (MCV):
  • Increased or normal - The RBCs may be macrocytic (larger than normal) or normocytic (normal size).
• Reticulocyte Counts:
  • Percent and absolute reticulocyte counts are decreased - Indicates reduced production of new red blood cells.
• Neutrophils, Monocytes, and Platelets:
  • All are decreased in the peripheral blood - This contributes to increased susceptibility to infections, bleeding, and bruising.
• RBC Morphology:
  • Macrocytic or normocytic - The RBCs themselves are usually normal in appearance.
• Toxic Granulation:
  • May be observed in neutrophils - Reflects the response to stress or infection.
• Leukemic Blasts and Other Immature Blood Cells:
  • Characteristically absent - Differentiates aplastic anemia from leukemias.
• Serum Iron and Transferrin Saturation:
  • Increased serum iron levels and percent transferrin saturation - Reflects decreased iron use for erythropoiesis.
• Liver Function Tests:
  • Abnormal in cases of hepatitis-associated aplastic anemia - Indicates liver involvement or damage.

Bone Marrow Features in Aplastic Anemia:

• Cellularity:
  • Hypocellular with severe depletion of hematopoietic stem and progenitor cells (HSPCs) - Bone marrow spaces are often replaced by fat and fibrous tissue.
• Hematopoietic Elements:
  • Markedly reduced or absent - Severe reduction in the production of RBCs, white blood cells, and platelets.
• Megakaryocytes:
  • Reduced or absent - Megakaryocytes are the bone marrow cells responsible for producing platelets.
• Other Features:
  • No evidence of fibrosis or malignancy - Marrow spaces appear empty or sparse with few remaining cells.

Classifying Aplastic Anemia Based on Lab Results:

• Non-Severe (MAA):
  • Hypocellular bone marrow plus at least two of the following criteria:
  • Neutrophil Count: 0.5–1.5 × 10⁹/L
  • Platelet Count: 20–50 × 10⁹/L
  • Hemoglobin (HGB): ≤ 10 g/dL plus reticulocytes < 30 × 10⁹/L
• Severe (SAA):
  • Bone marrow cellularity < 25% plus at least two of the following criteria:
  • Neutrophil Count: 0.2–0.5 × 10⁹/L
  • Platelet Count: < 20 × 10⁹/L
  • Reticulocytes: < 20 × 10⁹/L or < 1% corrected for HCT
• Very Severe (VSAA):
  • Same as SAA, plus:
  • Neutrophil Count: < 0.2 × 10⁹/L
  • Note: For SAA and VSAA, bone marrow cellularity can also be 25% to 50% with < 30% residual hematopoietic cells.

Treatment Modalities for Acquired Aplastic Anemia:

• Removal of the Causative Agent:
  • Discontinue immediately to prevent further damage.
• Blood Product Transfusions:
  • Provides immediate relief, but should be used judiciously to avoid complications like alloimmunization.
• Hematopoietic Stem Cell Transplantation (HSCT):
  • Considered the most promising therapy for patients with severe aplastic anemia.
  • HSCT is particularly beneficial for patients younger than 40 with an HLA-identical sibling donor.
• Immunosuppressive Therapy (IST):
  • Aims to suppress the autoimmune component of the disease.
  • Common agents used include antithymocyte globulin and cyclosporine.
  • IST is the primary treatment for patients older than 40 or those without an HLA-identical sibling donor.
• Supportive Therapies:
  • These include measures like antibiotic and antifungal prophylaxis in cases of prolonged neutropenia to prevent infections.
• Consideration of Risks:
  • All treatment options carry inherent risks, which should be carefully weighed against the potential benefits.

Treatment Modalities for Inherited Bone Marrow Failure Syndromes:

• Supportive Therapies:
  • Transfusions: Regular blood transfusions to manage anemia and maintain adequate hemoglobin levels.
• Cytokine Administration:
  • Use of cytokines to stimulate the production of blood cells and support bone marrow function.
• Hematopoietic Stem Cell Transplantation (HSCT):
  • Considered the most effective treatment for many inherited bone marrow failure syndromes.
  • It involves transplanting healthy stem cells to replace the defective bone marrow.
  • The feasibility and success of HSCT depend on various factors, including the availability of a suitable donor, the patient's age, and overall health condition.

Disorders Associated with Pancytopenia

• Pancytopenia is a condition characterized by a reduction in the production of cells: red blood cells (RBCs), white blood cells (WBCs), and platelets.
  • Fanconi anemia, dyskeratosis congenita, and Shwachman-Bodian-Diamond syndrome.
• Fanconi Anemia (FA):
  • Lab Tests: Pancytopenia, chromosomal breakage tests, genetic testing.
  • Bone Marrow Findings: Hypocellular marrow with reduced hematopoietic cells.
  • Clinical Findings: Short stature, abnormal thumbs, skin pigmentation changes, high cancer risk (especially leukemia).
• Dyskeratosis Congenita (DC):
  • Lab Tests: Pancytopenia, telomere length measurement, genetic testing.
  • Bone Marrow Findings: Hypocellular marrow, variable dysplasia.
  • Clinical Findings: Skin pigmentation changes, nail dystrophy, oral leukoplakia, high cancer risk.
• Shwachman-Bodian-Diamond Syndrome (SDS):
  • Lab Tests: Pancytopenia, genetic testing, pancreatic function tests.
  • Bone Marrow Findings: Hypocellular marrow with reduced hematopoietic cells, sometimes with dysplasia.
  • Clinical Findings: Exocrine pancreatic insufficiency, skeletal abnormalities, growth retardation, high infection risk.

Key Features of Inherited Bone Marrow Failure Syndromes

• Fanconi Anemia
  • Pathophysiology: Genetic disorder causing DNA repair defects resulting in chromosomal instability and increased cancer risk.
  • Clinical Picture: Physical abnormalities: short stature, limb anomalies, skin pigmentation changes and progressive bone marrow failure.
  • Laboratory Findings: Pancytopenia and Increased chromosomal breakage in cultured cells.
• Dyskeratosis Congenita
  • Pathophysiology: Telomere maintenance disorder caused by mutations affecting telomere structure and function.
  • Clinical Picture: Mucocutaneous features: skin pigmentation, nail dystrophy, oral leukoplakia, premature aging, and increased cancer risk.
  • Laboratory Findings: Pancytopenia over time and Critically short telomeres.
• Shwachman-Bodian-Diamond Syndrome
  • Pathophysiology: Mutation in the SBDS gene affecting ribosome function.
  • Clinical Picture: Exocrine pancreatic insufficiency, skeletal abnormalities, and growth delay. increased risk of leukemia.
  • Laboratory Findings: Neutropenia is common and variable cytopenias
• Transient Erythroblastopenia of Childhood
  • Pathophysiology: Temporary suppression of erythropoiesis, often post-viral infection.
  • Clinical Picture: Sudden onset anemia, typically resolves spontaneously.
  • Laboratory Findings: Normocytic, normochromic anemia and reduced reticulocyte count.
• Diamond-Blackfan Anemia
  • Pathophysiology: Genetic mutations affecting ribosomal protein function and erythropoiesis.
  • Clinical Picture: Severe macrocytic anemia presenting in infancy. Physical anomalies possible, like craniofacial and upper limb defects.
  • Laboratory Findings: Macrocytic anemia with high MCV and low reticulocyte count.
• Congenital Dyserythropoietic Anemia
  • Pathophysiology: Heterogeneous group of disorders that is a Genetic disorder affecting erythroblast maturation in the bone marrow.
  • Clinical Picture: Variable hemolysis and anemia severity and jaundice, splenomegaly might be present.
  • Laboratory Findings: Ineffective erythropoiesis with multinucleated erythroblasts in the bone marrow and variable degrees of anemia and bilirubin elevation.

Mechanisms Causing Cytopenia

• Myelophthisic Anemia
  • Bone Marrow Infiltration: Abnormal cells invade and destroy normal hematopoietic ones.
  • Cytokine and Growth Factor Suppression: Invading cells release suppressive cytokines.
  • Disruption of Marrow Architecture: Leads to premature release of immature blood cells.

Anemia of Chronic Kidney Disease (CKD)

• Anemia is a common complication and the severity has a positive correlation with renal disease.
• Erythropoietin Deficiency:
  • Diseased kidneys produce inadequate erythropoietin, essential for stimulating red blood cell production in the bone marrow.
  • Uremia’s Inhibitory Effects: Uremia suppresses erythropoiesis and increases red blood cell fragility.
  • Chronic Blood Loss: Frequent hemodialysis sessions and serial blood draws can culminate in persistent, cumulative blood loss, exacerbating the anemic state. Hematologic Profile:
  • The anemia observed in CKD is typically normocytic and normochromic, with reticulocytopenia.
  • Uremia: Burr cells (echinocytes) are commonly seen, especially in cases complicated by uremia.
• Iron Availability and Inflammation: Chronic inflammation in CKD
  • Increases the production of inflammatory cytokines and stimulates hepatic hepcidin production, which diminishes iron availability for erythropoiesis.