Hematology chapter 15

• Nonmegaloblastic anemias comprise various conditions with anemia but without megaloblasts in the bone marrow
• Megaloblasts are abnormally large, nucleated red blood cell precursors, typical of megaloblastic anemias, which stem from vitamin B12 or folate deficiencies
• Nonmegaloblastic anemias result from diverse mechanisms like iron deficiency, chronic inflammation, genetic disorders, and infections, which affects red blood cell production, survival, or structure

Anemia of Chronic Inflammation (ACI)

• Anemia of chronic inflammation is also known as anemia of chronic disease, a common anemia in chronic inflammatory, infectious, or neoplastic conditions
• Increased levels of inflammatory cytokines, such as interleukin-6 (IL-6), stimulate hepcidin production by the liver
• Hepcidin, a key iron homeostasis regulator, binds to ferroportin (the iron exporter on macrophages and enterocytes), causing its internalization and degradation
• This leads to reduced iron release from macrophages and decreased iron absorption from the gut, causing iron restriction and impaired erythropoiesis
• Other contributing factors to ACI include decreased red blood cell survival and blunted erythropoietin response
• Conditions linked to ACI:
• Chronic infections like tuberculosis and HIV
• Autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus
• Chronic kidney disease
• Cancer
• Typical lab findings for ACI:
• Low serum iron
• Normal or elevated ferritin (an acute phase reactant)
• Low total iron-binding capacity (TIBC)
• Normal or decreased transferrin saturation
• Elevated hepcidin levels
• ACI treatment focuses on the underlying cause of chronic inflammation
• Erythropoiesis-stimulating agents (ESAs) are sometimes used, but their effectiveness is limited due to the blunted erythropoietin response
• Iron supplementation is generally ineffective unless coexisting iron deficiency is present

Aplastic Anemia

• Aplastic anemia is a rare and serious disorder characterized by the failure of the bone marrow to produce adequate numbers of all blood cell types: red cells, white cells and platelets
• Pancytopenia, a deficiency of all three blood cell lines, results from this
• Aplastic anemia can be acquired or inherited
• Acquired aplastic anemia is more common, often due to:
• Autoimmune mechanisms where the immune system attacks and destroys hematopoietic stem cells in the bone marrow
• Exposure to certain drugs like chloramphenicol and chemotherapy agents
• Exposure to toxins such as benzene
• Viral infections like parvovirus B19 and Epstein-Barr virus
• Inherited aplastic anemia includes conditions such as Fanconi anemia, caused by genetic mutations affecting DNA repair mechanisms
• Clinical signs of aplastic anemia:
• Fatigue and weakness from anemia
• Increased susceptibility to infections because of leukopenia (low white blood cell count)
• Bleeding tendencies from thrombocytopenia (low platelet count)
• Aplastic anemia diagnosis is based on:
• Complete blood count (CBC) showing pancytopenia
• Bone marrow biopsy revealing hypocellularity (reduced number of cells) with a marked decrease in hematopoietic cells
• Aplastic anemia treatment includes:
• Immunosuppressive therapy to suppress the autoimmune attack on the bone marrow, often with drugs such as antithymocyte globulin (ATG) and cyclosporine
• Hematopoietic stem cell transplantation, which involves replacing the damaged bone marrow with healthy stem cells from a matched donor
• Supportive care, including blood transfusions to manage anemia and thrombocytopenia, and antibiotics to treat infections

Hemolytic Anemia

• Hemolytic anemia involves red blood cells being destroyed faster than the bone marrow produces them
• Anemia occurs if the bone marrow cannot compensate for the increased red cell destruction
• Hemolytic anemia is classified as either:
• Intrinsic: related to defects inside the red blood cells
• Extrinsic: due to factors outside the red blood cells that cause their destruction
• Intrinsic hemolytic anemia examples:
• Hereditary spherocytosis: a genetic disorder causing red blood cells to be spherical and fragile
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: an enzyme deficiency that makes red blood cells more susceptible to oxidative damage
• Sickle cell anemia: a genetic disorder causing red blood cells to be sickle-shaped and prone to premature destruction
• Extrinsic hemolytic anemia examples:
• Autoimmune hemolytic anemia: where the immune system attacks and destroys red blood cells
• Drug-induced hemolytic anemia: caused by certain medications that trigger red cell destruction
• Mechanical hemolytic anemia: due to physical trauma to red blood cells, such as from prosthetic heart valves or microangiopathic hemolytic anemia (MAHA)
• Clinical features of hemolytic anemia:
• Fatigue and weakness from anemia
• Jaundice because of increased bilirubin production when red cells break down
• Dark urine because of hemoglobinuria
• Splenomegaly from increased red cell destruction in the spleen
• Lab findings in hemolytic anemia:
• Low hemoglobin and hematocrit
• Elevated reticulocyte count (indicating increased red cell production)
• Elevated indirect bilirubin
• Elevated lactate dehydrogenase (LDH)
• Decreased haptoglobin (a protein that binds free hemoglobin)
• Hemolytic anemia treatment depends on the underlying cause and may include:
• Avoiding triggers (e.g., certain drugs or foods in G6PD deficiency)
• Immunosuppressive therapy for autoimmune hemolytic anemia
• Blood transfusions to manage anemia
• Splenectomy in some cases of hereditary spherocytosis or autoimmune hemolytic anemia

DNA Synthesis in Nonmegaloblastic vs. Megaloblastic Anemias

• In megaloblastic anemias, impaired DNA synthesis (typically due to vitamin B12 or folate deficiency) leads to a mismatch between nuclear and cytoplasmic maturation
• The nucleus matures slowly because of defective DNA replication, while cytoplasmic development (hemoglobin production) proceeds at a normal rate
• This results in large, abnormal cells (megaloblasts) with open, immature chromatin in the bone marrow
• In nonmegaloblastic anemias, DNA synthesis is generally not primarily affected
• Any disruption in DNA synthesis is typically secondary to other factors
• For example, in anemia of chronic inflammation or aplastic anemia, the problem lies in iron availability, bone marrow failure, or increased red cell destruction, rather than a direct defect in DNA replication
• Therefore, cells do not exhibit the characteristic nuclear-cytoplasmic asynchrony seen in megaloblastic anemias

Megaloblastic Anemia

• Etiology: Most commonly caused by vitamin B12 deficiency or folate deficiency
• Less common causes include certain drugs (e.g., methotrexate) that interfere with DNA synthesis and rare inherited disorders
• Pathophysiology:
• Vitamin B12 and folate are essential for DNA synthesis
• Deficiency leads to impaired production of thymidine, a building block of DNA
• This primarily affects rapidly dividing cells, such as those in the bone marrow
• Impaired DNA synthesis causes ineffective hematopoiesis, resulting in fewer and larger-than-normal red blood cells (macrocytic anemia)
• Laboratory findings:
• Macrocytic anemia (high MCV, typically >100 fL)
• Oval macrocytes and hypersegmented neutrophils on peripheral blood smear
• Low reticulocyte count
• Elevated serum lactate dehydrogenase (LDH) and indirect bilirubin due to ineffective erythropoiesis
• Bone marrow aspirate showing megaloblastic changes
• Low serum vitamin B12 or folate levels, depending on the cause

Pernicious Anemia

• Etiology:
• Autoimmune disorder where antibodies attack parietal cells in the stomach
• Parietal cells produce intrinsic factor (IF), necessary for vitamin B12 absorption in the ileum
• Pathophysiology:
• Loss of parietal cells leads to reduced or absent IF production
• Vitamin B12 cannot be absorbed properly, leading to vitamin B12 deficiency
• This causes impaired DNA synthesis and megaloblastic anemia
• Laboratory findings:
• Macrocytic anemia (high MCV)
• Oval macrocytes and hypersegmented neutrophils
• Low serum vitamin B12 levels
• Elevated serum gastrin levels (due to reduced gastric acid production)
• Presence of anti-parietal cell antibodies and anti-intrinsic factor antibodies
• Elevated methylmalonic acid (MMA) and homocysteine levels

Folic Acid Deficiency Anemia

• Etiology:
• Inadequate dietary intake of folate (vitamin B9)
• Increased folate requirements (e.g., pregnancy, hemolytic anemia)
• Malabsorption (e.g., celiac disease)
• Certain drugs (e.g., methotrexate, trimethoprim) that interfere with folate metabolism
• Pathophysiology:
• Folate deficiency impairs DNA synthesis, particularly in rapidly dividing cells
• This leads to ineffective hematopoiesis and megaloblastic anemia
• Laboratory findings:
• Macrocytic anemia (high MCV)
• Oval macrocytes and hypersegmented neutrophils
• Low serum folate levels
• Normal serum vitamin B12 levels
• Elevated homocysteine levels (but normal MMA levels, which helps differentiate from B12 deficiency)