Delta Sem (6) - Hematology Lecture (2) - Megaloblastic & Aplastic Anemia

Cytopenia

• Decrease in one blood element is called isolated cytopenia
• RBCs are decreased in anemia
• WBCs are decreased in leucopenia
• Platelets are decreased in thrombocytopenia
• Decrease in two blood elements is called bicytopenia
• Decrease in all three (WBCs, RBCs, Platelets) hematologic cell lines is called pancytopenia
• Cytopenias are not diseases in themselves, but rather a common pathway caused by various etiologies

Differential Diagnosis of Pancytopenia

• Acquired or inherited bone marrow failure
• Myelodysplastic syndrome
• Bone marrow infiltration, e.g., Hodgkin’s and non-Hodgkin’s lymphoma, multiple myeloma and metastatic carcinoma
• Myelofibrosis and myelosclerosis
• Megaloblastic anemia caused by Vit B12 and folic acid deficiency
• Paroxysmal nocturnal hemoglobinuria
• Overwhelming infections
• Hypersplenism

Megaloblastic Anemia

• These are a group of anemias caused by impaired DNA synthesis.
• Characterized by abnormal findings in peripheral blood smear (macro-ovalocytes) and bone marrow samples (megaloblastic hyperplasia).
• Megaloblasts are the hallmark, caused by asynchronous maturation between nucleus and cytoplasm due to DNA synthesis impairment
• Vitamin B12 deficiency and Folic acid deficiency can cause megaloblastic anemia

Vitamin B12 or Folic Acid

• Either vitamin B12 or folic acid is required for DNA synthesis
• Deficiencies in either can lead to defective DNA synthesis
• Dyspoiesis occurs in all cells
• Cytoplasmic maturity is greater than the nuclear maturity
• The megaloblast in the marrow and macro-ovalocytic RBCs enters the circulation
• Dyspoiesis increases intramedullary cell death (ineffective erythropoiesis) with resultant indirect hyperbilirubinemia and hyperuricemia
• Dyspoiesis affects all cell lines, leukopenia and thrombocytopenia
• Reticulocytopenia is another hallmark of the megaloblastic state
• Hypersegmentation of neutrophils is a standard finding

Vitamin B12 Deficiency Etiology

• Insufficient dietary intake, especially in strict vegans and some vegetarians
• Impaired absorption for several reasons
  • Intrinsic factor deficiency from gastric bypass surgery, or autoimmune gastritis (pernicious anemia)
  • Antibodies against parietal cells in the stomach decrease IF
  • Intestinal Competition from fish tape worm infestation or Ileal resection or bypass
  • Ileal dysfunction such as Crohn’s disease or intestinal lymphoma
  • Medication (Iatrogenic) like Metformin, proton pump inhibitors

Vitamin B12 Deficiency Clinical Findings

• Non-specific signs and symptoms of anemia
• Jaundice (lemon yellow) due to excess breakdown of hemoglobin resulting from increased ineffective erythropoiesis
• Increased indirect bilirubin level
• Purpura as a result of thrombocytopenia
• Swollen or sore tongue (Glossitis)
• Mild symptoms of malabsorption
• Neurological manifestations
  • Paresthesia, unsteady gait and motor weakness progressing to paralysis
  • Neuropsychiatric symptoms that may precede hematologic signs
  • Represented by myelopathy, neuropathy, and dementia
  • Cobalamin deficiency in the nervous system leads to defective myelin synthesis
  • Central and peripheral nervous system dysfunction
  • Subacute combined degeneration, the spinal cord manifestation, affects posterior and lateral columns of spinal cord
• Neural tube defect: anencephaly, spina bifida or encephalocele in fetus due to B12 deficiency in mothers

Vitamin B12 Deficiency Diagnosis

• Complete blood count
  • Macrocytic Anemia with increased MCV > 95 fL
  • WBC and platelets may be reduced especially in severely anemic patients (pancytopenia)
• Blood film
  • Decreased RBC count with Macrocytes (larger than normal RBCs)
  • Anisocytosis (increased variation in RBC size)
  • Poikilocytosis (abnormally shaped RBCs)
  • Neutrophil granulocytes may show multisegmented nuclei
• Reticulocyte count is decreased due to destruction of fragile and abnormal megaloblastic erythroid precursor
• There can be increased indirect bilirubin and LDH level (intramedullary hemolysis)
• The underlying cause for B12 deficiency should be identified
• There may be variable B12 level, less reliable unless quite low : Optimal/functional ranges of serum B12 range are likely: 800-1000 nanogram/L
• Homocysteine and methylmalonic acid (MMA) will both be HIGH

Vitamin B12 Deficiency Treatment

• Prophylaxis administered to patients who have gastric bypass surgery
• Therapeutic treatment involves
  • Treating the underlying cause
  • Parenteral or oral cobalamin replacement
  • Hydroxy cobalamin IM 1000 microgram
  • An initial dose of 6 X 1000 microgram over 2-3 weeks
  • A maintenance dose of 1000 microgram every 3 weeks

Folate Deficiency Etiology

• Insufficient dietary intake from malnutrition
• Alcoholism increases renal folate excretion and impairs its intracellular metabolism
• Increased requirements for folate occur in
  • Pregnant and lactating patients
  • Hemolytic anemias such as sickle cell anemia or warm autoimmune hemolytic anemia
  • Patients on long-term dialysis
• Impaired absorption from severe Crohn’s disease
• Medications (Iatrogenic) that interfere with folate metabolism or possibly absorption, with antimetabolites (e.g methotrexate)

Important things to note about Folate Deficiency

• It’s indistinguishable from B12 deficiency regarding peripheral blood and bone marrow findings
• Neural tube defect in fetus due to folate deficiency in mothers
• No neurologic lesions occur unlike in vitamin B12 deficiency
• The primary laboratory studies to reveal should be serum folate, RBC folate, homocysteine and MMA

Folate Deficiency Treatment

• Prophylaxis administered when folic acid is given in pregnancy or when patients undergoing chronic dialysis with severe chronic hemolytic anemias
• Can also be treated therapeutically by treating the underlying cause, and replenishing tissues with folic acid 1-5 mg/day P.O

Megaloblastic Anemia Important Warning

• On a clinical level there is much similarity between vitamin B12 deficiency and Folic acid deficiency
• If large doses of folic acid are given in B12 deficiency they may cause a hematological response but may aggravate the neuropathy
• Folic acid should therefore not be given alone unless B12 deficiency has been excluded
• In severely anemic patients who need treatment urgently, it may be safer to initiate treatment with both vitamins after blood has been taken for B12 and folate assay

Response to Treatment (of Megaloblastic Anemia)

• Reticulocytes begin to increase around the 3rd day, and gradually return to normal by the end of the 3rd week
• BM is normoblastic in about 48 hrs
• WBC & platelets counts become normal in 7-10 days
• Hb should rise by 2-3 g/dL each 2 weeks
• Peripheral neuropathy may partly improve (3-6 or 12 months) but spinal cord damage is irreversible (B12 deficiency)

Aplastic Anemia

• An intrinsic disorder of the BM, resulting in disrupted hematopoietic stem and progenitor cell homeostasis and function
• There is inadequate production of white blood cells, red blood cells, and/or platelets

Causes of Bone Marrow Failure

• Some are inherited conditions with chromosomal or gene mutations
• Some are acquired, can be idiopathic or transient

Causes of Bone Marrow Failure

• INHERITED
  • Fanconi anemia: Chromosomal breakdown
  • Dyskeratosis Congenita: Telomere affection
  • Diamond Blackfan anemia: Ribosomal abnormalities
  • Schwashman Diamond syndrome: gene mutation in (SDS gene)
• ACQUIRED
  • Acquired Aplastic Anemia
  • Acquired Pure Red Cell Aplasia
  • Hypocellular MDS
  • Paroxysmal Nocturnal Hemoglobinuria
  • Transient Drug Suppression
  • Transient Infection
  • Vitamin/Mineral Deficiency

Acquired Aplastic Anemia Incidence

• 2-8 cases per million/year with two peaks at mid-childhood and in older adults, but it can occur at any age

Acquired Aplastic Anemia Etiology

• Idiopathic/immune mediated (75-80%)
• Drug/chemical Effect (3-5%), like Chemotherapy, anti-epileptics, benzene exposure
• Hepatitis Associated (10-15%)
• Viral Infection (5-10%) such as EBV, HIV, parvovirus

Acquired Aplastic Anemia Pathogenesis

• Exposure triggers autoimmune T-cell response, that leads to T cell activation, expansion, and migration to bone marrow
• Bone marrow suppression due to T cell killing of marrow stem cells and by production of cytokines that inhibit blood production

Acquired Aplastic Anemia Clinical Features

• Onset is usually insidious, occasionally it is acute
• General symptoms of anemia
• Severe thrombocytopenia may occur, with bleeding into the skin and mucous membranes
• Agranulocytosis with life-threatening infections is common
• Signs vary with the severity of the pancytopenia. and also depend on which blood element is mainly affected
• No Organomegaly: Splenomegaly is absent
• No lymphadenopathy

Acquired Aplastic Anemia Classification

• MODERATE OR NON-SEVERE (NSAA): Bone marrow cellularity and peripheral blood cytopenia

• 500 × 106/L

• SEVERE (SAA): Bone marrow cellularity 25% of age normal and at least 2 of the following
  • Neutrophil count <500 x 106/L
  • Platelet count <20,000 x 106/L
  • Reticulocyte count <60,000 x 106/L
• VERY SEVERE (VSAA): criteria for SAA PLUS Neutrophil count < 200 x 106/L

Aplastic Anemia Laboratory Findings

• Complete blood count (CBC) with:
  • RBCs that are normochromic-normocytic anemia (sometimes marginally macrocytic)
  • Leukopenia (WBCs)
  • Thrombocytopenia (Platelets)
• Reticulocytes are decreased or absent
• Bone marrow aspiration is acellular or hypocellular
• Bone marrow biopsy is mandatory for diagnosis and shows replacement of normal hematopoietic elements with fat cells
• Investigations for underlying cause

Aplastic Anemia Treatment

• Supportive care administering blood products support with RBCs or platelets and antibiotics both for prophylaxis and therapy
• Restoration of cellularity is another key component
  • Use of cytokines (EPO, granulocyte or granulocyte- macrophage colony-stimulating factor, thrombopoietin receptor agonist)
  • Androgens are effective in some cases
  • Anti-thymocyte globulin (ATG)
  • Cyclosporine
  • Combined ATG and cyclosporine can be effective
  • Bone marrow transplantation from identical twin or HLA-compatible sibling for severe and very severe cases (age 40 and under)