أسئلة الثانية هيماتولوجي ثالثة الدلتا

Cytopenia Definitions

• Cytopenia refers to a decrease in one blood element.
• Isolated cytopenia involves a decrease in only one blood element.
  • Anemia is the reduction of RBCs.
  • Leukopenia refers to a decreased number of WBCs.
  • Thrombocytopenia indicates a decrease in platelets.
• Bicytopenia is defined as a decrease in two blood elements.
• Pancytopenia is characterized by a decrease in all three (WBCS, RBCs, Platelets) hematologic cell lines.
• Cytopenias are conditions caused by a common pathway with various etiologies and are not diseases.

Differential Diagnosis of Pancytopenia

• Includes inherited, or acquired bone marrow failure
• Myelodysplastic syndrome.
• Bone marrow infiltration is seen in Hodgkin's and Non-Hodgkin's lymphoma, multiple myeloma, metastatic carcinoma, myelofibrosis and myelosclerosis
• Megaloblastic anemia results from Vitamin B12 and folic acid deficiency.
• Paroxysmal nocturnal hemoglobinuria.
• Overwhelming infections
• Hypersplenism

Megaloblastic Anemia

• Group of anemias caused by impaired DNA synthesis.
• Impaired DNA synthesis causes asynchronous maturation between the nucleus and cytoplasm, consequently leading to megaloblasts.
• Characterized by abnormal findings in peripheral blood smear (macro-ovalocytes) and bone marrow samples (megaloblastic hyperplasia).
• Megaloblasts are the hallmark of these anemias.
• Deficiency in either Vitamin B12 or Folic acid can cause.

Vitamin B12 or Folic Acid in Megaloblastic Anemia

• Either Vit B12 or Folic acid needed for DNA synthesis.
• Deficiencies in either vitamin leads to defective DNA synthesis.
• Defective DNA synthesis leads to dyspoiesis (defective formation), where cytoplasmic maturity is greater than nuclear maturity, causing megaloblasts in marrow and macro-ovalocytic RBCs entering circulation.
• Dyspoiesis increases intramedullary cell death (ineffective erythropoiesis), which results in indirect hyperbilirubinemia and hyperuricemia.
• Dyspoiesis affects all cell lines, causing leukopenia and thrombocytopenia.
• Hallmark is reticulocytopenia from defective erythropoiesis is.
• Presence of hypersegmentation of neutrophils.

Vitamin B12 Deficiency

• Etiology of deficiency can occur in several ways:
  • Insufficient dietary intake like vegan diets.
  • Impaired absorption is a key etiological factor that is caused by the following:
    • Gastric bypass surgery
    • Autoimmune gastritis (pernicious anemia), where antibodies against parietal cells in the stomach that decreases intrinsic factor.
  • Intestinal Competition: Fish tapeworm infestation.
  • Ileal resection or bypass.
  • Ileal dysfunction: Crohn's disease, or intestinal lymphoma.
  • Medication can cause includes Metformin, and proton pump inhibitors.

Clinical Findings - Vitamin B12 Deficiency

• Non-specific signs and symptoms of anemia.
• Jaundice (lemon yellow) occurs due to excess breakdown of hemoglobin, resulting in elevated indirect bilirubin.
• Symptoms of Purpura is due to thrombocytopenia.
• Swollen or sore tongue (Glossitis).
• Mild symptoms of malabsorption.
• Neurological manifestations are paresthesia, unsteady gait, motor weakness progressing to paralysis.
• Neuropsychiatric symptoms may precede hematologic signs, including myelopathy, neuropathy, and dementia.
• Cobalamin deficiency leads to defective myelin synthesis in nervous system, causing central and peripheral nervous system dysfunction.
• Subacute combined degeneration affects posterior and lateral columns of the spinal cord.
• Neural tube defect: In fetus, anencephaly, spina bifida or encephalocele can occur if mothers are B12 deficient.

Diagnosis of Vitamin B12 Deficiency

• Complete blood count findings:
  • Macrocytic Anemia with increased MCV that is greater than 95 fL.
  • Platelets and WBC are often reduced, especially in severely anemic patients (pancytopenia)
• Blood film smear findings:
  • Decreased RBC count containing Macrocytes (larger than normal RBCs)
  • Anisocytosis (increased variation in RBC size)
  • Poikilocytosis (abnormally shaped RBCs).
  • Neutrophil granulocytes with multisegmented nuclei.
• Decreased is reticulocyte count due to destruction of fragile and abnormal megaloblastic erythroid precursor.
• Increased indirect bilirubin and LDH level (intramedullary hemolysis).
• Key is to identify the underlying cause for B12 deficiency.
• B12 levels are variable: optimal/functional serum levels range at 800-1000 nanogram/L but are less reliable unless critically low.
• Homocysteine and methylmalonic acid (MMA) levels are both elevated

Treatment of Vitamin B12 Deficiency

• Prophylaxis: needed for patients who have gastric bypass surgery.
• Treatment of the underlying cause.
• Parenteral, or oral cobalamin replacement with Hydroxy cobalamin IM 1000 microgram.
• Initial dose is 6 X 1000 microgram over 2-3 weeks
• Maintenance dose is 1000 microgram every 3 weeks

Folate Deficiency

• Dietary: -Insufficient dietary intake can occur with malnutrition
  • Alcohol intake can reduce folate excretion and impair intracellular metabolism.
• Increased folate use in:
  • Pregnant and lactating patients.
  • Hemolytic anemias: sickle cell anemia, warm autoimmune hemolytic anemia.
  • Long-term dialysis patients.
• Severe Crohn's disease can reduces absorption.
• Many medications such as antimetabolites (e.g methotrexate) interfere with folate absorption and metabolism.

Diagnosis - Folate Deficiency

• indistinguishable from B12 deficiency regarding peripheral blood and bone marrow findings.
• In fetus, due to folate deficiency neural tube defects can occur in mothers.
• Neurologic lesions aren't detectable as with vit B12 deficiency
• Diagnosis via lab work via:
  • Serum folate and RBC folate.
  • Elevated homocysteine, and normal MMA.

Treatment - Folate Deficiency

• Prophylaxis: -Administration of Folic acid when pregnant
  • For undergoing patients chronic dialysis with severe chronic hemolytic anemias, folic acid is administered.
• Management of the underlying cause.
• Replenish tissues with, Folic acid administered at 1-5 mg/day P.O.

Important Notes -Folates

• There is a great deal of clinical similarity between vit B12 and Folic acid deficiencies.
• High doses of folic acid when B12 is low can cause a hematological response, but may aggravate neuropathy.
• Check that there is no B12 deficiency before giving Folic acid.
• Treat severely anemic patients urgently, administering both Vitamins after completing blood assay.

Response to Treatment - Folate Deficiency

• If treatment is effective, reticulocytes:
  • Begins to increase around the 3rd day
  • Gradually returns to normal by the end of 3rd week.
• Within 48 hours the BM is normoblastic.
• After 7 to 10 days WBC & platelets counts become normal.
• Hemoglobin should rise by 2-3 g/dL each 2 weeks.
• If neuropathy is caused by B12 deficiency and peripheral neuropathy spinal cord damage may be irreversible.

Aplastic Anemia

• Bone Marrow (BM) failure is definition.

Definition of Bone Marrow Failure

• Intrinsic disorder of the BM: – Disrupts hematopoietic stem and progenitor cell homeostasis. – Inadequate production of white blood cells, red blood cells, and platelets.

Causes of Bone Marrow Failure

• Inherited causes:
  • Fanconi anemia presents as Chromosomal breakdown.
  • Telomere affection: is caused by Dyskeratosis Congenita
  • Diamond Blackfan anemia results from Ribosomal abnormalities
  • Schwann Diamond syndrome occurs by gene mutation of (SDS gene).
• Acquired causes: – By Acquired Aplastic Anemia. – Acquired Pure Red Cell Aplasia – Hypocellular MDS. – Drug induced – Paroxysmal Nocturnal Hemoglobinuria – Transient Drug Suppression: infection. – Vitamin or Mineral Deficiency

Acquired Aplastic Anemia

• Incidence & Etiology:
  • Incidence: Peaks at Mid-childhood, and older adults.
  • Occurs at any age with 2 to 8 cases per million population.
  • 75-80% is Idiopathic/immune mediated, 3 to 5 % occurs from Drug or Chemical.
  • Chemotherapy, anti-epileptics such as benzene are drugs that cause effects of chemical.
  • 10 to 15% Hepatitis Associated and 5-10% results from, EBV, HIV, parvovirus.

Clinical Features of Acquired Aplastic Anemia

• Signs vary with the severity of the pancytopenia.
• Onset of aplastic anemia is often insidious, but can be acute.
• Patients have classic anemia, but may have: -Severe thrombocytopenia, leading to bleeding into the skin and mucous membranes.
  • Agranulocytosis, which results in life-threatening infections.
  • There is No presence of:
    • Organomegaly.
    • Lymphadenopathy.

Classification of Acquired Aplastic Anemia

• MODERATE OR NON-SEVERE (NSAA is characterized by:
  • Reduced bone marrow cellularity, and peripheral blood cytopenia.
  • Over 500 × 106/L of Neutrophil count
  • Does not fulfil criteria for (SAA).
• SEVERE (SAA) has the following characterizations:
  • Bone marrow cellularity that is less than 25% of age normal
  • Need At least 2 of the following:
    • Neutrophil count under 500 x 106/L
    • platelet count under 20,000 x 106/L
    • Reticulocyte count below 60,000 x 106/L
• VERY SEVERE (VSAA) classification includes: – All SAA criteria needed and: – Plus with a Neutrophil count below 200 x 106/L

Acquired Aplastic Anemia- Lab Findings

• Complete blood (CBC) counts include:
  • Reduced RBC: that is normochromic, and normocytic anemia.
  • Leukopenia, where WBCs are reduced. – Reduced Platelets leading to Thrombocytopenia.
  • Reticulocytes either absent or reduced.
• Bone marrow acellularity or is hypocellular is seen from bone marrow aspiration.
• Crucial step is bone marrow biopsy, which shows replacement of normal elements with fat cells.
• Identification is sought by Investigation for the root cause.

Treatment of Acquired Aplastic Anemia

• Supportive through blood products: –Blood and platelets transfusions. –Broad spectrum antibiotics to treat and prevent prophylaxis.
  • Restoration of cellularity occurs through agents like: – Use of cytokines (EPO, granulocyte or granulocyte- macrophage colony-stimulating factor, thrombopoietin receptor agonist). – Cyclosporine & Anti-thymocyte globulin (ATG) may be effective.
  • Bone marrow transplants is the transfer from identical twin or HLA-compatible sibling to treat very severe cases of (age 40 and under....)