Erythropoiesis and Anemia

• Erythropoiesis describes the process of blood cell formation
• Erythropoiesis is for red cell production
• Leucopoiesis is for white cell production
• Megakaryopoiesis is for platelet production

Erythropoiesis

• Erythropoiesis defines new red blood cell formation.
• Gradual decrease in cell size.
• Condensation and expulsion of the nucleus.
• Increase in hemoglobin production.
• Normal adult values for Hemoglobin in males is 14-16 g/dl
• Normal adult values for Hemoglobin in females is 13-15 g/dl
• Normal adult values for PCV/HCT in males is 40-52%
• Normal adult values for PCV/HCT in females is 36-48%
• Normal adult values for Red cell count in males is 4.5-6.5 (x10^12/l)
• Normal adult values for Red cell count in females is 3.9-5.6 (x10^12/l)
• Normal adult values for MCV is 80-95 fL
• Normal adult values for MCH is 27-34 pg
• Normal adult values for MCHC is 30-35 g/dL
• Normal adult values for Reticulocyte count is 50-150 (x10^9/L)

Anemia

• Anemia involves a reduction in hemoglobin concentration, red blood cells, and hematocrit values below normal for age and sex.
• World Health Organization (WHO) values for anemia in adult males is below 130 g/L hemoglobin.
• The World Health Organization (WHO) values for anemia in adult females is below 120 g/L hemoglobin.
• Anemia signifies a disease process rather than being a disease itself.

Etiological Classification of Anemia:

• Decreased bone marrow function can lead to aplastic anemia

• Bone marrow infiltration (leukemia, lymphoma) may cause anemia

• A deficiency in essential substances for hematopoiesis such as iron, vitamin B12, or folic acid can cause anemia

• Excessive Red Blood Cell loss can lead to Hemorrhagic or Hemolytic anemia.

• Other causes include chronic disorders, endocrinal disorders, renal failure and liver disease

• The reticulocyte count aids in assessing red blood cell regeneration, indicating hyporegenerative or regenerative anemia.

Morphological Classification of Anemia:

• Microcytic Anemia: MCV is <80 fL Includes:

• Iron deficiency anemia

• Thalassemia

• Lead poisoning

• Sideroblastic anemia

• Anemia of chronic disease

• Normocytic Anemia: Normal MCV Includes:

• Hemolytic anemia (except thalassemia)

• Hemorrhagic anemia

• BM failure

• Anemia of chronic disease

• Renal disease

• Mixed deficiency

• Macrocytic Anemia: MCV is > 95-100 fL

• Megaloblastic includes Vit B12 and Folate deficiencies

• Non-megaloblastic includes Alcohol, Pregnancy, Liver Dieases, Smoking, and Reticulocytosis

• Mean Corpuscular Volume (MCV) indicates the size of red blood cells

• Mean Corpuscular Hemoglobin (MCH) indicates the hemoglobin concentration inside red blood cells

BM Proliferative Response

• Hypo-proliferative (Aregenerative) BM:
• BM failure (Aplastic anemia)
• Myelodysplasia
• Anemia of chronic disease
• Megaloblastic anemia
• Hyperproliferative (Regenerative) BM:
• Hemorrhage
• Hemolysis
• Reticulocytes' count range is 0.5-2.5%.

Clinical Manifestations of Anemia:

• Clinical features reflect diminished oxygen supply to the tissues, depending on the speed of onset, severity, age of patient, and underlying diseases like cardiovascular issues.

Symptoms:

• Central Nervous System (CNS) symptoms include lack of concentration, headache, tinnitus and blurring of vision
• Cardiovascular System (CVS) symptoms include low cardiac output, exertional dyspnea, palpitation, angina, intermittent claudication, and heart failure symptoms in severe cases.
• Skeletal symptoms include bone ache and fatigability.
• Genital symptoms may include menstrual disturbance, especially amenorrhea, and decreased libido.
• Renal symptoms include Polyuria.

Signs:

• Pallor, detected in palm and palmer creases, nail bed, tongue, and inner conjunctiva, differentiating from infective endocarditis, myocardial infarction, or myxedema.
• Cardiovascular signs include tachycardia, hemic murmur (aortic, soft midsystolic, no thrill), collapsing pulse, capillary pulsation, and congestive heart failure.
• Edema in lower limbs, with increased capillary permeability.
• Heart Failure (HF).
• Specific identifiers include:
• Koilonychia (spoon nails) and angular stomatitis indicate iron deficiency anemia
• Jaundice indicates Hemolytic and Megaloblastic anemias,
• Bone deformity & mongoloid facies indicates thalassemia
• Leg ulcers may indicate sickle cell anemia
• Purpura & infection may indicate decreased Bone Marrow and infiltration
• A beefy red tongue may indicate a painful tongue due to megaloblastic issues.
• Pain and paresthesia indicate B12 deficiency (subacute combined degeneration).

Laboratory Investigation

Complete Blood Count findings:

• Red blood cell characteristics can be normocytic, microcytic, or macrocytic,

• Pancytopenia: a decrease found in aplastic anemia, hypersplenism, myelofibrosis, A leukemic leukemia, BM infiltration, Megaloblastic anemia, PNH and SLE

• Examination assesses BMF, Leukemia, or Infiltration

• Reticulocyte Count: An elevated count indicates Hemolytic or Hemorrhagic anemia, and low levels signifies Bone marrow Failure or infiltration.

Investigation According to Morphology:

Microcytic Anemia

• Serum Iron levels are commonly between 90-150 ug%
• Serum Ferritin levels are between 20-250 ng
• TIBC levels are between 280-400 ug%
• Hemoglobin Electrophoresis is used in Thalassemia

Normocytic Anemia:

• Reticulocytes are elevated in hemolytic or hemorrhagic conditions and decreased in bone marrow failure.
• BMA (Bone Marrow Aspiration) and BMB (Bone Marrow Biopsy) in aplastic anemia show decreased cellularity and increased fatty spaces.

Investigations for Hemolytic Anemia:

• Investigations according to type: Increased Serum bilirubin (indirect), urine urobilinogen, and fecal stercobilinogen and Decreased serum haptaglobin, reticulocytosis, and BMA erythroid hyperplasia.
• Hereditary*:
• Hemoglobin electrophoresis detects hemoglobinopathies.
• Sickling test diagnoses sickle anemia.
• Osmotic fragility tests for spherocytosis.
• Enzyme assay is performed for GP6D.
• Acquired*:
• Direct Coombs' test identifies autoimmune hemolytic anemia. (hemolysis of RBCs at low pH serum).
• Ham's test and flow cytometry diagnose PNH

Macrocytic Anemia:

• Serum Folate levels should be assessed,
• The B12 level tests should be preformed.

Iron Deficiency Anemia

• The most common cause of anemia.
• The most important cause of microcytic hypochromic anemia.
• The most commonly affected demographics are young children, adolescent girls, and women.
• Iron is absorbed in the duodenum

Etiology of IDA

• Low Iron Diet: Can be found in young children and restricted diets such as vegetarians and vegans.
• External Blood Loss: Menstrual blood loss, gastrointestinal blood loss, and blood donation
• Malabsorption: Gastrointestinal conditions and Iron refractory iron deficiency anemia

Clinical Presentation of IDA:

Symptoms:

• General anemia signs
• Painless glossitis, angular stomatitis
• Pica, unusual dietary cravings
• Brittle, ridge or spoon nails, known as (koilonychia)
• Dysphagia is a result of pharyngeal webs (Paterson-Kelly or Plummer-Vinson syndrome)

Signs:

• Koilonychia
• Angular cheilosis
• Paterson-Kelly (Plummer – Vinson syndrome; barium swallow X-ray shows a filling defect due to the post-cricoid web)

Diagnosing IDA:

• Positive clinical history.
• Microcytic anemia on CBC (complete blood count).
• Microcytosis, hypochromia, pencil cells, and anisopoikilocytosis on blood film examination.
• Decreased reticulocyte count in relation to anemia.
• Low serum iron, increased TIBC, and low transferrin saturation.
• Low serum ferritin.
• Occult blood tests.
• Helicobacter pylori testing.
• Radiological imaging (pelviabdominal ultrasound or CT).
• Upper and lower gastrointestinal endoscopy.
• Consider other causes of microcytic anemia if the history is inconsistent or the iron panel is normal

Treatment of Iron Deficiency Anemia

• Address the underlying etiology.
• Implement a nutritional plan: iron-rich diet including meat, liver, and beans.
• Minimize blood loss through hormonal therapy and treatment of underlying uterine disorders.
• Oral supplementation: Ferrous sulfate is used commonly due to better absorption, Ferrous fumarate, and Ferrous gluconate are other options.
• Parenteral iron: Ferric hydroxide and Iron dextran can be used
• Not considered standard of care for most patients
• Used in patients with chronic kidney diagnosis, with intolerance to oral iron, with malabsorption, with persistent IDA despite oral iron therapy and for severe cases.

Etiology of Refractory IDA

• There may be an incorrect initial diagnosis.
• Ongoing blood loss
• Insufficient iron dose
• Non-adherence to treatment.
• Malabsorption due to inflammation or underlying gastrointestinal condition.
• Genetic mutations causing resistance to iron absorption

Key Points for clinical practice

• There are different types and different classifications of anemia.
• Not every microcytic anemia is IDA (iron deficiency anemia).
• Full iron profile investigations are needed for diagnosis confirmation.
• Identify, find, and correct the underlying cause if IDA is confirmed.