Haematopoiesis & Approach to anaemia
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Transcript of Haematopoiesis & Approach to anaemia
Haematopoiesis&
Approach to Anaemia
Dr (Brig) YD SinghMBBS, MD, FIACM, DIT
Professor (Internal Medicine)
SKN Medical College & Gen Hospital
Pune 411 041
12 Apr 2023
Dr (Brig) YD Singh
Haematopoiesis (1)
• Process by which formed elements of blood – Produced & Regulated through series of steps
• Pluripotent haematopoietic stem cell– Capable of producing red cells,– All classes of granulocytes, monocytes, platelets– Mechanism to become committed to a given
lineage Not fully known
12 Apr 2023
Dr (Brig) YD Singh
Haematopoiesis (2)• Following lineage commitment
– Haematopoietic progenitor & precursor cells Come under regulatory influence of growth factors
and hormones.
– For red cell production Erythropoietin (EPO) is regulatory hormone
– EPO is required for Maintenance of Committed Erythroid progenitor cells
– In absence of EPO hormone Undergo programmed cell death (apoptosis)
12 Apr 2023 Dr (Brig) YD Singh
Factors Regulating RBCProduction
Regulated process of RBC production is Erythropoiesis
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Dr (Brig) YD Singh
RBC Characteristics• Mature red cell is 8 micron in diameter
– Anucleate , Biconcave & discoid in shape– Extremely pliable
Needs to traverse microcirculation easily
– Membrane integrity maintained by Intracellular generation of ATP
• Average RBC lives 100–120 day• 1% of all circulating RBC daily replaced• Erythron: Organ for red cell production
– Pool of marrow erythroid precursor cells & large mass of mature circulating RBCs
12 Apr 2023
Dr (Brig) YD Singh
RBCs : Normal Indices
• Mean cell volume (MCV)(Haematocrit x10) / (RBC count x 106) =90 ± 8 fL
• Mean Cell Haemoglobin (MCH)(Hb x 10) / (red cell count x 106) = 30 ± 3 pg
• Mean cell Hb concentration (MCHC)(Hb x 10) / hematocrit or MCH/MCV = 33 ± 2%
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Dr (Brig) YD Singh
Leukocytes• All Leukocytes derived from
– Common Stem cell in Bone marrow– 3/4th of nucleated cells of bone marrow
Committed to production of Leukocytes
• Mediate Inflammatory / Immune Responses– Include Neutrophils, T & B Lymphocytes – Natural Killer (NK) cells, Monocytes– Eosinophils & Basophils
• These cells have specific functions– Antibody production by B Lymphocytes– Destruction of bacteria by Neutrophils
12 Apr 2023 Dr (Brig) YD Singh
Granulocytes Development (1)
12 Apr 2023 Dr (Brig) YD Singh
Granulocytes Development (2)
12 Apr 2023 Dr (Brig) YD Singh
Neutrophils
Neutrophil band with Döhle body
Normal Neutrophil
12 Apr 2023 Dr (Brig) YD Singh
Eosinophil Large bright orange granules
usually bilobed Nucleus
Basophil Large purple-black granules fill the cell & obscure nucleus
12 Apr 2023 Dr (Brig) YD Singh
Normal Bone Marrow
Low Power View
12 Apr 2023
Dr (Brig) YD Singh
Bone marrow
Normoblast Cell
Eosinophil Cell
Erythrocyte Cell
Myelocyte dividing
Myelocyte Cell
Normoblast with dividing Nucleus
Fat CellFat Cell
Fat Cell
Myelocyte Cell
12 Apr 2023 Dr (Brig) YD Singh
Bone Marrow: Erythroid Hyperplasia
12 Apr 2023 Dr (Brig) YD Singh
Bone Marrow: Myeloid Hyperplasia
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Dr (Brig) YD Singh
Anaemia: Introduction
• Serum Hb level or haematocrit < expected value for age & sex
• WHO criteria– Adult men
Blood Hb concentration <13 g/dL or Hematocrit <39%
– Adult women Blood Hb concentration <12 g/dL) or Hematocrit <37%
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Types
• Iron-Deficiency Anemia • Vitamin B12 Deficiency Anemia • Folate-Deficiency Anemia • Anemia of Chronic Disease• Haemolytic Anaemia • Aplastic Anemia • Myelodysplastic Syndromes
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Mechanisms
• 3 major physiologic mechanisms of anemia • Marrow production defects (Hypoproliferation)
– Reflects absolute or relative marrow failure – Erythroid marrow not proliferated appropriately– Can result from
Marrow damage Iron deficiency Inadequate erythropoietin stimulation
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Mechanisms
• Ineffective erythropoiesis (RBC maturation defects)– Nuclear maturation defects associated with
macrocytosis & abnormal marrow development – Cytoplasmic maturation defects associated with
microcytosis and hypochromia, usually from defects in hemoglobin synthesis
• Decreased erythrocyte survival: blood loss or hemolysis
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Symptoms & Signs (1)
• Often recognized by abnormal results on screening lab tests
• Signs and symptoms depend on– Level of anaemia – Time course over which it developed
Acute onset Anaemia Chronic Anaemia
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Symptoms & Signs (2)
• Acute anaemia (nearly always due to blood loss or haemoptysis)
• If Loss of 10–15% of total blood volume– Hypotension – Decreased organ perfusion
• Loss of >30% of blood volume – Postural hypotension – Tachycardia
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Symptoms & Signs (3)
• Loss of >40% of blood volume – Hypovolemic shock
Confusion Dyspnoea Diaphoresis Hypotension Tachycardia
• Haemolytic Anaemia – Presentation depends on mechanism that
leads to RBC destruction
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Symptoms & Signs (3)
• Chronic or progressive anaemia – Presentation depends on age of patient – Adequacy of blood supply to critical organs
• Possible Symptom / Sign – Fatigue and Loss of stamina – Breathlessness (specially on exertion)– Pale skin and mucous membranes (Pallor) – Palpitation (Tachycardia, after physical exertion) – Forceful heartbeat (Heaving Apex beat)– High Volume pulse & Systolic flow murmur
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Symptoms & Signs (4)
• In patients with coronary artery disease – Anginal episodes may appear or – Increase in frequency and severity
• In patients with carotid artery disease – Light-headedness – Dizziness may develop
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: DD (1)
• Hypoproliferative anaemias (75% of cases) – Marrow damage
Infiltration/fibrosis Aplasia
– Iron deficiency (mild to moderate) – Decreased stimulation
Inflammation Metabolic defect (Hypothyroidism) Renal disease
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: DD (2)• Maturation disorder
– Cytoplasmic defects Iron deficiency (severe) Thalassemia Sideroblastic
– Nuclear defects Folate deficiency , Vitamin B 12 deficiency Drug toxicity
– Methotrexate & Alkylating agents – Alcohol
Refractory anemia – Myelodysplasia
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: DD (3)
• Haemolysis / Haemorrhage – Blood loss – Intravascular haemolysis – Metabolic defect – Membrane abnormality – Haemoglobinopathy – Autoimmune defect – Fragmentation haemolysis
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Diagnostic Approach (1)• 02 questions need to be answered:
– Type of Anaemia & Cause of Anaemia
• Careful history – Nutritional history
Related to diet, drugs or alcohol
– Family history of anaemia (Genetic)– Geographic backgrounds and ethnic origins
G 6 PD deficiency Haemoglobinopathies
– Middle Eastern, Mediterranean, or African origin
– Exposure to toxic agents or drugs
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Diagnostic Approach (2)
• Physical examination – May provide clues to mechanisms / cause of
anaemia Infection Blood in the stool Splenomegaly & Lymphadenopathy Petechiae suggest platelet dysfunction.
• Laboratory assessment – Including review of past laboratory
measurements to determine time of onset
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Diagnostic Approach (3)
• Physiologic classification / Type of anaemia• Reticulocyte index <2.5 & Normocytic,
Normochromic anaemia – Hypoproliferative
Marrow damage: – Infiltration / fibrosis – Aplasia
Decreased stimulation:– Inflammation– Metabolic defect– Renal disease
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Diagnostic Approach (4)
• Reticulocyte index <2.5 & microcytic or macrocytic anemia – Maturation disorder
Cytoplasmic defects: – Iron deficiency, – Thalassemia, Sideroblastic
Nuclear defects: – Folate deficiency– Vitamin B deficiency– Drug toxicity
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Diagnostic Approach (5)
• Reticulocyte index ≥2.5 – Haemolysis / Haemorrhage
Blood loss Intravascular haemolysis Metabolic defect Membrane abnormality Haemoglobinopathy Autoimmune defect
12 Apr 2023 Dr (Brig) YD Singh
Anaemia Algorithm
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Dr (Brig) YD Singh
Normal Blood Smear (Wright’s stain)
Normal RBCs, single Neutrophil & few platelets seen
12 Apr 2023 Dr (Brig) YD Singh
Reticulocytes (Supravital Stain)
Reticulocyte count is key to initial classification of anemia Reticulocytes are RBCs recently released from marrow
12 Apr 2023
Dr (Brig) YD Singh
Severe Iron Def Anaemia(Wright’s stain)
Microcytic & Hypochromic RBCs smaller than nucleus of a Lymphocyte + marked variation in size (Anisocytosis) &
shape (Poikilocytosis)
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Dr (Brig) YD Singh
Macrocytosis
RBCs larger than small Lymphocyte & well haemoglobinized. Macrocytes are oval-shaped
(Macroovalocytes)
12 Apr 2023
Dr (Brig) YD Singh
Howell-Jolly bodies
In absence of functional spleen, nuclear remnants are not expelled from RBCs & remain as small homogeneously
staining blue inclusions on Wright stain
12 Apr 2023
Dr (Brig) YD Singh
Red cell changes in myelofibrosis
A Teardrop-shaped RBC & a Nucleated RBC is seen. These forms are seen in Myelofibrosis with Extramedullary
Haematopoiesis
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Dr (Brig) YD Singh
Red cell changes in Thalassemia & Liver disease
Target cells have a bull’s-eye appearance & are seen in Thalassemia & Liver disease
12 Apr 2023
Dr (Brig) YD Singh
Red cell changes in Sickle Cell Disease
Sickle shaped cells are seen in Sickle Cell disease
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Lab Tests• CBC
– Erythrocyte count Haemoglobin & Haematocrit Reticulocyte count Erythrocyte indices Mean cell volume (MCV) Mean cell haemoglobin Mean cell haemoglobin concentration
– Leukocyte count Cell differential Nuclear segmentation of Neutrophils
12 Apr 2023
Dr (Brig) YD Singh
Anaemia: Lab Tests
– Platelet count – Cell morphology
Cell size Anisocytosis (variations in cell size) Poikilocytosis (variations in cell shape) Polychromasia
– Iron supply studies Serum iron Total iron-binding capacity (TIBC) Serum ferritin, marrow iron stain
12 Apr 2023
Dr (Brig) YD Singh
Hypoproliferative Anaemia: Key Tests
• Serum iron & iron-binding capacity • Serum ferritin, to assess iron stores • Evaluation of renal & thyroid function • Marrow biopsy or aspirate
– Detect marrow damage or infiltrative disease
• Anemia of chronic inflammation shows– Low serum iron & Normal or low TIBC – Low percent transferrin saturation – Normal or high serum ferritin
12 Apr 2023
Dr (Brig) YD Singh
Hypoproliferative Anaemia: Key Tests• Mild to moderate iron deficiency anaemia:
– Low serum iron level & High TIBC – Low percent transferrin saturation – Low serum ferritin level
• Marrow damage by drug, infiltrative disease (Leukaemia / Lymphoma / Aplasia)– Peripheral blood and – Bone marrow morphology
• Infiltrative disease or fibrosis – Marrow biopsy will likely be required
12 Apr 2023
Dr (Brig) YD Singh
Maturation disorders Anemia: Tests
• Vitamin B12 • Folate • Serum iron and iron-binding capacity • Serum ferritin to assess iron stores • Haemoglobin electrophoresis
12 Apr 2023
Dr (Brig) YD Singh
Haemolytic Anemia: Tests
• Haemoglobin electrophoresis • Screen for red cell enzymes • Direct or indirect anti-globulin test • Cold agglutinin titre
12 Apr 2023
Dr (Brig) YD Singh
Anaemia Classification
• Based on defect in RBC production – Marrow production defects: Hypo-proliferation – Maturation defects: Ineffective Erythropoiesis – Decreased survival: Blood Loss / Haemolysis
• Classification by MCV – Microcytic: MCV <80 fL – Normocytic: MCV 80–100 fL – Macrocytic: MCV >100 fL
12 Apr 2023
Dr (Brig) YD Singh
Complications: Anaemia
• High-output Cardiac Failure • End-organ ischemia or infarct
– Myocardial infarction – Stroke
• Hypovolumic shock • Death
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Dr (Brig) YD Singh
Management Pearls: Anaemia
• Anaemia may be Multi-factorial – Finding one cause does not mean that no other
forms of anaemia are present – Iron deficiency may occur with folate / B12 def
Producing Dimorphic anaemia
• Iron deficiency often means – Occult blood loss– Worms infestation– Nutritional
12 Apr 2023
Dr (Brig) YD Singh
Treatment Approach: Anaemia
• Mild to Mod Anaemia– Initiate treatment when sp diagnosis is made
• Selection of treatment – Determined by cause of anaemia – Cause may be multi-factorial – Evaluate iron status before starting treatment
• Rarely anaemia may be so severe – RBC transfusions required before specific
diagnosis is made