Anemia - Pathophysiology

Pathophysiology for Physician Assistant Program

“Look at the sky. We are not alone.

The whole universe is friendly to us and conspires only to give the best to those who dream and work�

- Wings of Fire: An Autobiography of Dr. APJ Abdul Kalam.

Pathophysiology for Physician Assistant Program

Pathophysiology of Haemopoietic Disorders – Part 1- RBC (For Allied Health Courses)

Hemopoiesis, Anemia, IDA, MBA, Hemolytic, Polycthemia

Dr. Venkatesh M. Shashidhar.

Associate Professor & Head of Pathology

MX1002-PAS-Wk15: Hemopoietic system

Learning Objectives: • Review the formation of blood cells including differentiation into cell lines • Describe and differentiate RBC disorders i.e. Fe+ deficiency anaemia, megaloblastic anemia, pernicious anaemia and haemolytic anaemia and genetic disorders (ie. sickle cell, thalassemia, polycythemia.

• Describe and differentiate types of haemoatopoietic neoplasms. Differentiate between leukemia, lymphoma & Myeloproliferative disorders.

• Describe common diagnostic studies used in the evaluation of haematologic disorders

Success is going from failure to failure without loss of enthusiasm..! – Winston Churchill

MX1002-PAS-Wk15: Hemopoietic system

Haemopoiesis:

Bone Marrow

Blood

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MX1002-PAS-Wk15: Hemopoietic system

Hemopoietic organs: Yolk sac

Liver

&

Spleen

bone

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MX1002-PAS-Wk15: Hemopoietic system

Normal Bone Marrow:

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MX1002-PAS-Wk15: Hemopoietic system

Blood Smear - Normal PLT

PLT Lymph

RBC Many - bright pink, central pallor.

PLT Some - small particles, purple.

WBC Few - Blue – purple (lymphocyte) 8

MX1002-PAS-Wk15: Hemopoietic system

Blood Smear - Normal

RBC crenated RBC

Lymphocyte

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MX1002-PAS-Wk15: Hemopoietic system

Normal Blood Cells: Eosinophil <0.6 RBC 3.8-5.2 /1012/L

Neutrophil 2-8 x109/L Lymphocyte 1-4 x109/L

Basophil <0.2

Non granular, Mononuclear Leukocytes

Granulocytic Polymorphic Leukocytes

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MX1002-PAS-Wk15: Hemopoietic system

Blood count - C.B.C / F.B.C • Haemoglobin - 150±25, 140 ±25 - g/L. • PCV/HCT - 0.47 ±0.07, 0.42 ±0.05 - lit/lit (%) – RBC vol – better than Hb for anemia diagnosis.

Plasma ~ 55% Hct ~ 45%

• RBC count - 5.5 ±1, 4.8 ± 1 x1012/lit • MCHC - Hb/PCV - 30-36 – grams/deci lit.

– Hb synthesis within RBC

• MCH - Hb/RBC - 29.5 ± 2.5 pg picogram (wt) – Average Hb in RBC

• MCV - PCV/RBC 85 ± 8 – fl femto litres • Reticulocytes – 0.5 – 2.0 % - Immature RBC.

Volume

• WBC count: 4 - 11 x109 /L • WBC Differential: • Neutrophils 7, Eosinophils <0.6, Basophils <0.2, • Lymphocytes 2, Monocytes 1

• Platelets: 150,000 to 450,000 x106 /lit 11

MX1002-PAS-Wk15: Hemopoietic system

Normal CBC/FBC/Hemogram:

WBC Scattergram

RBC Histogram 12

Pathophysiology for Physician Assistant Program

Pathophysiology of

Anemia (For Allied Health Courses)

Iron Deficiency, Megaloblastic & Hemolytic

Dr. Venkatesh M. Shashidhar.

Associate Professor & Head of Pathology

MX1002-PAS-Wk15: Hemopoietic system

Definition of Anemia: “Anemia is, decreased red cell mass affecting tissue oxygenation” •

Low Hb* or Low HCT / PCV *

• Hb <130 g/l in male, <110.5 g/l in female adult *

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MX1002-PAS-Wk15: Hemopoietic system

Symptoms

-

Pathogenesis

Tiredness, dyspnoea

Tissue Hypoxemia ď&#x192; Fatty liver, heart, kidney, Angina,

Mucosal pallor

Decreased RBC - Anaemia

Glossitis

Epithelial damage - haematinic deficiency

(sore mouth/tongue)

Spoon-shaped nails

Due to iron deficiency

Jaundice

Bilirubin accumulation from haemolysis.

infections

Neutropenia, lymphopenia, low immunoglobulins, macrophage function. e.g. leukaemia, lymphoma, hypoplasia, chemotherapy.

Splenomegaly

expansion of haemopoiesis, pooling of RBC/WBC, excess destruction of RBC, infiltration in leukemia, lymphoma & other ca.

What is the Pathogenesisâ&#x20AC;Ś?

Also non-haematological causes, e.g. portal hypertension Lymphadenopathy

Non-neoplastic causes, e.g. infectious mononucleosis Infiltration with leukaemia or lymphoma

Bone pain and fractures

Osteoclast activation in myeloma

External bleeding Purpura,

Thrombocytopenia or platelet dysfunction

bruising, mucosal or traumatic

Internal bleeding Joint bleed, hematoma.

Coagulation factor deficiency

MX1002-PAS-Wk15: Hemopoietic system

Mechanism & Types of Anemia : • Decreased Production: – Nutrient Deficiency.

• Iron Deficiency Anemia (IDA).

• B12 / Folate deficiency or Megaloblastic anemia. (MBA)

– Hemopoietic cell damage • Aplastic & Hypoplastic anemia. – marrow failure – rare.

• Increased loss / destruction: – Blood loss anemia – bleeding - acute / Chronic.

– Hemolytic anemia – Congenital / Acquired.

• Acquired / External RBC defect – immune, mech, drugs & parasites

• Congenital / Internal RBC defect – Sickle, thalassemia, spherocytosis, etc.

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MX1002-PAS-Wk15: Hemopoietic system

Microcytic

MCV

Anemia clinical Types & Diagnosis

Normocytic

Macrocytic

Measure Ferritin Low Iron def Anemia

Measure B12 + Folate

Normal/high

Normal

Anemia of chronic disease/ Congenital Hb dis.

Low

Megaloblastic anemia

Reticulocyte count

Hemolytic anemia or blood loss

high

low

Anemia of chronic disease Renal failure Marrow failure

MX1002-PAS-Wk15: Hemopoietic system

Microcytic

MCV

Anemia clinical Types & Diagnosis

Normocytic

Macrocytic

Measure Ferritin Low Iron def Anemia

Measure B12 + Folate

Normal/high

Normal

Anemia of chronic disease/ Congenital Hb dis.

Low

Megaloblastic anemia

Reticulocyte count

Hemolytic anemia or blood loss

high

low

Anemia of chronic disease Renal failure Marrow failure

MX1002-PAS-Wk15: Hemopoietic system

Anemia Pathogenesis: MEGALOBLASTIC An. (pancytopenia) Less DNA   divisions  Big Few Cells*

Macrocytes

Iron Cytoplasm

B12 / Folate Nucleus:

NORMAL

Proerythroblast (Pronormoblast)

Polychromatophilic Normoblast

Basophilic Normoblast

Reticulocyte

Orthochromatophilic Erythrocyte Normoblast IRON DEFICIENCY An.

Less Hb, normal nucleus  more divisions  Many small RBC.

MX1002-PAS-Wk15: Hemopoietic system

IDA - Etiology • Blood loss – Parasites, Gynecologic/Obstetric, bleeding ulcers, polyps, cancers, Enteritis etc.

• Increased need – Pregnancy, children

• Poor diet / poor absorption – Malnutrition, malabsorption, intestinal surgery, gastric atrophy.

• Block in Iron transfer: – Anemia of Chronic Disease (TNF) 20

MX1002-PAS-Wk15: Hemopoietic system

CBC Analyzer Report - IDA

Normal

MX1002-PAS-Wk15: Hemopoietic system

Clinical Features: • General features of Anemia – Pallor, Weakness, Lethargy, – Breathlessness on exertion – Palpitations  heart failure.

• Special features in IDA: – – – – –

Angular cheilitis, atrophic glossitis, Koilonychia, brittle nails, Oesophageal atrophy/web, Gastric atrophy.

Angular chelitis

Pale conjuctiva

Pale creases

Bald Fissured - Glossitis 22

MX1002-PAS-Wk15: Hemopoietic system

IDA on therapy: Dimorphic RBC.

1. Microcytic, Hypochromic 2. Anisopoikilocytosis 3. Pencil cells.

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MX1002-PAS-Wk15: Hemopoietic system

Anemia of Chronic Disease • Any chronic disease.

• Failure of transfer of iron from store to RBC. • Mild Microcytic Hypochromic.

• Decreased RBC count.

• Low reticulocyte count.

• Normal or increased Iron studies.

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MX1002-PAS-Wk15: Hemopoietic system

Megaloblastic anemia: • • • • • • • •

Vitamin B12/Folic acid – DNA Synthesis.

Second most common type of anemia.

Vit B12 in Bacteria & animal food only.

Folate – in Plant foods only (uncooked)  DNA, in all cell lines  pancytopenia.  cell divisions  Megaloblasts.

Breakdown in marrow  hemolysis (jaundice).

Etiology: – Malnutrition – old age – Gastro-intestinal disorders.

• Gastrectomy, surgery, resection, Malabsorption syndromes - Sprue • Pernicious anemia – atrophic gastritis.

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MX1002-PAS-Wk15: Hemopoietic system

Megaloblastic Anemia :

• Mild Jaundice due to destruction of abnormal RBC within marrow – hemolysis.

• Glossitis – loss of epithelial integrity  inflammation 26

MX1002-PAS-Wk15: Hemopoietic system

CBC Analyzer Report - MBA

Normal

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MX1002-PAS-Wk15: Hemopoietic system

Megaloblastic Anaemia: Oval Macrocyte

Macropolycyte / Hypersegmented neutrophil 28

MX1002-PAS-Wk15: Hemopoietic system

Haemolytic An. Introduction Pathophysiology: • Increased RBC destruction – anemia.

• Decreased RBC life span (<120d) • Released Hb  ↑Bilirubin (Unconj)  Jaundice • Marrow hyperplasia: ↑ retics & bone chnages.

Diagnostic Features: • Pallor & Jaundice (No bile in urine) No itching* • Splenomegaly & Pigment gall stones (chronic) • Low Haptoglobins – Hb carrier proteins.

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MX1002-PAS-Wk15: Hemopoietic system

Hemolytic Anemia - Types: • Acquired / External causes: – Immune Hemolytic Anemia

Commonest

• Warm Antibody HA (WAHA) & Cold Ab (CAHA)

– Mechanical Damage • Valve disorders, Microangiopathy (DIC).

– Infection - Clostridia, malaria, septicemia

• Congenital / Internal causes: 1. Membrane - Hereditary Spherocytosis 2. Hemoglobin – Qualitative - Sickle cell anemia.

Quantitative – Thalassemias (α, β) 3. Enzyme - G6PD deficiency.

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MX1002-PAS-Wk15: Hemopoietic system

Laboratory Evaluation: • Features of RBC breakdown: – Hyperbilirubinemia (jaundice) – Low or absent Haptoglobins

• Features of increased RBC Production: – Reticulocytosis.

– Marrow hyperplasia – bone changes

• Damaged RBC – – – – –

Abnormal Morphology – sickle, thalassemia, Increased Osmotic Fragility Decreased RBC survival – 51Cr labelling.

Hemoglobin electrophoresis enzyme deficiency 31

MX1002-PAS-Wk15: Hemopoietic system

CBC Analyzer Report - Hemolytic

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MX1002-PAS-Wk15: Hemopoietic system

Hemolytic anemia: Morphology • Abnormal shapes (here a spherocyte)

• Polychromatophil (large, bluish, immature RBC)

• Nucleated RBC (small, pyknotic nucleus)

Warm Ab Hemolytic An. Thalassemia 33

MX1002-PAS-Wk15: Hemopoietic system

G6PD Deficiency Anemia: 1.

2.

3.

4.

5.

6.

G6PD def (older RBC) Oxidative Hb Denaturation Heinz bodies (globins) Splenic sequestration. blister cells.

Haemolysis

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MX1002-PAS-Wk15: Hemopoietic system

Sickle Cell Anemia

• • • •

Commonest congenital hemolytic anemia.

Hemoglobinopathy – β chain 6(ValGlu)  HbS Deoxigenation  rigid sickle cells BV obstruction & hemolysis.

Hemolytic anemia, Multiple Infarcts, autosplenectomy, pigment gall stones.

MX1002-PAS-Wk15: Hemopoietic system

Thalassemia: Anemia & Bone changes in Thalassemia major

• Quantitative Hb defect.

• Decreased protein chain synthesis of hemoglobin.

• α, β, , , … types.

• α thal  α  Hb   β (β β or β tetramers).

• Decreased normal Hb. • Abnormal protein (α/β tetramers)  hemolytic anemia.

• Thal. Minor: Mild anemia.

• Thal. Major: severe hemolysis.

Minor / Trait

Major / Disease 36

MX1002-PAS-Wk15: Hemopoietic system

Summary : Hemolytic anemia Immunohemolytic Anemias: • Caused by antibody binding to RBC, resulting in hemolysis or phagocytosis in the spleen. Warm IgG & Cold IgM types.

Hereditary Spherocytosis: • Inherited red cell membrane skeleton abnormality, leading to loss of membrane and formation of small round stiff spherocytes, which break down or phagocytosed and removed in the spleen. splenomegaly.

Sickle Cell Anemia: • Congenital Mutation in β-globin chain  HbS which crystalises on less oxygen forming distorted RBC sickle cells. Leads to blockage of BV (infarctions) & hemolysis  acute pain crises and tissue infarction & hemolytic anemia.

Thalassemias: • Mutations in the α- or β-globin genes result in reduced hemoglobin synthesis, Minor: mild micro/hypo anemia like IDA. Major: severe hemolytic anemia, marrow expansion and bone abnormalities.

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency: • X-linked, blacks, RBC undergo oxidative damage - flava beans, drugs etc.

MX1002-PAS-Wk15: Hemopoietic system

High Hb  Polycythemia • Compensatory:  Hypoxia.

– high altitude (>3000m), excess Fetal Hb.

• Spurious polycythaemia/Gaisbock’s sy.

– smoking, obesity (Pickwick sy), hypertension & excess alcohol (stress polycythaemia)

• Primary polycythaemia (neoplastic) – polycythaemia rubra vera – myeloproliferative.

• Inappropriate erythropoietin excess: Uterine fibroids, SCC lung, Renal CC. 38

MX1002-PAS-Wk15: Hemopoietic system

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