Anemia
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Overview of Anemia
Dr. Adnan Qureshi
Resident Haematology Aga Khan University Hospital
Red Cell Production (Erythropoiesis) Kidney
Bone Marrow
Epo
Multi-potent stem cell Erythroid stem cell
Oxygen sensor 3-4 days
Blood vessel
Peripheral blood RBC survival 100-120 days
Anemia
Definition
Understanding anemia • Condition - a secondary manifestation of another disease
Causes • Impaired red cell production • Increased rate of destruction • Blood loss
Classification of Anemia Different modes of classification Clinical findings • Acute / Chronic • Hereditary / Acquired
Red cell size • Determined by MCV
Red cell kinetics • Determined by reticulocyte count
Anemia - Causes
Blood loss • Acute • Chronic Increased destruction • Intrinsic – Membrane disorders: HS, HE … – Enzyme deficiencies: G6PD, PK … – Disorder of hemoglobin synthesis: Hemoglobinopathies, PNH …
• Extrinsic – Antibody mediated – Mechanical trauma: MAHA, TTP, DIC – Infections: malaria – Sequestration
Impaired production • • • • • • • •
Aplastic anemia PRCA Anemia of Chronic disease Anemia of renal failure Anemia of endocrine disorders Iron deficiency anemia Megaloblastic anemia Etc….
Laboratory Evaluation of Anemia
Commonly ordered test • CBC • Peripheral film
Supplementary test (depending upon the initial findings) • • • • •
Retic count Coomb’s test HB elctrophoresis G6PD Bone marrow
Reticulocyte Count
Relative reticulocyte count • Percent of all RBC
Corrected reticulocyte count • Retic % x
Pt. Hct Normal Hct
Absolute reticulocyte count • Relative reticulocyte count x RBC count
Reticulocyte production index (RPI)
Classification of Anemia Based on RBC Size MCV Microcytic < 76fl
Normocytic 76-96 fl
Macrocytic > 96 fl
Hypochromic Microcytic Anemia:
Causes: • Iron deficiency • Thalassemia • Lead toxicity • Sideroblastic anemia • Long standing anemia of chronic disease
Causes of Iron Deficiency Iron deficiency is a symptom, not a disease
Increased iron requirements • Blood loss – Gastrointestinal tract – Genitourinary tract – Blood donation
• Pregnancy and lactation
Inadequate iron supply • Insufficient dietary iron • Impaired iron absorption – Gastric surgery – Intestinal malabsorption – Celiac disease
Iron Deficiency Anemia
Iron profile • Serum Iron
Low
• TIBC
Raised
• Serum Ferritin
Low
• Transferrin Saturation
Low
Thalassemia: Impaired Globin Gene Production Hgb A tetramer
α globin
β globin
β globin
α globin
Thalassemia
Decreased production of normal globin chains ∀ α thalassemia - deficiency of α gene(s) ∀ β thalassemia - deficiency of β gene(s)
Alpha Thalassemia: Clinical Features
Absence of 1-2 alpha chains • Common • Asymptomatic • Does not require therapy
Absence of 3 alpha chains (Hgb H disease) • Microcytic anemia (Hgb 7-10) • Splenomegaly
Absence of 4 alpha chains • Hydrops fetalis (non-viable)
X α2
α1
α2
α1
X XX α2
α1
α2
α1
XX XX α2
α1
α2
α1
α2
α1
α2
α1
XX
X X α2
α1
α2
α1
Alpha Thalassemia: Laboratory Findings Hemoglobin α Chains Hgb (g/dl) αα/αα
MCV (fl)
Normal
Analysis
Normal
Normal
αα/-α
12-14
75-85
Normal
α-/α- or --/αα
11-13
70-75
Normal with Hgb Barts (γ4); Hgb H (β4) - small
--/-α
7-10
50-60
Normal with Hgb Barts (γ4); Hgb H (β4) - large
--/--
-
-
Not viable
Beta Thalassemia Clinical Syndrome
Genotype
Minor (Trait)
β/β+ or β/β°
10-13
Intermedia
β+/β+
7-9
↑ Hgb A2, ↑↑ Hgb F
Major (Cooleys)
β+/β° or β°/β°
<7
↑ Hgb A2, ↑↑↑ Hgb F
Hgb (g/dl)
Hgb Analysis ↑ Hgb A2, ↑ Hgb F
Normocytic Anemia with Low Retic Count
Decreased stimulation of RBC production in bone marrow • Anemia of chronic disease • Chronic renal insufficiency
Isolated decrease in RBC precursors (red cell aplasia) Bone marrow damage
• • • •
Aplastic anemia Fibrosis Stem cell damage Infiltration with tumor/infection
Disorder of hematopoeisis • Myelodysplasia/sideroblastic anemia
Anemia of Chronic Disease
Associated conditions • Infections – Viral, bacterial, TB, parasitic, fungal
• Autoimmune diseases – RA, SLE, sarcoidosis, IBD, vasculitis
• Cancer
Characteristics • • • •
WBC and platelet counts are normal Anemia of variable severity (mild-severe) Low erythropoietin level Low reticulocyte count
Normocytic Anemia with High Reticulocyte Count
General principles • Bleeding may have similar lab findings as hemolysis • High reticulocyte count may lead to macrocytosis • Classification – Hereditary vs. acquired – Extravascular vs. intravascular – Immune vs. nonimmune
Hemolytic Anemia with Extravascular Hemolysis
Extravascular (reticuloendothelial system) • Hereditary – Hemoglobinopathies (sickle cell anemia) – Enzymopathies (G6PD deficiency) – Membrane defects (hereditary spherocytosis)
• Acquired – Immune mediated Autoimmune
hemolytic anemia
– Nonimmune mediated Spur
cell hemolytic anemia
Sickle Cell Disease
Mutation in beta globin (β6 Glu Val)
Inherited as autosomal recessive
Protection against malaria
Glucose-6-Phosphate Dehydrogenase Deficiency
G-6-PD - reduces NADP/oxidizes glucose-6-phosphate • Detoxifies free radicals and peroxides
Sex-linked disorder Effects > 200 million people Hemolytic anemia occurs in the presence of stress (infection or drugs)
• African form - mild hemolysis • Mediterranean form - more severe – Unique sensitivity to fava beans
Hereditary Spherocytosis
Autosomal dominant disorder
Abnormality in RBC membrane protein
Clinical and laboratory findings • Splenomegaly • Chronic hemolytic anemia • Spherocytes on peripheral smear • Increased osmotic fragility
Acquired Hemolytic Diseases
Immune mediated hemolytic anemia
Non-immune mediated
Autoimmune Hemolytic Anemia
Warm antibodies (IgG-mediated) • Primary • Secondary – Lymphoproliferative disease – Connective tissue disease – Infectious disease
• Drug-induced
Laboratory testing • Normocytic/macrocytic anemia • Peripheral smear – spherocytosis • Coomb’s test - positive
Anti-Globulin (Coombs) Testing Direct antiglobulin testing
+ Patients RBCs
Anti-C3d Anti-IgG
Hemolytic Anemia with Intravascular Hemolysis
Mechanical damage (Microangiopathic hemolytic anemia)
Chemical damage (Burns)
Infection (Malaria)
Transfusion reaction (ABO incompatibility)
Differential Diagnosis of Microangiopathic Hemolytic Anemia
Thrombotic thrombocytopenic purpura (TTP)
Hemolytic uremic syndrome (HUS)
Disseminated intravascular coagulation (DIC)
Vasculitis
Malignant hypertension
Metastatic neoplasm with vascular invasion
Preeclampsia/HELLP syndrome of pregnancy
Macrocytic Anemia with Low Reticulocyte Count
Megaloblastic anemia • Vitamin B12 deficiency • Folate deficiency
Nonmegaloblastic macrocytic anemia • • • •
Liver disease Hypothyroidism Drug-induced (DNA synthesis block) Myelodysplastic syndrome
Morphology ….
Thank You !
Dr. Adnan Qureshi
Resident Haematology Aga Khan University Hospital
Red Cell Production (Erythropoiesis) Kidney
Bone Marrow
Epo
Multi-potent stem cell Erythroid stem cell
Oxygen sensor 3-4 days
Blood vessel
Peripheral blood RBC survival 100-120 days
Anemia
Definition
Understanding anemia • Condition - a secondary manifestation of another disease
Causes • Impaired red cell production • Increased rate of destruction • Blood loss
Classification of Anemia Different modes of classification Clinical findings • Acute / Chronic • Hereditary / Acquired
Red cell size • Determined by MCV
Red cell kinetics • Determined by reticulocyte count
Anemia - Causes
Blood loss • Acute • Chronic Increased destruction • Intrinsic – Membrane disorders: HS, HE … – Enzyme deficiencies: G6PD, PK … – Disorder of hemoglobin synthesis: Hemoglobinopathies, PNH …
• Extrinsic – Antibody mediated – Mechanical trauma: MAHA, TTP, DIC – Infections: malaria – Sequestration
Impaired production • • • • • • • •
Aplastic anemia PRCA Anemia of Chronic disease Anemia of renal failure Anemia of endocrine disorders Iron deficiency anemia Megaloblastic anemia Etc….
Laboratory Evaluation of Anemia
Commonly ordered test • CBC • Peripheral film
Supplementary test (depending upon the initial findings) • • • • •
Retic count Coomb’s test HB elctrophoresis G6PD Bone marrow
Reticulocyte Count
Relative reticulocyte count • Percent of all RBC
Corrected reticulocyte count • Retic % x
Pt. Hct Normal Hct
Absolute reticulocyte count • Relative reticulocyte count x RBC count
Reticulocyte production index (RPI)
Classification of Anemia Based on RBC Size MCV Microcytic < 76fl
Normocytic 76-96 fl
Macrocytic > 96 fl
Hypochromic Microcytic Anemia:
Causes: • Iron deficiency • Thalassemia • Lead toxicity • Sideroblastic anemia • Long standing anemia of chronic disease
Causes of Iron Deficiency Iron deficiency is a symptom, not a disease
Increased iron requirements • Blood loss – Gastrointestinal tract – Genitourinary tract – Blood donation
• Pregnancy and lactation
Inadequate iron supply • Insufficient dietary iron • Impaired iron absorption – Gastric surgery – Intestinal malabsorption – Celiac disease
Iron Deficiency Anemia
Iron profile • Serum Iron
Low
• TIBC
Raised
• Serum Ferritin
Low
• Transferrin Saturation
Low
Thalassemia: Impaired Globin Gene Production Hgb A tetramer
α globin
β globin
β globin
α globin
Thalassemia
Decreased production of normal globin chains ∀ α thalassemia - deficiency of α gene(s) ∀ β thalassemia - deficiency of β gene(s)
Alpha Thalassemia: Clinical Features
Absence of 1-2 alpha chains • Common • Asymptomatic • Does not require therapy
Absence of 3 alpha chains (Hgb H disease) • Microcytic anemia (Hgb 7-10) • Splenomegaly
Absence of 4 alpha chains • Hydrops fetalis (non-viable)
X α2
α1
α2
α1
X XX α2
α1
α2
α1
XX XX α2
α1
α2
α1
α2
α1
α2
α1
XX
X X α2
α1
α2
α1
Alpha Thalassemia: Laboratory Findings Hemoglobin α Chains Hgb (g/dl) αα/αα
MCV (fl)
Normal
Analysis
Normal
Normal
αα/-α
12-14
75-85
Normal
α-/α- or --/αα
11-13
70-75
Normal with Hgb Barts (γ4); Hgb H (β4) - small
--/-α
7-10
50-60
Normal with Hgb Barts (γ4); Hgb H (β4) - large
--/--
-
-
Not viable
Beta Thalassemia Clinical Syndrome
Genotype
Minor (Trait)
β/β+ or β/β°
10-13
Intermedia
β+/β+
7-9
↑ Hgb A2, ↑↑ Hgb F
Major (Cooleys)
β+/β° or β°/β°
<7
↑ Hgb A2, ↑↑↑ Hgb F
Hgb (g/dl)
Hgb Analysis ↑ Hgb A2, ↑ Hgb F
Normocytic Anemia with Low Retic Count
Decreased stimulation of RBC production in bone marrow • Anemia of chronic disease • Chronic renal insufficiency
Isolated decrease in RBC precursors (red cell aplasia) Bone marrow damage
• • • •
Aplastic anemia Fibrosis Stem cell damage Infiltration with tumor/infection
Disorder of hematopoeisis • Myelodysplasia/sideroblastic anemia
Anemia of Chronic Disease
Associated conditions • Infections – Viral, bacterial, TB, parasitic, fungal
• Autoimmune diseases – RA, SLE, sarcoidosis, IBD, vasculitis
• Cancer
Characteristics • • • •
WBC and platelet counts are normal Anemia of variable severity (mild-severe) Low erythropoietin level Low reticulocyte count
Normocytic Anemia with High Reticulocyte Count
General principles • Bleeding may have similar lab findings as hemolysis • High reticulocyte count may lead to macrocytosis • Classification – Hereditary vs. acquired – Extravascular vs. intravascular – Immune vs. nonimmune
Hemolytic Anemia with Extravascular Hemolysis
Extravascular (reticuloendothelial system) • Hereditary – Hemoglobinopathies (sickle cell anemia) – Enzymopathies (G6PD deficiency) – Membrane defects (hereditary spherocytosis)
• Acquired – Immune mediated Autoimmune
hemolytic anemia
– Nonimmune mediated Spur
cell hemolytic anemia
Sickle Cell Disease
Mutation in beta globin (β6 Glu Val)
Inherited as autosomal recessive
Protection against malaria
Glucose-6-Phosphate Dehydrogenase Deficiency
G-6-PD - reduces NADP/oxidizes glucose-6-phosphate • Detoxifies free radicals and peroxides
Sex-linked disorder Effects > 200 million people Hemolytic anemia occurs in the presence of stress (infection or drugs)
• African form - mild hemolysis • Mediterranean form - more severe – Unique sensitivity to fava beans
Hereditary Spherocytosis
Autosomal dominant disorder
Abnormality in RBC membrane protein
Clinical and laboratory findings • Splenomegaly • Chronic hemolytic anemia • Spherocytes on peripheral smear • Increased osmotic fragility
Acquired Hemolytic Diseases
Immune mediated hemolytic anemia
Non-immune mediated
Autoimmune Hemolytic Anemia
Warm antibodies (IgG-mediated) • Primary • Secondary – Lymphoproliferative disease – Connective tissue disease – Infectious disease
• Drug-induced
Laboratory testing • Normocytic/macrocytic anemia • Peripheral smear – spherocytosis • Coomb’s test - positive
Anti-Globulin (Coombs) Testing Direct antiglobulin testing
+ Patients RBCs
Anti-C3d Anti-IgG
Hemolytic Anemia with Intravascular Hemolysis
Mechanical damage (Microangiopathic hemolytic anemia)
Chemical damage (Burns)
Infection (Malaria)
Transfusion reaction (ABO incompatibility)
Differential Diagnosis of Microangiopathic Hemolytic Anemia
Thrombotic thrombocytopenic purpura (TTP)
Hemolytic uremic syndrome (HUS)
Disseminated intravascular coagulation (DIC)
Vasculitis
Malignant hypertension
Metastatic neoplasm with vascular invasion
Preeclampsia/HELLP syndrome of pregnancy
Macrocytic Anemia with Low Reticulocyte Count
Megaloblastic anemia • Vitamin B12 deficiency • Folate deficiency
Nonmegaloblastic macrocytic anemia • • • •
Liver disease Hypothyroidism Drug-induced (DNA synthesis block) Myelodysplastic syndrome
Morphology ….
Thank You !
