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Summary

ANEMIA It is a manifestation of a certain disease associated with:  Decreased in Red Blood Cells  Decreased in Hematocrit  Decreased in Hemoglobin DEFINITION OF ANEMIA Functional  Decreased in the oxygen carrying capacity of the blood. Operational  Reduction from the baseline value for the tota...

Description

ANEMIA It is a manifestation of a certain disease associated with:  Decreased in Red Blood Cells  Decreased in Hematocrit  Decreased in Hemoglobin DEFINITION OF ANEMIA Functional  Decreased in the oxygen carrying capacity of the blood. Operational  Reduction from the baseline value for the total number of RBCs, amount of circulating hemoglobin and RBC mass for a particular patient. Conventional  Decrease in RBCs, hemoglobin and hematocrit below the reference interval for healthy individuals of the same age, sex, and race, under similar environmental conditions. CLINICAL FINDINGS OF ANEMIA 1. History 2. Physical Examination 3. Signs and Symptoms 4. Laboratory Procedures  CBC  Iron Studies  Hemoglobin Electrophoresis Common Symptoms of Anemia  Shortness of Breath  Fatigue History of Patient  Diet  Bleeding History  Drug Ingestion  Occupation  Exposure to chemicals  Travels  Previous Medications  Ethnic Groups  Family History of Disease  Hobbies  Neurologic Symptoms

Physical Examination

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Skin  Pallor (hgb) , Jaundice (hemolysis) and Petechiae (breakage of the capillaries) Eyes (Hemorrhage) Mouth (Mucosal Bleeding) Sternal Tenderness Lymphadenopathy Cardiac murmurs Splenomegaly Hepatomegaly Vital Signs  Temperature, Blood Pressure and Heart Rate

GENERAL CAUSES OF ANEMIA 1. Decreased Red Blood Cell Production  Associated with Bone Marrow and Kidney Problems 2. Increased Red Blood Cell Destruction  Primary cause is Hemolysis (Hemolytic Anemia) 3. Blood Loss  Accident  Giving Birth Anemia Due to Decrease in RBC Production  Iron Deficiency Anemia (IDA)  Anemia of Chronic Inflammation (ACI)  Sideroblastic Anemia (SA)  Megaloblastic Anemia (MA)  Aplastic Anemia (AA)  Thalassemia (  and )  Anemia due to Chronic Renal Failure  Anemia due to Chronic Endocrine Disorder (Cushing Syndrome, Addison’s Disease)  Anemia due to Marrow Infiltration Anemia Due to Increase Destruction of RBC A. Intracorpuscular Abnormality 1. Membrane Defect (Spectrin, Ankidin and Protein 4.1)  Hereditary Spherocytosis  Hereditary Elliptocytosis  Hereditary Pyropoikilocytosis – Abnormal sensitivity to heat (severe Elliptocytosis).

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Hereditary Stomatocytosis Hereditary Acanthocytosis

 Hereditary Rh Null Disease 2. Enzyme Deficiency  G6PD Deficiency – decrease in Hgb, eating of beans, soya, Fava beans.  Pyruvate Kinase Deficiency – survival of the RBC  Porphyria – Heme synthesis 3. Paroxysmal Nocturnal Hemoglobinuria (PNH) 4. Globin Abnormality  Hemoglobinopathies (Hb SS, CC, SC) B. Extracorpuscular Abnormality 1. Mechanical  Microangiopathic Hemolytic Anemia (MAHA)  Thrombotic Thrombocytopenic Purpura (TTP) – decreased in platelets  Hemolytic Uremic Syndrome (HUS) – caused by 0157H:7 serotype of E. coli  Traumatic Cardiac Hemolytic Anemia 2. Infection  Hemolytic Anemia  Malaria  Babesia  Bartonella  Ehrlichia 3. Chemical and Physical Agents  Caused by drugs, toxins, burns 4. Antibody – Mediated Anemia  Acquired Hemolytic Anemia Anemia due to Blood Loss 1. Acute Post Hemorrhagic Anemia 2. Chronic Post Hemorrhagic Anemia Classification of Anemia Based on:  Reticulocyte Count  Mean Corpuscular Volume (MCV)  Red Blood Cell Distribution Width (RDW)

Laboratory Test for Anemia Assessment  Complete Blood Count

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Reticulocyte Count Peripheral Smear Bone Marrow Examination – used when the primary tests are doubtful. Iron Studies – Backbone test for Assessing Anemia; Serum Iron, Serum Ferritin, Total Iron – Binding Capacity Blood Chemistry (Kidney Function Test, Liver Function Test) Urinalysis Fecalysis – for occult blood Hematological Special Test Procedures

MORPHOLOGICAL CLASSIFICATION OF ANEMIA 1. Microcytic Hypochromic Anemia 2. Macrocytic Normochromic Anemia 3. Normocytic Normochromic Anemia I. MICROCYTIC HYPOCHROMIC ANEMIA  Decrease of all erythrocyte indices: MCV and MCHC.  Found in Thalassemia and severe IDA. IRON DEFICIENCY ANEMIA Cause: a. Inadequate Intake of Iron  1mg of iron cost every day. b. Increased need of Iron  Infancy, childhood, adolescence  Pregnancy c. Impaired Absorption d. Chronic Blood Loss  Heavy menstrual bleeding  GI bleeding from ulcers or tumors  Urinary tract with kidney stones  Iatrogenic cause Iron Deficiency Anemia Blood Features:  Decrease to normal Reticulocyte count  Decrease Serum Iron  Decrease Serum Ferritin  Increase Total Iron – Binding Capacity (TIBC) (Serum Transferrin)  Peripheral Blood Smear:  Microcytic Hypochromic type  Anisocytosis/Poikilocytosis  Decreased in Osmotic Fragility Test *Taking Vitamin C will help Clinical Features of Iron Deficiency:  Smooth Tongue – Iron deficiency can result in a painless, smooth, shiny and reddened tongue.

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Koilonychia – a condition also referred to as “spoon – shaped nails” is associated with iron deficiency in which the fingernails are thin, brittle and concave with raise edge. Pica – condition where in there’s craving for uncertain food.

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Iron is Distributed among 3 Compartments  Storage Compartment – principally as Ferritin in the bone marrow macrophages and liver cells.  Transport Compartment of Serum Transferrin  Functional Compartment of Hemoglobin, Myoglobin and Cytochrome

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 Stages of Iron Deficiency  Stage I: Iron Depletion  Normal Hgb  Normal Serum Iron  Normal TIBC  Decrease Ferritin  Stage II: Exhaustion  Normal Hgb  Decrease Serum Iron  Increase TIBC  Decrease Ferritin  Stage III: Frank Anemia  Decrease Hgb  Decrease Serum Iron  Increase TIBC  Decrease Ferritin

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LEAD POISONING  

Lab Diagnosis  Screening: CBC, RBC Indices  Diagnostic: Iron Studies  Specialized: Hgb Electrophoresis

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Lead interferes with iron storage in the mitochondria. Lead damage the activity of enzymes used for heme synthesis (Basophilic Stippling) Hallmark: Basophilic Stippling

Clinical Features of Lead Poisoning:  Gums in lead poisoning. Lead lines are shown in gums of the patient suffering from lead poisoning.  Peripheral blood film demonstrating coarse basophilic stippling. Normocytic or microcytic anemia may be present.

SIDEROBLASTIC ANEMIA Develop when the incorporation of iron into heme is blocked. Protoporphyrin pathway resulting in iron overload. Hallmark:  BM: Ringed Sideroblast  PB: Pappenheimer Bodies  2 Types:  Hereditary Sideroblastic Anemia – due to a congenital enzyme defect delta

Primary is genetic. Secondary caused by:  Certain therapeutic drugs  Chronic transfusion (Aplastic)  Alcoholism and Food pads Diagnostic lab finding is ringed sideroblast in the bone marrow and Pappenheimer bodies in the peripheral blood. Increased Serum Iron Increased Ferritin level Normal TIBC Decreased MCV Stain: Perl’s Prussian Blue – Ringed Sideroblast

Treatment  Pyridoxine – stimulate heme synthesis  Bone Marrow Transplant

Treatment  Oral Supplementation of Ferrous Sulfate

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aminolevulinic acid synthetase or heme synthetase. Primary Acquired Sideroblastic Anemia – due to somatic mutation of the erythroid progenitor cells that cause either defect in heme synthesis or defects in DNA synthesis.

Treatment  Chelators (EDTA)

PORPHYRIA 

Rare disease caused by accumulation of porphyrins in developing RBCs.

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Characterized by dermal photosensitivity and rash caused by the sun.

Clinical Features of Porphyria  Neurologic Complications  Impaired Production of Heme  Skin Problems ANEMIA OF CHRONIC INFLAMMATION      

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Second most common anemia Anemia of Chronic Disease Decreased TIBC Mild Anemia (7 – 11g/dL) Increase WBC Count Anemia associated with systemic disease: a. Arthritis b. Tuberculosis c. HIV d. Malignancies  Leukemia, Lymphoma, Myeloma Hallmark: Sideropenia

Acute Phase Reactant in Response to ACI  Hepcidin – regulator of iron homeostasis.  Lactoferrin – iron – binding protein in the granules of neutrophils.  Ferritin – Stores iron. Treatment  Therapeutic Erythropoietin THALASSEMIA 

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Inherited disorders caused by genetic alterations that reduce or preclude the synthesis of the globin chains of hemoglobin tetramer. Predominant in Mediterranean, African and Asian ancestry. Describe by Cooley and Lee in 1925.

Laboratory IDA ACI SA Thalassemia Test Retics    N Count Serum    N Ferritin Serum    N Iron Transferrin    N Saturation    TIBC N    FEP/ZPP N Prussian no Blue stainable /N  N reaction iron (BM iron) 3. Hereditary Persistence of Hb F (HPHF) – inactivation of delta/beta 4. Hemoglobin Lepore – crossing over of beta and delta. 5. Hemoglobinopathy + Thalassemia  Hemoglobin S – Thalassemia  Hemoglobin C – Thalassemia  Hemoglobin E – Thalassemia Beta () – Thalassemia Other Names Thalassemia minor Hgb: 10 – 13 mg/dL Normal or slightly decrease RBCs

Intermediate  Thalassemia

Heterozygous Thalassemia Cooley’s trait Rietti – Greppi – Micheli – Disease

Thalassemia Intermedia

Hgb: 7 mg/dL

Types of Thalassemia 1. Beta () Thalassemia – Chromosome 11 2. Alpha () Thalassemia – Chromosome 6

Thalassemia major

Homozygous Thalassemia

Description Results when one of the 2 genes that produce beta globin is defective. usually presents a mild asymptomatic anemia More severe anemia than minor  - Thalassemia but do not require regular transfusion. Occasional transfusions but do not require them on a regular basis.

Decrease or complete lack of beta globin

production. Death due to circulating iron overload. Cooley’s anemia

Hgb: 3 – 4 g/dL

Mediterranean anemia Target cell anemia

Possible of splenectomy 6 months – 2 years old Most severe form and transfusion dependent anemia. Slunted growth Frontal Bossing Presence of Hgb A

Alpha () – Thalassemia  Predominates hemolysis.

Silent Carrier (- /) Can be mistaken as IDA  - Thalassemia Trait/Minor Homozygous (-/-) Heterozygous (- -/)

Hemoglobin H disease (- -/-)

Hydrops Fetalis (- -/- -) Counterpart:  Thalassemia major

Description

Hemoglobin Present

Deletion of one  gene leaving 3 functional  globin genes.

Birth: 1% - 2% Hb Bart’s Adult: normal Hb A, Hb Bart

Deletion by the two  globin gene.

Birth: 2% - 10% Hb Bart’s Adult: normal Hb A

Caused by the presence of only one gene producing  chain.

Birth: 10% - 40% Hb Bart’s replaced by Hb H 10% 50% remainder Hb F, Hb A2, Hb Bart’s and Hb A Adult: 70% Hb A

results in the absence of all  chains synthesis incompatible with life Hepatomegaly Splenomegaly

Birth: 80% - 90% Hb Bart’s 5% - 20% Hb Portland trace of Hb H

Yellow color

Hereditary Persistence of Hb F (HPHF)  Thalassemia with increased levels of fetal hemoglobin.

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Partial or total suppression of beta and delta chains and Hb F increased to compensate.

Hemoglobin Lepore  Rare class of Thalassemia caused by crossing over of beta and delta genes. Hemoglobinopathy + Thalassemia a. Hemoglobin S – Thalassemia  Is a double heterozygous abnormality.  The abnormal genes for Hb S Thalassemia are co – inherited. Types: Hb S -  - Thalassemia Hb SS -  - Thalassemia Hb S -  - Thalassemia Hemoglobin C – Thalassemia   - Thalassemia with inherited Hb C.  Minimal amount or no . Hemoglobin E – Thalassemia  Co – inherited of hemoglobin E and  Thalassemia that result to a marked reduction of  chain production.  Similar to  - Thalassemia major  Common in Cambodia, Thailand and part of India. Treatment:  Chelators (EDTA) Laboratory Findings of Thalassemia 1. CBC  Hb and Hct RBC count RBC indices (MCV and MCHC) RDW 2. Peripheral Smear  Microcytic hypochromic  Exhibits anisocytosis and Poikilocytosis (target cells and elliptocytes)  Presence of NRBC  Polychromasia and basophilic stippling 3. Increased Reticulocyte Count 4. Bone Marrow Examination  Shows hypercellular with extreme erythroid hyperplasia.

5. Decreased OFT 6. Supravital stain  Shows Hb H inclusions 7. Electrophoresis  Differentiates hemoglobin variants.  Best 8. Mass Spectrophotometry  Assess the difference in mass of the globin chains.  Detects single amino acid substitutions in the globin chains. 9. DNA Analysis  Identify globin gene mutations.  Best a. PCR b. Single Amplification System 10. Increased Indirect Bilirubin II.

Laboratory Findings of Megaloblastic Anemia 1. CBC a. Pancytopenia – decreased WBC, RBC and platelets b. Hb and Hct: decreased c. MCV: increased (>120 fL) d. MCH and RDW: increased e. MCHC: normal 2. Decreased in Absolute Reticulocyte Count 3. Peripheral Smear a. Oval macrocytes/megalocytes b. poikilocytes  dacryocytes, fragments, microspherocytes c. NRBCs d. Howell – Jolly bodies e. Basophilic Stippling f. Cabot Rings 4. Hypersegmented Neutrophils (5 or more lobes) 5. Chemical Analysis  Decreased serum Folate level  Decreased serum Vitamin B12 level  Increased Homocysteine – Folate Def. and Cardiovascular disorder  Increased Methylmalonic Acid – Vitamin B12 Def.  Increased Lactate Dehydrogenase  Increased total and indirect bilirubin 6. Schilling Test  Used to distinguish malabsorption of Vitamin B12 from other causes of malabsorption.  Uses oral dose of radioactive Vitamin B12.

MACROCYTIC NORMOCHROMIC ANEMIA

MEGALOBLASTIC ANEMIA  

Disorder in the DNA synthesis of RBC. The maturation of nucleus is delayed relative to that of cytoplasm.

2 Types PERNICIOUS ANEMIA  Vitamin B12 (cobalamin) deficiency.  Memory loss  Neurologic symptoms FOLIC ACID DEFICIENCY  Nutritional Megaloblastic anemia  Neural defect  Spinal bifida Causes of Megaloblastic Anemia  Dietary deficiency 1. Inadequate Intake  Sources of Folic Acid  Leafy green vegetables, dried beans, liver, beef and some fruits.  Sources of Vitamin B12  Meat, eggs and dairy products 2. Increased need  During pregnancy, lactation and growth. 3. Impaired Absorption in the Intestine 4. Impaired Use due to Drugs such as Antiepileptic Drugs 5. Excessive Loss during Renal Dialysis

Treatment:  Vitamin Therapy

NON – MEGALOBLASTIC ANEMIA 

Anemia caused by conditions such as:

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III.

 Hemolysis occurs when blood is warmed after previous exposure to chilling.  Caused by an antibody (Donath – Landsteiner Antibody) present in the plasma.  Increased Retics  Increased Bilirubin

a. Alcoholism b. Chronic Liver Disease c. Hypothyroidism - Myxedema d. Myeloma No hypersegmentation. No increased in MCV and decreased in 120 days of RBCs. NORMOCYTIC NORMOCHROMIC ANEMIA

Primary Idiopathic

EXTRINSIC HEMOLYTIC ANEMIA 1. 2. 3. 4.

Characteristics of Autoimmune Hemolytic Anemia

Antibody Mediated Anemia Mechanical Chemical and Physical Agents Infection

ANTIBODY MEDIATED ANEMIA Classifications: 1. Autoimmune Hemolytic Anemia 2. Drug – Induced Immune Hemolytic Anemia 3. Alloimmune Hemolytic Anemia Autoimmune Hemolytic Anemia  Characterized by premature RBC destruction caused by autoantibodies that bind the RBC surface.  AIHA + Thrombocytopenia = Evan’s Syndrome

Secondary SLE, Viral Infection

ld – Reactive Autoimmune Hemolytic Anemia  Mediated by antibody with maximum binding affinity at 4oC or below 32oC. Primary

Type of Ig Maximum Temp. Reactivity Complement Activation Type of Hemolysis Autoantibod y Specificity Treatment

Warm Reactive

Cold Reactive

PCH

IgG

IgM

IgG

37oC

4oC

4oC

Variable

Yes

Yes

Extravascular Rh complex Corticosteroi d Splenectomy

Intra/Extravascula r anti – I anti – i Avoidance of Cold Plasmapheresis

Intravascular anti – P Avoidance of Cold Corticosteroid s

Drug – Induced Immune Hemolytic Anemia  Self – limiting, but severe even fatal following the administration of drug that can cause immune hemolytic anemia.

Types of Autoimmune Hemolytic Anemia a. Warm – Reactive Autoimmune Hemolytic Anemia  Responsible for approximately 70% of immune hemolytic cases.  Mediated by antibody with maximum binding affinity at 37oC.  Anisocytosis, Polychromasia, Spherocytosis, Macrocytosis, RBC, Increased Retics. Primary Idiopathic

Secondary Syphilis, Viral Respiratory Infection

Examples of Drugs: a. Penicillin b. Stibophen c. Alpha Methyldopa

b. Co

Alloimmune Hemolytic Anemia  Usually occurs in newborns following the transplacental passage of maternal anti – fetal red cells antibody. 2 Causes: 1. Erythroblastosis fetalis  Isoimmune HDN due to Rh incompatibility

Secondary

2. Isoimmune HDN due to ABO Incompatibility Idiopathic c. Paroxysmal Cold Hemoglobinuria (PCH) ANEMIA DUE TO MECHANICAL EXTRACORPUSCULAR ABNORMALITY  A rare acute form of cold – Accompanied with Mycoplasma pneumoniae

generated hemolysis.

Microangiophatic Hemolytic Anemia (MAHA)

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It is a group of clinical disorders characterized by RBC fragmentation in the circulation resulting in intravascular hemolysis. Fragmentation occurs as a result of:  RBCs passing through fibrin deposits inside the lumen of arterioles and capillaries.  Damaged epithelium and vessel walls. Hallmark: Schistocytes/Helmet Cells

Laboratory Findings  Anemia  Presence of Schistocytes  Decrease in Hgb and Hct  Increase Retics  Increase serum unconjugated bilirubin Disorders of Microangiopathic Hemolytic Anemia 1. Thrombotic Thrombocytopenic Purpura (TTP)  Is a rare potentially fatal characterized by disseminated thrombotic occlusions of the microcirculation.  Caused by deposition of microthrombi that contain platelets and Von Willebrand factor in arterioles and capillaries of many organs.  Can be found in adults and rare in children.  Laboratory Findings: o Platelets: 80% Hgb F: 1 – 20% Hgb A2: 2 – 5%

Hemoglobin Variants of Sickle Cell Disease 1. SS 2. SC

3. 4. 5. 6. 7.

S/D – Los Angeles S/O – Arab S/ - Thai S/HPFH SE

Laboratory Findings: 1. Peripheral Smear  Normocytic normochromic RBCs  Presence of numerous sickle cells and target cells  Howell – Jolly Bodies inclusions, Basophilic Stippling 2. Decreased OFT 3. Increased Mechanical Fragility Test 4. Positive for Hb Solubility Screening Test a. Metabisulfite Test  Examining blood smear for the presence of sickle cells.  Blood is deoxygenated by adding a reducing substance, 2% sodium metabisulfite. b. Dithionite Test 5. Electrophoresis  Increased Hb S and no Hb A 6.  Hgb 10 mg/dL 7. Hgb S Treatment:  Take Folic Acid to help for the production of RBC. Hemoglobin Migration Patterns  Based in the order of increasing mobility of hemoglobin in electrophoretic field.  Alkaline Electrophoresis (pH = 8.4) A2, E=O=C, G=D=S=Lepore, F,A, K,J,Bart’s,N,I and H  Acid Electrophoresis (pH = 6.0 – 6.2) F, A=D=G=E=O=Lepore, S and C Sickle Cell Trait  Heterozygous hemoglobin AS state.  A benign condition that generally does not affect mortality and morbidity.  Generally asymptomatic and present with no significant clinical or hematologic manifestations.

Hb Distribution: Hb S: 40% Hb A: 60%

Hb A2: slightly increase Hb F: normal Laboratory Findings 1. Peripheral Smear ...