Microcytic and Macrocytic Anemia PDF

Red Blood Cell Disorder Objectives At the end of this chapter you will be able to: Define anemia Discuss types of anemia, causes and pathophysiologic mechanisms Discuss Clinical features and complications of anemia Differentiating diagnostic features of anemia...

Red Blood Cell Disorder Objectives At the end of this chapter you will be able to: Define anemia Discuss types of anemia, causes and pathophysiologic mechanisms Discuss Clinical features and complications of anemia Differentiating diagnostic features of anemia 2  Chapter Outline ▪ Introduction (definition, diagnosis, classification of anemia) ▪ Microcytic hypochromic anemia Iron deficiency anemia Anemia of chronic disease Sideroblastic anemia Thalassemia ▪ Macrocytic anemia Megaloblastic anemia Non-megaloblastic anemia ▪ Normocytic normochromic anemia Bone marrow failure Hemolytic anemias 3  Definition of Anemia ▪ Decrease Hgb values as compared to normal reference range for age, sex and altitude. ▪ Anemia may develop: When RBC loss exceeds production or production is impaired ▪ In most cases the two values relate to one another roughly by a factor of three (hemoglobin × 3 ≈ hematocrit). ▪ Functionally anemia is defined as tissue hypoxia 4 Hematologic Response to Anemia ▪ Increased renal release of erythropoietin (EPO) to accelerate bone marrow erythropoiesis (in response to tissue hypoxia) Signs of accelerated erythropoiesis ▪ Hypercellular bone Marrow; M:E ratio falls (erythroid hyperplasia) ▪ Nucleated RBCs may be released along with reticulocytes Increased polychromasia ▪ If demand exceeds maximal marrow activity, production can occur in extramedullary sites 5 Signs of Accelerated Bone Marrow Erythropoiesis Nucleated Red Cell Polychromasia Wright’s stained blood smear  Symptoms and signs of anemia ▪ The signs and symptoms of anemia correlate with Hypoxia Ability of the affected individual to compensate for this defect. ▪ Rapid loss of blood may be associated with shock and collapse of the circulatory system.  Symptoms of anaemia Decreased oxygen delivery to the tissues/organs causes Fatigue Decreased exercise tolerance Dyspnea (shortness of breath) Weakness and lethargy Dizziness, headaches Leg cramps, intermittent claudication Angina, and confusion  Signs of anaemia ▪ Conjunctival Pallor. ▪ Tachycardia (rapid heart beat), cardiomegaly ▪ Congestive cardiac failure and neurological problems ▪ Visual disturbances due to retinal hemorrhages ▪ Cardiac failure ▪ IDA: cracking of the edges of the lips (angular chelitis) and with spooning of the nails (koilonychia). Physical Signs of Anemia Classification of anemia  Anemia classification ▪ There is No "perfect" classification method so a combination is used. A. Morphologic - anemias are divided into three groups on the basis of the MCV & MCHC B. Etiologic - anemias are divided using two main causes/mechanisms. 1. Decreased delivery of red cells to the circulation: defective maturation or decreased production. 2. Increased loss of red cells from the circulation: acute bleeding or accelerated destruction. Classification of anemia based on MCV 20 Classification of Anemia Based Etiology Microcytic- Hypochromic Anemias Characterized by impaired hemoglobin synthesis 15  Microcytic- Hypochromic Anemia ▪ Many RBCs smaller than normal lymphocytes nucleus ▪ Increased central pallor. ▪ Includes Iron deficiency anemia Thalassemia Anemia of chronic disease Sideroblastic anemia Lead poisoning 16 Cause of Microcytic-Hypochromic Anemia Iron Protoporphyrin Iron deficiency Chronic inflammation Sideroblastic anemia or malignant (ACD) Heme + Globin Thalassemia ( or ) Hemoglobin Iron Deficiency Anemia (IDA)  Iron Deficiency Anemia (IDA) Iron deficiency anemia occurs when the intake and absorption of iron are insufficient to replenish the body’s loss. IDA is the final stage in the progressive depletion of iron in the body Lack of iron results in reduced red blood cell & hemoglobin production ▪ More than half of all anemias are due to iron deficiency (1st) ▪ Most common in three populations: 1. Infants and preschool children. 2. Women of child - bearing years. 3. Elderly  IDA…. Causes: – Inadequate iron intake: not enough iron is consumed to meet the normal, daily required amount of iron (Each day 1mg lost must be replaced ) – Malabsorption: celiac disease, autoimmune gastritis, H. pylori infection – Inefficient transport, storage or utilization of iron – Increased need: adolescents, pregnant women – Chronic blood loss : GI bleeding, Urogenital bleeding, Intravascular hemolysis  Iron storage ▪ If there is any excess iron Combines with the apoferritin protein to generate ferritin. If the amount of apoferritin is insufficient, the remaining iron will be deposited and stored in tissues as hemosiderin And can be mobilized from these storage deposits and transported back to erythroid precursors when needed. CLINICAL FEATURES IRON DEFICIENCY ▪ Patients may be asymptomatic or present with signs/symptoms of anemia, including Fatigue, weakness, pallor, palpitations, lightheadedness, headaches, tinnitus, dyspnea, behavioral changes ▪ Signs/symptoms related to the direct effects of iron deficiency on tissues Glossitis (a smooth, waxy - appearing, red tongue). Angular cheilitis (ulcerations at the corners of the mouth). Pica → obsessive consumption of substances with no nutritional value, such as ice, starch, clay, paper). Gastric atrophy. Glossitis CLINICAL FEATURES IRON DEFICIENCY ▪ Tongue atrophy/ glossitis - raw and sore, ▪ Spoon-shaped nails (koilonychia), concave nails ▪ Brittle nails and hair. ▪ Esophageal webs and strictures ▪ Restless leg syndrome ▪ Thrombocytosis; unexplained reason Glossitis Koilonychia Angular Cheilosis  Lab Investigation of IDA ▪ CBC Increasing RDW, followed by a decrease in the MCV Low RBC, Hgb, Hct, MCH, MCHC Low retics count Normal WBC and PLT may be elevated ▪ RBC morphology Hypochromia Microcytosis Anisocytosis Poikilocytosis Pencil (cigar) cells Target cells 41 no RBC inclusions Lab Investigation ….. ▪ Serum iron (SI) Measures the amount of iron bound to transferrin Serum iron levels fall, and TIBC increases after storage iron is depleted. Does not include the free form of iron Reference: 50 – 160 µg/dl ▪ Total Iron Binding Capacity (TIBC) Is an indirect measure of the amount of transferrin protein in the serum Any unbound iron is removed Inversely proportional to the serum iron level If serum iron is decreased, total iron binding capacity of transferrin increased (transferrin has more empty space to carry iron) Transferrin is normally ~33% saturated with iron Reference: 250 - 400µg/dl 25 Lab Investigation ….. ▪ Serum ferritin Indirectly reflects storage iron in tissues (It is in equilibrium with store iron) Found in trace amount in plasma Bone marrow iron (Tissue iron): Prussian blue staining ▪ Bone marrow biopsy is a gold standard for diagnosing iron deficiency ▪ Type of iron is hemosiderin 26 Anemia of chronic disease  Anemia of chronic disease/inflammation ▪ Anemia of chronic disease (ACD) – inability to use iron and decreased response to EPO Very common anemia, #2 ▪ Associated with systemic disease, including chronic inflammatory conditions: Rheumatoid arthritis Chronic renal disease Thyroid disease Malignancies Tuberculosis Chronic fungal infections etc  ACI pathogenesis ▪ The cause is due to impaired ferrokinetics. ▪ It is sideropenia in the face of abundant iron stores. Explained by the role of hepcidin in regulation of body iron. ▪ Hepcidin is a hormone produced by hepatocytes to regulate body iron levels, particularly absorption from intestine and release from macrophages. ▪ Hepcidin interacts with the transmembrane protein ferroportin Ferroportin, exports iron from enterocytes into the plasma  ACI pathogenesis….. ▪ When body iron levels decrease, hepcidin production decreases, and Enterocytes export more iron into the plasma. Macrophage and hepatocyte release of iron also increases. ▪ When iron levels are high, hepcidin increases Enterocytes export less iron into the plasma Macrophages and hepatocytes retain iron. Thus iron is unavailable for developing RBCs ▪ As a result, during inflammation, there is a decrease in iron absorption from the intestine and iron release from macrophages and hepatocytes. Because Hepcidin is an acute phase reactant that increase during inflammation regardless of iron level in the body Lab Diagnosis ▪ Blood findings Early stage: normocytic normochromic Late stage: hypochromic microcytic, Low serum iron, low TIBC, normal or high serum ferritin ▪ Leukocytosis ▪ Abundant storage of iron in macrophage (Prusian blue) Sideroblastic Anemia (SA)  Sideroblastic Anemia (SA) Block(s) in protoporphyrin synthesis leads to iron overload and microcytic/hypochromic anemia The iron accumulation in the mitochondria is the result of blocks in the protoporphyrin pathway.  Sideroblastic Anemia (SA) SIDEROCYTE: Mature RBCs in the blood containing iron granules called Pappenheimer bodies → ABNORMAL SIDEROBLAST: Immature nucleated RBCs in the bone marrow containing small amounts of iron in the cytoplasm → NORMAL RINGED SIDEROBLAST: immature nucleated RBCs in the bone marrow containing iron in the cytoplasm and this iron forms a ring around the nucleus → ABNORMAL 34 Sideroblastic Anemia (SA) Blood Bone marrow Bone marrow Ringed Sideroblast Pappenheimer bodies Sideroblast RBC with iron NRBC with iron NRBC with ring of iron Wright’s stain Prussian blue stain Prussian 35 blue stain Sideroblastic Anemia (SA) Blood Blood Basophilic stippling/stippled Pappenheimer bodies Wright’s stain RBCs Blood findings: Pappenheimer bodies Blood – Variable Prussian blue iron stain microcytic/hypochromic anemia – RBC inclusions – High serum iron; Low TIBC; High serum ferritin Sideroblastic Anemia (SA) Bone marrow findings (if done): 1. *Ringed sideroblasts(Hall mark of Sideroblastic Anemia) demonstrated with Prussian blue stain 2. Increased stainable iron in macrophages. Bone marrow 100x Ringed Sideroblasts Prussian blue iron stain  Types of Sideroblastic Anemia Blocks in the synthesis of protoporphyrin may be: o primary and irreversible (idiopathic, cause unknown) OR o secondary and reversible (can identify cause) Types of Sideroblastic anemia cont’d ▪ Primary - cause unknown (can't identify blocks) and are not reversible....called Idiopathic or primary Sideroblastic anemia. 1. Elderly, responds to no treatment. Requires transfusion support if severe anemia. 2. Characterized by a dimorphic red cell population - micro/hypo red cells with normocytic and/or macrocytic red cells....MCV is variable and RDW is high. 3. Primary type of sideroblastic anemia is one of myelodysplastic syndromes called Refractory Anemia with Ringed Sideroblasts; may terminate in leukemia  Secondary Types of Sideroblastic Anemia Alcohol inhibits vitamin B6/pyridoxine Anti-tuberculosis drugs inhibit vitamin B6 Stippled RBCs → Lead poisoning  Lead Poisoning ▪ Blocks placement of Fe into heme ▪ May cause neurological damage and anemia ▪ Usually related to lead-based paints and industrial exposures ▪ Treatment – chelation with deferoxamine Stippled RBCs – Lead poisoning Wright’s stained blood smear Thalassemias ▪ Inherited decrease in alpha or beta globin chain synthesis needed for Hgb A; quantitative defect All have microcytic/hypochromic RBCs and target cells  Thalassemia ▪ Impaired alpha or beta globin synthesis results in an unbalanced number of chains that leads to: RBC destruction in beta Thalassemia major Production of compensatory Hgb types in beta thals Formation of unstable or non-functional Hgb types in alpha thals 43 Thalassemia 1. Major → severe anemia; no α (or β) chains are produced, so cannot make normal hemoglobin (s). 2. Minor/trait → mild anemia; slight decrease in normal hemoglobin types made. 44  Beta-Thalassemia ❑ β globin chain genes are located on chromosome 11 and there are normally two genes in total (β/β) one inherited from each parent. ❑ β-thalassemia is usually due to point mutations in the β globin genes. ❑ These point mutations cause production of β globin chains to be reduced (β+) or abolished completely (Β0) β-Thalassemia Silent Carrier (βSilent/β) ❑ β globin chain genes mutation does not result in any abnormal hematological findings and β globin chain production is normal or nearly normal. ❑ All hematological parameters are Normal Beta Thal Minor (β0/β or β+/β) ▪ One mutated beta gene Slight decreased rate of beta chain production Blood picture can look Stippled RBC similar to iron deficiency ▪ Lab findings Mild anemia, target cells, Target cell no nRBCs, stippled RBCs No Heinz bodies Ovalocytes Normal iron tests Wright’s stained blood smear Compensates with Hgb A2 47 β-Thalassemia Intermedia (β+/βSilent or β0/βSilent or βSilent/βSilent) ❑ One mutated and one silent beta gene or both silent beta genes ❑ Mutations in the β genes result in reduced β globin chain production. ❑ Clinical symptoms are variable, and more severe than β-Thalassemia Minor, though patients do not require transfusions to survive. ❑ Moderate decreased rate of beta chain production ▪ Lab findings Moderate anemia, target cells Basophilic stippled RBCs No Heinz bodies Normal iron tests Variable in anisocytosis and poikilocytosis Polychromasia Beta Thal Major (β+/β+ or β+/β 0 or β0/β0) ▪ Both beta genes mutated Marked decrease/absence of beta chains leads to alpha chain excess…no Hgb A is produced Rigid RBCs with Heinz bodies destroyed in bone marrow and blood (ineffective erythropoiesis) Heinz bodies Excess alpha chains Supravital stain 49 Beta Thal Major ….. ▪ Lab findings Severe anemia, target cells, nucleated red cells RBC inclusions Pappenheimer bodies Heinz bodies Normal iron tests No hemoglobin A; compensatory Hgb F HJB Target cell Stippled NRBC NRBC Wright’s stained blood smear 50 Beta Thal Major ……. Blood smear Howell-Jolly body Target cells NRBC Pap bodies Target Transfused cell RBC Blood smear Transfused RBC ▪ Treatment Transfusion Splenectomy Hypercellular Bone Marrow (10x)  Alpha-Thalassemia ❑ α globin chain genes are located on chromosome 16 and there are normally four genes in total (αα/αα), two inherited from each parent. ❑ α-thalassemia results when there is a deletion in any number of the α globin gene. ❑ The severity of anemia and amount of α globin chain production is dependent the number of genes that are deleted. Alpha Thal Trait (αα/α-)) ▪ One alpha genes deleted (group) Slight decrease in alpha chain production No anemia, few target cells 53 Alpha Thal Minor (αα/–) or (α-/α-)) ▪ Two alpha genes deleted (group) Slight decrease in alpha chain production Mild anemia, few target cells 54 Alpha Thal Intermedia = Hgb H Disease (α-/–) ▪ Three alpha genes deleted Moderate decrease in alpha chains leads to beta chain excess…unstable Hgb H Moderate anemia Heinz bodies Excess beta chains Supravi tal stain Target cells Wright’s stain blood smear 55 Alpha Thal Major (–/–) ▪ Deletion of all 4 alpha genes results in complete absence of alpha chain production No normal hemoglobin types made ▪ Known as Barts Hydrops Fetalis Die of hypoxia….Bart’s Hgb 56 Alpha Thalassemia summary Alpha Thalassemia summary Differential Diagnosis of Microcytic Anemia + Macrocytic Normochromic Anemias (Anemia due to DNA synthesis defect) 60 Macrocytic Normocytic Anemias Characteristics ?????? Macrocytic Anemia….. Signs & Symptoms: Pallor & jaundice (“lemon yellow”) Loss of papillae of tongue (“beefy red”) Neurological deficit (Only with B12 def) Can also cause dementia & depression Signs of associated conditions: vitiligo, thyroid disease etc. 62 Other causes of megaloblastosis (Myelodysplastic syndrome, FAB –M6) 4/22/2024 63 87 Macrocytic Normocytic Anemias 64 4/22/2024 A. Megaloblastic Anemia ▪ Macrocytosis due to a deficiency of vitamin B12 or folic acid that causes impaired nuclear maturation Vitamin B12 & folate are DNA coenzymes necessary for DNA synthesis and normal nuclear maturation Results in megaloblastic maturation…nucleus lags behind the cytoplasm and leads unbalanced growth called maturation asynchrony ▪ Both deficiencies cause enlarged fragile cells Many cells die in the marrow (ineffective) Show a similar blood picture and clinical findings ▪ Only vitamin B12 deficiency causes neurological symptoms…required for myelin synthesis 65 Vitamin B12 (Cobalamin) Deficiency Dietary deficiency – rare Lack of intrinsic factor ❑ Pernicious anemia most common cause ▪ PA is defined as the absence of IF and/or the presence of antibodies to IF or parietal cells; autoimmune factors ❑ Total gastrectomy ▪ May develop B12 and iron deficiency with macro and micro red cells…a dual (dimorphic) RBC population Competition Malabsorption 66 Folate (Folic acid) Deficiency ◼ Dietary deficiency – leading cause, low Two RBC populations stores Dimorphism ◼ Increased need  Pregnancy; may develop Macrocytic RBCs concurrent iron deficiency and a dimorphic population of red cells Microcytic with a falsely normal MCV RBCs ◼ Malabsorption ◼ Anti-folate drugs Folate and B12 deficiency Lab Findings of Megaloblastic Anemia Mild to severe anemia, Increased MCV & MCH, normal MCHC Low RBC, HGB, WBC and PLT counts (fragile cells) due to ineffective hematopoiesis. Low reticulocyte count Macrocytic ovalocytes and teardrops; Marked anisocytosis and poikilocytosis Erythroid hyperplasia - low M:E ratio (1:1) Iron stores increased. Increase Bilirubin Decrease Vit B12  Howell-Jolly body Teardrop Schistocyte Blood NRBC Blood Macrocytic Ovalocytes Stippled RBC & Giant Platelet Pap bodie s Hypersegmented Neutrophil >5 lobes Megaloblastic Anemia – Bone Marrow  Pernicious Anemia ▪ Is a type of megaloblastic anemia resulting from defective secretion of Intrinsic factor (IF) associated with autoimmune attack on the gastric mucosa or Abs that block IF action. ▪ Abs block the site of IF where vit B12 binds. ▪ The diagnosis is confirmed by low serum B12 level and typically abnormal results of schilling test ▪ Schilling test is used to diagnose pernicious anemia and determine if IF is available.  Pernicious Anemia (PA) ▪ Early graying of hair ▪ Blue eyes ▪ Vitiligo ▪ Red beefy tongue Non-Megaloblastic Anemia ▪ Macrocytosis that is NOT due to vitamin B12 or folate deficiency ▪ Caused by liver disease and alcoholism ▪ Accelerated erythropoiesis Regenerating marrow or marked reticulocyte response following recent blood loss NRBC Polychromatophilic RBCs Wright’s stain Differential Diagnosis of Macrocytic Anemia ▪ Megaloblastic and non-Megaloblastic Perform B12 and folate levels Specific morphology Hypersegmented neutrophil Macro-Ovalocytosis Vs macrocytosis Giant platelet CNS involvement