Hematology - Red Blood Cell and Anemia 11-24 PDF

Red Blood Cells Anemias Kim Joho, MS, MT(ASCP)SM, MB, CLT(NYS) MI 216 General Pathology Wagner College Blood The average human adult has more than 5 liters (6 quarts) of blood in their body An average-sized man has about 12 pints of blood in his body An averag...

Red Blood Cells Anemias Kim Joho, MS, MT(ASCP)SM, MB, CLT(NYS) MI 216 General Pathology Wagner College Blood The average human adult has more than 5 liters (6 quarts) of blood in their body An average-sized man has about 12 pints of blood in his body An average-sized women has about nine pints Whole blood runs through the veins, arteries, and capillaries Blood is composed of formed elements (cells and cell fragments) which are suspended in the liquid fraction known as plasma Blood carries oxygen and nutrients to all the cells and removes waste products It also delivers the cells of the immune system to help fight infection and contains platelets that can form a plug in a damaged blood vessel to prevent blood loss Through the circulatory system, blood adapts to the body’s needs 2 Plasma The plasma is composed of 90% water and is mixture of water, sugar, fat, protein, and salts It acts as a solvent, to suspend the components of blood, in adsorption of molecules and their transport and in the transport of thermal energy Proteins make up 7% of the plasma and are composed of more than 100 distinct plasma proteins each with specific function and produce a colloid osmotic pressure Protein types include albumin, globulins (immunoglobulins) and fibrinogen The other main solutes in plasma include electrolytes, nutrients, gases (some O 2, large amounts of CO2 and N2), regulatory substances (enzymes and hormones), and waste products (urea, uric acid, creatine, creatinine, bilirubin, and ammonia) being transported between the various organ systems within the body Plasma also contains clotting factors, antibodies, enzymes, hormones, glucose and fat particles The main function of the plasma is to transport blood cells throughout the body along with nutrients, waste products, antibodies, clotting proteins, chemical messengers such as hormones and proteins that help maintain the body’s fluid balance 3 Blood Blood is a specialized body fluid having four main components If the tube of blood is allowed to stand for 30 minutes, the blood separates into three layers as the denser components sink to the bottom of the tube and fluid remains at the top The straw-colored fluid that forms the top layer is the plasma and forms about 60% of blood The middle layer is composed of white blood cells and platelets The bottom layer is the red blood cells 4 Cellular components of Blood The cells in the blood are formed in the bone marrow by the stem cells Erythrocytes are the red blood cells Leukocytes are the white blood cells Megakaryocytes are the platelets 5 Hematopoiesis The production of blood cells Begins early in embryonic development in the yolk sac Later it is taken over by the liver and lymphatic organs Finally assumed entirely by the red bone marrow Precursor of new blood cells is a pool of undifferentiated pluri-potential stem cells Erythropoiesis Erythrocytes (Red Blood Cells) Erythrocytes (Red blood cells) are deformable, non-nucleated and biconcave disks The most abundant blood cell When blood is separated by centrifugation the red cell portion is approximately 45 % of the total volume, this is the packed cell volume or hematocrit The erythrocyte is an oxygen-carrying cell because it is rich in hemoglobin The biconcave shape provides a large surface area for oxygen diffusion The mature erythrocyte has no nuclear material, so new protein cannot be synthesized Red Blood Cells In an embryo the liver is the main site of red blood cell production The production can be stimulated by the hormone erythropoietin synthesized by the kidney In a healthy individual these cells live in blood circulation for about 100 to 120 days At the end of their life span they are removed from circulation In many chronic diseases the lifespan of the erythrocytes is markedly reduced Erythropoiesis The reticulocyte is a precursor of the RBC produced in the bone marrow and is released at a steady state If the reticulocyte in the bone marrow is shifted to the circulation earlier than the usual 2-3 day maturity, it is called a shift or stress reticulocyte containing residual RNA Every second, 2-3 million RBCs are produced in the bone marrow and released into the circulation 10 Red Blood Cells The first person to describe red blood cells was Jan Swammerdam RBCs take up oxygen in the lungs and release it into tissues while squeezing through the body’s capillaries The cytoplasm of erythrocytes is rich in hemoglobin, an iron-containing biomolecule and complex metalloprotein that can bind oxygen molecules in the lungs and release them throughout the body and carries some of the waste produce carbon dioxide back from the tissues Hemoglobin is responsible for the red color of the cells The cell membrane is composed of proteins and lipids and provides properties essential for the physiological cell function such as deformability and stability Red Blood Cells By light microscopy, erythrocytes appear as uniform round cells with central pallor (concavity) Red Blood Cells Large surface area Contains hemoglobin which picks up oxygen Has no nucleus to make room for more oxygen Function: Carry oxygen from lungs to the body and carbon dioxide from the body back to the lungs. Red Blood Cells By light microscopy, erythrocytes appear as uniform round cells with central pallor Variation in Red Blood Cells Anisocytosis is the variation in the size of the Red blood cell Normocytic red blood cells are of normal size Macrocytosis the red blood cells are larger than normal (elevated MCV) Microcytosis the red blood cells are smaller than normal (decreased MCV) The Mean Corpuscular Volume (MCV) is measure of the average volume or size of an RBC 15 Red Blood Cell Count This test is a count of the number of circulating Red Blood Cells (RBCs) in 1 mm3 of peripheral venous blood Normal RBC values vary according to gender and age Women tend to have lower values than men and RBC counts tend to decrease with age When the value is decreased below the range of the expected normal value, the patient is said to be anemic Low RBC values are caused by hemorrhage, hemolysis, dietary deficiency, genetic aberrations (as in sickle cell anemia), drug ingestion (chloramphenicol), marrow failures, chronic illness and other organ failure Red Blood Cell Count RBC counts greater then normal can be physiologically induced as a result of the body’s requirements for greater oxygen- carrying capacity (high attitudes) Diseases that produce chronic hypoxia (e.g. congenital heart disease) increase RBC count Polycythemia vera is a neoplastic condition causing uncontrolled production of RBCs In dehydration the RBC count will be falsely elevated In overhydrated patients the RBC count will be falsely decreased In most Laboratories the RBC count is performed on an automated analyzing with an error range of about 4 to 5% Red Blood Cells Red blood cells are flexible and oval biconcave disks A typical erythrocyte has a disk diameter of approximately 6.2-8.2um and thickness at the thickest point of 2-2.5 um and a minimum thickness in the of 0.8- 1um RBCs are anucleate (lack a cell nucleus) and most organelles in order to accommodate maximum space for hemoglobin Approximately 2.4 million new erythrocytes are produced per second in human adults The cells develop in the bone marrow and circulate for about 100-120 days in the body before their components are recycled by macrophages Approximately a quarter of the cells in the human body are red blood cells Oxygen-sensing cells in the kidney respond by increasing the production of erythropoietin stimulating the proliferation of the bone marrow to increase red blood cell production Red Blood Cell Count Normal RBC decreases are seen during pregnancy as a result of normal body fluid increases that dilute the RBCs There is an element of nutritional deficiency that is often associated with pregnancy that may play a role in the anemia of pregnancy Drug that may cause increased RBC levels include erythropoietin and gentamicin Drugs that may cause decreased RBC levels include those that decrease marrow production or cause hemolysis Blood is collected in EDTA (lavender-top tube) The tube must be inverted 7 times after collection to mix the blood with the anticoagulant by gentle tilting the tube Avoid hemolysis Red Blood Cells When erythrocytes undergo shear stress in constricted blood vessels, they release ATP, which cause the vessel walls to relax and dilute so as to promote normal blood flow Human red blood cells take on average 20 seconds to complete one cycle of circulation Human erythrocytes are produced through a process called erythropoiesis, developing from committed stem cells to mature erythrocytes in 7 days Through this process erythrocytes are continuously produced in the red bone marrow of large bones at a rate of about 2 million per second Polychromatic Erythrocyte Up to 1% of cells stain with a purplish tinge and are of greater diameter These are polychromatic cells, the purple color is due to residual RNA of the immature erythrocyte Reticulocyte Count Increased reticulocyte counts indicate the marrow is releasing an increased number of RBCs into the bloodstream, usually in response to anemia The reticulocyte index in a patient with a good marrow response to the anemia should be 1.0 If it is below 1.0, the bone marrow response is inadequate in its ability to compensate Reticulocyte index = Reticulocyte count (%) x Patient’s hematocrit Normal hematocrit​ Reticulocyte Count (%): The percentage of reticulocytes in the total number of red blood cells. Normal Hematocrit: The typical or reference range for hematocrit in the general population. Patient’s Hematocrit: The hematocrit level of the specific patient. Reticulocyte Count The reticulocyte count is an important piece of information When markedly elevated this is usually noticeable in a Wright stain peripheral blood smear Reticulocytes appear as large, polychromatic red blood cells Anemia due to production defect is associated with a normal to low reticulocyte count Such hyporegenerative anemias include iron deficiency anemia, anemia of chronic disease, lead poisoning, folate deficiency, B12 deficiency, myelodysplastic syndrome, aplastic anemia, and pre red cell aplasia Reticulocyte Nucleated Red Blood Smear Abnormal Red Blood Cell Morphology Blood Cell Count Normal Ranges RBC x 106/uL or RBC x 1012/L Adult/elderly Male: 4.7 – 6.1 Female: 4.2 - 5.4 Child 2-8 weeks: 4.0 - 6.0 2-6 months: 3.5 - 5.5 6 months-1year: 3.5 - 5.2 1-6 years: 4.0 - 5.5 6-18 years: 4.0 - 5.5 Newborn: 4.8-7.1 Interfering Factors Hemodilution due Hemoconcentratio Failure to use the to drawing the n due to prolonged proper sample from the tourniquet anticoagulant same arm used for constriction IV infusion of fluids Disease the causes High white blood Hemolysis due to RBC to agglutinate cell counts rough handling or form rouleaux 28 Hematocrit Hematocrit = indirect measurement of the red blood cell (RBC) number and volume Used as a rapid measurement of RBC quantity in blood Repeated in patients with ongoing bleeding or routine complete blood cell count Integral part of the evaluation of anemia patients Hematocrit is a measure of the percentage of the total blood volume that is made up by the RBCs The height of the RBC column is measured after centrifugation It is compared to the height of the column of total whole blood The ratio of the height of the RBC column compared with the original total blood column is multiplied by 100% Hematocrit (Hct) Larger RBCs are associated with The Hematocrit can be Abnormalities in RBC higher Hct levels Extremely high white altered by many size may alter because the larger blood cell counts factors other than RBC Hematocrit values RBCs take up a decrease Hct production greater percentage of the total blood volume Hct values may not be Living at high reliable immediately Pregnancy usually attitudes causes after hemorrhage Hemodilution and causes slightly increased Hct values because the dehydration may decreased values as a result of a percentage of total affect the Hct level because of chronic physiologic response blood volume taken hemodilution to the decreased up by the RBC has not oxygen available changed 30 Hemoglobin (Hgb) The Hemoglobin concentration is a measure of the total amount of Hgb in the peripheral blood The test is performed as part of the complete blood count Hemoglobin serves as a vehicle for oxygen and carbon dioxide transport The oxygen-carrying capacity of the blood is determined by the Hgb concentration Hemoglobin acts as an important acid-base buffer system Normal values vary with gender and age Women tend to have lower values then men and Hgb tend to decrease with age Hgb closely reflects the hematocrit and RBC values The Hct in percentage points usually is approximately three times the Hgb concentration in grams per deciliter when RBC’s are of normal size and contain normal amounts of Hgb Hemoglobin (Hgb) Male: 14-18 g/dL Female: 12-16 g/dL Pregnant female: >11 g/dL Elderly: Values are slightly decreased Child/adolescent ○ Newborn: 14-24 g/dL ○ 0-2 weeks: 12-20 g/dL ○ 2-6 months: 10-17 g/dL ○ 6 months – 1 year: 9.5 – 14 g/dL ○ 1-6 years: 9.5 -14 g/dL ○ 6-18 years: 10-15.5 g/dL Hemoglobin (Hgb) Slight Hgb decreases normally occur during pregnancy because of the dilution effect of the expanded blood volume There is a slight diurnal variation in Hgb levels Hgb levels are highest around 8AM and are lowest around 8PM Heavy smokers have higher Hgb than nonsmokers Living in high attitudes causes increased Hgb values as a result of a physiologic response to the decreased oxygen available at these high altitudes Blood transfusions within the previous 12 weeks may alter test results  Hemoglobulin Synthesis Hemoglobulin molecules are formed Usually by 12 months In the newborn, fetal by two pairs of globulin Fetal hemoglobin has a of life, the gamma hemoglobin consists of chains forming a higher affinity for globin is replaced by two alpha globlins and tetramer with a heme oxygen beta globin to form two gamma globins compound joined to hemoglobin A each chain Hemoglobin A has two Hemoglobin A2 is alpha globin chains The remaining composed of a pair of and two beta globin hemoglobin comprises alpha globin chains chains and makes up hemoglobin A2 and F and a pair of delta 97% of hemoglobin in globin chains the normal person 34 Breaking Down Hemoglobin Old or damaged RBCs are removed from the circulation by macrophages in the spleen and liver The hemoglobin is broken down into heme and globin The globin protein may be recycled or broken down further to its constitute amino acids which can be recycled or metabolized The heme iron is conserved and reused in the synthesis of new hemoglobin molecules During metabolism, heme is converted to bilirubin and the plasma protein albumin binds to bilirubin and carries it to the liver where it is secreted in bile 35 Mean Corpuscular Volume (MCV) The MCV is a measure of the average volume, or size, of a single RBC and is therefore used in classifying anemias MCV is derived by dividing the hematocrit by the total RBC count Normal values vary according to age and gender When the MCV is increased, the RBC is said to be abnormally large or macrocytic, which is seen in megaloblastic anemia When the MCV is decreased, the RBC is said to microcytic which is associated with iron deficiency anemia or thalassemia MCV = Hematocrit (%) x 10 RBC (million/mm3) 36 Mean Corpuscular Hemoglobin(MCH) The MCH is a measure of the average amount of hemoglobin within an RBC MCH is derived by dividing the total hemoglobin concentration by the number of RBCs Macrocytic cells generally have more hemoglobin and microcytic cells have less hemoglobin MCH = Hemoglobin (g/dL x 10 RBC (million/ mm3) 37 Mean Corpuscular Hemoglobin Concentration (MCHC) The MCHC is a measure of the average concentration or percentage of hemoglobin within a single RBC MCHC is derived by dividing the total hemoglobin concentration by the hematocrit When values are decreased, the cell has a deficiency of hemoglobin and is said to be hypochromic This is frequently seen in iron-deficiency anemia and thalassemia When values are normal the anemia is said to be normochromic RBCs cannot be considered hyperchromic as only 37 g/dL of hemogloblin can fit into the RBC MCHC = Hemoglobin (g/dL) x 100 Hematocrit (%) 38 Red Blood Cell Distribution Width (RDW) The RDW is an indication of the variation in RBC size It is calculated by a machine using the MCV and RBC values Variations in the width of the RBCs may be helpful when classifying certain types of anemia The RDW is essentially an indicator of the degree of anisocytosis, a blood condition characterized by RBC’s of variable and abnormal size Red Blood Cell Indices Mean Corpuscular Volume (MCV) Adult/elderly/child: 80-95 fl (femtoliter) Newborn: 96-108 fl Mean Corpuscular Hemoglobin (MCH) Adults/elderly/child: 27-31 pg Newborns: 32-34 pg Mean Corpuscular Hemoglobin Concentration (MCHC) Adult/elderly/child: 32-36 g/dL (or 32% - 36%) Newborn: 32-33 g/dL (or 32%-33%) Red Blood Cell Distribution Width (RDW) Adult: variation of 11%-14.5% Checkpoint Question Carries oxygen to all cells, tissues, and organs A.Hematocrit B.Erythrocytes C.Hemoglobin Checkpoint Question The packed red blood cell volume is called: A.Hemoglobin B.Hematocrit C.Red blood cell count Checkpoint Question What can alter the hematocrit? A.Abnormal size in red blood cells B.High white blood cell count can decrease hematocrit C.Hemodilution and dehydration D.Pregnancy E.Living at high altitudes F.All of the above Checkpoint Question The life span of a red blood cell is: A.100 days B.120 days C.150 days D.180 days Checkpoint Question Red blood cells that are larger than normal are called: A.Polychromatic B.Microcytic C.Macrocyctic Checkpoint Question Oxygen sensing cells in the kidney respond by increasing the production of stimulating the proliferation of the marrow to increase red blood cell production. A.Erythroporitin B.Oxygen C.Hemoglobin Anemia Anemia is present when the hemoglobin and hematocrit are reduced Anemias may be classified according to red cell size (MCV) and hemoglobin content (MCH) Further diagnostic information is obtained by the microscopic examination of the red blood cell morphology (shape) on a blood smear A state of red blood cell deficiency that lowers the oxygen-carrying capacity of the blood Anemia can result from blood loss, increased red blood cell destruction (hemolysis) or decreased red cell production Hemolytic anemia s can be sub-classified based on whether they are caused by defects that are intrinsic or extrinsic to the red cell Hemolytic anemias are those in which red blood cell survival is shortened Premature destruction of erythrocytes may occur within the bloodstream(intravascular hemolysis), or within the reticuloendothelial system (extravascular hemolysis) Intravascular Hemolysis Can be caused by Mechanical red cell trauma such as microangiopathic hemolytic anemia (MHA) Mechanical heart valve Complement fixation on the red cell surface ABO incompatibility Paroxysmal cold hemoglobinuria (PCH) Snake envenomation Infectious agents Malaria Babesiosis Clostridium Extravascular Hemolysis The cause of hemolysis may be inherited or acquired Inherited forms of hemolytic anemia usually, but not always present in early childhood Hemolytic Anemia Hemolytic anemia present with jaundice, fatigue, tachycardia, and pallor If chronic, enhanced excretion of hemoglobin breakdown products often leads to the development of pigmented gallstones Intravascular hemolysis may present with dark urine and back pain Leg ulcers are common in sickle cell disease and hereditary spherocytosis (HS) Splenomegaly is a common finding in extravascular hemolysis Blood Diseases Involving the Red Blood Cells Anemia is defined as a reduction of the total circulating red cell mass below normal limits and are characterized by low oxygen transport capacity of the blood Hemolysis is a general term for excessive breakdown of red blood cells which can have several causes and can result in hemolytic anemia Polycythemias are diseases characterized by a surplus of red blood cells, the increase viscosity of the blood can cause a number symptoms Hemolytic transfusion reaction is a destruction of donated red blood cells after a transfusion mediated by host antibodies The deficit in oxygen-carrying compensated by adaptive increases in plasma volume, cardiac output, respiratory rate, and other metabolic changes that increase oxygen delivery to tissues Classification of Anemia by Pathophysiology Production Defect Anemia of chronic disease Renal disease (low erythropoietic states) Fanconi Anemia Blackfan-Diamond Syndrome Parvovirus infection Drugs or toxins Survival Defect Hemoglobinopathies Immune hemolytic anemia Infectious Disease of hemolysis Membrane abnormalities Metabolic abnormalities Mechanical hemolysis Drugs or toxins Wilson disease Classification of Anemia by Pathophysiology Maturation defect Vitamin B 12 deficiency Folate deficiency Iron deficiency Sideroblastic anemia Lead poisoning Hemorrhage Hypersplenism Anemia Anemia may present with pallor, fatigue, dyspnea, or evidence of poor tissue oxygenation (chest pain due to poor cardiac oxygenation, altered mental status due to poor cerebral oxygenation Anemia stimulates several compensatory mechanisms The cardiopulmonary system compensates by attempting to make the most of the blood it has by exchanging more gases (tachypnea) and circulating more volume (tachycardia) The marrow responds with increased erythropoiesis, stimulated by an increase in renal production of erythropoietin in response to hypoxia Anemia of Blood Loss Acute Blood Loss The rapid loss of 10% or more of the circulating blood volume through hemorrhage will result in shock The effects of acute blood loss are mainly due to the loss of intravascular volume, which if massive can lead to cardiovascular collapse, shock and death Bleeding can be internal or external The blood volume is rapidly restored by the intravascular shift of water from the interstitial fluid compartment This fluid shift results in hemodilution and a lowering of the hematocrit If bleeding is massive there will be a decrease in blood pressure Acute Blood Loss Acute blood loss (hemorrhage) is seen most often as a result of surgery, trauma, or gastrointestinal pathology Hemorrhage is usually obviously present but may be occult and internal (large retroperitoneal or pelvic hemorrhages The cardinal manifestation of acute blood loss is tachycardia, tachypnea, and hypertension Not as much a decreased oxygen-carrying capacity as a decreased intravascular volume A shift of water from the interstitial fluid compartment into the plasma leads to hemodilution and lowered hematocrit Initial treatment is intravenous fluid resuscitation with normal saline If this is unsuccessful a blood transfusion is considered Anemias of Blood Loss Chronic Blood Loss Chronic blood loss induces anemia only when the rate of loss exceeds the regeneration capacity of the marrow or when iron reserves are depleted and iron deficiency anemia appears Iron Deficiency anemia is the most common anemia It occurs when the dietary intake or absorption of iron is insufficient, and hemoglobin which contains iron cannot be formed Hemolytic Anemia Hemolytic anemias share the following features: Due to a defect of the red cell itself and is almost always are hereditary Those due to abnormality outside the red cell A shortened red cell life span below the 120 days Elevated erythropoietin levels and a compensatory increase in erythropoiesis Accumulation of hemoglobin degradation products that are created as part of the process of red cell hemolysis Most hemolytic anemias are caused by intrinsic red blood cell defects or damage induced by extrinsic factors that increase red cell destruction by phagocytes Hemolytic Anemia The physiologic destruction of red cells takes place within macrophages, which are abundant in the spleen, liver and bone marrow This process is triggered by age-dependent changes in red cell surface proteins, which lead to recognition and phagocytosis The premature destruction of red cells within phagocytes is referred to as extravascular hemolysis and is generally caused by alterations that render the red cell less deformable Pathogenesis of Hemolytic Anemia Hyperbilirubinemia and jaundice due to degradation of hemoglobin by macrophages Splenomegaly due to work hyperplasia of phagocytes in the spleen Bilirubin-rich gallstones (pigment stones) Bilirubin is breakdown product of hemoglobin Increased risk of cholecystitis secondary to bile duct obstruction Checkpoint Question Anemia lowers the oxygen-carrying capacity of the blood and may result from: A.Blood loss B.Increased red blood cell destruction C.Decreased red blood cell production D.All of the above Checkpoint Question What adaptive measures compensate for the deficit in oxygen-carrying capacity? A.Increase in plasma volume B.Cardiac output C.Respiratory rate D.Other metabolic changes that increase oxygen delivery E.All of the above Intravascular hemolysis Can be caused by mechanical injury Trauma caused cardiac valves – turbulent blood flow Thrombotic narrowing of the microcirculation Repetitive physical trauma (marathon running) Caused by injuries that are so severe the red blood cells burst within circulation Complement fixation Antibodies recognize and bind red cell antigens Intracellular parasites (e.g. malaria) Exogenous toxic factors Clostridial sepsis which results in the release of enzymes that digest the red cell membrane Intravascular hemolysis is manifested by anemia, hemoglobinemia, hemoglobinuria, hemosiderinuria and jaundice Plasmodium Infection (Malaria) Clostridium perfringens with Gas gangrene Checkpoint Question Red blood cells are removed from circulation by phagocytes. What type of hemolysis is this referred to? A.Intravascular B.Extravascular Hereditary Spherocytosis Hereditary spherocytosis is an inherited disorder (autosomal dominant) caused by intrinsic defects in one of the structural proteins of the erythrocyte membrane such as spectrin Caused by inherited defects in red cell membrane skeleton proteins that lead to membrane loss and the formation of spherocytes that lose deformability Cells are vulnerable to splenic sequestration and destruction Biconcave erythrocytes are released from the marrow but they rapidly loss membrane and assume the spherical shape The loss of membrane relative to cytoplasm forces the cells to assume the smallest possible diameter for a given volume namely a sphere Hereditary Spherocytosis (HS) Morphological finding is spherocytosis on a smear as small, dark staining (hyperchromic) red cells lacking the central zone of pallor Moderate splenomegaly is characteristic Autosomal dominant inheritance pattern is seen in about 75% of cases The remaining patients have a more severe form of the disease that is usually caused by the inheritance of two different defects The lifespan of the affected red cell is decreased on average to 10 to 20 days from the normal 120 days The cells cannot pass through the narrow slit-like opening that separate the splenic red pulp from the splenic venous circulation, resulting in extravascular hemolysis Hereditary Spherocytosis (HS) In two thirds of the patients the red cells are abnormally sensitive to osmotic lysis when incubated in hypotonic solution, which causes the influx of water into spherocytes with little margin for expansion Red cells have increased mean cell hemoglobin concentration (MCHC) due to dehydration caused by the loss of K+ and H2O The characteristic clinical features are anemia, splenomegaly and jaundice Diagnosis depends on the family history, evidence of extravascular hemolysis, the presence of spherocytes in the peripheral smears Following splenectomy patients have an excellent prognosis but are at risk for sepsis with encapsulated bacteria due to loss of splenic function They are also prone to aplastic crises during infections by parvovirus B19 which infects and kills erythroid progenitors in the marrow Spherocytes A - No area of central pallor B - Polychromatic reticulocyte Spherocytes A - No area of central pallor B - Polychromatic reticulocyte Hereditary Spherocytosis (HS) The severity varies greatly In small minority HS presents at birth with marked jaundice and requires exchange transfusion In 20% to 30% of patients disease is so mild that patients are asymptomatic Most patients have chronic hemolytic anemia of mild to moderate severity Stable clinical course is sometimes punctuated by aplastic crisis usually triggered by an acute Parovirus infection Parvovirus infects and kills red blood progenitors, effectively causing red cell production to cease until an immune response commences Hereditary Spherocytosis (HS) Because of the reduced life span of HS red cells, cessation of erythropoiesis for even short time periods leads to sudden worsening of the anemia Transfusion maybe necessary to support the patient until the immune response clears the infection Hemolytic crises lead to increased splenic destruction of red cells (e.g. infectious mononucleosis); these are clinically less significant than aplastic crises Gallstones can also produce symptoms Splenectomy treats anemia and its complications, but brings with it an increased risk of sepsis, since the spleen acts as an important filter for blood borne bacteria The diagnosis is based on family history, hematologic findings, and laboratory evidence Hereditary Elliptocytosis (HE) This autosomal dominant disorder is due to defective tetramerization of cytoskeletal spectrin resulting in elliptocytes also called ovalocytes The common type of HE is seen primarily in African Americans and manifests as a mild lifelong hemolytic anemia Hereditary pyropoikilocytosis is a variant of HE in which RBCs are sensitive to damage from heat The peripheral blood smear is notable for profound degree of poikilocytosis with red cells of every size and shape This condition is usually most pronounced in infancy and tends to abate with age A stomatocytic type of HE exists that is called Southeast Asian ovalocytosis Elliptocytosis Hemolytic Disease Due to Red Cell Enzyme Defects: Glucose-6-Phosphate Dehydrogenase Deficiency Deficiency or defect of glucose-6-phosphate dehydrogenase (G6PD) results in impaired reduction of glutathione Abnormalities in the hexose monophosphate shunt or glutathione metabolism resulting from deficient or impaired enzyme function reduce the ability of red blood cells to protect themselves against oxidative injuries and lead to hemolysis Reduced glutathione protects hemoglobin and red cell membrane from oxidative damage Inherited G6PD deficiency is uncommon in the UK , but is among the most common genetic disorders worldwide G6PD Deficiency G6PD deficiency is an inherited condition. It is when the body doesn't have enough of an enzyme called G6PD (glucose-6-phosphate dehydrogenase). This enzyme helps red blood cells work properly. A lack of this enzyme can cause hemolytic anemia. This is when the red blood cells break down faster than they are made. 6PD catalyzes NADP+ to its reduced form, NADPH, in the pentose phosphate pathway. (G6PD = glucose-6-phosphate dehydrogenase; ATP = adenosine triphosphate; ADP = adenosine diphosphate; NADP+ = nicotinamide adenine dinucleotide phosphate [oxidized form]; NADPH = reduced NADP; GSSG = oxidized glutathione; GSH = reduced glutathione.) G6PD Deficiency Hemolytic Disease Due to Red Cell Enzyme Defects: Glucose-6-Phosphate Dehydrogenase Deficiency G6PD deficiency is a recessive X-linked trait, placing males at higher risk for symptomatic disease Several hundred G6PD genetic variations are known, but most are harmless Two variant, designated G6PD and G6PD Mediterranean cause most of the clinically significant hemolytic anemia G6PD is present in about 10% of American blacks and G6PD present in the Middles East Natural protection from Plasmodium falciparum Hemolytic Disease Due to Red Cell Enzyme Defects: Glucose-6-Phosphate Dehydrogenase Deficiency G6PD variants associated with hemolysis result in misfolding of the protein making it more susceptible to proteolytic degradation Enzyme activities fall quickly to levels inadequate to protect against oxidant stress as red cells age Older red cells are much more prone to hemolysis than younger ones The most common triggers are infection, in which oxygen-derived free radicals are produced by activated leukocytes Many infections can trigger hemolysis (viral hepatitis, pneumonia, and typhoid fever are among those likely to do so) Drugs are also important initiators ( antimalarial, sulfonamides, nitrofurantoin) Fava beans can also be an initator G6PD Deficiency Poikilocytosis Sickle Cell Disease Sickle cell disease is a common autosomal recessive disorder caused by a single point mutation in the genetic code resulting in an amino acid substitution in the alpha or beta globin chain of hemoglobin The point mutation is in the sixth codon of B-globin that leads to the replacement of a glutamate residue with a valine residue resulting in sickle Hemoglobin (HbS) Normal adult red cells contain mainly Hemoglobin A (a 2B2) along with fetal hemoglobin (HbF), (a2B2) Most common familial hemolytic anemia In Africa the gene frequency approaches 30% because of a protective effect of HbS against malaria Sickle Cell Disease Depending on the site of the substitution, four main types of functional defects result A hemoglobin that becomes crystalline at low oxygen tension, e.g. HbS causing hemolysis and microvascular occlusion An unstable hemoglobin causing chronic hemolysis with Heinz bodies (red cell inclusions composed of denatured hemoglobin Hemoglobin of increased oxygen affinity causing polycythemia A hemoglobin that tends to the oxidized state causing cyanosis Checkpoint Question An anemia caused by inherited defects in red blood cell membrane skeleton membrane proteins that lead to membrane loss and the formation of red blood cells that lack central pallor and decreased life span. A.G6PD deficiency B.Sickle cell anemia C.Hereditary spherocytosis D.Thalassemia Sickle Cell Anemia Sickle cell disease is an inherited genetic condition that involves defects in the shape and function of hemoglobin in the blood. This increases the likelihood of blockages in the blood vessels and disrupted blood flow, which can result in serious complications. Sickle Cell Anemia Sickle Cell Anemia Sickle Cell Anemia Sickle Cell Disease The gene for HbS is common in the West and Central African populations, the Mediterranean, Middle East and some parts of Indian subcontinent Carriage of the gene may confer some protection against falciparum malaria The gene is carried by 8% of black Americans and 30% of black Africans The heterozygous state or sickle cell trait, results in less than 40% HbS, the remainder being mostly normal HgA The carrier is clinically and hematologically normal, sickling occurs uncommonly and only under conditions of severe hypoxia Hematuria is occasionally seen Sickle Cell Disease In the homozygous, the hemoglobin concentration is low Sickle cells and target cells are present on the blood film Splenomegaly due to chronic hemolysis is present during childhood but the spleen shrinks progressively due to microvascular occlusion and infarction There is anemia and jaundice from infancy Sickle cell crises of various clinical types occur from an early age Vascular occlusion with resultant ischemia causes severe pain, often in the long bones, abdomen or chest Pain crises are caused by localized obstruction of the microvasculature by sickled cells Stroke is common Sickle Cell Disease The major pathologic manifestations are chronic hemolysis, microvascular occlusions and tissue damage all stemming from the tendency of HbS molecules to stack into polymers when deoxygenated A decrease in pH reduces the oxygen affinity of hemoglobin, increasing the fraction of deoxygenated HbS at any given oxygen tension and augmenting the tendency for sickling Mean cell hemoglobin concentration (MCHC) will be increased due to higher HbS concentrations and intracellular dehydration Conditions that decrease the MCHC reduce the disease severity A decrease in intracellular pH reduces the oxygen affinity of hemoglobin thereby increasing the fraction of deoxygenated HbS at any given oxygen tension and augmenting the tendency for sickling Much of the pathology of sickle cell disease is related to vascular occlusion caused by the sickling with microvascular beds Obstruction of blood flow in the spleen leads to splenic autoinfarction, markedly increasing the risk for sepsis with encapsulated bacteria Sickle Cell Disease Morphology The peripheral blood demonstrates variable numbers of irreversibly sickled cells, reticulocytes and target cells resulting from red cell dehydration Howell-Jolly bodies are small nuclear remnants due to asplenia The bone marrow is hyperplastic as a result of compensatory erythroid hyperplasia The increased breakdown of hemoglobin can cause pigment gallstones and hyperbilirubinemia In childhood the spleen is enlarged up to 500 gm by red pulp congestion caused by trapping of the sickle cells Sickle cell causes moderately severe hemolytic anemia Thalassemia Mutations in genes that encode globin chains may result in two broad categories of disease Some mutations lead to the production of a structurally abnormal globin chain, resulting in a hemoglobinopathy Other mutations lead to reduced production of a structurally normal globin-chain as seen in Thalassemia Hemoglobin is composed of four polypeptide chains The major adult hemoglobin A (HgA) is composed of two alpha chains and two beta chains The alpha chain genes are located on chromosome 16 Each chromosome 16 contains two separate alpha genes, for a total of four genes per normal cell, each transcriptionally active To render an individual completely deficient of alpha chains, inheritance of four mutated genes is required With decreased alpha chain production , alpha thalassemia arises Thalassemia Thalassemia is due to abnormalities of alpha or beta globin chain synthesis Inherited disorder caused by mutations in globulin genes that result in decreased synthesis of alpha and beta globulin The associated anemia results from reduced hemoglobin synthesis and hemolysis due to imbalance in globin chain synthesis Characterized by a microcytic, hypochromic blood picture Beta thalassemia major results in severe, transfusion-dependent anemia from infancy, splenomegaly, marrow expansion with bony deformities and premature death Beta-thalassemia minor is clinically mild Alpha-thalassemia include disorders resulting in intrauterine death from severe anemia and heart failure and those producing clinically insignificant disease Thalassemia In Thalassemia the globin chains are of normal composition, but the rate of which the globin chains (alpha or beta) is synthesized is reduced Accumulation of an excess of the unaffected globin chains results in damage to the developing and mature erythrocytes Each chromosome 16 has a pair of alpha globin genes, each cell has four genes coding for the alpha globin, all of them functional In the alpha-thalassemia syndromes there is a deletion of all four genes or of three of four In alpha-thalassemia trait there is deletion of two or only one gene More than 200 genetics defects responsible for beta-thalassemia have been described, predominately point mutation Thalassemia Syndromes Heterogeneous group of disorders caused by inherited mutations that decrease the synthesis either the a-globin or B-globin chains that compose adult hemoglobin leading to anemia, tissue hypoxia, and red cell hemolysis related to the imbalance in globin chain synthesis The two a-chains in HbA are encoded by an identical pair of a-globin genes on chromosome 16 The two B-chains are encoded by a single B-globin gene on chromosome 11 B-thalassemias are caused by deficient synthesis of the B-chains while a- thalassemias are caused by deficient synthesis of the a-chains The hematological consequences of diminished synthesis of one globin chain stem not only from hemoglobin deficiency but also from a relative excess of the other globin chain Thalassemia Syndromes Are endemic in the Mediterranean basin as well as Middle East, tropical Africa, the Indian subcontinent, and Asia The defects in globin synthesis cause decreased red cell production and decreased red cell life span B-Thalassemia Major is most common in Mediterranean countries, parts of Africa, and Southeast Asia The anemia manifests 6 to 9 months after birth as hemoglobin synthesis switches from HgF to HgA In nontransfused patients, hemoglobin levels are 3 to 6 gm/dL The red cells may completely lack HgA (B0/B0 genotype) or contain small amounts (B+/B+ or Bo/B+ genotypes Beta-Thalassemia Major Also called Mediterranean or Cooley’s anemia This is a very severe disorder due to the inheritance of two genes for beta-thalassemia The blood picture is that of severe microcytic, hypochromic anemia developing from 2 to 6 months of age when beta chain production would have normally replaced the great majority of gamma chain production, leading to the dominance of HbA and only 1% residual fetal hemoglobin Clinical features are those of severe anemia, including growth retardation, and iron overload secondary to red cell transfusions and a tendency to absorb excess iron B-Thalassemia Major Morphology Blood smears show severe red cell abnormalities, including marked variation in size (anisocytosis) and shape (poikilocytosis), microcytosis and hypochromia The reticulocyte count is elevated Variable numbers of poorly hemoglobinized nucleated red cells Beta Thalassemia Major Morphology Beta thalassemia major (Cooley’s anemia). There are two damaged genes. Codocytes, also known as target cells, are red blood cells that have Polychromasia is a disorder where there is an the appearance of a shooting target with a bullseye. In optical abnormally high number of immature red blood cells microscopy these cells appear to have a dark center (a central, found in the bloodstream as a result of being hemoglobinized area) surrounded by a white ring (an area of relative pallor), followed by dark outer (peripheral) second ring containing a band prematurely released from the bone marrow during of hemoglobin. Thalassemia Major Morphology B-Thalassemia Minor Much more common than B-Thalassemia major Most patients are heterozygous carriers of B+ or Bo allele Patients are usually asymptomatic Anemia, if present is mild The peripheral blood smear typically shows some red cell abnormalities, including hypochromia, microcytosis, basophilic stippling, and target cells Mild erythroid hyperplasia is seen in the bone marrow Hemoglobin electrophoresis usually reveals an increase in HgA2 Thalassemia minor Morphology Thalassemia minor is an inherited form of hemolytic anemia that is less severe than thalassemia major. This blood smear from an individual with thalassemia shows small (microcytic), pale (hypochromic), variously-shaped (poikilocytosis) red blood cells. These small red blood cells (RBCs) are able to carry less oxygen than normal RBCs. Thalassemia minor Morphology a-Thalassemia Caused by inherited deletions that result in reduced or absent synthesis of a-globin chains Normally there are four a-globin genes The severity of a-Thalassemia depends on how many of these genes are affected The anemia stems from a lack of adequate hemoglobin and the presence of excess unpaired globin chains The clinical syndromes are determined and classified by the number of a-globin genes that are deleted Silent Carrier State Associated with the deletion of a single a-globin gene, which causes a barely detectable reduction in a-globin chain synthesis Individuals are completely asymptomatic but have slight microcytosis Thalassemia Trait Caused by the deletion of two a-globin genes from a single chromosome (a/a-/-) or the deletion of one a- globin gene from each of two chromosomes a/-a/- Both genotypes produce similar quantitative deficiencies of a-globin and are clinically identical, but have different implications for the children of affected individuals, who are at risk of clinically significant a- thalassemia (HbH) disease or hydrops fetalis Hemoglobin H Disease HbH Disease is caused by deletion of three a- globin genes Most common in Asian populations One only one normal a-globin gene, the synthesis of alpha chains is markedly reduced, and tetramers of B-globin HbH has an extremely high affinity for oxygen and therefore is not useful for oxygen delivery, leading to tissue hypoxia disproportionate to the level of hemoglobin HbH is prone to oxidation, which causes it to precipitate and form intracellular inclusions that promote red cell sequestration and phagocytosis in the spleen Patients have a moderately severe anemia Hydrops Fetalis Hydrops fetalis is the most severe form of a-thalassemia and is caused by deletion of all a-globin genes In the fetus, excess y-globin chains form tetramers (hemoglobin Barts) that have such a high affinity for oxygen that they deliver little to tissues Signs of fetal distress usually become evident by the third trimester of pregnancy In the past, severe tissue anoxia led to death in utero or shortly after birth With intrauterine transfusion many infants are now saved The fetus shows severe pallor, generalized edema, and massive hepatosplenomegaly similar to that seen in hemolytic disease of the new born There is a lifelong dependence on blood transfusions for survival, with the associated risk of iron overload Hematopoietic stem cell transplantation can be curative Paroxysmal Nocturnal Hemoglobinuria Is a disease that results from acquired mutations in the phosphatidylinositol glycan complementation group A gene (PIGA), an enzyme that is essential for the synthesis of certain membrane-associated complement regulatory proteins PNH has an incidence of 2 to 5 per million in the United States It is the only hemolytic anemia caused by an acquired genetic defect Hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) is RBC membrane defect (DAF) increases susceptibility to complement mediated lysis X-linked and subject to random inactivation of one X chromosome in cells of females A single acquired mutation in the active PIGA gene of any given cell is sufficient to produce a deficiency state Paroxysmal Nocturnal Hemoglobinuria Checkpoint Question An anemia that is an autosomal recessive disorder caused by a single amino acid substitution in B-globin that leads to production of Hemoglobin S. A.Hereditary Spherocytosis B.G6PD Deficiency C.Sickle Cell Anemia D.Thalessemia Checkpoint Question Inherited disorder caused by mutations in globulin genes that result in decreased synthesis of alpha, or beta globin resulting in reduced hemoglobin synthesis and hemolysis due to the imbalance in globin chain synthesis. A.Sickle Cell Anemia B.Thalassemia C.G6PD Deficiency D.Iron Deficiency Checkpoint Question The anemia associated with chronic blood loss is: A.G6PD deficiency B.Iron Deficiency C.Sickle Cell anemia Immunohemolytic Anemia Caused by antibodies that bind to red cells, leading to their premature destruction The diagnosis of immunohemolytic anemia requires the detection of antibodies and/or complement on red cells from the patient Direct Coombs Anti-globulin Test is where the patient’s red blood cells are mixed with sera containing antibodies that are specific for human immunoglobulin or complement If either immunoglobulin or complement is present on the surface of the red blood cells, the antibodies cause agglutination which is demonstrated by visible clumping Antibodies can either be of the warm or cold agglutinin type Hemolytic Anemia from Trauma to Red cells Seen in individuals with cardiac valve prostheses and microangiopathic disorders Artificial mechanical cardiac valves are more frequently implicated than are bioprosthetic porcine or bovine valves The hemolysis stems from shear forces produced by turbulent blood flow and pressure gradient across damaged valves Microangiopathic hemolytic anemia is most commonly seen with disseminated intravascular coagulation (DIC), but it may occur with thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), malignant hypertension, systemic lupus erythematous, and disseminated cancer Mechanical Trauma to Red Cells Intravascular hemolysis of red cell due to exposure to abnormal menchanical forces Traumatic hemolysis due to defective cardiac valve prostheses which may shear red cells Microangiopathic hemolytic anemia occurs when small vessels become narrowed by thrombi Disseminated intravascular coagulation (DIC) Anemias of Diminished Erythropoiesis Megaloblastic Anemia Impairment of DNA synthesis that leads to ineffective hematopoiesis and distinctive morphologic changes including abnormally large erythroid precursors and red blood cells Vitamin B12 Deficiency caused by decreased intake or impaired absorption Folic Acid Deficiency caused by decreased intake, increased requirement or impaired utilization Immunohemolytic Anemia Caused by antibodies that bind to antigens found on red cell membrane May arise spontaneously or be induced by exogenous agents such as drugs or chemicals Classified on the basis of the nature of the antibody and the presence of predisposing conditions Hemolytic Disease of the Newborn Cytotoxic – responsible for the tissue damage in hemolytic disease of the newborn Antigen on a plasma membrane is first recognized as foreign, B cells become sensitized and stand ready for antibody production upon subsequent antigen exposure, antibodies bind to antigen and activate complement This disorder results from an antibody-induced hemolytic anemia caused by blood group incompatibility between the mother and the fetus The fetus inherits red cell antigenic determinants from the father that are foreign to the mother Fetal red cells enter maternal circulation during the last trimester of pregnancy or during childbirth sensitizing the mother to paternal red cell antigens and leading to the production of anti-red cell antibodies that cross the placenta and cause hemolysis of fetal red cells Hemolytic Disease of Newborn Type II Hypersensitivity Reaction Cytotoxic – responsible for the tissue damage in hemolytic disease of the newborn Antigen on a plasma membrane is first recognized as foreign, B cells become sensitized and stand ready for antibody production upon subsequent antigen exposure, antibodies bind to antigen and activate complement Folate Deficiency Folate and vitamin B12 deficiency are the classical causes of megaloblastic anemia Megaloblastic refers to the appearance of hematopoietic precursor cells in the marrow Their nuclei appear abnormally large and immature resulting from nuclear maturation that lags behind cytoplasmic maturation This megaloblastic change affects not only erythroblasts but other rapidly dividing cells as well, including maturing granulocytes, megakaryocytes, and enterocytes Results from impairment of DNA synthesis Erythropoiesis becomes ineffective, resulting in a hypercellular marrow Many erythroblasts are destroyed while still in the marrow Folate deficiency does not cause the same neurologic defect that vitamin B12 deficiency causes Supplementation of folate in early pregnancy is known to reduce the incidence of neural tube defects Pernicious Anemia Specific form of megaloblastic anemia caused by autoimmune gastritis that impairs the production of intrinsic factor, which is required for vitamin B 12 uptake from the gut Vitamin B12 is a complex organometallic compound also known as cobalamin Humans are totally dependent on dietary vitamin B12 Adsorption of vitamin B12 requires intrinsic factor, which is secreted by the parietal cells of the fundic mucosa Vitamin B12 is freed from binding proteins in food through the action of pepsin in the stomach and binds to a salivary protein called haptocorrin In the duodenum, bound vitamin B12 is released from haptocorrin by the action of pancreatic proteases and it associates with intrinsic factor Pernicious Anemia Occurs in all racial groups however more prevalent in Scandinavian and other Caucasian populations It is a disease of older adults, the median age of 60 years and is rare in people less than 30 A genetic predisposition is strongly suspected but no definable genetic pattern of transmission has been discerned It is believed to result from an autosomal attack on the gastric mucosa Vitamin B12 Pernicious Anemia- B12 deficiency B12 Anemia (Pernicious Anemia): This is a specific type of anemia caused by a lack of intrinsic factor, a protein needed for the absorption of vitamin B12. Without sufficient B12, the body cannot produce enough healthy red blood cells. Megaloblastic: This term describes abnormally large and immature red blood cells (megaloblasts) that are seen in the bone marrow before they mature into normal-sized red blood cells. Hypersegs: This likely refers to hypersegmented neutrophils. In pernicious anaemia, this process is impaired because of loss of parietal cells, resulting in insufficient absorption of Neutrophils are a type of white blood the vitamin, which over a prolonged period of time ultimately cell involved in the body's immune leads to vitamin B12 deficiency and thus megaloblastic response. anaemia. Pernicious Anemia Macrocytic Red Blood Cells Iron Deficiency Anemia Within the cytoplasm of the marrow erythroblast, the predominant activity is the production of hemoglobin molecules into which iron must be incorporated Iron from the diet is absorbed in the duodenum It is carried by transferrin to the marrow where it is internalized into erythroblasts and incorporated into protoporphyrin to yield heme Iron not utilized is stored bound to ferritin When there is inadequate iron intake or excessive iron loss, the ferritin-iron stores of the reticuloendothelial system become progressively depleted Red blood cells are produced that contain an inadequate concentration of hemoglobin Red blood cells are hypochromatic and microcytic Fewer mature red cells are produced, lowering the hematocrit  Iron Deficiency Anemia The most common nutritional disorder in the world and results in a clinical signs and symptoms that are mostly related to inadequate hemoglobin synthesis The prevalence of iron deficiency anemia is higher in developing countries but is common in United States in toddlers, adolescent girls, and women of child bearing age Iron in the body is recycled between the functional and storage pools It is transported in plasma by an iron-binding glycoprotein called transferrin, which is synthesized by the liver In normal individuals, transferrin is about one third saturated with iron, yielding serum iron levels that average 120ug/dL in men and 100 ug/dL in women Iron Deficiency Anemia The major function of plasma transferrin is to deliver iron to cells Free iron is highly toxic and it is important that storage iron be sequestered This is achieved by binding of iron in the storage pool to either ferritin or hemosiderin Ferritin is a protein-iron complex found at highest levels in the liver, spleen, bone marrow, and skeletal muscles Iron Deficiency Anemia Iron is both essential for cellular metabolism and highly toxic in excess and total body iron stores must therefore be regulated Iron balance is maintained by regulating the absorption of dietary iron in the proximal duodenum There is no regulated pathway for iron excretion Iron absorption is regulated by hepcidin, a small circulating peptide that is synthesized and released from the liver in response to increases in intrahepatic iron levels Iron deficiency can result from dietary lack, impaired absorption, increased requirement, or chronic blood loss Diagnosis of Iron Deficiency Anemia The Complete Blood Count (CBC) and peripheral blood findings are highly characteristic Low red blood cell count Low mean corpuscular volume (MCV) Low mean corpuscular hemoglobin concentration (MCHC) High red blood cell distributions width (RDW) The platelet count is often elevated The peripheral blood shows hypochromatic, microcytic red blood cells with scattered elliptocytes To confirm the diagnosis of iron deficiency, the best single tests is the serum ferritin, a ferritin above 15 ug/L excludes iron deficiency and the serum ferritin in iron deficiency is often below 10 ug/L Lowered ferritin is the earliest finding in iron deficiency and persists throughout the course of the illness In established iron-deficiency, the serum iron is typically low, the total iron-binding capacity (TIBC) is elevated, and the percent transferrin saturation is low Lead Poisoning (Plumbism) Lead toxicity affects RBCs, renal epithelium, and the nervous system Nonspecific features are abdominal pain and cognitive impairment Abrupt onset of vomiting, seizures, and altered mental status Lead poisoning may present as a microcytic, hypochromic anemia Exposure to lead occurs through environmental sources, such as lead-based household paint, contaminated soil, lead plumbing and manufacturing facilities Lead exerts its hematologic effect into two ways Inhibition of heme synthesis in the maturing erythrocyte Decreased survival of mature erythrocytes Lead has a strong affinity for certain amino acids particularly the sulfhydryl group of cysteine and certain organelles, particularly the mitochondria Anemia develops when blood levels are above 50 ug/dL A blood level >10 ug/dL is considered elevated Basophilic stippling is noted in the peripheral blood smear Basophilic Stippling Sideroblastic Anemia In the developing erythrocyte, it is within mitochondria that iron is incorporated into porphyrin to make heme Ringed sideroblasts are the morphologic expression of the abnormal sequestration of iron within mitochondria When increased ringed sideroblasts are found, the differential diagnosis include myelodysplastic syndrome, alcohol abuse, copper deficiency (Wilson disease), lead toxicity, medication effect(Isoniazid, pyrazinamide), pyridoxine (vitamin B)deficiency and hereditary sideroblastic anemia In the peripheral blood there is an anemia with a dimorphic red blood cell population with normocytic macrocytes and hypochromic microcytes Sideroblastic Anemia Sideroblastic anemia is a type of anemia that results from abnormal utilization of iron during erythropoiesis There are different forms of sideroblastic anemia, and all forms are defined by the presence of ring sideroblasts in the bone marrow Ring sideroblasts are erythroid precursors containing deposits of non-heme iron in mitochondria forming a ring-like distribution around the nucleus. The iron-formed ring covers at least one-third of the nucleus rim Sideroblastic anemia is known to cause microcytic and macrocytic anemia depending on what type of mutation led to it Unlike iron deficiency anemia, where there is depletion of iron stores, patients with sideroblastic anemia have normal to high iron levels Other microcytic anemias include thalassemia and anemia of chronic disease Sideroblastic Anemia Sideroblastic anemia is a result of abnormal erythropoiesis during heme production. 85% of heme is produced in the cytoplasm and mitochondria of the erythroblast cells while the remaining is produced in hepatocytes In the Shemin pathway, eight different enzymes help to coordinate heme synthesis These enzymes include aminolevulinic acid synthase ALAS, porphobilinogen synthase, porphobilinogen deaminase, uroporphyrinogen III synthase, uroporphyrinogen decarboxylase (UROD), coproporphyrinogen oxidase (CPOX), protoporphyrinogen oxidase (PPOX), and ferrochelatase (FECH) There are two forms of sideroblastic anemia-hereditary and acquired Symptoms of Sideroblastic Anemia The presentation of patients with sideroblastic anemia include the common symptoms of anemia such as fatigue, malaise, shortness of breath, palpitations, and headache Physical examination may reveal conjunctival pallor, pale skin; some may have bronze-colored skin due to iron overload Infants and young children born with sideroblastic anemia may have life-threatening medical issues stemming from iron overload Adults who develop sideroblastic anemia may develop heart disease or cirrhosis Sideroblastic Anemia Ringed Sideroblasts stained with Prussian Blue Iron Stain Anemia of Chronic Disease Sustained systemic inflammation alters iron utilization in the marrow and suppresses hematopoiesis This leads to mild, refractory, hyporegenerative anemia that is usually normocytic and normochromic but is microcytic in up to one-third of cases Most common cause of anemia in both hospitalized and ambulatory hospital patients in the US The vast majority of the cases are due to rheumatoid arthritis, collagen vascular disease such as lupus, chronic infection and malignancy Marrow biopsies in patient with ACD display bountiful iron stores despite decreased iron uptake by erythroid precursors Decreased transferrin receptors have been demonstrated on erythroblasts in ACD Anemia of Chronic Disease Impaired red cell production associated with chronic diseases that produce systemic inflammation is perhaps the most common cause of anemia among hospitalized patients in the United States Chronic microbial infections, such as osteomyelitis, bacterial endocarditis, and lung abscess Chronic immune disorders such as rheumatoid arthritis, Polymyalgia Rheumatica (PMR) and regional enteritis Neoplasms, such as carcinomas of the lung and breast, and Hodgkin lymphoma Occur in the setting of persistent systemic inflammation and is associated with low serum iron, reduced total iron-binding capacity, and abundant stored iron in tissue macrophages Sideroblastic Anemia Aplastic Anemia A syndrome of chronic primary hematopoietic failure and attendant pancytopenia Disorder caused by suppression of multipotent hematopoietic stem cells, leading to bone marrow hypocellularity and pancytopenia Disease can be acquired, induced by chemical agents and physical agents or inherited Acquired can be idiopathic, acquired stem cell defects or immune mediated Inherited is Fanconi Anemia or Telomerase defects Aplastic anemia can occur at any age and in either sex Pure Red Cell Aplasia A primary marrow disorder in which only erythroid progenitors are suppressed In severe cases, red cell progenitors are completely absent from the marrow It may occur in association with neoplasms, particularly thymoma and large granular lymphocytic leukemia, drug exposures, autoimmune disorders, and parvovirus infection Polycythemia Abnormally high red cell count, usually with a corresponding increase in the hemoglobin level It may be relative when there is hemoconcentration due to decreased plasma volume which may occur in dehydration It may be absolute when there is an increase in the total red cell mass and results from an intrinsic abnormality of hematopoietic precursors and secondary when the red cell progenitors are responding to increased levels of erythropoietin Polycythemia vera is a myleoproliferative disorder associated with mutations that lead to erythropoietin- independent growth of red cell progenitors