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Hematology PPT Flashcards Unit 2

What is the shape of a mature erythrocyte?

The mature erythrocyte is a biconcave disc with a central pallor that occupies the middle one third of the cell.

What is the function of hemoglobin in the mature cell?

In the mature cell, the respiratory protein, hemoglobin, performs the function of oxygen–carbon dioxide transport.

What is the lifespan of a mature erythrocyte?

Throughout the life span of the mature cell, an average of 120 days, this soft and pliable cell moves with ease through the tissue capillaries and splenic circulation.

What changes the cell go through as it ages?

As the cell ages, cytoplasmic enzymes are catabolized, leading to increased membrane rigidity (density), phagocytosis, and destruction.

What is erythropoiesis? The term used to describe the process of erythrocyte production is erythropoiesis.

What does erythropoiesis encompass? Erythropoiesis encompasses differentiation from the hematopoietic stem cell (HSC) through the mature erythrocyte.

How is the transport of oxygen and carbon dioxide accomplished?

Transport of oxygen to the tissues and transport of carbon dioxide from the tissues is accomplished by the heme pigment in hemoglobin, which is synthesized as the erythrocyte matures.

What are the basic substances which are needed for a mature erythrocyte?

The basic substances needed for normal erythrocyte and hemoglobin production are amino acids (proteins), iron, vitamin B12, vitamin B6, folic acid (a member of the vitamin B2 complex), and the trace minerals cobalt and nickel.

What happens when there are not enough of these substances?

Abnormal erythropoiesis can result from deficiencies of any of these necessary substances.

Which organ makes erythropoietin? Erythropoietin is produced primarily by the kidneys.How are tissue oxygenation and blood erythropoietin related?

Blood levels of erythropoietin are inversely related to tissue oxygenation.

What are the effects of erythropoietin? Erythropoietin produces an increase in the production of several types of ribonucleic acid (RNA) followed by an increase in deoxyribonucleic acid (DNA) activity and protein synthesis.

How long time does the erythroid cell spend in the nucleated cell stage?

Once the stem cell differentiates into the erythroid cell line, a cell matures through the nucleated cell stages in 4 or 5 days.

How long is the average maturation period for a bone marrow reticulocyte?

Bone marrow reticulocytes have an average maturation period of 2.5 days.

How long do the young reticulocytes remain in the reticulocyte stage in the blood stream?

Once young reticulocytes enter the circulating blood, they remain in the reticulocyte stage for an average of 1 day.

What is the percentage of reticulocytes in the circulating erythrocytes?

Reticulocytes represent approximately 0.5% to 1.5% of the circulating erythrocytes.

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Describe the general characteristics of cells during erythrocyte development

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Describe a mature erythrocyte After the reticulocyte stage, the mature erythrocyte (RBC red blood cell) is formed. An RBC has an average diameter of 6 to 8 mm.

What are Reticulocytes? A supravital stain, such as new methylene blue, precipitates the ribosomal RNA in these cells to form a deep-blue, mesh-like network.

What is a reticulocyte count? - The reticulocyte count procedure (see Chapter 26) is frequently performed in the clinical laboratory as an indicator of the rate of erythrocyte production.- Usually, the count is expressed as a percentage of total erythrocytes. The normal range is 0.5% to 1.5% in adults. In newborn infants, the range is 2.5% to 6.5%, but this value falls to the adult range by the end of the second week of life.

What is a corrected reticulocyte count? The corrected reticulocyte count be made mathematically by correcting the observed reticulocyte count to a normal packed red blood cell volume.

What is a Reticulocyte production index? - A simple percentage calculation of reticulocytes does not account for the fact that prematurely released reticulocytes require from 0.5 to 1.5 days longer in the circulating blood to mature and lose their net-like reticulum.- The RPI measures erythropoietic activity when stress reticulocytes are present. The rationale for obtaining this value is that the life span of the circulating stress reticulocytes is 2 days instead of the normal 1 day.- To compensate for the increased maturation time and consequent retention of residual RNA of the prematurely released reticulocytes, the corrected reticulocyte count is divided by a correction factor derived from the maturation timetable.

How do you calculate Reticulocyte production index (RPI)?

RPI = [ corrected reticulocyte count in % ] [maturation time in days]

What is polycythemia? Polycythemia is the term used to refer to an increased concentration of erythrocytes (erythrocytosis) in the circulating blood that is above normal for gender and age.

What is secondary, or absolute, polycythemia? Secondary, or absolute, polycythemias 3


reflect an increase in erythropoietin production and should not be confused with polycythemia vera (see Chapter 21) or relative polycythemias.

What is associated with red cell increase? Increases in erythrocytes can result from conditions that are not related to increased erythropoietin production. These conditions include the relative polycythemias.

How is megaloblastic maturation associated with anemia?

A defect in maturation known as megaloblastic maturation can be seen in certain anemias, such as vitamin B12 or folate deficiencies.

In megaloblastic maturation, what are the most noticeable characteristics?

The most noticeable characteristic of this type of defect is that nuclear maturation lags behind cytoplasmic maturation. Because of an impaired ability of the cells to synthesize DNA, both the interphase and the phases of mitotic division are prolonged.

How can megaloblastic maturation make cells look younger than they actually are?

The nuclear development is halted, meanwhile the cytoplasmic development continues. And nuclear development is determined by the cytoplasmic development.

How is the hemoglobin gene inherited? Normal adult hemoglobin A is inherited in simple mendelian fashion.

What is the role of 2,3-diphosphoglycerate? Regulate the oxygen affinity of the hemoglobin molecule.

Where is 2,3-diphosphoglycerate located? In the erythrocyteHow is 2,3-diphosphoglycerate abbreviated? 2,3-DPGWhat is the basic manner in which 2,3-DPG binding to reduced hemoglobin (deoxyhemoglobin) affects oxygen affinity?

2,3-DPG combines with the beta chains of deoxyhemoglobin and diminishes the molecule’s affinity for oxygen.

What mechanism is responsible for approximately three fourths of the activity for removing carbon dioxide?

The predominant indirect erythrocyte mechanism

In the predominant indirect erythrocyte mechanism, carbon dioxide is catalyzed by what enzyme?

carbonic anhydrase

What is carbon dioxide transformed into at the end of the predominant indirect erythrocyte mechanism?

Carbonic acid

What is the formula for the predominant indirect erythrocyte mechanism?

H2O + CO2 --------- H2CO3

What happens to the hydrogen ion of carbonic acid?

It is accepted by the alkaline deoxyhemoglobin

What happens to the bicarbonate ion? It diffuses back into the plasmaWhat is the chemical formula for this? H2CO3 ----------- H+ + HCO3 -

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What enzyme is the a key regulator of the entry of iron into the circulation.

Hepcidin.

Starting from 5’ to 3’ what is the order of globin gene clusters for Beta Globulin and Alpha Globulin.

For Beta Globulin Gene Cluster:Epsilon, Gamma, Delta, Beta

For Alpha Globulin Gene Cluster:Zeta2, Zeta 1, Alpha 2, Alpha 1

During the Beginning stage of Hemoglobin formation, what does Glycine and Succynyl CoA form and what enzyme catalyzes the reaction.

Succinyl-CoA and glycine are combined by ALA synthase to form δ-aminolevulinic acid (dALA)

What are porphyrias and how are they classified? Porphyrias are disorders in the synthesis of porphyrin.

Porphyrias can be classified by:

Clinical presentation (acute versus chronic)

Source of enzyme deficiencySite of enzyme deficiency in the heme biosynthetic pathway

What are disorders of Iron Metabolism? Genetic Defect of Iron Iron Overload Sideroblastic Anemia

What are the causes of Sideroblastic Anemia? congenital defect, acquired effect, association with malignant marrow disorders, Secondary to drugs, and toxins.

What is Type 1 Hereditary Hemochromatosis Hereditary Hemochromatosis that is HFE-1 Gene Related.

What is Type 2 Hereditary Hemochromatosis? Hereditary Hemochromatosis that is fromDifferent mutations of the HJV gene.

When does Type 3 Hereditary Hemochromatosis appear?

Type 3 Hereditary Hemochromatosis appear in midlife.

What is Type 4 Hereditary Hemochromatosis? Hereditary Hemochromatosis Type 4 is related to the SLC40A1 gene that encodes for ferroportin.

What is the disorders of globulin synthesis? Is a highly coordinated with porphyrin synthesis. When globin synthesis is impaired, protoporphyrin synthesis is correspondingly reduced. Similarly, when porphyrin synthesis is impaired, excess globin is not produced

What is porphyrin? Important substances in the body, one of 5


these is hemoglobin, the protein in red blood cells that carries oxygen in the blood.

What is globulin? Globulin is a protein in plasma like albumin.What is Iron? Iron is an important ingredient for the

synthesis of hemoglobin, lack of iron can cause Iron Deficiency Anemia.

What is ferritin? Ferritin act as a storage to store Iron in the liver.

What is Thalassemias? A family of inherited blood disorders that is characterized by decreased production of either alpha or beta-globin chains of the hemoglobin molecule

What is Ontogeny of Hemoglobin? Ontogeny of Hemoglobin is an Embryonic Hemoglobins(HbsE)

What is HbsE? Are primitive hemoglobins formed by immature erythrocytes in the yolk sac. They are found in the human embryo and persist until approximately 12 weeks ofGestation.

What is Fetal Hemoglobin? Is the predominant hemoglobin variety in the fetus and the newborn. This hemoglobin type has 2 alphaAnd two gamma chains.

What is Hemoglobin A? Is an adult hemoglobin is predominantly of the A variety (95% to 97%)

What is Glycosylglyated Hemoglobin (HbA1)? A subfraction of normal HbA is HbA1.

This subfraction can be termed Glycosylated hemoglobin and includes the separate Hb fractions A1a, A1b, and A1c.

This type of hemoglobin is formed during the maturation of the erythrocyte. Because proteins are vulnerable to modification after being synthesized by the ribosomes, this modification takes the form of glycosylation of hemoglobin in hyperglycemic persons.

The concentration of glycosylated hemoglobin accurately reflects the patient’s blood glucose level over the preceding weeks and has been recently used to monitor the control of diabetes.

The concentration of hemoglobin A1 is 3% to 6% in normal persons and 6% to 12% in both insulin-dependent and non–insulin-

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dependent diabetics.List the variant forms of normal hemoglobin: – Carboxyhemoglobin

– SulfhemoglobinMethemoglobin

Where are abnormal hemoglobin molecules found?

o Abnormal hemoglobin molecules such as those seen in sickle cell anemia result from mutant, codominant genes.

What method is used for identification of abnormal hemoglobin?

o A method for the preliminary identification of abnormal hemoglobin is electrophoresis.

How was hemoglobin separated on electrophoresis?

o In this method, hemoglobins are separated on the basis of a complex interaction between hemoglobin, agar, and citrate buffer ions.

How was hemoglobin migrated on Citrate agar electrophoresis?

o Citrate agar separates hemoglobin fractions that migrate together on cellulose acetatehemoglobins S, D, G, C, E, and O.

When should hemoglobin specimens undergo electrophoresis on acid citrate agar?

o All hemoglobin specimens that show an abnormal electrophoretic pattern in alkaline media should undergo electrophoresis on acid citrate agar.

What is the Kleihauer-Betke procedure? It’s commonly used to determine the amount of fetal blood that has mixed with maternal blood following delivery.

How can chromatography be used in the analysis of hemoglobin?

Quantitation of hemoglobin A1 can be accomplished by cation exchange minicolumn chromatography. However, the results of this technique can be affected by several types of hemoglobin in addition to hemoglobin A1. Cellulose acetate and citrate agar electrophoresis should be used in conjunction with cation exchange chromatography to eliminate the possibility of interference by hemoglobin variants. Other assay methods for glycosylated hemoglobin include high-pressure liquid chromatography (HPLC) and colorimetric methods.

What are the membrane characteristics and The mature erythrocyte has no nucleus of

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metabolic activities of erythrocytes? other organelles but is capable of existing in the blood circulation for an average of 120 days. An erythrocyte has a limited ability to metabolize fatty acids and amino acids and lacks mitochondria for oxidative metabolism.

How is energy for metabolic process generated for erythrocytes?

It’s generated almost exclusively through the breakdown of glucose and acts in these processes are essential for the erythrocyte to transports oxygen and to maintain the physical characteristics required for survival in the blood circulation.

What might the overall pathway of erythrocyte glycolysis be subdivided into?

Into the major anaerobic Embden-Meyerhof glycolytic pathway that generates ATP and maintains the function of hemoglobin or into the three supplementary pathways.

What are the three supplementary pathways? The methemoglobin reductase pathway, the Luebering-Rapoport pathway and the phosphogluconate pathway.

The shape of the erythrocyte constantly changes when?

It moves through the circulation and performs extremely complex maneuvers.

The cellular membrane is composed of? A protein-lipid bilayer with associated antigens.

The cell membrane is deformable and tolerant against?

Mechanical stress and various pH and salt concentrations in vivo and in vitro.

When does the cell shape reversibly changes? Depending on ATP level in the cell and intracellular calcium ion concentration.

In addition to hemoglobin, the cytoplasmic contents of the erythrocyte include?

Potassium ions in excess of the concentration of sodium ions, glucose, the intermediate products of glycolysis, and enzymes.

In addition to hemoglobin, the enzymes synthesized during early cell development have to be sufficient to provide the energy needed for?

1) Maintaining hemoglobin iron in an active ferrous (Fe 2+) state2) Driving the cation pump needed to maintain intracellular sodium ion (Na+) and potassium ion (K+) concentrations despite the presence of a concentration gradient3) Maintaining the sulfhydryl groups of globins, enzymes, and membranes in an active reduced state4) Preserving the integrity of the membrane

If metabolic pathways are blocked or inadequate, the life span of the erythrocyte is reduced and hemolysis results. Therefore, defects in metabolism can occur. What are some of the defects?

1) Failure to provide sufficient reduced glutathione, which protects other elements in the cell from oxidation2) Insufficient energy-providing coenzymes such as reduced nicotinamide-adenine dinucleotide (NADH), nicotinamide-adenine dinucleotide phosphate hydrogenase

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(NADPH), and ATPWhat is the most common erythrocytic enzyme deficiency, which involves the Embden-Meyerhof glycolytic pathway?

Pyruvate kinase.

What are 4 metabolic activities? 1) Embden-Meyerhof pathway2) Oxidative pathway or hexose monophosphate shunt3) Methemoglobin reductase pathway4) Luebering-Rapaport pathway

Where can anexceptions to the normal erythrocytic life span be found?

In premature infants, whose erythrocytes have a mean life span of only 35 to 50 days, and in fetuses, in which case erythrocytes have an average life span of 60 to 70 days.

What happens to an erythrocyte as it ages? 1) The membrane becomes less flexible.2) The concentration of cellular hemoglobin increases.3) Enzyme activity, particularly glycolysis, diminishes.

What happends when an erythrocyte is phagocytized and digested by macrophages of the mononuclear phagocytic ?

system the hemoglobin molecule is disassembled

What are the resulting components when molecules are disassembled ?

Iron, protoporphyrin, globin

The iron required for heme production is transported to the _________from other areas in the _____via the bloodstream by a ______called _____

Bone marrowBodyTransportProteinTransferrin

What is the function of hemoglobin To transport O2 and to a lesser extent CO2In order for the heme iron to be capable of binding O2 it must be in its ___________-

Reduced state ferrous state, Fe2+

What is oxyhemoglobin? It is hemoglobin with oxygen bound to its heme molecules transporting O2

What is deoxyhemoglobin? Hemoglobin that is not currently transporting O2

No O2 bound to its hemes ready to transportWhat is carbaminohemoglobin? Hemoglobin that is transporting carbon

dioxide CO2 instead of O2Mean corpuscular volume ? A measure of the average red blood cell

size calculated by dividing the volume of packed red blood cells by the total number of red blood cells

Mean corpuscular hemoglobin concentration (mchc)

a calculation of the average hemoglobin concentration in each red blood cell using hgb and hct results

mchc=hgb/hct

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Mcv equation Hct (%) rbc count millions /mm3) x10 85-89 cubic microns

Mchc equation Hbg(g/l) /hct(%)x100 32-36 of rbc is hemoglobin

Haptoglobin takes the hemoglobin dimer to the _____ and then what happens_______

Reticuloendothelial system process continues as normal

Haptoglobin is made in the ____ LiverIf RBC are being broken down by the intravascular system at 90% how does haptoglobin response

Haptoglobin levels decrease because the liver cannot keep up with the over breakdown

What does corpuscular hemoglobin (MCH) mean?

– The MCH expresses the average weight (content) of hemoglobin in an average erythrocyte. It is directly proportional to the amount of hemoglobin and the size of the erythrocyte.

– MCH = picograms (pg)– The reference value of MCH

is 27 to 32 pg.

What does corpuscular hemoglobin concentration (MCHC) mean?

– The MCHC expresses the average concentration of hemoglobin per unit volume of erythrocytes. It is also defined as the ratio of the weight of hemoglobin to the volume of erythrocytes.

– MCHC = g/dLa. The normal value of MCHC is

32% to 36%.What is bilirubin? • Hemoglobin in RBC’s is

broken down to bilirubinWhere bilirubin is excreted in? • It excreted in bile and urine,

and elevated levels may indicate certain diseases.

What color is responsible for bilirubin? • The yellow color of bruises, the straw-yellow color of urine, the yellow color of jaundice, and brown color of feces.

What happen when red blood cell are old (RBC’s breakdown)?

Their cell membranes become irregular and they become trapped in the reticular fibers in the spleen.

• A macrophage engulfs it, and breaks down the hemoglobin, which is made from heme (a porphyrrin ring with iron in

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the center), and globin chains. These three segments of hemoglobin are detached from each other and liberated.

What is the globin chains (proteins)? The globin chains (proteins) are broken down into amino acids (the building blocks of proteins), which are used for synthesis of any other proteins wherever they are needed.

What are the alpha and beta chains? The globins.What are The heme units The porphyrin rings.Is Iron is quite toxic? Iron is essential to nearly all cells but also is

quite toxicWhat is Iron essential for its role? It’s role in oxidation-reduction reactions

needed for metabolism.Where Iron’s toxicity is comes from? It’s propensity to form oxygen radicals that

damage cells.Therefore, it has to be transported in the blood by special proteins, taken to cells that need it, and stored in those cells by being bound to other special proteins.

What happen when hemoglobin is broken down? The iron (Fe+2) is released into plasma; a protein called apoferrin binds to it (now the apoferrin is called transferrin), and takes it into cells that can use or store it.

Where the iron is stored in? Most body cells as ferritin (Fe+3) or as hemosiderin in white blood cells

Hemoglobin in RBC’s is broken down to what? bilirubinBilirubin is excreted in bile and urine, and ? levels may indicate certain diseases.

elevated

what is responsible for the yellow color of bruises, the straw-yellow color of urine, the yellow color of jaundice, and brown color of feces?

Bilirubin

When RBC’s are old, their cell membranes become irregular and they become trapped in the reticular fibers in the spleen. A macrophage engulfs it, and breaks down 1, which is made from heme (a porphyrrin ring with iron in the center), and 2. These three segments of hemoglobin are detached from each other and liberated.

1. hemoglobinglobin chains

What type of chains are broken down into amino acids (the building blocks of proteins), which are used for synthesis of any other proteins wherever they are needed?

– globin chains (proteins)

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Tor F? Iron is essential to nearly all cells but also is quite toxic.

– True

Iron is essential for its role in oxidation-reduction reactions needed for what?

– metabolism.

Its toxicity comes from its propensity to form oxygen radicals that damage what?

– cells.

When hemoglobin is broken down, the iron (Fe+2) is released into plasma; a protein called apoferrin binds to it (now the apoferrin is called transferrin), and takes it into cells that can use or store it. The iron is stored in most body cells as what in white blood cells?

– ferritin (Fe+3) or as hemosiderin

What happens to RBC’s when they are old? Cell membranes become irregular and they become trapped in the reticular fibers in the spleen

What does a macrophage do? Engulfs and breaks down the hemoglobinWhat is the broken form of hemoglobin? Heme-What are globulin chains? ProteinWhat are amino acids? Building blocks of proteinsWhat is essential to nearly all cells but also is quite toxic?

Iron

What role is iron essential for metabolism? Oxidation-reduction reactionsWhere does irons’ toxicity come from? Its propensity to form oxygen radicals that

damage cellsHow is blood transported in the blood? By special proteins, taken to cells that need

it, and stored in those cells by being bound to other special proteins

When hemoglobin is broken down, the iron (Fe+2) is released into what?

Plasma

How does transferrin come about? By a protein called apoferrin binds to Iron.How is Iron stored in most body cells? As FerritinHow is Iron stored in White Blood cells? HemosiderinWhat is converted in the macrophage to unconjugated bilirubin, which is released into the blood?

The porphyrin ring.

Where does unconjugated bilirubin taken to be conjugated?

The liver

What does hydrophobic mean? Not soluble in waterWhat does unconjugated bilirubin have to bind to since it is hydrophobic?

Albumin

What is albumin? A protein carrierWhat does total bilirubin consist of? Conjugated and Unconjugated BilirubinConjugated bilirubin is also known as? DirectUnconjugated bilirubin is also known as? IndirectHow do you calculate unconjugated bilirubin? By subtracting direct bilirubin from total

bilirubinUnconjugated Hyperbilirubinemia is? A high level of unconjugated bilirubin in a

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blood test.What does Hyperbilirubinemia occur? Result from increased production of

bilirubin because too many RBC’s are broken down

A liver problem that causes impaired conjugation, or impaired hepatic reuptake of bilirubin

Most commonly occurs naturally in what age range?

Newborns.-

Where is the unconjugated bilirubin taken and where does it enter?

Liver, hepatocyte(liver cell)

Within the hepatocyte, it is conjugated(joined) with what?

Glucuronic acid

Describe the process of enterohepatic circulation The conjugated bilirubin first travels to the gallbladder as bile, then into small intestine, back to liver, gallbladder, and put back into intestines again

What is the process/pathway that the conjugated bilirubin travels called?

Enterohepatic circulation

What percentage of conjugated bilirubin is reabsorbed?

95.00%

What percentage of conjugated bilirubin goes through the intestines?

5.00%

How is urobilinogen formed? Conjugated (direct) bilirubin is metabolized by colon bacteria

Urobilinogen is further oxidized to which substance that gives feces its brown color?

Stercobilin

Which gives urine its yellow color? A small amount of the urobilinogen is oxidized to uribilin and is excreted in the urine.

The high levels of uribilin turns the urine into what color?

Deep orange yellow

True or False: white stools indicate obstruction in the bile duct

TRUE

True or False: Without the brown color in the feces, they will look black.

FALSE

The conjugated bilirubin can only exit the body by the urine when what occurs:

If there is a blockage of the bile duct

What does high serum levels of conjugated bilirubin mean?

The liver is conjugating the bilirubin, but the bilirubin is not being excreted in the stools.

What are the causes of hyperbilirubinemia? Liver disease esp. hepatitis, bile duct obstruction, obstructed bowels, systemic illness

What causes the bile duct to be obstructed? Hemolytic diseases such as malaria, sickle cell disease may predispose patients to biliary obstruction through pigment

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gallstones formation.Obstructed bowels result from: Parasite infections like tapewormsWhat is systemic illness? Sepsis or cardiogenic shockLiver disease, bile duct, obstruction, obstructed bowels, and systemic illness cause which condition?

Hyperbilirubinemia

5% of conjugated bilirubin goes to where? And is broken down by what?

Colon, bacteria

What are the effects of conjugated and unconjugated bilirubin?

If there is excess unconjugated bilirubin, it will cause jaundice.If there is excess conjugated bilirubin, it will turn the urine dark amber.

What does bilirubinuria implies? An elevated level of conjugated serum bilirubin implies liver disease because only conjugated bilirubin appears in urine, bilirubinuria can implies liver disease.

Why Unconjugated bilirubin is not found in urine?

Unconjugated bilirubin is tightly bound to albumin, not filtered by the kidney, so it is never in the urine even with raised serum levels of unconjugated bilirubin

What kind of bilirubin can be found in urine? If there is bilirubin in the urine (called bilirubinuria), it is always conjugated. Usually, their blood levels of conjugated bilirubin are also high.In the assessment of a patient with raised total bilirubin, urinalysis for bilirubin and urobilinogen may be helpful in identifying the underlying pathology.

Describe the fetus hemoglobin When a deoxygenated RBC from the capillary bed in the placenta of the fetus passes close to an oxygenated RBC in the mother’s blood vessel, the oxygen is pulled off the mother’s red blood cell and is pulled into the fetus’ red blood cell.

What are the types of Hemoglobin? There are two types of hemoglobin: fetal hemoglobin and adult hemoglobin.Fetal hemoglobin has a higher affinity for oxygen (attracts and holds onto oxygen more strongly) than does adult hemoglobin

How does the fetus oxygenate their own RBC’s ? Since fetal hemoglobin has a high affinity for oxygen, it will not release the oxygen into the tissues very easily, so the old RBC’s with fetal hemoglobin need to go to the spleen to be destroyed during the first week of life, while new RBC’s with adult hemoglobin are made in the bone marrow

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and released into the blood stream.

How does jaundice usually present itself in a newborn child?

When the liver has reached its maximum capacity for conjugating the bilirubin, the excess unconjugated bilirubin leaks into the bloodstream, causing jaundice, which is common in newborns and not usually harmful.

What is the treatment for a newborn with jaundice?

Treatment is exposure to ultraviolet light, to assist the breakdown process of bilirubin.

What is the term for too much unconjugated bilirubin in the bloodstream?

Hyperbilirubinemia

If hyperbilirubinemia is manifested in a newborn, how would this affect the child if not treated in time?

Hyperbilirubinemia in a newborn can lead to accumulation of bilirubin in the brain, causing irreversible damage, manifesting as seizures or abnormal reflexes and eye movements.

Bilirubin-induced brain dysfunction KernicterusWhen a person has jaundice, is it high levels of conjugated or unconjugated bilirubin?

It depends on what is causing the jaundice.

What type of jaundice is formed when the bilirubin has not been conjugated yet because there is too much of it from hemolytic anemia?

Pre-hepatic jaundice

How is hepatic jaundice manifested in the body? The bilirubin has not been conjugated yet because of liver damage such as alcoholism

What type of jaundice is formed if the bilirubin has been conjugated but bile duct is obstructed?

Post-hepatic jaundice

Pre-hepatic jaundice is caused by anything which causes an increased rate of hemolysis; what are some examples that would lead to pre-hepatic jaundice.

Malaria, sickle cell anemia, Hereditary Spherocytosis, Hemolytic Disease of the Newborn (HDN), G6DH deficiency.

What type of jaundice could result from acute hepatitis, hepatotoxicity or alcoholic liver disease?

Hepatic jaundice

True or FalseIn alcoholics, their unconjugated bilirubin levels are high in the serum because their hepatocytes are not damaged.

False (hepatocytes ARE DAMAGED)

What causes the elevation of the conjugated bilirubin in alcoholics?

Lack of albumin, ascites occurs, and the abdominal fluid puts pressure on bile duct, so the conjugated bilirubin is not reabsorbed into the enterohepatic circulation.

When ascites occurs, the abdominal fluid puts pressure on bile duct, conjugated bilirubin was not reabsorbed into the enterohepatic circulation, what happens to the level of the conjugated bilirubin?

Increases

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Treatment for ___________ is to drain the excess fluid out of the abdominal cavity and have the patient take a diuretic.

Ascites

True or FalseWhen blood leaves a ruptured blood vessel, the red blood cell dies, and the hemoglobin of the cell is released into the intracellular

False (Extracellular space)

What causes the purple color of 2-day old bruises? HemosiderinWhite blood cells called macrophages engulf (phagocytose) the hemoglobin to degrade it, what is being produce from the iron and biliverdin from the porphyrin ring?

Hemosiderin

What do you call the pigment responsible for the greenish color of 5-day old bruises?

Biliverdin

Biliverdin breaks down into what, causing the bruise to turn yellow in 7-10 days, and then brown.

Bilirubin

The heme portion (porphyrin ring) of hemoglobin breaks down into biliverdin (which is green), which breaks down into unconjugated bilirubin. What is the color of the unconjugated bilirubin?

Yellow

When a bruise is brand new, it appears reddish what causes this color?

Due to the color of the blood that leaked from the capillaries under the skin.

At 1-2 days old, a bruise will take on a bluish or purple color. This is caused by what?

The swelling at the site of the bruise will cause oxygen to be cut off, and hemoglobin will turn blue.

A bruise will turn a greenish color as the hemoglobin breaks down to biliverdin, at how many days?

6 days

An 8-9 days old bruise, the ______will break down to unconjugated bilirubin, which is yellow.

Biliverdin

In a 10-14 days old bruise, what is being oxidized and causes the bruise to turn brown.

Bilirubin

The appearance of a bruise changes over time and you can tell how old a bruise is by its ____.

Color

My neighbor slipped on a wet floor and it caused her a big bruise on her buttocks. She is concern about the color and wondering when (how many weeks?) will it disappear and turn back to its normal color?

The skin should look normal 2-3 weeks after an injury.

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How old are these bruises? (please see table for the answers)

What is the morphology of a normal erythrocyte? Biconcave disc without a nucleus.On microscopic exam, erythrocyte color can be best seen using which stains?

Wright or similar Romanowsky-type stain.

Abnormal erythrocytes can be classified with the following five variations:

Size, shape, color, inclusions and distribution on a peripheral smear

A normal erythrocyte varies in diameter from ___ to ___ with an average of ___.

6.8nm to 7.5nm7.2nm

Erythrocytes from 6.2nm to 8.2nm are considered ___.

Normocytic

Erythrocytes with diameter larger than 8.2 are ___. MacrocyticErythrocytes with a diameter smaller than 6.8 are ___.

Microcytic

The term for increased variation in erythrocyte size is ___.

Anisocytosis

What kind of cells are characteristic of Heinz body-mediated hemolysis?

Blister cells

What are schistocytes? Irregular, fragmented erythrocytesKinds of variations in erythrocytes shape -Ovalocyte (elliptocyte)

-Pyknocyte (blister)-Schistocytes and increased reticulocytes in a patient with thrombotic thrombocytopenic purpura.-Drepanocyte (sickle)-Hereditary spherocytosis-Stomatocyte

polychromatophilia or polychromasia is: When non-nucleated erythrocytes have a faint blue color when stained with Wright stain.

What does the alteration in color that occurs with polychromasia in erythrocytes reflect?

cell immaturity

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reticulocytes are slightly immature RBC's that lack the full amount of hemoglobin, and the blue colored objects, seen within the RBC’s, when stained are?

diffusely distributed residual RNA in the cytoplasm.

what stain is used to determine a reticulocytes count?

The Supravital Stain, New methylene blue

Babesia and malaria are examples of what? Red blood cell parasitic inclusions.The following are examples of?Basophilic stippling (both fine and coarse forms)Cabot ringsHeinz bodiesHowell-Jolly bodiesPappenheimer bodies

Siderotic granules

Nonparasitic red blood cell inclusions

The "stippling" in Basophilic stippling represents? granules composed of ribosomes and RNA that are precipitated during the process of staining of a blood smear.

Clinically, basophilic stippling is associated with...

disturbed erythropoiesis (defective or accelerated heme synthesis), lead poisoning, and severe anemias.

The two types of basophilic stippling are? Fine and coarseWhich type of basophilic stippling appears as tiny, round, solid-staining, dark-blue granules, usually evenly distributed throughout the cell and often require careful examination to detect them?

Fine basophilic stippling

Which type of basophilic stippling is sometimes referred to as punctate stippling, has larger granules and is considered to be more serious in terms of pathological significance?

Coarse basophilic stippling

What is the typical size of Heinz bodies? 0.2-2.0 mm in sizeWhat stains are used to view Heinz bodies? Crystal violet or brilliant cresyl blueWhat are Heinz Bodies? Represent precipitated denatured

hemoglobinWhat are Heinz bodies clinically associated with? 1) Congenital hemolytic anemia

2) G6PD deficiency3) Hemolytic anemias secondary to

drugs such as phenacetin4) Some hemoglobinopathies

What do Howell-Jolly (H-J) bodies look like? Round, solid-staining, dark blue to purple inclusions (1 or 2), usually 1-2mm in size

What are Howell-Jolly bodies? Nuclear remnants predominantly composed of DNA and not seen in normal erythrocytes

How are H-J bodies believed to develop? They develop in periods of accelerated or abnormal

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erythropoiesis, because the spleen can’t keep up with pitting these remnants from the cell.

What are the presence of H-J bodies clinically associated with?

1) Hemolytic anemias2) Pernicious anemia, particularly

postsplenectomy Physiological atrophy of the spleen

The following Inclusions are seen in what type of cell?-Pappenheimer bodies (siderotic granules)-May be observed in wright-stained smears as purple dots.-Are infrequently seen in peripheral blood smears.-Are aggregates of mitochondria, ribosomes, and iron particles-Are clinically associated with iron-loading anemias hyposplenism, and hemolytic anemias.

Erythrocytes

_____ bodies and sideritic granules are probably identical structures.

Pappenheimer

These type of granules are dark-staining particles of iron in the erythrocyte that are visible with a special iron stain-Prussian blue. They appear as blue dots and represent ferric (Fe3+) ions.

Siderotic granules

This formation abnormality of erythrocytes is associated with the presence of cryoglobulins.

Rouleaux formation

True agglutination is caused by the presence of antibodies reacting with ____ on the erythrocyte.

Antigens

What is the name of the erythrocyte alteration depicted above?

Rouleaux

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What disease cycle is depicted above?

Malaria disease cycle

What is the 1st stage in the Malaria disease cycle?

Sporozoite invades the red blood cell

What is the name of the 2nd stage in the Malaria disease cycle?

Ring stage

What is the name of the 3rd stage in the Malaria disease cycle?

Ameboid stage

What happens in the 4th stage of the Malaria disease cycle?

Asexual division


Cell rupture with release of spore

What happens in stage 5a of the Malaria disease cycle?

Reinfection of RBC by some spores


Development of other spores into sexual forms


Development into egg and sperm cells after mosquito sucks them in


Fertilized cell develops into a cyst


Ruptured cyst releases sporozoites

What types of parasitic inclusions are depicted above?

Schizonts, trophozoites, and unlysed leukocytes

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What types of parasitic inclusions are depicted above?

Microgametocytes and several ring forms

What type of parasitic inclusion is depicted above?

Ring forms from P. Falciparum

What type of parasitic inclusion is depicted above?

A Gametocyte

Identify: Parasitic inclusions in erythrocyte (Malaria)

Identify: Parasitic inclusion in erythrocyte (Leishmania sp)

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Identify: Parasitic inclusion in erythrocyte (Babesiosis)

What is general term for mature erythrocytes that have a shape other than the normal round, biconcave appearance on a stained blood smear, or variations

Poikilocytosis

What are the kinds of variations in erythrocyte shape?

TeardropTarget

What does a normal erythrocyte looks? A normal erythrocyte has a moderately pinkish-red appearance with a lighter-colored center when stained with a conventional blood stain.

What is normochromic? The color reflects the amount of hemoglobin present in the cell. The lighter color in the middle, thinner portion of the cell does not normally exceed one third of the cell’s diameter and is referred to as the central pallor.

What is the general term for a variation in the normal coloration?

Anisochromia

What does it determine if an alteration in the color of an erythrocyte occurs?

Cell immaturity

What term is used if a nonnucleated erythrocyte has a faintly blue-orange color?

Polychromatophilia

If the hemoglobin concentration of the RBCs or hematocrit is below the limit of the 95% interval for the patients age, gender, and geographical location, what is considered to be present?

Anemia

What 3 major categories does anemia fall under? Blood loss, impaired red cell production, and accelerated red cell destruction

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(hemolysis in excess of the ability of the marrow to replace these losses)

True or False?Anemia may be a sign of an underlying disorder

True

The dilution of anemia with normal or increased total red cell mass is seen in?

Pregnancy, macroglobulinemia, and splenomegaly

True or False?Anemias only have one pathogenic mechamism and go through only one morphological state.

False. Some anemias have more than one pathogenic mechanism and go through more than one morphological state such as blood loss anemia

What occurs in accelerated red cell destruction? Hemolysis in excess of the ability of the marrow to replace these losses

What are clinical signs and symptoms of anemia a result of?

diminished delivery of oxygen to the tissues.

What are the signs and symptoms of anemia related to?

lowered hemoglobin concentration

What else do the signs reflect? the rate of reduction of hemoglobin and blood volume

If anemia develops slowly in a patient who is not otherwise severely ill how low can concentration of hemoglobin get?

hemoglobin concentration of as low as 6 g/deciliters may develop without producing any discomfort or physical signs if the patient is sedentary

What are the usual complaints of an anemic patient?

are easy fatigability and dyspnea on exertion

What are other general manifestations of anemia? vertigo, faintness, headache, and heart palpitations

What are the most common physical expressions of anemia?

are pallor, low blood pressure, a slight fever, and some edema

How is anemia classified? morphology, physiology, or probable etiology

How did Wintrobe categorize anemias? by the size of the erythrocytes.How else can anemia be classified by red cell morphology?

as macrocytic, normocytic, or microcytic.

What is the limitation of red cell morphology classification of anemia?

it tells nothing about the etiology or reason for the anemia.

What is the limitation of classifying anemia by etiology?

within each classification the various subdivisions are not completely inclusive

What is the advantage of etiology? describes the basic mechanism or probable mechanism responsible for the anemia

What are three major categories in this system? are accelerated erythrocyte destruction, blood loss, and impaired RBC production.

What are the most frequent forms of anemia? result from either blood loss or iron deficiency conditions

What does laboratory investigation of anemias involve?

quantitative and semiquantitative measurements of erythrocytes and supplementary testing of blood and body fluids.

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The results of these analyses provide the foundation for what two things?

both the diagnosis and treatment of anemia

What is physiologically defined as a condition in which the circulating blood lacks the ability to adequately oxygenate body tissues?

Anemia

How many major laboratory manifestations of anemia are?

These are:A decreased hemoglobin concentrationA reduced packed cell volume (microhematocrit) levelA decreased erythrocyte concentration

What are assessments to the direct measurement of hemoglobin, packed cell volume (microhematocrit), and erythrocyte count, a variety of other measurements or calculations can yield additional information?

These assessments include the following:Red blood cell indicesThe red cell histogramRed cell distribution width (RDW) or red cell morphology index (RCMI)

Where is the best area on a blood smear for the examination of red cell morphology?

That is where the red cells are barely touching each other but not overlapping

Under 10x (low-power), is it possible to evaluate the relative number of white blood cells?

Yes, approximately one WBC for every 1000 and rbc's, and one platelet that for every 10 rbc's.

How is semiquantitive grading of erythrocyte morphology?

Erythrocyte are reported using the following descriptive terms, such as moderate or marked, or grades on a numerical scale, such as 1+, 2+, 3+, or 4+.The characteristics of such a grading scale may vary from one laboratory to another

What are assays performed in the hematology laboratory and others may be performed in another section of the clinical laboratory?

A bone marrow examination may be performed and may reveal an abnormal ratio of leukocytes to erythrocytes, the myeloid-erythroid (M:E) ratio.Fetal hemoglobin (Hb F) concentrationMalarial smearsPlatelet countReticulocyte countSickle cell testingGlucose-6-phosphate dehydrogenase (G6PD) assayHemoglobin electrophoresis

What are additional procedures, usually performed in other sections of the clinical laboratory?

These procedures include the following:Antibody screening and identification testsDirect antiglobulin (AHG) testMeasurements of bilirubin levelsFolic acid assayMeasurement of haptoglobin levelLactic dehydrogenase (LDH) determinationSerum iron and total iron-binding capacity

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(TIBC)Vitamin B12 assayOccult blood testingUrobilinogen screening

What are the etiology of the acute blood loss anemia?

• Etiology• The acute loss of blood is

usually associated with traumatic conditions such as an accident or severe injury.

Occasionally, acute blood loss may occur during or after surgery.

What are the physiology of the acute blood loss anemia?

• Physiology• An acute blood loss does not

produce an immediate anemia.• A severe hemorrhage or rapid

blood loss amounting to more than 20% of the circulating blood volume reduces an individual’s total blood volume and produces a condition of shock and related cardiovascular problems.

1. Even if enough hemoglobin remains in the circulation, and oxygen and impairment can exist because of circulatory failure.

What are the physiology of the acute blood loss anemia?

• Physiology• However, severe acute bleeding

can be fatal as a result of the collapse of the circulatory system; immediate expansion of the blood volume is required.

• In acute blood loss, the body itself adjusts to the situation by expanding the circulatory volume, which produces the subsequent anemia.

1. Fluid from extra vascular spaces enters the blood circulation and has a diluting effect on the remaining cells.

What are the laboratory findings of the Acute blood loss anemia?

• Laboratory findings• Hematological findings are very

different in the patient who has experienced an acute bleeding episode within the past 24 to 48 hours compared with a patient who has

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suffered from chronic bleeding for several months.

What are the laboratory findings of the acute blood loss anemia?

• Laboratory findings• The earliest hematological

change in acute blood loss is a transient fall in the platelet count, which may rise to elevated levels within 1 hour (inflammatory reaction).

• The next change is the development of neutrophilic leukocytosis (from 10 to 35 x 109/L) with a shift to the left.

1. The hemoglobin and hematocrit do not fall immediately but fall as tissue fluids move into the blood circulation. It can be 48 or 72 hours after the hemorrhage until the full extent of the red cell loss is apparent.

What are the laboratory findings of the acute blood loss anemia?

• Laboratory findings• The earliest hematological

change in acute blood loss is a transient fall in the platelet count, which may rise to elevated levels within 1 hour (inflammatory reaction).

• The next change is the development of neutrophilic leukocytosis (from 10 to 35 x 109/L) with a shift to the left.

The hemoglobin and hematocrit do not fall immediately but fall as tissue fluids move into the blood circulation. It can be 48 or 72 hours after the hemorrhage until the full extent of the red cell loss is apparent.

After acute blood loss how long does it take for the total white blood cell count and the red blood cell profile to return to normal?

It takes about 2 to 4 days after the blood loss for the total white blood cell count to return to normal.The return of the red cell profile to previous values takes longer.

What disorders are associated with chronic blood loss?

Chronic blood loss is frequently associated with disorders such as the following:Gastrointestinal (GI) tractHeavy menstruation in womenUrinary tract abnormalities

How long does the blood loss occur in chronic anemias?

In chronic anemias, blood loss of small amounts occurs over an extended period,

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usually months.How does chronic blood loss influence the blood volume?

The chronic and continual loss of small volumes of blood does not disrupt the blood volume.

What are the laboratory findings in small amounts of blood loss during and extended period?

If blood is lost in small amounts over an extended periodBoth the clinical and hematological features seen in acute bleeding are absent.Regeneration of red blood cells occurs at a slower rate.The reticulocyte count may be normal or only slightly increased.

What is aplastic anemia? Aplastic anemia is one of a group of disorders, known as hypoproliferative disorders, that are characterized by reduced growth or production of blood cells.

What are the other anemias in the same category? Other anemias in this category include the following:Deficiencies of erythropoietinIronFolic acid and vitamin B12

What is the cause of aplastic anemia? Aplastic anemia is an unusual disease of bone marrow failure.

What are aplastic anemias considered secondary to?

Etiologic agents that are drug related (iatrogenic) and chemically related.

When is anemia iatrogenic? When the transient marrow failure follow cytotoxic chemotherapy or radiation therapy.

What causes injury to proliferating and quiescent hematopoietic cells?

Chemical or physical agents, which lead to DNA damage and apoptosis.

Drug related and chemically realted aplastic anemia account for what percent of cases?

20%

What has been well documented as a cause of aplastic anemia?

Ionizing radiation.

What are some examples of iatrogenic agents? Benzene/benzene derivatives, Trinitrotoluene, insecticides, weed killers, inorganic arsenic, antibiotics, etc.

What is a feature of patients with acquired aplastic anemia?

Rarely is there exposure to any substance that is toxic to the bone marrow.

What inhibits the maturation and amplification of bone marrow stem and blast cells?

Metabolization in the liver of new benzene to a series of structures.

In which cases are chemically aplastic anemia reversible?

depends on the extent of damage

What are viral infections secondary to? bone marrow aplasiaWhat is the mechanism associated with the induction of aplastic anemia?

Includes the possibility of drug exposure during treatment, direct stem cell damage by the virus, depressed Maddow policies by the

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viral genome, and virus-induced autoimmune damage.

Do patients with aplastic anemia have a increased number of activated cytotoxic lymphotcytes? Will therapy with anti-thymus site globulin (ATG) therapy?

Blood and Marrow from patients also contained increased numbers of activated cytotoxic lymphocytes, and the activity and numbers of these cells decreased with successful anti-thymus site globulin (ATG) therapy.

Do INF-alpha and TNF suppress the proliferation of early and late hematopoietic progenitor cells and stem cells?

Yes

What helps to increase the rate of suppression associated with INF-alpha and TNF?

This suppression is greater when these factors are secreted into the marrow microenvironment then when they are added to cultured cells.

Is there any information that describes the events that precede the destruction of hematopoietic cells?

The immunological events that precede the destruction of hematopoietic cells are not as clear as the mechanism of suppression of proliferation.

Do we know what leads to the destruction of hematopoietic stem cells?

Both the dish regulatory events that lead to the loss of tolerance and to autoimmune destruction of hematopoietic cells and the initial antigen exposure that triggers immune system activation are unknown.

Do laboratory studies of patients lymphocytes and their products support the concept of pathophysiological roles for lymphocytes and lymphokines in the destruction of hematopoietic cells?

Yes

Is alpha-INF a specific marker for aplastic anemia?

Alpha-INF suppression is prevalent in acquired aplastic anemia and may be a specific marker of this disease.

What may be an important mediating factor for aplastic anemia?

Local production of this inhibitory lymphokine in the target organ, the bone marrow, may be important in mediating aplastic anemia.

Would measurement of lymphokines be able to help distinguish between aplastic anemia and other forms of bone marrow failure?

Yes, measurement of this lymphokines message may be useful in distinguishing acquired aplastic anemia from other forms of bone marrow failure.

What are characteristics of acquired aplastic anemia?

Acquired aplastic anemia is characterized by total bone marrow failure with a reduction in circulating levels of red blood cells, white

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blood cells, and platelets.Is acquired aplastic anemia a common disease? NoIs acquired aplastic anemia acute or chronic? The clinical course may be acute and

fulminating, with profound pancytopenia and a rapid progression to death, or the disorder may have an insidious onset and a chronic course.

What are some signs and symptoms of acquired aplastic anemia?

The signs and symptoms depend on the degree of the deficiencies and include bleeding from thrombocytopenia, infection from neutropenia, and signs and symptoms of anemia. Splenomegaly and lymphadenopathy are absent.

Recent studies have shown that long-term survivors of acquired aplastic anemia may be at high risk for what complications?

Subsequent malignant diseases or late clonal hematologic diseases.

At what point after the disease can survivors of acquired aplastic anemia experience complications?

Any point up to even years after successful immunosuppressive therapy.

What percentage of patients does Peroxisomal nocturnal hemoglobinuria (P and H) occur in?

10%

At what cumulative incidence rate does mild load dysplasia (MDS) and acute myelogenous leukemia (AML) occur in ten years after treatment of in patients?

15%

Solid tumors increase after what incidence? Immunosuppression and after bone marrow transplantation.

What is aplastic anemia caused by? Damage or destruction of the hematopoietic tissue of the bone marrow that results in deficient production of blood cells.

If all the cell lines are affected, what is the disorder referred to as?

Pancytopenia

If only one cell line is involved, what cells? ErythrocytesWhen is a diagnosis of sever aplastic anemia made?

When at least two of the three peripheral blood values fall below critical levels.

In aplastic anemia, the marrow is either significantly or moderately hypo cellular, with what percentage of residual hematopoietic cells?

Less than 30%

In this anemia, concentration of hemoglobin in the red blood cells is within the standard range. However, there are insufficient numbers of red blood cells. What is the term for this?

Normochromatic

What is a red cell distribution whit (RDW) like in non-transfused patients?

Normal

In aplastic anemia, leukopenia with an increase or Decrease

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decrease in granulocytes is noticeable?Is thrombocytopenia typically present in patients with aplastic anemia?

Yes

What happens to serum iron levels in patients with aplastic anemia?

It is increased

What is increased serum plasma a valuable sign of in patients with aplastic anemia?

Erythorid hypoplasia

What does erythorid hypoplasia reflect in patients with aplastic anemia?

The decreased plasma iron turnover

Is the erythrocyte use of iron increased or decreased due to the increased serum iron level in patients with aplastic anemia?

Decreased

What happens to effective and total erythropoiesis in patients with aplastic anemia?

It is decreased

The bone marrow reveals very few early erythroid and myeloid cells at what stage of differentiation?

Any

How common are mega cario sites in the bone marrow at any stage of differentiation?

Scanty if present at all

What happens to primitive progenitor and stem cells?

They cannot be identified by their parents

Primitive progenitor and stem cells constitute approximately what percent of marrow cells?

1%

If acute exposure to radiation is the inciting agent, the production of new red blood cells (reticulocyte count) rises or falls?

Falls

Why do the red blood cells decline slowly if acute exposure to radiation is the inciting agent?

Because of their long survival

When does a decrease in lymphocytes occur? After the first dayWhat is this decrease in lymphocytes responsible for?

Early leukopenia

How long does it take for granulocytes to begin decreasing?

Five days

What type of cells are often last to return to normal in the recovery phase?

Platelets

Aplastic anemia responds to what treatment? Immunosuppressive therapy, or stem cell transplantation

What sort of damage to the body can result from the treatment for aplastic anemia?

Organ destruction, the capacity for tissue regeneration, and perhaps most importantly, a drug regimen that can control a misdirected and extraordinarily potent immune response.

What factors determine treatment strategy for a patient?

Age of the patient, and the availability of an identical familial donor.

If a suitable donor is available, patients younger than what age are indicated for allergenic bone marrow transplantation?

40 years of age

What is the recommended treatment for younger Bone marrow transplantation

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patients who have an identical twin donor or an HLA-matched donor?What are the two year survival rates for patients who receive the transplant procedure?

70%

What is the death rate? 10%What is the treatment of choice for Aplastic Anemia in patients without donors and older patients?

Immunosuppression.

What can be combined with immunosuppression when treating Aplastic Anemia?

Anti-lymphocyte globulin (ALG), cyclosporine-A, splenectomy and lymphocytophoresis have been developed.

What are inherited bone marrow failure syndromes (IBMFS) that initially exhibit aplastic anemia?

Fanconi anemia, Congenital amegokaryocytic thrombocytopenia, and Diamond-Blackfan anemia

What mutations in telomerase genes can lead to aplastic anemia?

Heterozygotes mutations in TERC, telomerase RNA component, the gene for the RNA component of telomerase, have been found to cause short to low mirrors in congenital aplastic anemia.

What are telomeres enzymes in humans? In humans, telomerase are the nucleic acid sequence TTAGGG that is found on the ends of our chromosomes. That sequesnce is repeated and forms an extra thread attached onto the ends of our DNA.

Why do the telomeres shorten every cell division? Because Telomeres cannot be fully duplicated during cell division

How is the shortening of telomeres prevented? To counter telomere shortening, stem cells and lymphocytes express the enzyme telomerase.

How does the rate of telomere shortening look like in peripheral blood leukocytes as it ages?

Telomeres are long at birth but rapidly he rode in the first two decades of life, continuing to shorten with age at a slower rate thereafter.

What causes defects in telomere repair and protection?

Mutations in genes that function to repair telomerase in hematopoietic tissue results in defects in telomere repair and protection

What are techniques that measure telomere length?

Southern Blot, PCR, and Flow-FISH

What does excessive telomere shortening lead to? Excessive telomere loss permeates the pathogenesis of bone marrow failure and malignancy.

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What is Bone Marrow Failure Syndromes? • Peripheral cytopenias range from absent to severe.

• Unexplained red cell macrocytosis, especially if a family history of marrow failure exists.

• In many cases, red cell macrocytosis is the only hematologic abnormality.

• Macrocytosis may be masked, if a concurrent iron deficiency or thalassemia trait is present.

• Elevated levels of hemoglobin F are common.

• Cells in the bone marrow may exhibit dysplastic changes, for example, abnormal nuclei,pseudo-Pelger Huet anomalies, mild mega low blasted features with nuclear: cytoplasmic dis-synchrony or multinucleated erythroid precursors.

• A minority of patients with aplastic anemia have heterozygous mutations in genes encoding for telomerase. These patients have an increased risk of developing cancer, particularly AML.

• Hypo proliferation of the erythroid elements, without corresponding decreases in other cell lines, is characteristic of pure red cell aplasia.

This condition exists in three forms but a number of variant and intermediate forms have been recognized.

What is examples of Red Cell Aplasia? • 1) congenital – diamond-black fan syndrome

• 2) acquired chronic – idiopathic, associated with thymoma and lymphoma

3) acute (transient) – parvovirus, other infections, drugs, riboflavin deficiency

What is AML? Acute Myelogenous LeukemiasWhat is Aplastic Anemia? • Aplastic anemia is one of a group of

disorders, known as hypoproliferative disorders that are characterized by reduced growth or production of blood cells.

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What is Pure red Cell Aplasia? • This is a disorder primarily involving disturbed every throw polices. New immune suppression of erythropoiesis is believed to play a role in this form of red cell aplasia.

• An immune system etiology is supported by the fact that some patients respond to steroid treatment.

• Patients with pure red cell aplasia have antibodies against erythroid precursor cells and lymphocytes capable of inhibiting erythropoiesis.

• Erythroid precursors are absent from the bone marrow, and evidence of hemolysis or hemorrhage is not present in red cell aplasia.

• The level of serum erythropoiesis and is usually increased.

• And a plastic crisis can develop in some patients with hemolytic anemia and can't commit tent infection.

• Other causes of acquired red cell aplasia include malnutrition and neoplasia.

• Thymoma (tumor of the thymus gland) is a frequent finding.

• Acquired pure red cell aplasia characterized by selective failure of red blood cell production rarely occurs in middle-aged adults.

• Reticulocytopenias and a cellular marrow devoid of all but the most primitive erythroid precursors are characteristic.

• Leukocyte and platelet production are normal.

• Approximately half of reported cases have been associated with thymoma. Only 10% of patients with thymoma have anemia. New remission of anemia occurs in 25% of cases after surgical removal of the thymoma

• Has been associated with other conditions, such as drugs, collagen vascular disorders, and lymphoproliferative disorders.

• Most of these anemias appear to be part of a spectrum of autoimmune

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cytopenias in which the target cells are either erythroid stem cells or normal blasts.

• Antibodies that react with these cells have been identified in some patients.

– Corticosteroids and immunosuppressive drugs have been used as therapy, but less than 50% of patients achieve satisfactory remission.

What is Etiology? – The cause, set of causes, or manner of causation of a disease or condition.

What are the clinical signs and symptoms of Fanconi anemia?

Clinical signs commonly include low birth weight, skin hyperpigmentation (café au lait spots), and short stature. Other manifestations can include skeletal disorders (aplasia or hypoplasia of the thumb), renal malformations, microcephaly, hypogonadism, mental retardation, and strabismus.

What percentage of patients with congenital malformations are diagnosed before the onset of hematologic manifestations?

30%

Progressive pancytopenia is usually apparent by what age?

Five years of age.

What do patients with Fanconi anemia have a predisposition to?

Neo-plasma.

What is the best way to diagnose Fanconi anemia?

With the demonstration of increased chromosomal breakage following exposure to clastogenes, distinguishing Fanconi anemia from most of the other chromosomal breakage syndromes.

What is the traditional therapy for Fanconi anemia?

Bone marrow transplantation to ward off hemorrhage and infection as well as administration of steroids and androgens. Bone marrow transplantation has been the treatment of choice for patients with an HLA-identical unaffected sibling however transplantation from other donors has produced poor results.

What are some other treatment alternatives for Fanconi anemia?

Cryopreserved umbilical cord blood transplantationfrom a sibling shown by prenatal testing to beunaffected by the disorder or using recombinantgranulocyte colony-stimulating factor (CSF).New this treatment has been successful in reducing neutropenia but is ineffective in stimulating

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erythrocyte or thrombocyte cell lines.What is a subset of Fanconi anemia? Familial aplastic anemia with a low incidence of

congenital abnormalities.What does the age of diagnosis vary from for Fanconi anemia?

Younger than a year old to 77 years old.

What symptoms do few children present with? Bleeding manifestations secondary to thrombocytopenia.

What do patients develop as the disease progresses?

Pancytopenia and hypo cellular bone marrow however patients may have pancytopenia and hypo cellular marrow without major developmental anomalies.

What might some cases of Fanconi anemia present?

There may be skin hyperpigmentation or stunted growth.

What is hepatitis-associated aplastic anemia? - Hepatitis-associated aplastic anemia is a variant of aplastic anemia in which aplastic anemia follows an acute attack of hepatitis.- Severe pancytopenia can occasionally occur two months after an episode of apparent viral hepatitis.- The stereo typical syndrome of post hepatitis aplasia would seem to offer the opportunity to identify a specific infectious cause of aplastic anemia.

What type of hepatitis is present for hepatitis-associated aplastic anemia?

• In most patients, the hepatitis is non-A, non-B, non-Sea, and non-Jeep.

• The hepatitis does not appear to be caused by any of the known hepatitis viruses.

Several features of the syndrome suggest that it is mediated by immuno pathologic mechanisms.

How rare is hepatitis-associated aplastic anemia? Although aplastic anemia is a rare sequela of hepatitis, there is a striking relationship between fulminant seronegative hepatitis and aplastic anemia.

Where is aplastic anemia most common? • Epidemiological studies suggests the involvement of an enteric microbial agent in the causation of aplastic anemia.

Aplastic anemia not only is more common in the far east (10% compared to 5% in the West), where hepatitis viruses are prevalent, but also is associated with poverty, rice farming, and past exposure to hepatitis A.

How lethal is hepatitis-associated aplastic Hepatitis-associated aplastic anemia 35


anemia? is often fatal if untreated.What happens when HLA-matched donor is not available for bone marrow?

If a human leukocyte antigen (HLA)-matched related donor is not available for bone marrow transplantation, immunosuppressive treatment is given.

Impaired erythrocyte production can be caused by a variety of factors:

- Proinflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) may play a role

- Heterozygous mutations in genes including TERC and TERT, the genes for the RNA component of telomerase, may be a risk factor for marrow failure.

What is the pathophysiology of aplastic anemia? - The pathophysiology of aplastic anemia is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated.- The molecular basis of the apparent immune response and deficiencies in hematopoietic cells is now being defined genetically; examples are telomere repaired gene mutations in the target cells and dis-regulated T cell activation pathways.- Cellular immune suppression may occur transiently with certain viral infections such as parvovirus or as a result of drug action.- Pure red cell aplasia is often associated with thymomas.

What is the relationship between hematopoietic failure and aplastic anemia?

- Hematopoietic failure may occur at any level in the differentiation of bone marrow precursor cells. New line there may be insufficient or defective pluripotent stem cells (colony-forming units, stem cells, CFU-S) or committed stem cells (colony-forming unit, committed cells, CFU-C).- The microenvironment may be unable to provide for the normal development of hematopoietic cells.- The appropriate humoral and cellular stimulators for hematopoiesis may be absent.- In addition, bone marrow failure could result from excessive suppression of hematopoietic's this by T lymphocytes or macro phages.- Finally, stem cells could interact among themselves with one clone inhibiting the

36


growth of another.- In most cases of aplastic anemia, it is likely that the damage to the hematopoietic stem cell by unknown or unknown agent in some way alters the ability of the cell to proliferate or differentiate.

What is the relationship between bone marrow and aplastic anemia?

• In most patients with acquired aplastic anemia, bone marrow failure results from immunologically mediated, tissue-specific organ destruction. New the course of the disease can be separated into distinct phases.

• The bone marrow is unlikely to recover spontaneously, and most patients die of infection or bleeding complications within a few years.

What is the more common diagnosis for a child with pure red cell aplasia?

Acquired transient erythroblastopenia of childhood (TEC).

TEC occurs in previously healthy children, usually younger than 80 years of age, with most cases occurring between what ages?

One and three years old

Someone that has TEC has a history of viral infection that has been frequent within the last past ____ months?

Three months

Is there a treatment for TEC? It is usually self-limited with recovery occurring within one or two months without therapy.

In TEC, the pathogenesis appears to involve humoral inhibition of 1)___or decreased 2)____ in many of the patients who have been studied, but parvovirus is not a cause.

1) Erythropoiesis2) Stem cells

What is TEC characterized by? A moderate to severe normocytic anemia and severe reticulocytopenia.

In TEC, generally the bone marrow is? Is normocellular and shows virtual absence of erythroid precursors.

How many types of congenital Dyserythropoietic Anemia CDA

4 types of CDA

How are the 4types of CDA characterized? They are characterized by hyperbilirubinemia, ineffective erythropoiesis, and peculiarly shaped multi-nuclear and re-throw blasts.

What does type one CDA demonstrates? A mildly macrocytic anemia with prominent anisocytosis and poikilocytosis. New and this form is apparent at birth and is not a threat to life.

What is the most common type of CDA? Type 237


What type of CDA has a positive acidified serum test.

Type 2

What are the erythrocytes of CDA similar to? They are similar to those of patients with PNH because the red cells in both abnormalities are susceptible to hemolysis in acidified normal serum.

When does blood become acidic? during the night, as respirations become more shallow.

In CDA are the pathogenesis of bone marrow failure entirely certain or not?

It is not entirely certain.

One hypothesis of CDA states that a foreign agent, such as a drug or virus, may enter the body and attach itself to?

Pluripotent hematopoietic stem cells.

This attachment may then provoke the body into defending itself against what is perceived as what?

A foreign body.

In CDA, the patient's own body defense mechanism may destroy what cell?

The stem cell

Cellular and humoral abnormalities in hematopoietic regulation and an altered marrow microenvironment have been implicated as possible factors in what?

Aplastic anemia

in CDA, what will happen to the patient if all cells are involved?

The patient will have a decreased hemoglobin, he Maddock red, and red cell count with decreased leukocyte and platelet counts.

In CDA, what will happen if only the red cells are affected?

Only the hemoglobin, hematocrit, and red cell count will be affected.

What will a bone marrow examination demonstrate in CDA?

The erythroid cell line and perhaps the leukocyte and thrombocyte cell line will all demonstrate a lack of maturational activity.

When did the Diamond Blackfan anemia (DBA) first reported?

Diamond Blackfan anemia (DBA), first reported in 1936.

What is Diamond Blackfan anemia? is one of a group of disorders characterized by bone marrow failure, low stature, birth defects, and predisposition to cancer known as the inherited bone marrow failure syndromes

How many cases with Diamond Blackfan anemia disease were reported in North America in 2010?

In 2010, there were only about 600 patients with this disease in North America.

What was the first diagnosed of DBA? DBA was the first recognized inherited bone marrow failure syndrome in which a ribosomal disorder was identified.

How were the anemia and other hematologic abnormalities being formed?

Mutations in genes encoding ribosomal proteins and the resulting defects in ribosome biogenesis or function appeared to

38


be capable of causing anemia and other hematologic abnormalities.

What are the central hematopoietic defected in DBA?

The central hematopoietic defects in DBA are thought to be the hypo-proliferation of erythroid cells and the enhanced sensitivity of hematopoietic progenitors to apoptosis.

When is the right time for diagnosed DBA? The majority of DBA patients are diagnosed in the first year of life, with pallor and lethargic he being the most common presenting symptoms.

What are the classic diagnosis criteria for DBA? • anemia appearing prior to the first birthday

• normal or slightly decreased neutrophil count

• variable platelet counts, often increased

• macrocytosisnormal bone marrow cellularity with few red cell precursors

Is there existing evident of nonclassical cases of DBA?

2. it is now evident that nonclassical cases of DBA occur.

When has a patient been suffering from DBA disease?

3. In patients beyond one year old, those with mild or no anemia and consistent congenital anomalies may be suffering from DBA

Is the DBA disease more common now? 4. DBA may be present more commonly than previously thought, but other causes of red cell failure are more common.

What are the characteristics disorder in DBA? 5. The disorder is characterized by slowly progressive and refractory anemia, with no concurrent leukopenia or thrombocytopenia

What is the effect of severe anemia? 6. This severe anemia is normochromic and slightly macrocytic, reticulocyte level is low, leukocytes are normal or slightly decreased, platelets are normal or increased, the marrow usually shows a reduction in all developing erythroid cells but normal granulocytic and megakaryocytic cell lines.

Are there any residual erythroid detected in DBA?

7. in a small number of cases, residual erythroid precursors are detected.

How many DBA patients are respond to steroids treatment?

8. Approximately 75% of patients respond at least partially to steroids.

What is the long-term survival rate in DBA 9. The overall long-term survival rate 39


patients? is about 65%, although many patients require long-term steroid treatment.

What is the aplastic anemia? 10. Fanconi anemia is the best described congenital form of aplastic anemia.

How many subtypes are there in Fanconi anemia disease?

11. There are at least 13 different Fanconi anemia subtypes.

How many cases are diagnosed of childhood aplastic anemia?

12. Although aplastic anemia is rare during childhood, Fanconi anemia occurs most frequently, accounting for 30% of cases of childhood aplastic anemia.

What is the characteristic of Fanconi anemia? 13. Fanconi anemia is inherited through and autosomal recessive mode.

Is Fanconi anemia present more in male? 14. It is twice as common in males as in females and can be confused with peer red cell aplasia and thrombocytopenia-absent radius syndrome.

Iron deficiency anemia is limited to developing countries or un developing countries. True or False

False

Iron Deficiencies in children are associated with infections.

True or False

True

An iron deficiency is a clinically significant diagnosis and should be screened immediately with:A. Non anemic infantsB. Toddlers under 2 years of ageC. Pregnant womenAll of the above

D

Iron Defiency has several contributing factors including:A. Increased Physiological Demand, Faulty

or Incomplete AbsorptionB. Excessive LossC. Nutritional DefiencyAll of the Above

D

For etiological purposes an Iron Defiency can be caused by a meat-poor diet. True or False

True

Can growth spurts, pregnancies, or menstruation cause Iron Deficiencies?

Yes

Iron Deficiency Anemia was very prevalent in the _______. Until efforts were made to combat it. A subgroup has benifited from it. For example, infants.

B

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A. 1950’sB. 1960’sC. 1970’sNone of the aboveThree subgroups remain at high risk. Identify them.A. ToddlersB. Adolescent GirlsC. Women of a child bearing ageAll of the above

D

Humans have ___ to ___ of iron per kilogram of body weight.

35mg to 50mg

The average adult has ___ to ___ of total iron. 3.5g to 5.0gNormal iron loss is very small, about ___ per day.

1 mg

Iron is lost the following 3 ways: 1. exfoliation of intestinal epithelial and skin cells 2. Through bile 3. Through urinary excretion

To compensate, the adult male must replace how much iron per day?

1 mg

Operational iron consists of iron used for ___ and ___.

Oxygen binding and biochemical reactions.

Operational iron is found in the heme portion of ___ and ___.

Hemoglobin and myoglobin

Hemoglobin contains ___% of iron in the body.

Two thirds.

In the normal infant at term, iron stores are adequate to maintain iron sufficiency for approximately ___ of postnatal growth.

4 months

In premature infants, total body iron is lower than in the full-term newborn. They have a faster rate of postnatal growth than infants born at term, so unless the diet is supplemented with iron, they become iron-depleted more rapidly than full-term infants. Iron deficiency can develop by ___ to ___ months of age in premature infants.

2-3

Breast milk and cow’s milk both contain about ___ to ___ of iron per liter, but its bioavailability differs significantly

0.5 to 1.0 mg

The absorption of iron from breast milk is uniquely high, about ___ on average, and tends to compensate for its low concentration.

50%

By contrast, only about ___ of iron in whole cow’s milk is absorbed. About ___ of iron is absorbed from iron-fortified cow’s milk formulas that contain ___ of iron per liter.

10%, 4%, 12 mg

41


Reasons for high bioavailability of iron in breast milk are unknown.Approximately 90% of iron from food is in the form of iron salts and is referred to as ___ iron

nonheme

The other 10% of dietary iron is in the form of heme iron, which is derived primarily from the ___ and ___ of meat

hemoglobin and myoglobin

Sequential phases of iron deficiency: Stage 1 (Prelatent), Decrease in storage ironStage 2 (Latent), Decrease in iron for erythropoiesisStage 3 (Anemia), Decrease in circulating red blood cell parameters &Decrease in oxygen delivery to peripheral tissues

Iron deficiency anemia often presents initially with symptoms of:

symptoms of paleness, fatigue, and/or weakness.

Iron deficiency anemia in children is associated with ___ and ___ in the first 2 years of life.

psychomotor and mental impairment

Currently, more than ___ of children in the United States demonstrate evidence of iron insufficiency, ___% have iron deficiency without anemia, and

___% have iron deficiency anemia.

one third, 7%, 10%

Which blood counts should be evaluated for IDA. Complete blood count including observation of the peripheral blood smear, platelet count and WBCs

About a third of patients with IDA will present with normal rbc morphology because:

They are in the early phase of iron depletion

What is the most sensitive and specific parameter of functional iron deficiency?

Percentage of hypochromic RBCs (%HYPO)

A reticulocyte count equal to or greater than ___% demonstrates increased erythropoiesis.

2.5%

4 chemical studies for IDA are: Serum iron, Transferrin sat, serum ferritin and soluble transferrin receptor

Anemia of chronic disease is also known as: Anemia of inflammationAnemias can result from illness, inflammation, ___, ____ and ___.

Infection, malignancy, systemic disease

Half of AOI/ACD are caused by ___. Subacute or chronic infectionsMicrobial agents associated with anemia of inflammation are:

Bacterial, fungal, viral

6 Other causes of AOI/ACD are: Neoplasms, Rheumatoid arthritis, Rheumatic fever,Systemic lupus erythematosus (SLE), Uremia,Chronic liver disease

AOI/ACD is a ___ defect not related to any Hypoproliferative

42


nutritional deficiency.The principal pathogenesis of ACD is believed to be related to ___, a small plasma protein, that is a key molecule in controlling iron absorption and recycling.

hepcidin

6 mechanisms associated with anemia of inflammation:

Increased hepcidin production, alterations in Proinflammatory cytokines, hemolysis, effects of chemotherapy, nutritional deficiencies, blood loss

What does direct bone marrow infiltration by malignant tumor cells or by primary marrow cell malignancies cause?

Decreased erythrocyte production

What acute-phase reactants are released in the blood in systemic diseases that produce AOI (anemia of inflammation)?

C-reactive protein, fibrinogen, haptoglobin, ceruloplasmin

What initiates a common pathway of metabolic events in response to AOI?

Interleukin-1b from activated macrophages

What is interleukin-1b specifically responsible for?

production of fever, neutrophilia, leukocytosis, acute-phase protein synthesis, stimulation of production of lymphokines, and the release of lactoferrin from granulocytes

What do laboratory assays that suggest inflammation or infection include?

Elevated platelet counts, elevated total leukocyte counts, evidence of acute-phase reactants

AOI is usually a mild hypoprolific anemia trueWhat is the hematocrit range in AOI? 28-32%The peripheral blood smears usually show normochromic and normocytic erythrocytes, but one fourth to one third of patients display hypochromic and microcytic erythrocytes

true

What do clinical chemistry studies of AOI include?

Serum iron,transferrin, total iron-binding capacity, transferrin saturation levels, serum ferritin, soluble transferrin receptor

In megaloblastic anemia, hemoglobin, microhematocrit, and RBC are low.

True

What is MCV? Mean corpuscular volumeMCV may be as high as ____. 130 fLWhat is MCH? Mean corpuscular hematocritMCH varies but is usually ______ in 90% of cases.

Increased

In megaloblastic anemia, a peripheral blood smear with show moderate to significant anisocytosis and poikilocytosis.

True

It will also show many macrocytic, ovalocytic red cell precursors, notably ________.

Metarubricytes

Basophilic stippling, Howell-Jolly bodies, cabot True

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rings may be observed in a peripheral blood smear.A neutrophil is considered _______ if it contains more than four lobes.

Hypersegmented

Platelets are also typically _____ in number. DecreasedBone marrow is usually ________ with megaloblastic changes in either the erythroid line or all lines, but it can be ________ and mimic aplastic anemia.

Hypercellular, hypocellular

Erythrocyte precursors are _______ with a _______ nuclear-cytoplasmic ratio.

Enlarged, decreased

Nuclear-cytoplasmic asynchrony, with relative immaturity of the nucleoplasm, is _______.

Typical

_______ _________ may also display nuclear-cytoplasmic dissociation and enlargement.

Granulocytic precursors

Giant __________ with with large, incompletely segmented nuclei are characteristically seen.

Metamyelocytes

The number of mitoses are ______, and the M:E ratio is diminished to 1:1 or less.

Increased

What is the M:E ratio? Myeloid:Erythroid ratioIron store are _______, unless iron deficiency is coincidentally present.

Increased

What is the standard treatment for vitamin B12 deficiency?

Regular monthly intramuscular injections of at least 100 mg of vitamin B12 to correct the vitamin deficiency.

Reticulocyte count begins to increase __to__ days after treatment and peaks in __to__ days.

2 to 3, 5 to 8

Higher and later peaks occur in more ______ anemia.

Severe

________ begins to increase in approximately 1 week and will normalize within 4 to 8 weeks.

Hematocrit

MCV typically increases for the first 3 to 4 days, presumably because of ___________ and then begins to decrease.

reticulocytosis

When is The normal MCV reference range is expected to be reached?

In 25 to 78 days

What are the 2 major categories of megaloblastic anemia?

Vitamin B12 deficiency, Folic acid deficiency

What does the term megaloblastic refer to? the abnormal marrow erythrocyte precursor seen in processes such as pernicious anemia

Megaloblastic anemia reveals an abnormal nuclear maturation and imbalance between nuclear and cytoplasmic maturation

true

What is vitamin B12 deficiency associated with? increased utilization of vitamin B12, Malabsorption syndrome, Nutritional deficiency, Pernicious anemia

44


What percentage of adults over 60 years have undiagnosed pernicious anemia?

1.9%

What is the median age of diagnosis? 60 yearsMore men than women are affected falseWhat would suggest a genetic predisposition to pernicious anemia?

Gastric autoantibodies in families

Pernicious anemia may be associated with autoimmune endocrinopathies and antireceptor autoimmune disease.

true

What are some hematological factors that normal red cell maturation is dependent on ?

vitamin B12 coenzymes, Folates

What occurs when one of these factors is absent? Megaloblastic dyspoiesisHemolytic disruption of the erythrocyte involves an alteration in the erythrocytic membrane.

true

The causes of this membrane alteration can be divided into inherited hemolytic disorders by the following: _________ and _________ hemolytic anemia

Intrinsic, extrinsic

What term refers to the site of destruction of the red blood cell within the circulating blood?

Intravascular

What term refers to the site of destruction of the red blood cell outside the circulating blood?

Extravascular hemolysis

Inherited hemolytic disorders may affect the basic membrane structure, the erythrocytic enzymes, or the hemoglobin molecules within the red cell.

True

The ability of erythrocytes to deform and subsequently return to their original biconcave disc shape is determined by what?

Flexibility of the membraneCytoplasmic viscosityCell surface area-to-volume ratio

Flexibility of the membrane relies on the structural and functional integrity of the ________ _________.

Membrane skeleton

Cytoplasmic viscosity is determined primarily by _______.

Hemoglobin

Mutations in any of the genes coding for the major membrane proteins can:

Alter the amount or function of expressed proteinsCompromise the integrity of the membraneContribute to abnormal erythrocyte morphology

What is HPP? Hereditary pyropoikilocytosisWhat is hereditary pyropoikilocytosis? It is a rare autosomal recessive disorder,

representing a subset of common hereditary elliptocytosis HE, seen primarily in blacks.

What is hereditary xerocytosis? A permeability disorderIn vitro, the thermal instability of spectrin suggests a defect in qualitative spectrin

True

45


abnormality.The net loss of intracellular ____ exceeds the passive ____, yielding a net ____ gain.

K+, Na+, Na+

This causes the red cell to __________. DehydrateWhat is Rh null disease also called? Rh deficiency syndromeWhat is Rh null disease? A rare hereditary disorder causing mild,

compensated chronic hemolytic anemiaThis disorder is associated with stomatocytosis and spherocytosis.

True

What are 2 other forms of hemolytic anemia? Spur cell hemolytic anemiaNeuroacanthocytosis

What is spur cell hemolytic anemia? A form of acanthocyte-associated hemolytic anemia is seen in patients with established alcoholic cirrhosis

What is neuroacanthocytosis? A heterogeneous group of neurodegenerative disorders associated with acanthocytosis in peripheral blood.

Acquired hemolytic anemia can be classified according to the agent or condition responsible for inducing the hemolysis.

46


Example of agents and conditions associated with acquired hemolytic anemia

47


Representative microorganisms associated with hemolytic anemia

48


Acquired hemolytic anemia immune mechanisms (antibodies)

Autoimmune hemolytic anemia caused by an altered immune response resulting in production of antibody against the patient’s own erythrocytes, with subsequent hemolysis. The definitive cause of autoantibody production is unknown.

Some unusual aspects of the epidemiology of AIHA are association with the following:

-Blood transfusion-Immune hemolysis with allogeneic hematopoietic cell transplantation-Immune hemolysis with orthotopic solid-organ transplantation

Comparison of warm and cold autoimmune hemolytic anemia

Cold-type autoimmune hemolytic anemia associated with cold-type autoantibody (e.g., cold hemagglutinin disease), the erythrocytes are usually coated with IgM.

49


Warm- and cold-type autoimmune hemolytic anemias

AIHA associated with both warm and cold autoantibodies is mediated by IgG warm antibodies and complement as well as IgM cold hemagglutinins.

Other types of hemolytic anemia • Isoimmune hemolytic anemia• Drug-induced immune hemolytic

anemia• Physical agents

Microangiopathic red cell destruction DIC is one example of a microangiopathic hemolytic anemia.

15.Other examples of microangiopathies include -Thrombotic thrombocytopenic purpura

(TTP)-Hemolytic uremia syndrome (HUS)-HELLP syndrome (Hemolysis, Elevated Liver enzyme levels, Low Platelet count)

Paroxysmal nocturnal hemoglobinuria: etiology is a rare, acquired, clonal blood disorder caused by a nonmalignant clonal expansion of one or more stem cell lines.

Paroxysmal nocturnal hemoglobinuria: epidemiology

-Twenty-five percent of cases will evolve into or from aplastic anemia.-Approximately 5% to 10% of patients will have terminal acute myelogenous leukemia.-The median age of patients at diagnosis is 42 years (range, 16 to 75 years).-Median survival after diagnosis is 10 years. Spontaneous long-term remission can occur.

Paroxysmal nocturnal hemoglobinuria: pathophysiology

Mutations occur in a gene termed PIG-A and result in the failure to present a large class of proteins on the hematopoietic cell surface

Clinical signs and symptoms -PNH begins insidiously in patients between the age of 30 and 60 years.-Irregular episodes of hemoglobinuria associated with sleep are a startling manifestation of this disorder.

Most patients have severe anemia with hemoglobin concentrations

less than 6 g/dL.

Peripheral blood smears may reveal hypochromic, microcytic red cells if

an iron deficiency state has developed to cell lysis

Autohemolysis is increased after 48 hours, and hemolysis may increase with the addition of glucose to the test. Both the sucrose hemolysis (sugar-water) test and Ham test (acid-serum lysis) are diagnostic procedures.

50


Hemosiderinuria the excretion of an iron-containing pigment derived from hemoglobin on disintegration of red cells, is a classic manifestation of chronic intravascular hemolysis.

The diagnosis of PHN The use of flow cytometry for immunophenotyping erythrocytes is increasing

is increasing -is the least common type of AIHA-It is transient and self-limiting but can produce serious hemolysis of erythrocytes.-It occurs almost exclusively in children in association with viral disorders.

Hemoglobin defect The hemoglobinopathies encompass a heterogeneous group of disorders associated with genetic mutations in both the α-globin and β-globin genes.

SCD and b-thalassemias are the most common monogenic diseases of man. They are found in the “malaria belt” that extends from the Mediterranean and sub-Saharan Africa through Southeast Asia and southern China.

These hemoglobin mutations occur at high incidences in these regions because

heterozygotes have a selective advantage against infection with Plasmodium falciparum

-are inherited single-gene disorders that affect the amino acid residual sequence or production of normal hemoglobin-It is estimated that around 7% of the world population carries a globin-gene mutation, and in the majority of cases, it is inherited as an autosomal recessive trait. Disorders associated with autosomal recessive genes need to be in the homozygous state to produce the disease.-Some disorders are caused by the inheritance of an autosomal dominant gene that will produce hemolytic disease in its heterozygous state.

Hemoglobinopathies, for example, SCD

Hemoglobinopathies may have a hemolytic manifestation.

Approximately 25% of all hemoglobinopathies demonstrate the decreased red cell survival due to red cell membrane deformity that characterizes hemolytic disease.

Although hemoglobinopathies and thalassemias are two genetically distinct disease groups

the clinical manifestations of both include anemia of variable severity and variable pathophysiology

In the genetic manifestation of the hemoglobinopathies, the distinction between the disease state and the trait condition is made.

Disease versus trait

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A disease is defined as either the homozygous occurrence of the gene for the abnormality or the possession of a heterozygous, dominant gene that produces a hemolytic condition

A trait is described as the heterozygous and normally asymptomatic state. In the case of sickle cell anemia, the trait must be inherited from both parents

Abnormal hemoglobins including hemoglobinopathies and thalassemias can be classified into three major categories:

-Abnormal molecular structure of one or more of the polypeptide chains of globulin in the hemoglobin molecule, for example, sickle cell anemia-A defect in the rate of synthesis of one or more particular polypeptide chains of globulin in the hemoglobin molecule, for example, the thalassemias-Disorders that are a combination of abnormal molecular structure with a synthesis defect, for example, Hb E–β-thalassemia

In sickle cell disease, what other RBC form is commonly present, other than drepanocytes (sickles)?

Target cells (codocytes)

What are acceptable, reliable, and accurate methods of testing for sickle cell disease?

Hemoglobin electrophoresis, IEF, and HPLC

An alternate method for sickle cell testing that is expensive and limited in the number of genotypes that it can identify is known as?

Globin DNA analysis

What tests are performed on a suspected sickle cell patient to obtain a definitive diagnosis?

-Reassessment of the hemoglobin phenotype-Measurement of hemoglobin concentration and red cell indices-Inspection of red cell morphology-Correlation of laboratory findings with the clinical history

At how many weeks gestation can fetal diagnosis of sickle cell disease be determined through amniocentesis?

14 weeks

Which test allows DNA diagnosis to be performed at the 7th to 10th week of gestation.

chorionic villus biopsy

what is the most abundant form of hemoglobin in a newborn?

Hemoglobin F (fetal hemoglobin)

what is the normal hemoglobin distribution in a normal term infant?

80% Hb F and 20% Hb A in a normal term infant

Adult normal Hemoglobin A has 2 alpha and 2 beta chains, what is fetal hemoglobin (Hb F) made up of?

Hb F is composed of two α- and two γ-globulins

During which trimester is there a progressive During the last trimester (3rd)52


increase in β-globin synthesis and a decrease in γ-chain synthesis.True or FalseIn a normal term infant, approximately 80% of the non-α globulin is γ-globin and 20% is β-globin.

True

True or FalseScreening for SCD in newborns at birth is mandated in all 50 states and the District of Columbia.

True

Sickle cell disease affects 1 in 375 African American newborns a year. Without quick diagnosis and prophylactic antibiotics with pneumococcal conjugate vaccination before 2 months of age what are the newborns with sickle cell disease vulnerable to?

life-threatening pneumococcal infections

Screening tests will identify approximately 50 sickle cell carriers for every infant diagnosed with SCD. What type of hemoglobin is expected with an infant with sickle cell trait?

Hb F, Hb A, Hb S

Which hemoglobin is always in more abundance in infants with sickle cell trait? Why?

Hb Abecause α chains preferentially pair with normal β chains

True or FalseThe initial sickle cell screen performed after birth isn't conclusive and a confirmatory test should always be performed on an infant no later than 2 months of age.

True

For hemoglobin screening, blood collected by heel stick onto filter paper remains stable for how long?

At least 1 week at room temperature

what tests are commonly used in the United States for sickle cell screening?

Thin Layer Isoelectric Focusing (IEF), or High Performance Liquid Chromatography (HPLC)

What part does the clinical lab take in monitoring sickle cell disease?

-Monitoring the severity of the anemia and transfusing blood only when necessary-Testing to help diagnose organ failure. (recurrent vasoocclusion and its associated vasculopathy result in significant progressive organ failure.)

What is the only potential cure for sickle cell disease?

Bone marrow transplant

What is most probable reason the Hb S mutation has remained somewhat common in people with African descent?

Sickle cell trait provides a survival advantage over individuals with normal hemoglobin in regions where malaria, P. falciparum, is endemic

what hemoglobin disorder is becoming an increasing public health issue and is expected to

Thalassemia

53


become increasingly identified in many parts of the world where it has previously not been seen?which thalassemia’s account for much of the projected increase?

Hb E–β-thalassemia and Hb H disease

which thalassemia is one of the most frequent hemoglobinopathies worldwide, reaching 60% of the population in many regions of Southeast Asia?

Hb E–β-thalassemia

Which thalassemia diseases often considered benign, are now recognized to be more severe than originally reported.

α-thalassemia diseases

what is the cause of thalassemia? an abnormality in the rate of synthesis of the globin chains

How does thalassemia differ from sickle cell? Thalassemia is caused by an abnormality in the rate of synthesis of the globin chains. Whereas sickle cell is due to an inherited structural defect in one of the globin chains that produces hemoglobin with abnormal physical or functional characteristics.

Inheritance of thalassemia is? AutosomalThalassemias are characterized by the ____ or ____ in the synthesis of one of the two constituent globin subunits of a normal hemoglobin molecule.

absence, decrease

In α-thalassemia, decreased synthesis of ____ results in accelerated red cell destruction because of the formation of insoluble Hb H inclusion in the mature erythrocyte.

α-globulin

The more severe ____ reflects the extreme insolubility of α-globin, which is present in excess in the red cell because of decreased β-globin synthesis.

β-thalassemia

Studies of RNA metabolism in erythroid cells have suggested that many patients with ____ have a defect in RNA processing. This defect affects efficient RNA splicing during protein globin synthesis.

α-thalassemia

one of the most common single-gene disorders. β-thalassemiaThis type of thalassemia can occur due to any of 200 or more single-gene point mutations which result in the decrease in production if β-globin.

β-thalassemia

The reduction in β-globin results in an increase of what? And what does this cause?

α-globin chains, causing ineffective erythropoiesis and reduced red cell survival

ineffective erythropoiesis found in β-thalassemia is now thought to occur do to?

Accelerated apoptosis of the red blood cells

In β-thalassemia, hematological findings include. Decreased hemoglobinDecreased hematocrit

54


Decreased red cell countWhat would the hemoglobin concentration be for someone with β-thalassemia?

2-3g/dL

What type of RBC's would be found in a blood smear from someone with β-thalassemia?

anisocytosis, poikilocytosis, hypochromia, target cells, polychromatophilia, and few to many nucleated red cells Erythrocytes are significantly microcytic and hypochromic

how would the red cell indices appear with a blood sample from a patient with β-thalassemia?

All indices will be reduced

In a patient with β-thalassemia, what would you expect the RDW to be? Why?.

The RDW would be increased due to anisocytosis

Knowing the disease state and processes of β-thalassemia, what would be expected of the following tests?Reticulocyte countOsmotic fragility of RBCBilirubinSerum ironTIBC

increased reticulocyte formation (5% to 10%)decreased osmotic fragilitymoderately increased bilirubinincreased serum ironIncreased saturated total iron-binding capacity (TIBC).

why is the soluble transferring receptor index test more specific than serum ferritin test?

because serum ferritin may be increased due to other pathology

In β thalassemia, hemoglobin electrophoresis reveals an change in which two hemoglobins?

An increase in Hb F and decrease in Hb A.

A variable form of homozygous α thalassemia demonstrates changes in which hemoglobins?

There is no Hb A, an increase in Hb A2, and a decrease in Hb F.

Why is there an absence of Hb A is this situation? Because there is an absence of β ChainsHeterozygous β thalassemia could be mistaken for what condition on a peripheral blood smear?

A mild iron deficiency anemia

What are some other laboratory findings? Decreased MCV, Increased Hb A2 on electrophoresis and decreased osmotic fragility

What is the ideal time period for prenatal diagnosis of β Thalassemia?

First trimester

How is this test preformed? Chorionic villus tissue is used for DNA analysis by PCR to detect point mutations or deletions.

Why is second trimester fetal blood analysis done?

It is done to estimate the relative rates of synthesis of globin chains of hemoglobin and then base the diagnosis on the beta to alpha biosynthetic ratio

When were methods developed to perform diagnostic testing before implantation in high-risk patients?

In the early 1990s

What is preimplantation genetic diagnosis (PGD)?

It involves performing conventional in vitro fertilization followed by extracting one or two cells from the resulting blastomeres on day 3. PCR is used to detect thalassemia

55


mutation within the cells. Unaffected cells are selected for implantation

PGD has been extended to HLA typing of embryonic biopsies. What has this allowed for?

This allows for the selection of an embryo that is not affected by thalassemia and that may also serve as a stem cell donor or a previously affected child in the same family. This can be ethically controversial or even illegal in some contries.

Why is testing for hemoglobinopathies incorporated into existing programs?

There is an increase in the prevalence of hemoglobinopathies in the United States.

What are the initial screening methods used? Most screening programs employ HPLC or IET as the preferred first-line technique to make a presumptive diagnosis of a clinically significant hemoglobinopathy.

If an abnormal is identified what information is helpful in guiding the sequence of diagnostic tests for specifics?

Ethnicity information and parental studies

What treatment is required for severe anemias? Blood transfusion, bone marrow, or PSC transplant

How can homozygous β thalassemia be prevented?

Careful counseling and prenatal diagnosis in Sardinia reduced the incidence of homozygous β Thalassemia by more than 90 percent.

What is the cause of α Thalassemia? In contrast to β Thalassemia with most cases caused by point mutations, the major cause of α thalassemia is deletion that remove one or both α globulin genes from the affected chromosome 16

What are the four types of α Thalassemias based on genotype and the total number of abnormal genes that result?

1) Silent carrier state (one inactive α gene)

2) Α Thalassemia trait (two inactive α genes)

3) Hb H disease (Three inactive α genes)

Hydrops fetalis with Hb Bart (four inactive α Genes)

Which hemoglobinopathy is prevalent in the same geographic area as Hb S (sickle cell) disease?

Hemoglobin C disease

How does Hb C differ from Hb A? It differs by the substitution of a single amino acid residual, Lysine, for Glutamic acid in the sixth position from the amino NH2 terminal end of the beta chain.

This is the exact point of substitution of Hb S. So how is it different?

The amino acid is different

What disorder results from the inheritance of one gene for Hb S from one parent and one gene for Hb C from the other parent?

Hemoglobin SC disease

How is SCD different from Hemoglobin SC The course of the disease is usually milder 56


disease? than SCD although Hb C tends to aggregate and potentiate the sickling of Hb S

What are the clinical signs and symptoms? They are similar to mild sickle cell anemia. Lab examination of a peripheral blood smear usually reveals target cells, folded erythrocytes, and occasionally intracellular crystals

Hb D has several variants. What are the symptoms of patients who are homozygous or heterozygous?

They are asymptomatic

What kind of cells may be seen on examination of a peripheral blood smear?

Target cells

Which hemoglobinopathy occurs with the greatest frequency in southeast asia?

Hemoglobin E disease

In Thailand what is the frequency of the Hb E trait?

Almost 50 percent

When do Hb E syndromes appear? Syndromes appear in homozygous and heterozygous forms. They also appear as compound heterozygotes in combination with alpha and beta thalassemias, and other structural variants

What amino acid substitution causes Hb E?

The substitution of lysine for glutamic acid in the beta chain of hemoglobin.

What are the clinical presentations of Hb E?

Clinical presentation is diverse. It can range from entirely asymptomatic to mildly anemic to severely anemic.

What is Hb H? It is a mild to severe chronic hemolytic anemia.

What causes Hb H? It frequently results from an absence of three of the four alpha-globin genes.

In what regions does Hb H primarily affect individuals?

1) Southeast Asia2) Mediterranean islands3) Parts of the middle east

Why has the prevalence of Hb H increased in the United States?

Because of the large influx of immigrants from southeast Asia in the past 20-30 years

What is methemoglobinemia (Hb M)? It is a disorder associated with elevated methemoglobin levels in the circulating blood

What are the causes of methemoglobinemia?

1) Toxic substances2) Hb M variants3) NADH methemoglobin reductase

(also called diaphorase) deficiencyHow many variant forms does Hb M have?

It has five variant forms.

What is the process by which Hb M affects the body?

It has a dominant inheritance resulting from a single substitution of an amino acid in the

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globin chain that stabilizes iron in the ferric form. NADH-diaphorase is the enzyme that reduces cytochrome b5, which converts naturally occurring ferric iron back to the ferrous state

What are unstable hemoglobins? Unstable hemoglobins are hemoglobin variants in which amino acid substitutions or deletions weaken the binding forces that maintain the internal portion of the globin chains of the hemoglobin molecule

How are most unstable hemoglobins acquired?

They are inherited as autosomal dominant disorders

What does this unstable hemoglobin cause?

May cause abnormal hemoglobin to denature and precipitate in erythrocytes such as Heinz bodies of an oxidizing drug or an infection

What are Heinz bodies associated with? They are associated with alpha or beta chain abnormalities.

Tetramers of normal chains, such as Hb Bart and Hb H, appear in what disease?

Thalassemias

What is Hb F? Fetal hemoglobinIs expression in adult life normal? NoWhat is the level of expression? 15%-30% of the total hemoglobinWhat is the abnormality referred to as? Hereditary persistence of Hb FWhat are normal adult hemoglobin components? Hb A (95% to 98%), Hb A2 (2% to 3%), Hb

A1 (3% to 6%), and fetal hemoglobin (Hb F) (<1%). The major fraction is Hb A

What is Sickle Cell Disease? SCD is a general term for abnormalities of hemoglobin structure in which the sickle gene is inherited from at least one parent

What is Sickle cell anemia (Hb SS)? Is an expression of the inheritance of a sickle gene from both parents

What is the most common form of hemoglobinopathy?

Sickle cell anemia

Hb S is different from Hb A because of? A single nucleotide change (GAT to GTT) that results in the substitution of valine for glutamic acid at the sixth position on the b chain of the hemoglobin molecule.

In which ethnic background is SCD most commonly found?

African ancestry, but it also affects persons of Mediterranean, Caribbean, South and Central American, Arab, and East Indian ancestry.

What occurs under conditions of extremely reduced oxygen and increased acidity in the blood?

Polymerization of Hb S

What happens when sickling occurs? It subsequently leads to an increased mean

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corpuscular hemoglobin concentration (MCHC) in proportion to the number of molecules in the deoxygenated state. Deoxyhemoglobin S is less soluble than deoxyhemoglobin A or oxyhemoglobin S.

What leads to repeated cycles of sickling and unsickling?

RBC’s becoming permanently damaged.

What is the adherence of sickled erythrocytes to the vascular endothelium?

Vasoocclusion

What cause by recurrent obstruction of the microcirculation by intravascular sickling?

Acute crises

What splenic dysfunction is a potentially life-threatening complication that develops during infancy?

Sickle cell anemia

What is the most frequent cause of death in patients younger than 5 years?

Infectious crises

In what age does vasoocclusive disease develops? Between the ages of 12 months and 6 years.In pregnancy, there is no increase in disease manifestation but there is an increase in the following:

Maternal mortality of 20%Fetal mortality of 20%

The two main causes of erythropoietic suppression are the following:

Aplastic crisesMegaloblastic erythropoiesis

Aplastic crises result from which virus infection? ParvovirusWhat is a significant cause of death in patients of all ages who have sickle cell anemia?

Acute chest syndrome

What percentage of patients with sickle cell anemia survive beyond the fifth decade?

50%

What are the general signs and symptoms of sickle cell anemia?

PainPulmonary complicationsStroke

What can be seen on peripheral smears if patient is in acute crisis state?

Sickled red cells (drepanocytes)

What are the laboratory features? • Reticulocytosis (8% to 12%)• An increased mean corpuscular

volume (MCV) to levels up to 100 fL

• Elevated serum; unconjugated bilirubin and methemalbumin

• Decreased serum haptoglobin and hemopexin

• Increased serum lactate dehydrogenase (LDH)

• Mildly increased aspartate transaminase (AST)

• Increased urine urobilinogen

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