Anemia

Question 1

Anemias

Answer 1

• Anemias are abnormalities in the concentration of hemoglobin, and subsequent alterations in erythrocytes.
• They can be caused by specific deficits in dietary intake or loss of essential nutrients important to the synthesis of hemoglobin and red blood cells.

Question 2

Iron and Hemoglobin

Answer 2

• Each of the four globin chains in adult hemoglobin contain a heme prosthetic group with a single atom of iron that needs to be maintained in the reduced ferrous (Fe⁺²) state.
• In the Fe⁺² state, O2 can be bound to each of the four heme groups present in hemoglobin.
• Dietary lack of or excessive loss of iron adversely affects the function of hemoglobin.

Question 3

Dietary Free Iron

Answer 3

• Dietary free iron is absorbed primarily in the proximal small intestine and reduced to Fe⁺² and the oxidized to Fe⁺³ (ferric state) in the blood.
• Ferric iron is rapidly complexed with circulating transferrin (TF) for distribution to tissues. The transferrin-iron complex is taken into cells by the transferrin receptor.
• Once in red blood cells, the majority of iron is incorporated into the heme structure. Iron in excess of what is needed for synthesis is stored in tissues, and particularly in liver (hepatocytes) in a complex with ferritin.

Question 4

Iron Deficiency Anemia - Hemoglobin Lab Values

Answer 4

• Normal Hb in females is 12-16 g/dL and in males is 14-18 g/dL. Anemia is defined as a Hb less than normal (hypochromia) and is usually accompanied by lower hematocrit (<31% = deficiency).
• Because Fe deficiency causes inadequate hemoglobin production, red cells contain less Hb than normal resulting in decreased red cell size (microcytosis).
• Often red cells may be of different sizes (anisocytosis) and shapes (poikilocytosis). Thus, the common term for iron deficiency anemia is hypochromic, microcytic anemia.

Question 5

MCV Calculation

Answer 5

MCV = HCT x10/RBC count (106 /uL)

*HCT measures volume

Question 6

MCH Calculation

Answer 6

MCH = Hb x 10/ RBC count (106 /uL)

Question 7

Hemoglobin

Answer 7

•amount of hemoglobin in the blood

Question 8

Hematocrit

Answer 8

•The hematocrit is the proportion, by volume, of the blood that consists of red blood cells.

Question 9

MCV

Answer 9

•Mean corpuscular volume (MCV) is the average volume of red cells.

Question 10

MCH

Answer 10

•MCH stands for “mean corpuscular hemoglobin.” An MCH value refers to the average quantity of hemoglobin present in a single red blood cell.

Question 11

Blood

Answer 11

• 45% RBC (erythrocytes)
• 54.3% plasma
• composed of mostly water (90% by volume) plus dissolved proteins, glucose, clotting factors, mineral ions, hormones and carbon dioxide.
• 0.7% WBC (leukocytes) and platelets (thrombocytes)

Question 12

Progression of Fe Deficiency

Answer 12

• Iron stores drop. Because iron is stored as ferritin, low plasma ferritin is an initial index of depleted iron storage.
• After iron stores are depleted, iron cannot be supplied to the plasma so that plasma iron begins to decrease.
• With a decrease in plasma iron, compensation occurs by increasing the amount of transferrin, however with less iron and more transferrin the extent of saturation decreases.
• Hemoglobin synthesis then begins to decrease because of lower delivery of iron to bone marrow. Small pale red cells are produced.
• Finally, anemia due to reduced red cell synthesis leads to decreased oxygen carrying capacity of the blood. Fatigue, shortness of breath, headaches and difficulty concentrating become clinical symptoms.

Question 13

Vitamin B₁₂ (Cobalamin)

Answer 13

• Humans cannot synthesize cobalamin and thus depend on dietary sources.
• Its absorption and activation is complex.

-Difficulties in this process cause medical problems.

•There are two “active” forms of B12: adenosylB12 (mitochondrial form) and methyl B12 (cytoplasmic form).

-However, dietary and synthetic (vitamin supplements) is in neither of these forms and instead is taken as either hydroxo- or cyano B12. These dietary forms must be absorbed and then undergo conversion to the “active” forms.

• Dietary B12 enters the stomach where it binds to intrinsic factor (IF), which is manufactured and secreted by the stomach parietal cells.
• The IF/B12 complex then passes through the length of the duodenum and jejunum.
• The terminal ileum contains receptors for the complex on the surface of the ileal mucosa.
• The complex is absorbed, the cobalamin released, and bound to transcobalamin II, which enters the blood stream.
• The TCII/B₁₂ complex is taken up by receptors on the surfaces of cells.
• The B₁₂ enters the cytoplasm and then mitochondria.
• In B₁₂ metabolism note the important link between methyl-B₁₂ and folate metabolism

Question 14

Vitamin B₁₂ (Cobalamin) Deficiency

Answer 14

• Most cases of B₁₂ deficiency result from malabsorption rather than insufficient intake.
• The most common cause for malabsorption is lack of intrinsic factor.
• Lack of IF may be due either to autoimmune destruction of the parietal cells or the production of antibodies against IF.
• In either case, absorption of B₁₂ is impaired causing pernicious anemia (PA), a type of megaloblastic anemia.
• The time period for B₁₂ deficiency to appear is lengthy, hence the slow development of anemia inherent in the word pernicious.
• Failure to absorb the B₁₂/IF complex in the terminal ileum is another cause of pernicious anemia.
• Autoimmune disorders such as Crohn’s disease may reduce absorption.
• Surgical removal of the terminal ileum results in failure of absorption.

•After absorption of B₁₂, it may be subjected to a variety of rare defects that have been described.

• Genetic mutations resulting in absence of transcobalamin II cause macrocytic anemia in infancy.
• Once absorbed in cells, genetic mutations in the activating enzymes cause combined or isolated defects in production of either methyl- or adenosyl B₁₂.

Question 15

Vitamin B₁₂ (Cobalamin) Deficiency -Methylcobalamin

Answer 15

•It is likely, that alterations in production of sufficient methyl cobalamin cause many of the clinical signs and symptoms of B12 deficiency.

• This is because of the very important transfer of single carbon methyl groups.
• The methyl group from S-adenosylmethionine is used in a large number of other synthetic reactions including the formation of myelin, and homocysteine can receive a methyl group from methyl cobalamin to become methionine again.
• The source of the methyl group for methyl cobalamin is methyltetrahydrofolate, which is generated from folate intermediates that get their methyl groups from a variety of sources. Thus, methyl groups are being transferred to and from a variety of sources.
• If B12 is deficient, then there is accumulation of methyltetrahydrofolate causing the methyl groups to become “trapped”. This trap may affect a variety of pathways including DNA synthesis.

Question 16

Vitamin B12 (Cobalamin) Deficiency - Diagnosis

Answer 16

•Diagnosis of B₁₂ deficiency rests upon recognition of classic clinical signs and symptoms. B₁₂, like folate, is important in the synthesis of DNA. Patients deficient in B₁₂ (and or folate) have multisystem involvement due to the importance of DNA synthesis in all cells. The major findings are as follows.

• anemia
• GI findings
• nervous system findings

Question 17

Vitamin B₁₂ (Cobalamin) Deficiency - Anemia

Answer 17

• Since the bone marrow has constant cell production, B₁₂ deficiency is particularly manifest in this organ.
• First, patients have reduction in red cell number and concomitant reduction in hemoglobin - hence anemia.
• Because of problems with DNA metabolism, nuclei are lost later than usual and red cell volume is large resulting in macrocytosis.
• Leukocytes also show abnormalities, and develop hyperlobulated (or hypersegmented) nucleic

Question 18

Vitamin B₁₂ (Cobalamin) Deficiency - GI findings

Answer 18

• Approximately 50% of patients have a smooth tongue with loss of papillae. The tongue may be painful and beefy red.
• Patients may report constipation or having several semisolid bowel movements daily attributed to megaloblastic changes of the cells of the intestinal mucosa.
• Anorexia, nausea, vomiting symptoms might also be present.

Question 19

Vitamin B12 (Cobalamin) Deficiency - Nervous System findings

Answer 19

• Alterations in neurologic function may be an early sign of PA.
• The most common symptoms are paresthesias, weakness, clumsiness, and an unsteady gait due to myelin degeneration and loss of nerve fibers in the dorsal and lateral columns of the spinal cord and cerebral cortex.
• Other signs and symptoms may include memory loss, irritability, and personality changes; at times these signs and symptoms mimic Alzheimer disease.

Question 20

Vitamin B12 (Cobalamin) Deficiency - Lab Values

Answer 20

• Patients typically have macrocytic, normochromic (but may also be hyperchromic) anemia on complete blood count.
• Leukocytes may have hypersegmented nuclei.
• Since B₁₂ deficiency affects production of methyl- and adenosylB₁₂, metabolism of homocysteine and methylmalonic acid are affected, respectively.
• These two metabolites can be measured in blood and are sensitive measures of B₁₂ function.
• It is important to note that homocysteine, but not methylmalonic acid, is affected by folate deficiency.

•The Schilling test is used as a measure of vitamin B₁₂ deficiency. The patient is given radiolabeled (57Co or 56Co) vitamin B₁₂ to drink. Simultaneously an i.m. injection of unlabeled B₁₂ is given. The injection is intended to saturate the stores of B₁₂ bound in tissues so that any radiolabeled B₁₂ that is absorbed passes through to the urine. The urine is collected over a 24- hour period and analyzed for radiolabeled B₁₂. Normally the labeled B₁₂ will appear in the urine with at least 5% of the ingested label appearing in the 24-hour collection. However, an individual with pernicious anemia (intrinsic factor deficiency) or impaired absorption for some other reason will excrete significantly less than 5% of the ingested label in the collection period. To then determine if the patient has pernicious anemia or an absorption defect caused in some other way, the test is repeated with the patient also given oral intrinsic factor. A normal test result in this instance would confirm the diagnosis of pernicious anemia. If the test remains abnormal then the patient has some other general absorptive problem.

Question 21

Folic Acid

Answer 21

• Folic acid, like cobalamin, is a complex molecule.
• The base molecule is modified to a number of forms used in different biochemical reactions, typically methyl or hydrogen donor reactions.

-The form of folate used depends on the specific reaction.

•Two examples are methyltetrahydrofolate and methylene-tetrahydrofolate.

• Methyltetrahydrofolate donates its methyl group directly to B₁₂ to produce methylB₁₂.
• This exchange shows the interactive relationship between folate and B₁₂ and this likely explains some of the similar deficiency symptoms in these conditions.
• The production of thymidine for the synthesis of DNA requires methylenetetrahydrofolate.

Question 22

Floate Deficiency Diagnosis

Answer 22

•The signs and symptoms of folate deficiency are similar to B12 deficiency.

-Both produce a macrocytic anemia likely due to effects of deficiency on DNA synthesis.

•However, folate deficiency does not result in the similar neurological symptoms highlighting some differences in metabolism (or suggesting involvement of the methylmalonic acid pathway in production of the neurological symptoms.

Question 23

Folate Deficiency Lab Values

Answer 23

• The complete blood count abnormalities seen in folate deficiency are similar to cobalamin and the two may be mistaken for each other.
• Definitive diagnosis of folate deficiency depends on measurement of serum and red cell amounts of folate.

-The latter is considered more sensitive and accurate than the former.

Question 24

Sickle Cell Disease - Lab Results

Answer 24

Question 25

SCD - Lab Values Interpreted

Answer 25

•Gallstones are pigmented because of the excess hemolysis leading to overproduction of total/direct bilirubin as seen in the lab results.

-Her increased red blood cell turnover typical of SCD exacerbated by recent hemolytic crisis led to overproduction of bilirubin causing the formation of pigmented gallstones.

•Additionally, reduced blood flow in the liver due to vaso-occlusion (also typical of SCD) has caused an acute hepatic dysfunction.

-The evidence for acute liver failure included lactic acidosis, elevated clotting times, low fibrinogen, and elevated liver enzymes.

Question 26

Management of an SCD patient during anesthesia/sedation…

Answer 26

1) Appropriate fluid administration to maintain euvolemia and correct lactic acidosis - dehydration and acid promotes sickling crisis and vaso-occlusion while excess fluids may result in pulmonary edema and lung complications
2) Minimize risk of hypothermia in the operating room
3) Careful monitoring, with maintenance of adequate oxygenation. Avoid hypoxia, hypercarbia and acidosis (all elements that promote vaso-occulsion).
4) Consider pre-operative RBC transfusion, particularly in patients requiring prolonged anesthesia (reduces the ratio of sickle cells/normal cells).
- Care should be exhibited to avoid overtransfusion in the acute situation, as resulting polycythemia may also contribute to sickling manifestations.

Question 27

Acute Chest Syndrome

Answer 27

•Acute pulmonary events in patients with SCD are associated with a high degree of morbidity and mortality.

• Any pulmonary lesion that produces a deoxygenation induces further sickling and vaso-occlusion.
• This results in worsening of pulmonary function and oxygenation, and patients may experience a rapid progression of pulmonary failure.
• Inflammatory responses in the pulmonary vasculature also contribute to the vaso-occlusive crisis and lung injury.
• Because the clinical course and management options for acute pulmonary illness in SCD differ substantially from the general population, the term acute chest syndrome (ACS) has been used to emphasize the uniqueness of acute pulmonary problems in SCD patients.
• ACS has been defined as a new infiltrate on chest radiograph with at least one of the following clinical signs or symptoms: chest pain, cough, wheezing, tachypnia and/or fever.
• There is not one specific etiology of ACS, but infection is the most frequent cause in children with SCD, while fat embolization to the lung during a painful bone crisis is the most frequent cause in adult SCD patients.
• ACS also occurs postoperatively in some SCD patients undergoing anesthesia.
• The average onset of ACS following surgery is 3 days.
• Mechanisms that may contribute to post-surgical ACS include inflammatory changes induced by surgery.
• Some patients with ACS have an acute hemolysis with decrease in their hemoglobin.
• Simple transfusion with sickle negative RBC is beneficial during the early stages of ACS.

-Simple RBC transfusion should be limited to keep the patient’s hematocrit <35%.

• Patients with more severe illness may require RBC exchange transfusion or erythocytapheresis.
• Patients with ACS require close monitoring and observation with institution of mechanical ventilation if adequate oxygen saturation cannot be maintained with administration of oxygen by nasal cannula.

Question 28

SCD Biochemistry

Answer 28

•The biochemistry of Sickle Cell Disease is a Single nucleotide substitution: glutamate (GAG codon) becomes a valine (GTG codon) in position 6 of the β-chain of Hb.

• This glutamate residue resides on the surface of the beta-globin molecule where it is charged and interfaces with the aqueous environment.
• Valine is a hydrophobic amino acid residue and being positioned on the surface of the beta-globin molecule is unfavorable.
• When Hb is in the deoxy T-state, the valine binds to a hydrophobic area on other HbS molecules.
• Consequently, the Hb tetramers then aggregate.
• The aggregated tetramers form fibers across the RBC causing it to form a sickle shape and ultimately lyse.
• In patients with SCD, HbF, which lacks beta-globin, can be overproduced to modulate the clinical and hematologic features of SCD.
• Treatment of SCD patients with hydroxyurea can increased the amount of HbF in the blood.

Question 29

Other hereditary blood disorders associated with anemia

Answer 29

• Spherocytosis/Elliptocytosis are hereditary blood disorders that causes red blood cells to become abnormally shaped (spherical or elliptical/oval, respectively).
• The genetic disorders causing these defects have been found to be the result of mutations in cytoskeleton proteins of the red cell membrane that are required for the typical biconcave structure of the red blood cell.

-The irregular shape of the red blood cells can cause the spleen to break them down faster. This breakdown process is a hemolytic anemia.

• A normal red blood cell can live for up to 120 days, but red blood cell with structural abnormalities might live for as few as 10 to 30 days.
• The increased red cell turnover in these disorders results in the clinical manifestation of disease just as with other hemolytic anemias and sickle cell disease.
• The degree of anemia in an individual can lead to progressive symptoms of fatigue, shortness of breath, increased heart rate, etc.
• Increased hemoglobin turnover results in elevated bilirubin (jaundice) and risk of gallstones.
• Events of accelerated clearance results in splenic enlargement and in its most severe form, a splenic sequestration crisis that is life threatening.

•Treatment consists of supplementation with folate as this supports the increased demand for hemoglobin turnover. Splenectomy is often times curative as removal of the spleen will limit clearance of the abnormally shaped cells and thus increased the life span of the affected red blood cells.

• Splenectomy also decreases the likelihood of gallstone formation as a direct result of lower hemoglobin turnover.
• Splenectomy is not without consequences as the spleen plays an important role in the immunologic process. There is a resulting increased risk of infection including bacteremia and additional immunizations are recommended.