Quiz Questions 1 Flashcards
(17 cards)
Anemia of chronic disease (ACD) is characterized by normocytic, normochromic red cells and a lack of an appropriate reticulocyte count. It is a kind of iron restricted anemia in that inflammatory cytokines (e.g. IL-6) up-regulate plasma hepcidin levels which in turn prevents the normal absorption of elemental iron from the GI tract and inhibits the release of iron from the RES by down-regulating ferroportin. Ferroportin is the carrier protein responsible for transporting iron across cell membranes. As a result, less iron is available to the red cell precursors for Hb development.
True or False. The patients with the ACD characteristically have a low serum iron, elevated transferrin (or TIBC), decreased transferring saturation, and low ferritin.
false
Patients with the anemia of chronic disease often have low serum iron levels, decreased iron binding capacity and transferrin (because protein synthesis in the liver is down-regulated), and serum ferritin is normal or elevated (ferritin reflects increased iron stores to due iron entrapment in the RES). This is contrast to another iron restricted anemia called iron deficiency anemia in which patients have a hypochromic, microcytic hypoproliferative anemia with a low serum iron, high iron binding capacity and transferrin, and depleted ferritin. In the case, there are decreased iron stores due to blood loss, hemolysis, or more rarely a nutritional deficiency. When a patient is otherwise thought to have the ACD in the setting of a normal or decreased ferritin, it is likely that concurrent iron deficiency is present. To absolutely confirm that a combination of ACD and iron deficiency is present often requires a bone marrow examination to be performed and an iron stain of the bone to be examined. The lack of stainable iron confirms the presence of the iron deficiency. When only ACD is present, stainable iron is present in excess (a reflection of the entrapment of iron in the RES (bone marrow macrophages) and there is decreased stainable iron in red cell precursors (due to decrease incorporation of iron in the RBC).
The site of normal hematopoiesis depends upon the age of the patient. Up to about 3 months after fertilization production occurs in the Liver and spleen; thereafter production switches gradually from the liver and spleen to the long bones.
True or False
false
The sites of normal hematopoiesis depend upon the age of the patient. Up to about 3months after fertilization production occurs in the yolk sac; thereafter production switches gradually from the yolk sac to the liver and spleen (while in utero to 3 months of age), to the long bones (from 3 months of age to 30 years), and then to the axial an proximal skeleton. This is of practical importance. In adults bone marrow sampling is best performed from axial skeleton sites. If radiation therapy is delivered to the axial skeleton in older patients, a greater proportion of the bone marrow may be affected than when the same radiation port is used in younger patients.
Hb‘s ability to act as an oxygen transport is facilitated by the association of beta globin chains in the tetramer, the modulation of oxygen loading and unloading by 2,3 BPG (biphosphogluconate) and the pH. These relationships are reflected by the oxygen-Hemoglobin dissociation curve are often referred to as the Hb affinity for oxygen. The oxygen-Hb dissociation curve is derived from measuring the oxygen saturation of Hb relative to the partial pressure of oxygen (pO2). As the pO2 increases do also as does the O2 saturation. The curve takes on sigmoidal shape because accession of each oxygen molecule to heme facilitates the binding of others. Alteration in pH, CO2 content, temperature, Hb affinity, 2,3 BPG can affect binding and release of oxygen.
True or False. Increasing acidosis causes more oxygen to be retained by the hemoglobin molecule and as a consequence less oxygen is released to the tissues resulting in functional hypoxemia and tissue malfunction.
false
The addition 2,3 BPG to the hemoglobin tetramer results in a restructuring of the relationship between the globin chains making it difficult for oxygen to reach heme. When 2,3 BPG is not associated with the hemoglobin molecule the globin chains assume a “relaxed” position to each other allowing oxygen to bind to heme. Acidosis shifts the curve to the right (decreased Hb affinity for oxygen) and alkalosis shifts the curve to the left (increased Hb affinity for oxygen). Chronic COPD may produce chronic respiratory acidosis and concurrently increased 2,3 BPG production. In this setting, the curve which is shifted to the right by acidosis is partially corrected by the addition of 2,3-BPG which counter-shifts the curve to the left.
Myelofibrosis is a disorder of the microenvironment of the bone marrow in which fibroblasts proliferate in excess.
True or False. Proliferation of fibroblasts leads to excess blood cell production in the marrow and expansion of the bone marrow cavity resulting in intense pain and inability of the red cell precursors to develop normally and move from the marrow cavity into the peripheral blood.
true
Myelofibrosis is a disorder of the microenvironment of the bone marrow. Fibroblast proliferation and release of cytokines in the bone marrow causes blood production to shift to other extra-medullary (aka: myeloid metaplasia; outside of the marrow space) sites such as the spleen, liver, and lymph nodes. This process can be characterized by both splenic and hepatic enlargement. Common causes of extramedullary hematopoiesis includes infiltration of the marrow space with various kinds of hematologic and nonhematologic cancers, hepatocellular injury, chronic hemolysis, growth factor treatment, marrow regeneration after injury, autoimmune assaults, or for reasons unknown.
Erythropoietin (Epo) is a 34 kd glycoprotein produced in the peritubular interstitial cells of the kidney (90%) and also to a small degree in the liver (10%). It is sensitive to the presence of oxygen in the blood.
True or False.
true
Peritubular cells produce increasing amounts of Epo when they detect a decrease of oxygen in their vicinity (because of hypoxia, ischemia, hemoglobinopathies that do not normally release oxygen at the tissue level). As a consequence to this, patients who have blood loss anemia or hemolysis may have marked increases in the amount of Epo detected in their serum. Patients who have a condition in which red cell production is not under the control of Epo (e.g. polycythemia Vera) have low or undetectable levels of Epo. Paradoxically, patients who have secondary polycythemia (caused by pulmonary disease in which not enough oxygen gets to the Hb molecule), Epo levels are usually normal. This is because once compensation occurs (i.e., the number red blood cells increases to a point that a sufficient concentration of oxygen is detected by the peritubular cells), Epo production decreases to within the expected range. Also, Epo is a product available commercially that can used to treat some kinds of anemia.
Reticulocytes provide an indication of effective erythropoiesis. Stored in the bone marrow, they are released into circulation where they complete maturation within 24 hours. Detection in the peripheral blood requires a special stain, although their presence can be inferred by the presence of ‘polychromatic red cells’ or “shift cells”. With bleeding or hemolysis, reticulocytes may be ‘shifted’ into the circulation due to stress. These ‘shift cells’ may require 2 days or more to mature. One way to categorize anemia is according to the accompanying reticulocyte response. A hyperproliferative anemia may have a high reticulocyte count or increased reticulocyte production index and a hypoproliferative anemia is characterized by an inadequate reticulocyte response and a lack of increase in the reticulocyte production. The absolute reticulocyte count can be determined by an automated cell counter and can be estimated clinician by taking into account the proportion of reticulocytes relative to the amount of RBCs in the peripheral blood.
True or False. The determination of the reticulocyte production index requires examination of the peripheral blood smear.
true
One way to categorize anemia is by the reticulocyte response. In order to do this you must either look at the absolute reticulocyte number which is derived from the automated cell counter or estimate the reticulocyte production index (RPI) from the reported uncorrected reticulocyte count (reported as a % of the red blood cells). First, the corrected reticulocyte count is determined by multiplying the uncorrected reticulocyte count by the proportion of the patient’s hematocrit (or Hb concentration) relative to a normal gender-specific hematocrit (or Hb concentration). This product is then multiplied by 100 and reported as a %. Second, the peripheral blood smear is inspected for the presence of shift cells (presumed to be reticulocytes). If present, the previously determined corrected reticulocyte count is divided by the estimated of maturation time of the circulating reticulocytes. This estimated maturation time depends upon the patient’s hematocrit (or Hb concentration). An RPI > 3 implies the presence of hemolysis or blood loss and an RPI
Aplastic anemia is characterized by pancytopenia; may be the result of injury to the bone marrow microenvironment or to the HSC or as a result of immune dysregulation of HSC development.
True or False.
true
Present data indicates that all blood cells are likely derived from the same hematopoietic stem cell (HSC). The HSC diverges early in development into the GEMM ( a precursor cell to granulocytes, rbcs, megakaryocytes, and monocytes) and a lymphoid precursor cell. Hematopoiesis is hierarchical (e.g. development progresses in a series of daughter cells of increasing maturity); clonal or polyclonal (the emergence of a predominance of a specific type of daughter cell), and deterministic or stochastic (a specific type of descendent cell predominates due to survival advantage or simply by chance). Under ideal conditions the bone marrow microenvironment provides a favorable milieu for rbc development and survival. The HSC ‘home” to the bone marrow and bind to adhesion molecules expressed on specific accessory cells, and are subsequently stimulated to proliferate. Unfortunately some individuals have either damage to the bone marrow micro-environment (e.g. chemical exposure), damaged or dysfunctional HSC, or abnormal immune regulation of HSC development which leads to aplastic anemia.
Sideroblastic anemia is a disorder caused by the excessive administration of iron supplements to a patient incorrectly thought to be iron deficient or the excessive delivery of packed red cell replacement (there is approximately 250mg of elemental iron in each unit of packed red cells transfused).
True or False.
false
Sideroblastic anemia is a disorder caused by the ineffective production of heme, results in the accumulation of iron-laden mitochondria. It is sometimes responsive to pyridoxine (a cofactor for the initial steps in heme synthesis), may be idiopathic, and may be commonly seen in patients with alcohol abuse. This disease is characterized by >15% of normoblasts in the bone marrow having excessive iron deposits or iron located as a ring around the nucleus because the iron is retained in the mitochondrial. Keep in mind that normal heme synthesis depends upon the delivery of elemental iron via its transport protein ferritin to red cell precursors. The iron-transferrin complex is internalized in the precursor and the iron is either stored as ferritin or incorporated into the heme synthesis process. Heme synthesis occurs in both the cytoplasm and mitochondria in a step wise fashion. Glycine and succinyl choline combine to form aminolevulinic acid (ALA) in the mitochondria. A series of reactions occur in the cytoplasm which converts ALA to porphobilinogen, uroporphorinogen, and coproporphrynogen which is converted to protophorphyrin. Within the mitochondria protophoryrin is converted to heme by the addition of elemental iron. It is the disruption of incorporation of elemental iron into the heme molecule that leads to sideroblastic changes.
Gastrointestinal absorption of vitamin B12 occurs in the small bowel only when it is bound to a protein called intrinsic factor (IF) which is made by specialized cells in the gastric mucosa.
True or False
true
The mechanism that humans acquire vitamin B12 from the diet allows us to understand the reason for the many ways in which we are vulnerable to develop deficiency of this extremely important vitamin. There are three important proteins in the gastric juice that are intricately involved with B12 absorption: Pepsin, R-protein (haptocorrin), and Intrinsic Factor (IF). B12 is released from the food by Pepsin and acid induced proteolysis. Important to note is that Pepsin acts best in an acidic environment. Once released from food, the B12 preferentially binds to R-protein over Intrinsic Factor in the stomach. As the food passes into the duodenum the pH rises and the pancreatic digestive enzymes degrade the R-protein releasing B12. Intrinsic Factor is resistant to proteolytic cleavage by the pancreatic digestive enzymes and has a higher affinity for B12 at a higher pH and thus B12 now complexes with Intrinsic Factor. Now the Intrinsic Factor-B12 complex traverses the small bowel to the ileum. On the ileal mucosa are receptors specific for the Intrinsic Factor-B12 complex which allow for the absorption of the complex.
Deficiency of vitamin B12 or deficiency of iron can cause a macrocytic anemia.
True or False
false
On review of a peripheral blood smear, macroovalocytes and hypersegmented polymorphonuclear leukocytes are characteristic findings of megaloblastic anemia.
True or False
true
Abnormalities noted on the peripheral blood smear are macroovalocytes, hypersegmented polymorphonuclear leukocytes (PMN), giant bands, and giant platelets. The morphologic expression of megaloblastosis is nuclear-cytoplasmic dyssynchrony. The finding can be confused with acute leukemia to the untrained eye. All proliferating cells exhibit megaloblastic changes including the lining of the mucosa where there is also atrophy of the epithelial cells. The blood and bone marrow display the features the best. The disorder is characterized by ineffective hematopoiesis, so called because there is severe pancytopenia in the setting of a hypercellular marrow.
Folic acid deficiency results in a type of macrocytic anemia similar to that caused by B12 deficiency or from cytotoxic chemotherapy drugs like methotrexate.
True or False
true
Macrocytic anemias are subclassified into two categories: megaloblastic and non-megaloblastic. The megaloblastic anemias are vitamin B12 (Cobalamin) deficiency, folate deficiency, myelodysplastic syndrome, and drug induced. The megaloblastic anemias are largely indistinguishable from one another.
Iron deficiency, B12 deficiency, and folic acid deficiency all interfere with DNA synthesis and it is by this mechanism that the hematopoietic cells cannot proliferate appropriately and the result is a megaloblastic anemia, a subtype of macrocytic anemia.
True or False
false
The megaloblastic anemias share a common biochemical feature – a defect in DNA synthesis, with lesser alterations in RNA and protein synthesis which leads to a state of unbalanced cell growth and impaired cell division. Each of the megaloblastic anemias perturb normal DNA synthesis in some way: B12 and folate are important cofactors in the synthesis of DNA; the myelodysplastic syndromes have a variety of acquired genetic disorders that affect DNA synthesis; and many drugs, particularly methotrexate and other chemotherapeutic drugs, affect DNA synthesis. Iron deficiency results in disruption of the hemoglobinization of the red blood cells. The result is microcytic (small) red blood cells.
Nuclear-cytoplasmic dyssynchrony is the cytopathologic hallmark of the megaloblastic anemias, a subtype of macrocytic anemia.
True or False
true
The cell cycle in normal cells involves the coordinated synthesis of DNA, RNA and protein. There is a resting phase (which most normal cell are in) followed by a rapid doubling phase of cellular DNA (S-phase) followed by mitosis and then division into two cells. In contrast, the majority of megaloblastic cells are not in the resting phase, but are vainly engaged in an attempt to double their DNA. There are frequent episodes of cell cycle arrest in the S-phase but less arrest in the other parts of the cell cycle. The net result is megaloblastosis, namely, a cell whose nuclear maturation is arrested (immature) while its cytoplasmic maturation proceeds normally – independent of nuclear events. The microscopic finding is called nuclear-cytoplasmic dyssynchrony.
Signs and symptoms of iron deficiency anemia (IDA) include those associated with anemia (tachycardia, tachypnea, pallor) but there are also unique clinical features of iron deficiency anemia. Cheilosis (angular fissures at the corners of the mouth) may be observed. Fingernails may form a ‘spoon’ termed koilonychia. Patients may complain about dysphagia due to the development of esophageal webs (Plummer-Vinson syndrome). Finally, a unique symptom seen in patients with IDA is pica, the compulsive eating of clay, corn starch or ice (pagophagia). Causes of IDA are increased demand for iron (rapid growth, pregnancy, response to erythropoietin therapy), increased loss of iron (acute or chronic blood loss; menses; blood donation; phlebotomy as treatment for polycythemia Vera), and decreased intake, absorption, or use of iron (inadequate diet; malabsorption (disease: sprue, Crohn’s disease; surgery: post-gastrectomy); acute or chronic inflammation. It is imperative that gastrointestinal bleeding be ruled out since this is the most common cause of IDA in males and post-menopausal females. Stool hemoccult cards should be tested yearly and non-menstruating individuals with IDA should be considered for a GI evaluation to eliminate peptic ulcer disease, polyps or cancer as etiologies for the IDA.
A 15 year old boy is active in cross-country and has become an accomplished long distance runner for his age. He attributes this at least partly to the fact that his stride ahs increased since he first started cross-country at age 13 years. On occasion, after a long run, he notices that his urine has changed color and sometimes appears to be red tinged. Lately he has noticed that he has less “energy” than usual and although he can complete his runs his timing is a bit off. The coach arranges for him to be seen by the team physician, who draws some blood for testing. The results are the following: Hb low, MCV
false
A GI bleed in a patient of this age group would be rare and is unlikely. On occasion, long distance runners will develop GI bleeding secondary to what is thought to be decreased blood flow to the intestine resulting in transient bowel ischemia, tissue damage, and localized bleeding. At age 15 years, he has entered the time when a growth spurt is expected. This appears to be the case since his height and running stride has increased during the course of his athletic endeavors. Also, he reports, a change in color of his urine. Sometimes runners develop what is referred to as “March Hemoglobinuria” in which RBCs are mechanically broken down (presumably from trauma as the blood passed through the blood vessels of the feet while the individual is running). Although this “loss” of hemoglobin may contribute to his iron deficiency, it is unlikely to be its major cause.
A way to categorize anemia is according to the size of the RBC. The mean RBC volume (MCV) is an expression of the average size of the red cells evaluated on an automatic cell counter. Although there are variations according to the laboratory and population evaluated, generally an MCV 100 implies the presence of a macrocytic anemia.
True or False. A common cause of a microcytic anemia is the presence of either a deficiency in folate or vitamin B12.
false
Common causes of microcytic anemia include iron deficiency, sideroblastic anemia, lead intoxication, anemia of chronic disease, and some hemoglinopathies (e.g. Hb E). Elemental iron is essential for normal hemoglobin production. In the presence of iron restriction (where iron is not available to red cell precursors), less hemoglobin is produced in the individual red cells. For this reason, the cells will often take on a hypochromic appearance (the cells are pale and the central pallor of the cell is increased) and are smaller than normal. When iron restriction is severe (e.g. severe iron deficiency), the RBCs may become fragmented, hypochromic elliptocytes begin to appear (these are elongated cells in which the opposite cell membranes are parallel to each other), and begin show some targeting (due to the presence of excess cell membrane relative to the Hb content within the cell).
Iron deficiency anemia (IDA) and the Anemia of Chronic Disease (ACD) (also referred to as the Anemia of Inflammation) are both “iron restricted” anemias in which not enough irn is available to the RBC precursors to produce appropriate amounts of hemoglobin. Although the anemia of chronic disease is often normochromic and normocytic, if sever enough it can present with peripheral blood smear findings similar to that seen in iron deficiency (hypochromic, microcytic RBCs). Sometimes the only way you can tell the difference is to examine the bone marrow. In IDA, there is no stainable iron. In ACD, stainable iron is present in the reticulum of the bone marrow, but there is poor incorporation of iron the RBC precursor cells.
A 60 year old lady with severe, poorly controlled rheumatoid arthritis comes to your with the complaint of fatigue. She appears pale. You suspect that she is anemic. A CBC shows a Hb12)
True or False. This patient’s anemia is definitely caused by the presence of the ACD.
false
This patient is presenting with a common diagnostic dilemma. She more than likely has a mixed cause of her anemia (ACD+IDA). Patients with severe RA often have both iron deficiency and the ACD. The ACD is caused by intense inflammatory process which leads to increases in cytokines (e.g. IL6) which in turn stimulates increased hepcidin production from the liver. Hepcidin inhibits ferroportin. Ferroportin is the carrier protein which allows iron to leave the intestinal wall and macrophages in the bone marrow and elsewhere so that it can be transported by transferrin to the red cell precursors for incorporation into Hb. Because of increased hepcidin, iron is not absorbed from the GI tract and also becomes trapped within the reticuloendothelial cells in the bone marrow. The major source of serum iron and iron bound by transferring is the iron released from the reticuloendothelial system. Only a small amount of iron is absorbed via the GI tract on a daily basis. GI iron absorption contributes little to the total amount of iron circulating in the serum at any one time. Patients with RA often suffer from GI blood loss resulting in a concurrent iron deficiency. In this case the serum iron and transferring saturation are both depressed. These findings can indicate that presence of either ACD or IDA. The TIBC is normal. In iron deficiency The TIBC is expected to be raised. In ACD it is expected that it would be decreased. The fact that it is normal in this patient implies the presence of both ACD and IDA. The ferritin is in a range higher than expected for IDA. However, when considering concomitant ACD+IDA, a ferritin
