Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
246 Cards in this Set
- Front
- Back
1. Classification and functions of leukocytes and thrombocytes
|
The leukocytes can be classified either as polymorphonuclear leukocytes (granulocytes) or mononuclear leukocytes, depending on the morphology of the nucleus in these cells.
The mononuclear leukocyte has a rounded nucleus, whereas the polymorphonuclear leukocytes have a multilobed nucleus. |
|
2. Granulocytes
|
Named b/c of the presence of secretory granules visible on staining.
Include: 1. Neutrophils 2. Eosinophils 3. Basophils Are activated in response to chemical stimuli and release their granule contents (degranulation) |
|
3. Staining color of neutrophils, eosinophils, and basophils?
|
Neutrophils: pink
Eosinophils: red Basophils: blue |
|
4. Role of neutrophils
|
Phagocytic cells that migrate rapidly to areas of infection or tissue damage. As part of the response to acute infection, neutrophils engulf foreign bodies and destroy them, in part, by initiating the respiratory burst.
The respiratory burst creates oxygen radicals that rapidly destroy the foreign material found at the site of infection. |
|
5. Role of eosinophils
|
Destroy parasites such as worm.
The eosinophilc granules are lysosomes containing hydrolytic enzymes and cationic proteins, which are toxic to parasitic worm. Eosinophils have also been implicated in asthma and allergic response, although their exact role in the development of these disorders is still unknown. |
|
6. Role of basophils
|
The least abundant of the leukocytes, participate in hypersensitivity reactions, such as allergic responses.
Histamine, produced by the decarboxylation of histidine, is stored in the secretory granules of basophils. Release of histamine during basophil activation stimulates smooth muscle cell contraction and increases vascular permeability. Th granules also contain enzymes such as proteases, β-glucoronidase, and lysophospholipase. These enzymes degrade microbial structures and assist in the remodeling of damaged tissue. |
|
7. Mononuclear leukocytes
|
Consist of various classes of lymphocytes and the monocytes.
|
|
8. Three major types of lymphocytes
|
1. T-cells
2. B-cells 3. NK-cells |
|
9. What are the roles of macrophages in the spleen?
|
Play an important role in maintaining the oxygen-delivering capabilities of the blood by removing damaged red blood cells that have a reduced oxygen carrying capacity.
|
|
10. Platelets
|
Heavily granulated disc-like cells that aid in intravascular clotting.
Like the erythrocyte, platelets lack a nucleus. They arise by budding of the cytoplasm of megakaryocytes, multinucleated cells that reside in the bone marrow. |
|
11. Anemia
|
The major function of erythrocytes is to deliver oxygen to the tissues. To do this, a sufficient concentration of hemoglobin is necessary for efficient oxygen delivery to occur.
When the Hb concentration falls below normal values, the patient is classified as anemic. |
|
12. Classifications of anemia
|
Based on red cell size and hemoglobin concentration
|
|
13. Microcytic, hypochromic anemias
|
Functional deficit: Impaired hemoglobin synthesis
Possible causes: 1. Iron deficiency 2. Thalassemia mutation 3. Lead poisoning |
|
14. Macrocytic, normochromic anemias
|
Functional deficit: Impaired DNA synthesis
Possible causes: 1. Vitamin B12 or folic acid deficiency 2. Erythroleukemia |
|
15. Normocytic, normochromic anemias
|
Functional deficit: Red cell loss
Possible causes: 1. Acute bleeding 2. Sickle cell disease 3. Red cell metabolic defects 4. Red cell membrane defects |
|
16. MCV
|
Mean corpuscular volume
This is the average volume of the red blood cell, expressed in femtoliters. Normal MCV values range from 80-100 fL A value of < 80 fL indicates microcytic cells |
|
17. MCHC
|
Mean corpuscular hemoglobin concentration
This is the average concentration of hemoglobin in each individual erythrocyte, expressed in grams per liter. The normal range is 32-37 g/L A value of < 32 g/L indicates hypochromic cells |
|
18. Unique aspects of erythrocytes
|
1. No nucleus
-no DNA, RNA or protein synthesis 2. No mitochondria -no TCA cycle, oxidative phosphorylation, electron transport chain to generate ATP 3. Must survive oxidative environment -passage thru lungs 4. Larger than capillaries -must deform to pass thru |
|
19. Glycolysis and shunts in RBCs
|
No mitrochrondria, no ATP from TCA cycle
Use glycolysis to produce ATP Provide substrates for Hexose monophosphate shunt and Rapaport-Luberin Shunt, NADH, and NADPH for other reactions. |
|
20. Rapaport-Luberin Shunt
|
Erythrocyte glycolysis uses this shunt to generate 2,3-BPG
|
|
21. In order for hemoglobin to bind oxygen, what is necessary?
|
The iron of Hb must by in the ferrous (+2) state.
However, reactive oxygen species can oxidize the iron to the ferric (+3) state, producing methemoglobin. |
|
22. What does the NADH produced by glycolysis accomplish?
|
The NADH is used to regenerate hemoglobin from methemoglobin by the NADH-cytochrome b5 methemoglobin reductase system.
Cytochrome b5 reduces the ferric form of iron (+3) of methemoglobin. The oxidized cytochrome b5 is then reduced by a flavin-containing enzyme, cytochrome b5 reductase, using NADH as the reducing agent. |
|
23. How is NADPH generated by RBCs?
What is the role of NADPH? |
Approx 5 - 10% of the glucose metabolized by RBCs is used to generate NADPH by way of the hexose monophosphate shunt.
The NADPH is then used to maintain glutathione in the reduced state. The glutathione cycle is the RBC's chief defense against damage to proteins and lipids by reactive oxygen species. |
|
24. What enzyme catalyzes the first step of the hexose monophosphate shunt?
|
G6PD
Glucose 6-phosphate dehydrogenase The lifetime of the RBC correlates with G6PD activity. Lacking ribosomes, the RBC cannot synthesize new G6PD protein. Consequently, as the G6PD activity decreases, oxidative damage accumulates. |
|
25. Hexose monophosphate shunt
|
1. Present in many cell types
2. Produces 5-carbon sugars (i.e. ribose) 3. Returns carbons to glycolysis in RBC's 4. Produces NADPH, which reduces glutathione for antioxidant effect 5. Protects cell |
|
26. Cytochrome b5
|
Hb can become methemoglobin by a change in oxidation state of iron in heme
Will not carry oxygen to tissues - about 3% normally NADH reduces cytochrome b5 which reduces iron |
|
27. What is the structure of the heme molecule?
|
Heme consists of a porphyrin ring coordinated w/an atom of iron.
Four pyrrole rings are joined by methenyl bridges to form the porphyrin ring. Eight side chains serve as substituents on the porphyrin ring, two on each pyrrole. In heme, the order of these groups is characteristic of the porphyrins of the type III series, the most abundant in nature. |
|
28. Synthesis of heme
|
Heme is synthesized from glycine and succinyl CoA which participate in a series of reactions to generate heme.
Two produce one molecule of heme: 1. 8 molecules each of glycine and succinyl CoA are required. 2. A series of porphyrinogens is generated in sequence 3. Finally, iron is added to produce heme. |
|
29. Regulation of heme synthesis
What else does heme regulate? |
Heme regulates its own production by repressing the synthesis of δ-aminolevulinic acid (δ-ALA) and by directly inhibiting the activity of this enzyme (allosteric modifier)
Thus, heme is synthesized when heme levels fall; as they rise, the rate of synthesis decreases. Heme also regulates the synthesis of hemoglobin by stimulating synthesis of the protein globin. Heme maintains the ribosomal initiation complex for globin synthesis in an active state. |
|
30. δ-ALA dehydratase
|
Contains zinc and ferrochelatase, which are inactivated by lead.
Thus, in lead poisoning, δ-ALA and protoporphyrin 9 accumulate, and the production of heme is decreased. Anemia results from a lack of Hb, and energy production decreases b/c of the lack of cytochromes for the electron transport chain. |
|
31. Iron for heme
|
1. Iron from diet must reach organs
2. Transferrin is major serum carrier 3. Ceruloplasmin changes oxidation state 4. Stored in liver as ferritin 5. Serum ferritin levels rise w/excess iron 6. Hemosiderin is storage form, and is not mobilized easily. |
|
32. Because free iron is toxic, how does the body handle it?
|
It is usally found in the body bound to proteins.
Iron is carried in the blood as Fe 3+ by the protein apotransferrin, with which it forms a complex known as transferrin. |
|
33. Ferritin
|
Storage of iron occurs in most cells but esp those of the liver, spleen and bone marrow.
In these cells, the storage protein, apoferritin, forms a complex with iron (Fe 3+) known as ferritin. Normally, little ferritin is present in the blood. This amount increase, however, as iron stores increase. Therefore, the amt of ferritin in the blodo is the most sensitive indicator of the amt of iron in the body's stores. |
|
34. Excess iron goes to where?
|
When excess iron is absorbed from the diet, it is stored as hemosiderin, a form of ferritin complexed w/additional iron that cannot be readily mobilized.
|
|
35. Degradation of heme
|
Heme is degraded to form bilirubin, which is then conjugated w/glucoronic acid and excreted in the bile.
Although heme from cytochromes and myoglobin also undergoes conversion to bilirubin, the major source of this bile pigment is Hb. |
|
36. Steps in the degradation of heme
|
1. After RBCs die, the globin is cleaved to its constituent AAs, and iron is returned to the body's iron stores.
2. Heme is then oxidized and cleaved to produce carbon monoxide and biliverdin. 3. Biliverdin is reduced to bilirubin, which is transported to the liver complexed w/serum albumin. 4. In the liver, bilirubin is converted to a more water soluble compound by reacting with UDP-glucuronate to form bilirubin monoglucuronide, which is converted to the diglucuronide. This conjugated form of bilirubin is excreted into the bile. |
|
37. What happens to the bilirubin diglucuronide in the intestine?
|
Bacteria deconjugate bilirubin diglucuronide and convert the bilirubin to urobilinogens.
Some urobilinogen is absorbed into the blood and excreted in the urine. However, most of the urobilinogen is oxidized to urobilins, i.e. stercobilin, and excreted in the feces. These pigments give feces their brown color. |
|
38. The red cell membrane
|
To survive in the circulation, the red cell must be highly deformable. Damaged red cells that are no longer deformable become trapped in the passages in the spleen, where they are destroyed by macrophages.
The reason for this deformability lies in its shape and in the organization of the proteins that make up the red blood cell membrane. |
|
39. Red cell membrane proteins
|
1. Membrane proteins can have a variety of functions. Major proteins are:
a. spectrin b. actin c. band 4.1 d. band 4.2 e. ankyrin 2. Glycophorin provides large negative change, and prevents aggregation 3. Band 3 is a chloride-bicarbonate exchange transporter 4. Associate with cytoskeleton. |
|
40. Spectrin
|
Is the major protein in the cell membrane; multiple spectrins can bind to each actin filament, resulting in a branched membrane cytoskeleton
|
|
41. Ankyrin
|
The first membrane-cytoskeleton anchor.
The spectrin cytoskeleton is connected ot the membrane lipid bilayer by ankyrin, which interacts with beta-spectrin and the integral membrane protein, band 3. Band 4.2 helps to stabilize this connection. |
|
42. Band 4.1
|
The other membrane-cytoskeleton anchor.
Membrane proteins associate with ankyrin and band 4.1 proteins. Band 4.1 anchors the spectrin skeleton with the membrane by binding the integral membrane protein glycophorin C and the actin complex. |
|
43. What happens when the RBC is subjected to mechanical stress?
|
The spectrin network rearranges.
Some spectrin molecules become uncoiled and extended; others become compressed, thereby changing the shape of the cell, but not its surface area. |
|
44. Agents that affect oxygen binding
|
1. Hydrogen ions
2. 2,3-BPG 3. Covalent binding of CO2 |
|
45. 2,3-BPG
|
Formed in RBCs from the glycolytic intermediate 1,3-BPG.
2,3-BPG binds to Hb in the central cavity formed by the four subunits, increasing the energy required for the conformational changes that facilitate the binding of oxygen. Thus, 2,3-BPG lowers the affinity of Hb for oxygen. Therefore, oxygen is less readily bound (i.e. more readily released from tissues) when Hb contains 2,3-BPG. |
|
46. Bohr effect
|
The binding of protons by Hb lowers it affinity for oxygen, contributing to a phenomenon known as the Bohr effect.
As the pH decreases, the affinity of Hb for oxygen decreases, shifting the curve to the right. |
|
47. CO2 and oxygen binding
|
Although most of the CO2 produced by metabolism in teh tissues is carried to the lungs as bicarbonate, some of teh CO2 is covalently bound to Hb.
In the tissues, CO2 reacts with the amino groups of the deoxyhemoglobin and stabilizes the deoxy conformation. |
|
48. Erythropoiesis
|
1. Start as hematopoietic stem cells
2. These form pluripotent stem cells 3. Stem cells form mixed myeloid progenitor cells (GFU-GEMM) 4. GFU-GEMM form burst forming unit - erythroids (BFU-E) 5. BFU-E forms colony forming unit - erythroids (CFU-E) 6. CFU-E forms the first recognizable red cell precursor, the normoblast. |
|
49. Final steps in RBC differentiation
|
1. Normoblasts are committed progenitors
2. They divide 4 times after which Hb synthesis begins 3. Nucleus becomes inactive, and then extruded 4. Released in circulation as reticulocyte; later matures in 1-2 days. |
|
50. Regulation of erythropoiesis
|
Regulated by the demands of oxygen delivery to the tissues.
In response to reduced tissue oxygenation, the kidney releases the hormone erythropoietin, which stimulates the multiplication and maturation of erythroid progenitors |
|
51. Nutritional anemias
|
1. Vitamin deficiencies
-Folate and vitamin B12 needed for nucleotide synthesis 2. Deficiency slows mitosis of progenitors 3. Cells divide too few times |
|
52. Iron deficiency
|
These cells are microcytic and hypochromic. The lack of iron results in decreased heme synthesis, which in turn affects globin synthesis.
Iron deficient RBCs continue dividing past their normal stopping point, resulting in small red cells. They are also pale, because of the lack of Hb, compared with normal cells. |
|
53. Folate or vitamin B12 deficiencies
|
Can cause megalobastic anemia, which the cells are macrocytic.
Folate and B12 are required for DNA nucleotide synthesis, and when these are deficient, DNA replication and nuclear division do not keep pace w/ the maturation of the cytoplasm. Consequently, the nucleus is extruded before the requisite number of cell divisions has taken place, and the cell volume is greater than it should be, and fewer blood cells are produced. |
|
54. Thalassemias
|
For optimum function, the Hb α- and β- globin chains must have the proper structure and be synthesized in a 1:1 ratio.
A large excess of one subunit over the other results in thalassemia. These anemias are clinically very heterogeneous, and they provide resistance to malaria in the heterozygous state. |
|
55. Causes of thalessemias?
α-thalessemias and β-thalessemias? |
1. Hemoglobin single AA replacement mutations that give rise to a globin subunit of decreased stability
2. More common are mutations that result in decreased synthesis of one subunit: α-thalessemias usually result from complete gene deletions β-thalessemias can result from deletions, promoter mutations and splice-junction mutations |
|
56. α-thalessemias
|
Two copies of the α-globin gene are found on each chromosome 16, for a total of 4 α-globin genes per precursor cell.
If one copy of the gene is deleted, the size and Hb concentration of the individual RBCs is minimally reduced. The more copies that are deleted, the more the RBCs will become microcytic and hypochromic Absence of 3 α-globin genes causes moderately severe microcytic hypochromic anemia with splenomegaly Absence of all four α-globin chains is usually fatal in utero (hydrops fetalis) |
|
57. β-thalessemias
|
Many different variations; can be asymptomatic all the way to severe anemia. β°β° homozygotes are the most severely affected.
In general, disease of β-chain deficiency are more severe than disease of α-chain deficiency. |
|
58. Why are diseases of β-chain deficiency are more severe than diseases of α-chain deficiency?
|
Excess β-chains form a homotetramer, HbH, which is useless for delivering oxygen to the tissues b/c of its high oxygen affinity. As RBCs age, HbH precipitates in the cells, forming inclusion bodies.
RBCs with inclusion bodies have shortened lifespans, b/c they are more likely to be trapped and destroyed in the spleen. Excess α-chains are unable to form a stable tetramer. However, excess α-chains precipitate in erythrocytes at every developmental stage. The α-chain precipitating results in their widespread destruction. They also damage RBC membranes, particularly band 4.1. |
|
59. Hereditary persistence of fetal hemoglobin
|
HbF, the predominant Hb of teh fetal period, consists of two α-chains and two γ-chains, whereas adult Hb consists of two α- and two β-chains.
The process that regulates the conversion of HbF to HbA is called hemoglobin switching. Hb switching is not 100%; most individuals continue to produce a small amt of HbF in place of HbA. |
|
60. What is the relationship between patients with sickle cell anemia or β-thalassemia and HbF levels?
|
Those patients with hemoglobinopathies frequently have less ever illnesses if their levels of HbF are elevated.
|
|
61. Hereditary persistence of fetal hemoglobin (HPFH)
|
These individuals express HbF past birth
Caused by: 1. Point mutations in the Aγ and Gγ promoters; these mutations can have ameliorating effects on sickle cell or β-thalassemia, b/c of increased production of the γ-chain 2. Both the entire δ- and β-genes have been deleted from one copy of chromosome 11 and only HbF can be produced. |
|
62. Difference between individuals w/ δ°β°-thalassemia and those with deltion HPFH?
|
Difference between the two is believe to be the site at which the deletions end within the β-globin gene cluster.
In deletion HPFH, power enhancer sequences 3' of the β-globin gene are resituated b/c of the deletion so that they activate the γ-promoters. In individuals w/ δ°β°-thalassemia, the enhancer sequences have not been relocated so that they can interact w/ the γ-promoters. |
|
63. Hb switching
|
1. Globin genes are in two complex loci
2. Several genes in each, in order of appearance during development 3. Embryonic and fetal forms are present 4. Fetus not affected by many mutations; premature newborns convert from HbF to HbA on schedule w/their gestational ages. |
|
64. Spherocytosis
|
The red blood cells are deficient in spectrin. This deficiency impairs the ability fo the erythrocytes to maintain teh redundant surface area necessary to maintain deformability.
Mechanical stresses in the circulation cause progressive loss of pieces of membrane. As membrane components are lost, the RBCs become spherical and unable to deform. Splenomegaly occurs b/c of the large numbers of RBcs that have become trapped within it. This hemolytic process results in anemia. |
|
65. What causes hereditary spherocytosis?
|
Mutations in the genes for ankyrin, β-spectrin, or band 3 account for 3/4ths of the cases of hereditary spherocytosis.
Mutations in the genes for α-spectrin or band 4.2 account for the remainder. Results in improper pformation of the membrane cytoskeleton. Splenectomy is often recommended as the spleen is the major source of RBC destruction that causes anemia. |
|
66. What happens with an inherited deficiency in pyruvate kinase?
|
Leads to hemolytic anemia.
B/c the amt of ATP formed from glycolysis is decreased by half, RBC ion transporters cannot function effectively. The RBCs tend to gain calcium and lose potassium and water. The water loss increases the intracellular Hb concentration, the internal viscosity of the cell is increased to the point that the cell becomes rigid, and, therefore more susceptible to damage by shear forces in the circulation. However, the effects of the anemia are freq moderated by the 2-3x elevation in 2,3-BPG concentration that results form the blockage of the conversion of phoenolpyruvate to pyruvate. |
|
67. Congenital methemoglobinemia
|
The presence of excess methemoglobin
Found in people w/an enzymatic deficiency in cytochrome b5 reductase or in people who have inherited hemoglobin M. Methemoglobinemia Can be acquired by ingestion of certain oxidants such as nitrites, quinone, aniline, and sulfonamides. Can be treated by the administration of reducing agents, such as methylene blue or ascorbic acid. |
|
68. Hemoglobin M
|
A single AA substitution in the heme-binding pocket stabilizes the ferric Fe 3+ oxygen.
|
|
69. G6PD deficiency
|
The most common enzyme defiency in humans, probably, in part, b/c individuals w/ this are resistant to malaria.
The resistance to malaria counterbalances the deleterious effects of the deficiency. G6PD-deficient red cells have a shorter life span and are more likely to lyse under conditions of oxidative stress. |
|
70. G6PD deficiency gene and variants
|
Gene is found on the X chromosome.
All known G6PD variant genes contain small in frame deletions or missense mutations. The corresponding proteins, therefore, have decreased stability or lowered activity, leading to a reduced half-life or life span of the red cell. |
|
71. Pyridoxine (vitamin B6) deficiencies are often associated w/microcytic, hypochromic anemia.
Why? |
In a B6 deficiency, the rate of heme production is slow b/c the first reaction in heme synthesis requires pyridoxal phosphate.
Thus, less heme is synthesized, causing red blood cells to be small and pale. Iron stores are usually elevated. |
|
72. Porphyrias
|
A group of rare inherited disorders resulting from deficiencies of enzymes int he pathway for heme biosynthesis.
Intermediates of the pathway accumulate and may have toxic effects on the nervous system that cause neuropsychiatric symptoms. When prophyrinogens accumulate, they may be converted by light to porphyrins, which react w/molecular oxygen to form oxygen radicals, which may cause severe damage to the skin. Related to werewolf legends due to increased scarring and facial hair seen in some porphyrias. |
|
73. Phenobarbital
|
Induce enzymes of the drug metabolizing systems of the ER that contain cytochrome p450.
b/c heme is used for synthesis of cytochrome p450, free heme levels fall and δ-ALA synthase is induced to increase the rate of heme synthesis. |
|
74. In an iron deficiency, what characteristics will blood exhibit?
|
Results in a microcytic, hypochromic anemia.
|
|
75. Leukemias
|
Malignancies of the blood
Arise when a differentiating hematopoietic cell does not complete its developmental program but remains in an immature, proliferative state. Leukemias have been found in every hematopoietic lineage. |
|
76. X-linked severe combined immunodeficiency disease (SCID)
|
In the most common form of SCID, circulating T lymphocytes are not formed, and B lymphocytes are not active.
The affected gene encodes the γ-chain of the IL2 receptor. Mutant receptors are unable to activate JAK3, and the cells are unresponsive to the cytokines that stimulate growth and differentiation. |
|
77. Mutant erythropoietin (epo) receptor
|
The receptor is unable to bind SHP-1, a tyrosine phosphatase necessary for proper development of myeloid and lymphoid lineages.
Individuals w/the mutant epo receptor have a higher than normal percentage of RBCs in the circulation, b/c the mutant epo receptor cannot be deactivated by SHP-1. |
|
78. Perturbed JAK/STAT signaling is associated with development of ...?
|
1. Lymphoid and myeloid leukemias
2. Severe congenital neutropenia 3. Fanconi anemia, which is characterized by bone marrow failure and increased susceptibility to malignancy. |
|
79. A sickle cell crisis can lead to ...?
|
Increased formation of gallstones.
A sickle cell crisis accompanied by the intravascular destruction of RBCs increases the amt of unconjugated bilirubin that is transported to the liver. If the concentration of this unconjugated bilirubin exceeds the capacity fo the hepatocytes to conjugate it to the more soluble diglucuronide thru interaction w/hepatic UDP glucuronate, both the total and the unconjugated bilirubin levels in the blood increase. This results in precipitation within the gallbladder lumen, leading to the formation of pigmented gallstones. |
|
80. HbS/HbC
|
HbS/HbC individuals have significantly more hematopathology than individuals w/ sickle cell trait (HbA/HbS)
Polymerization of deoxygenated HbS is dependent on the HbS concentration within the cell. The presence of HbC in the compound heterozygote increases the HbS concentration by stimulating potassium and water efflux from the cell. B/c the HbC globin is produced more slowly than HbA or HbS, the proportion of HbS tends to be higher in HbS/Hbc cells than in the cells of individuals with sickle cell trait (HbS/HbA). |
|
81. Does HbF have a lower or higher affinity for 2,3-BPG compared to adult Hb?
|
HbF has a lower affinity for 2,3-BPG than adult hemoglobin (HbA)
Therefore, the oxygen released from the mother's hemoglobin is readily bound by HbF in the fetus. Differences due to the structural changes caused by the different composition of hemoglobin subunits |
|
82. F-cell-producing locus on the short arm of the X chromosome
|
Is thought not to be susceptible to X inactivation.
Both normal individuals and individuals w/hemoglobinopathies vary in the amount of HbF they produce. The FCP locus is responsible for a substantial amt of the variation in hemogloin F seen among sickle cell patients. |
|
83. A and B antigens
|
Two antigens, type A and type B occur on teh surfaces of the RBCs in a large proportion of humans.
It is these antigens that cause most blood transfusion reactions. Because of the way these agglutinogens are inherited, people may have neither of them on their cells, they may have one, or they may have both simultaneously. |
|
84. Type O blood
|
Genotype OO
Neither A nor B agglutinogen is present Anti-A and Anti-B agglutinins |
|
85. Type A blood
|
Genotype OA or AA
A agglutinogens Anti-B agglutinins |
|
86. Type B blood
|
Genotype OB or BB
B agglutinogens Anti-A agglutinins |
|
87. Type AB blood
|
Genotype AB
A and B agglutinogens No agglutinins are present |
|
88. Titer of the agglutinins at different ages
|
Immediately after birth, the quantity of agglutinins in the plasma is almost zero. 2-8 months after birth, an infant begins to produce agglutinins.
A maximum titer is usually reached at 8-10 years of age, and this gradually declines throughout the remaining years of life. |
|
89. Origin of agglutinins in the plasma
|
The agglutinins are gamma globulins, as are almost all antibodies an they are produced by the same bone marrow and lymph gland cells that produce antibodies to any other antigens. Most of them are IgM and IgG immunoglobulin molecules.
|
|
90. Why do these agglutinins produce in people that do not have the respective agglutinogens in their RBC's?
|
Small amts of type A and B antigens enter the body in food, in bacteria, and in other ways, and these substances initiate the development of the anti-A and anti-B agglutinins.
|
|
91. What happens when bloods are mismatched during tranfusions?
|
The red cells agglutinate as a result of the agglutinins' attaching themselves to the RBCs.
B/c the agglutinins have two bindings sites (IgG type) or 10 binding sites (IgM type), a single agglutinin can attach to two or more RBCs at the same time, thereby causing the cells to be bound together by agglutinin. This causes the cells to clump, which can cause plugs in the small blood vessels throughout the circulatory system. During ensuing hours to days, either physical distortion of the cells or attack by phagocytic white blood cells destroys the membranes of the aggultinated cells. |
|
92. Acute hemolysis in some transfusion reactions
|
Sometimes, when a recipient and donor bloods are mismatched, immediate hemolysis of RBCs occurs in the circulating blood.
The antibodies activate the complement system, which releases proteolytic enzymes that rupture cells membranes. |
|
93. Which is more common, immediate intravascular hemolysis or delayed hemolysis?
|
Delayed hemolysis, because not only does there have to be a high titer of antibodies for lysis to occur, but also a different type of antibody seems to be required, mainly the IgM antibodies; these antibodies are called hemolysins.
Immediate hemolysis is far less common than agglutination followed by delayed hemolysis |
|
94. Rh blood type system
|
Unlike the OAB type system, in the Rh type system, spontaneous agglutinins almost never occur.
Instead, the person must first be massively exposed to an Rh antigen, such as by transfusion of blood containing the Rh antigen, before enough agglutinins cause a significant transfusion reaction to occur |
|
95. Rh Antigens
|
There are six common types of Rh antigens, each of which is called an Rh factor, designated C, D, E, c, d, and e.
A person who has a C antigen does not have the c antigen, but the person missing the C antigen always has the c antigen. Huh? The same is true for the D-d and E-e antigens. Also, b/c of the manner of inheritance of these factor, each person has one of each of the three pairs of antigens. |
|
96. Type D Rh antigen
|
Type D antigen is widely prevalent in the population and considerably more antigenic than the other Rh antigens. Anyone who has this antigen is said to be Rh positive, whereas a person who does not have type D antigen is said to be Rh negative.
About 85% of all white people are Rh positive, and about 15% Rh negative. In American blacks, 95% are Rh positive, whereas in African blacks - virtually 100% positive. |
|
97. Rh immune response; formation of Anti-Rh agglutinins
|
When RBCs containing Rh factor are injected into a person whose blood does not contain the Rh factor, anti-Rh agglutinins develop slowly, slowly reaching maximum concentration of agglutinins about 2-4 mos later.
With multiple exposes to the Rh factor, an Rh-negative person eventually becomes strongly sensitized to Rh factor. |
|
98. Characteristics of Rh transfusion reactions
|
Acute reactions are not likely if Rh-negative people have never been exposed to Rh-positive blood.
However, anti-Rh antibodies can develop in sufficient quantities during the next 2-4 weeks to cause agglutination of those transfused cells that are still circulating in the blood. |
|
99. Erythroblastosis fetalis
|
A disease of the fetus and newborn child characterized by agglutination and phagocytosis of the fetus's red blood cells.
In most instances of this, the mother is Rh negative and the father Rh positive. The baby has inherited the Rh+ antigen from the father, and the mother develops anti-Rh agglutinins from exposure to the fetus's Rh antigen. In turn, the mother's agglutinins diffuse through the placenta into the fetus and cause RBC agglutination. |
|
100. Incidence of erythroblastosis fetalis
|
An Rh- mother having her first Rh+ child usually does not develop sufficient agglutinins to cause any harm.
However, about 3% of second Rh+ babies exhibit some signs of erythroblastosis fetalis; about 10% of third babies exhibit the disease; and the incidence rises progressively w/subsequent pregnancies. |
|
101. Clinical characteristics of newborns w/erythroblastosis fetalis
|
The jaundiced, erythroblastotic newborn baby is usually anemic at birth, and the anti-Rh agglutinins from the mother usually circulate in the infant's blood for another 1 to 2 months after birth, destroying more and more RBCs.
The heatopoietic tissues of the infant attempt to replace the hemolyzed RBCs. The liver and spleen become greatly enlarged and produce RBCs in the same manner that they normally do during the middle of gestation. B/c of the rapid rpoduction of red cells, many early forms of RBCs, including many nucleated blastic forms, are passed from the baby's bone marrow into the circulatory system, ant it is b/c of the presence of these cells that the disease is called erythroblastosis fetalis. Mental impairment is not uncommon b/c of kernicerus |
|
102. Treatment of newborn w/erythroblastosis fetalis
|
Replace the neonate's blood w/Rh- blood.
This procedure may be repeated several times during the first few weeks of life, mainly to keep the bilirubin level low and thereby prevent kernicterus. By the time these transfused Rh- cells are replaced w/the infant's own Rh+ cells, the anti-Rh agglutinins that had come from the mother will have been destroyed. |
|
103. Prevention of erythroblastosis fetalis
|
The D antigen of the Rh blood group system is the primary culprit in causing immunization of an Rh- mother to an Rh+ fetus.
Giving Rh immunoglobulin globin, an anti-D antibody to the mother starting at 28-30 wks of gestation greatly reduces the risks of developing large amounts of D antigens. |
|
104. Mechanism by which Rh immunoglobulin globin prevents sensitization of the D antigen
|
Not completely understood, but one effect of the anti-D antibody is to inhibit antigen induced B lymphocyte antibody production in teh expectant mother.
The administered anti-D antibody also attaches to D-antigen sites on Rh+ fetal RBCs that may cross the placenta and enter the circulation of the mother, thereby interfering with the immune response to the D antigen. |
|
105. When a transfusion reaction occurs, whose blood agglutinates - donor or recipient?
|
The RBCs of the donor's blood are agglutinated b/c the plasma portion of the donor blood immediately becomes diluted by all the plasma of the recipient, thereby decreasing the titer of the infused agglutinins to a level usually too low to cause agglutination.
Will eventually cause either immediate or delayed hemolysis resulting from hemolysins or from phagocytosis of agglutinated cells, respectively. |
|
106. What is one of the most lethal effects of transfusion reactions?
|
Kidney failure, which can begin within a few minutes to a few hours and continue until the person dies of renal failure
|
|
107. What causes the renal failure in transfusion reactions?
|
Results from three causes:
1. The antigen-antibody reaction of the transfusion reaction releases toxic substances from the hemolyzing blood that cause powerful renal vasoconstriction. 2. Loss of circulating red cells int he recipient, along w/production of toxic substances from the hemolyzed cells and from the immune reaction, often causes circulatory shock. The arterial BP falls very low, and renal blood flow and urine output decrease. 3. If the total amt of free Hb released into the circulating blood is greater than the quantity that can bind with haptoglobin, much of the excess leaks thru the glomerular membranes into the kidney tubules - this causes Hb to precipitate and block many of the kidney tubules. |
|
108. Autograft
|
Transplant of a tissue or whole organ from one part of the same animal to another part
No reactions |
|
109. Isograft
|
From one identical twin to another
No reactions |
|
110. Allograft
|
From one human being to another or from any animal to another animal fo the same species
|
|
111. Xenograft
|
From a lower animal to a human or from an animal of one species to one of another species
High risk of reactions within 1 day to 5 weeks. |
|
112. HLA complex of antigens
|
The most important antigens for causing graft rejection are a complex called the HLA antigens.
Six of these antigens are present on teh tissue cell membranes of each person, but there are about 150 different HLA antigens to choose from. Therefore, this represents more than a trillion possibilities. Thus, it is virutally impossible for two persons, except for twins, to have the same six HLA antigens. Development of significant immunity against any one of these antigens can cause graft rejection. |
|
113. If no two people have the same six HLA antigens, how can transplants occur?
|
Some of the HLA antigens are not severly antigenic, for which reason a precise match of some antigens between donor and recipient is not always essential to allow allograft acceptance.
The best success has been with tissue type matches between siblings and between parent and child. |
|
114. What are three different therapeutic agents that have been used to prevent graft rejection?
|
1. Glucocorticoid hormones isolated from adrenal cortex glands, which suppress the growth of all lymphoid tissue and, therefore, decrease formation of antibodies and T cells.
2. Various drugs that have a toxic effect on the lymphoid system and, therefore, block formation of antibodies and T cells, especially the drug azathioprine. 3. Cyclosporine, which has a specific inhibitory effect on the formation of helper T cells and, therefore, is especially efficacious in blocking the T-cell rejection reaction. This drug is especially useful b/c it does not depress some other portions of the immune system. |
|
115. Role of blood in the body
|
1. Transport of nutrients and oxygen directly to cells
2. Transport of wastes and carbon dioxide away from cells 3. Delivery of hormones and other regulatory substances to and from cells and tissues 4. Maintenance of hemostasis by acting as a buffer and by participating in coagulation and thermoregulation 5. Immune function |
|
116. Hematocrit (HCT)
|
Percentage of the volume of cellular elements vs. total volume
39-50% in males 35-45% in females |
|
117. Percentage of neutrophils in granulocytes
|
50-70%
|
|
118. Percentage of eosinophils in granulocytes
|
2-5%
|
|
119. Percentage of basophils in granulocytes
|
0.3%
|
|
120. Percentage of lymphocytes in the agranulocytes
|
25-30%
|
|
121. Percentage of monocytes in the agranulocytes
|
8%
|
|
121. Percentages of erythrocytes vs. leukocytes/platelets and derivatives in the blood
|
Erythrocytes & derivatives: 99%
Leukocytes, platelets, and derivatives: 1% |
|
122. What do blood cells and their derivatives include?
|
1. Erythrocytes, RBCs
2. Leukocytes, WBCs 3. Thrombocytes, platelets |
|
123. Plasma
|
91-92% water
7-8% protein 1% electrolytes, nonprotein nitrogen substances, nutrients, blood gases, and regulatory substances |
|
124. Albumin
|
Smallest plasma protein
Maintains colloid osmotic pressure Is a carrier protein for hormones (thyroxine), metabolites (bilirubin), and drugs (barbituates) |
|
125. γ-globulins vs. α- and β-globulins
|
γ-globulins: immunoglobulins
α- and β-globulins: nonimmunoglobulins -secreted by the liver -helps clot formation -maintains colloid osmotic pressure -carrier protein for: 1. copper (coeruloplasmin) 2. iron (transferrin) 3. hemoglobin (haptoglobin) |
|
126. Fibrinogen
|
Largest plasma protein secreted by the liver; involved in a series of cascade reactions with other coagulation factors.
Soluble fibrinogen is made into fibrin, which then rapidly polymerize to form long, insoluble fibers. These fibers become cross-linked and form an impermeable net at the site of damaged blood vessels that prevents further blood loss. |
|
127. Morphology of the erythrocyte
|
1. Anucleate eosinophilic cells devoid of typical organelles
2. Biconcave disc, 7.8 um 3. Extremely deformable 4. Binds oxygen and carbon dioxide 5. 120 days life span 6. Broken down in the spleen, bone marrow and liver |
|
128. What are the integral membrane proteins that maintain the shape of the RBC?
|
Two major families:
1. Glycophorins -Glycophorin C plays an important role in attaching the underlying cytoskeletal protein network to the cell membrane 2. Band 3 protein -binds hemoglobin and acts as an additional anchoring site for the cytoskeletal proteins |
|
129. What are some of the peripheral membrane proteins that help maintain the shape of the RBC?
|
1. The lattice of the membrane is composed of :
1. Spectrin tetramers 2. Actin 3. Band 4.1 4. Adducin 5. Band 4.9 6. Tropomyosin 7. Ankyrin 8. Band 4.2 These are organized into a hexagonal lattice network. |
|
130. Heriditary elliptocytosis
|
Caused by a deficiency in band 4.1 protein that results in elliptic erythrocytes.
Results in hemolysis |
|
131. Hemoglobin
|
1. Transport oxygen and carbon dioxide
2. Responsible for the eosinophilic staining of the RBC 3. Consists of 4 polypeptide subunits 4. Each subunit contains a heme 5. Four different types of globin chains, α,β,γ,δ bound in pairs |
|
132. HbA
|
Most prevalent in adults, accounting for about 96% of the total Hb.
Consists of two α- and two β- chains |
|
133. HbA2
|
Accounts for 1.5 - 3% of total Hb in adults.
Consists of two α- and two δ- chains |
|
134. HbF
|
Accounts for less than 1% of total Hb in adults
Contains two α- and two γ- chains and is the prinicpal form of Hb in the fetus. Although it persists in slightly higher percentages than normal in sickle cell disease and thalassemia, it does not appear to have a pathologic role. |
|
135. Cause of sickle cell anemia
|
Caused by a single point mutation in the gene that encodes the β- globin chain of HbA.
Valine is substituted with glutamic acid in position 6 |
|
136. Neutrophils
|
Named after the lack of the characteristic cytoplasmatic staining
Nucleus: -Multilobed nucleus (usually tri-lobed) -Heterochromatin in periphery of nucleus -Euchromatin in the middle of nucleus -Barr bodies in females Granules are small, barely visible Small golgi apparatus and few mitochondria |
|
136. Neutrophil granules
|
1. Azurophylic granules 1˚
-Larger granules, more numerous -Lysosomes containing myeloperoxydase that generates bactericidal hypoclorite -Cationic proteins called defensins which also have bactericidal properties 2. Specific granules 2˚ -Smallest granules, most numerous -Contains: i. Enzymes (type IV collagenase, phospholipidase) ii. Complement activators iii. Bactericidal agent (lysosyme) Tertiary granules 3˚ Two types: i. Phosphatase containing ii. Metalloproteinase (gelatinase and collagenase) containing which facilitate migration of neutrophils thru the connective tissue. |
|
137. Important property of neutrophils
|
Their motility.
They are the most numerous of the first wave of cells to enter an area of tissue damage. Their migration is controlled by the expression of adhesion molecules on the neutrophil surface that interact w/the corresponding ligands on endothelial cells. |
|
138. Migration of neutrophils to injury site
|
1. Selectins interact w/selectin receptor on the endothelium
2. Integrins are activated by chemokine signals of the endothelium 3. Integrins and immunoglobulins on the neutrophils bind to their receptors on the endothelium 4. Mast cells release histamine and heparin that opens a gap on the capillary 5. Neutrophil migrates in to the connective tissue 6. Further migration is directed by chemoattractant molecules to the injury site - chemotaxis. |
|
139. Neutrophil phagocytosis
|
1. Fc receptors recognize the antibodies coating the antigen
2. Antigen is engulfed by the neutrophil 3. Phagosome is formed, digestion is started by oxidases 4. Specific and azurophilic granules fuse with phagosome (degranulation) 5. Digestion is completed by the enzymes 6. Digested material is either exocytosed or stored w/in the cell as a residual body |
|
140. Eosinophils
|
Names after the large eosinophilic granules in the cytoplasm.
Nucleus: -Typically bilobed -Herterchromatin in the periphery of the nucleus -Euchromatin in the middle of the nucleus Small golgi apparatus Few mitochondria |
|
141. Eosinophil granules
|
Specific granules:
1. Crystalloid body -Major basic protein, cytotoxic to protozoans and helmintic parasites 2. Granule matrix i. eosinophil cationic protein ii. eosinophil peroxydase iii. eosinophil derived neurotoxin - causes nervous system dysfunction in parasites iv. Histaminase - neutralizes histamine v. Arylsulfatase vi. Collagenase vii. cathepsins Azurophylic granules -lysosomes containing hydrolytic enzymes |
|
142. Basophils
|
Names after the large basophilic granules in the cytoplasm
Closely related to mast cells of the connective tissue Nucleus: -Typically bilobed nucleus obscured by the granules -Heterochromatin in the periphery -Euchromatin in the middle Small golgi apparatus Few mitochrondria |
|
143. Basophil granules
|
Specific granules: grainy texture
-Heparan sulfate; responsible for basophilia -Histamine; vasodilation -SRS-A; slow reacting substance A; vasodilation Azurophylic granules -lysosomes containing acid hydrolases |
|
144. Basophil plasma membrane
|
1. Possesses Fc receptors for IgE
-IgE triggers the release of substances from the granules 2. Expresses CD40L protein that interacts w/the complementary receptor on the B lymphocytes; this increases IgE synthesis |
|
145. B-lymphocytes
|
1. 20-30% of lymphocytes
2. Matures in the bone marrow 3. Variable life span, involved in production of circulating antibodies 4. Mature B cells express IgM, IgD, and MHC-II molecules 5. Express CD9, CD19, CD20, and CD24 marker proteins on their surface |
|
146. T-lymphocytes
|
1.Differentiate and mature in the thymus
2. Long life span, involved in cell mediated immunity 3. Express CD2, CD3, CD7 marker proteins on their surface 4. DO NOT express antibodies on the cell surface 5. Subclassified on the basis of the presence of CD4 and CD8 proteins 6. 60-80% of lymphocytes |
|
147. Subclassifications of T-lymphocytes
|
1. Cytotoxic CD8+ lymphocytes
2. Helper CD4+ lymphocytes 3. Suppressor CD8+, CD45RA+ lymphocytes |
|
148. Cytotoxic CD8+ lymphocytes
|
1. Primary effector in cell mediated immunity
2. Recognize antigen-bound MHC-I molecules on virus infected and neoplastic cells 3. Secretes lymphokines and perforins that produce ion channels in the infected cell membrane leading to its lysis 4. Play role in rejection of allografts and in tumor immunology |
|
149. Helper CD4+ lymphocytes
|
1. Recognize antigen-bound MHC-II molecules on antigen presenting cells
2. Activated helper cell produces interleukins stimulating proliferation and differentiation of more CD4+ cells 3. Newly differentiated cells secrete lymphokines that affect differentiation of B cells, T cells, and NK cells and turn B cells into plasma cells |
|
150. Natural killer cells (NK cells)
|
1. 5-10% of lymphocytes
2. Programmed to kill certain virus infected cells and tumor cells 3. Larger than T and B cells 4. Kidney shaped nucleus, several large cytoplasmic granules 5. Express CD16, CD56, CD94 marker proteins on their surface |
|
151. Suppressor CD8+, CD45A+ lymphocytes
|
1. Suppress antibody formation by B cells
2. Suppress the ability of T cells to initiate the immune response 3. May also regulate the erythroid cell maturation of the bone marrow. |
|
152. Monocytes
|
1. Largest of leukocytes
2. Travel from bone marrow to the body tissues where they differentiate into various tissue macrophages 3. Phagocytize and degrade antigens, presenting their fragments on MCH II molecules sitting on the cell surface to helper CD4+ lymphocytes for recognition 4. Remain in the blood for only 3 days 5. Nucleus is bean (embryo) shaped 6. Cytoplasm contains small mitochondria, sER, rER, and small azurophillic granules. |
|
153. Zones of platelet structure: from outside to inside
|
1. Peripheral zone
2. Structural zone 3. Organelle zone 4. Membrane zone |
|
154. Peripheral and structural zones of platelets
|
Peripheral zone:
Cell membrane covered by glycocalyx Structural zone: 1. Microtubules 2. Actin filaments 3. Myosin 4. Actin-binding proteins supporting the plasma membrane (disc shape) |
|
155. Organelle zone of platelets
|
1. Mitochondria
2. Peroxisomes 3. Glycogen particles 4. α-, *δ-, **λ-granules *δ-granules contain ADP, ATP, serotonin, and histamine which facilitate platelet adhesion and vasoconstriction **λ-granules contain several hydrolytic enzymes similar to lysosomes which help function in clot resorption during later stages of vessel repair |
|
156. Membrane zone of platelets
|
Open canalicular system (remnant of demarcation zones)
Dense tubular system (storage of calcium ions) |
|
157. Stages of erythrocytic differentiation
|
1. Proerythroblast
2. Basophilic erythroblast 3. Polychormatophillic erythroblast 4. Orthochromatophillic erythroblast (normoblast) 5. Polychromatophillic erythroblast (reticulocyte) 6. Erythrocyte |
|
158. Which stage of erythrocytic differentiation has a small, compact, densely stained nucleus?
|
The orthochromatophilic erythroblast (normoblast)
No longer capable of division at this stage |
|
159. Which stage of erythrocytic differentiation has a large spherical nucleus w/one or two visible nucleoi?
|
Proerythroblast
|
|
160. Which stage of erythrocytic differentiation has extruded its nucleus?
|
The polychromatophilic erythrocyte (reticulocyte)
Constitute about 1-2% of the total erythrocyte count. |
|
161. Which stages of erythrocytic differentiation have mitotic division?
|
1. Proerythroblasts
2. Basophilic erythroblasts 3. Polychromatophilic erythroblasts. |
|
162. Band cells
|
In the neutrophil line, the band cell precedes development of the first distinct nuclear lobs.
The nucleus of the band cell is elongated and of nearly uniform width, giving it a horseshoe like appearance. The % of band cells in the circulation is almost always low, however, they may increase in acute or chronic inflammation |
|
163. Developmental stages of granulocytes
|
1. Myeloblasts
2. Promeylocytes 3. Myelocytes 4. Metamyelocytes |
|
164. Which type of immature granulocytes are the only ones to produce aurophilic granules?
|
Promyelocytes
|
|
165. Which type of immature granulocytes are the first to exhibit specific granules?
|
Myelocytes
|
|
166. Which type of immature granulocytes clearly exhibit their lines of differentiation as well as numerous specific granules?
|
The metamyelocyte is the stage at which neutrophil, eosinophil, and basophil lines can be clearly identified by the presence of numerous specific granules
|
|
167. Granulocyte macrophage colony stimulating factor GM-CSF
|
Source: T cells, endothelial cells, fibroblasts
Targets: 1. CFU-GEMM 2. CFU-E 3. CFU-GM 4. CFU-Eo 5. CFU-Ba 6. CFU-Meg 7. All granulocytes 8. Erythrocytes |
|
168. Granulocyte colony stimulating factor G-CSF
|
Source: endothelial cells, monocytes
Targets: 1. CFU-E 2. CFU-GM 3. CFU-Eo 4. CFU-Ba 5. CFU-Meg |
|
169. Monocyte colony stimulating factor M-CSF
|
Source: monocytes, macrophages, endothelial and adventitial cells
Targets: 1. CFU-GM 2. CFU-M 3. Monocytes 4. Macrophages 5. Osteoclasts |
|
170. Erythropoietin EPO
|
Source: kidney, liver
Targets: CFU-E and CFU GEMM |
|
171. Thormbopoietin
|
Source: bone marrow
Targets: CFU-Meg and megakaryocytes |
|
172. IFN-γ
|
Source: CD4+ T cells, NK cells
Targets: 1. B cells 2. T cells 3. NK cells 4. Neutrophiles 5. Monocytes |
|
173. IL-1
|
Source: neutrophils, monocytes, macrophages, and endothelial cells
Targets: CD4+ T cells and B cells |
|
174. Normocellular bone marrow
|
THe number of hemopoietic cells decreases with age.
Bone marrow with a normal age-specific index is called normocellular bone marrow |
|
174. Hypocellular bone marrow
|
Occurs in aplastic anemia or after chemo
Only a small number of blood forming cells can be found in a marrow biopsy. |
|
175. Hypercellular bone marrow
|
Characteristic of bone marrow affect by tumors originating from hematopoietic cells.
|
|
176. Red bone marrow
|
Active bone marrow
The cords of hemopoietic cells contain predominantly developing blood cells and megakaryocytes. The cords also contain macrophages, mast cells, and some adipose tissue. |
|
177. Yellow bone marrow
|
Inactive bone marrow - contains predominantly adipose tissue.
It is the chief form of bone marrow in the medullary cavity of bones in the adult that are no longer active, such as the long bones of the arms, legs, fingers, and toes |
|
181. Differences between acute blood loss and chronic blood loss
|
Clinical and morphological reactions depend on the rate of hemorrhage.
Acute blood loss can lead to shock and death Chronic blood loss can cause anemia when iron reserves are depleted. |
|
182. Hemolytic anemias
|
Characterized by premature RBC destruction, accumulation of Hb catabolites (e.g, bilirubin) and markedly increased erythropoiesis with associated reticulocytosis.
Can occur intravascularly or extravascularly |
|
183. Intravascular hemolysis
|
RBCs are damaged by mechanical injury or complement (e.e.g mismatched blood transfusion)
Patients exhibit: 1. hemoglobinemia 2. hemoglobinuria 3. hemosiderinuria 4. jaundice 5. reduced serum haptoglobin |
|
184. Extravascular hemolysis
|
Occurs in mononuclear phagocytes of spleen (and other organs)
Predisposing factors include red blood cell membrane injury, reduced deformability, or opsonization. Manifestations are similar to intravascular hemolysis but w/o hemoglobinemia and hemoglobinuria |
|
185. Hereditary spherocytosis
|
Autosomal dominant disorder in which RBC cytoskeletal membrane protein defects render erythrocytes spheroidal, less deformable, and vulnerable to splenic sequestration and destruction
|
|
186. Pathophysiology of hereditary spherocytosis
|
Defects in several different membrane proteins can cause HS; all lead primarily or secondarily to deficiencies in spectrin.
Spectrin-deficient RBCs have unstable membranes and spontaneously lose fragments - thus they are easily trapped in the splenic cords. |
|
187. Morphology of HS
|
In the peripheral blood, spherocytic RBCs appear small and lack central pallor.
There is marked congestion and prominent phagocytosis of RBCs in the splenic cords of Billroth. Bone marrow exhibits normoblastic hyperplasia. |
|
188. Clinical features of HS
|
1. Anemia
2. Moderate splenomegaly 3. Jaundice 4. Infection triggered hemolytic crisis or aplastic crisis by parvovirus infection 5. Gallstones in 50% of those affected. The MCHC is increased as a result of cellular dehydration. |
|
189. G6PD Deficiency
|
G6PD is an enzyme in the hexose monophosphate shunt that produces reduced glutathione, a molecule that protects RBCs from oxidative injury
In G6PD deficient cells oxidant stresses induce hemoglobin denaturation. The altered Hb precipitates as Heinz bodies, which attach to the inner cell membrane. Heinz bodies damage cell membranes sufficiently to cause both intravascular and extravascular hemolysis. |
|
190. G6PD Deficiency prevalence
|
This is an X linked disorder
Although there are sever variants, only two, G6PD A- and G6PD Mediterranean, lead to clinically significant hemolysis. A- is present in about 10% of American blacks, and is associated with progressive loss of G6Pd in older RBCs. B/c the younger cells are not affected, hemolytic episodes are self limited. In the Mediterranean variant, G6PD levels are much lower and hemolytic episodes are more severe. Ingestion of fava beans can cause hemolysis in G6PD deficiency b/c these legumes generate oxidants. |
|
191. Sickle cell disease
|
This is a hereditary hemoglobinopathy resulting from the substitution of a valine for a glutamic acid at the sixth position of the β-globin chain, transforming normal hemoglobin A into the mutant hemoglobin S.
|
|
192. What is the most important factor in the sickling phenomenon?
|
The amount of HbS and its interaction with other Hb chains in the cell.
Heterozygotes have little tendency to sickle, whereas homozygotes have mostly HbS and will have full blown sickle cell anemia. |
|
193. When do newborns present with sickle cell anemia?
|
They do not manifest disease complications until 5-6 months of age; at that time, RBC HbF concentration approaches adult levels.
|
|
194. HbC
|
Another variation of hemoglobin
Has a greater tendency to aggregate with HbS than HbA Individuals w/HbSC have more severe disease than patients with sickle cell train alone. |
|
195. MCHC in sickle cell anemia
|
High HbS concentrations increase the rate of contact and interaction between individual HbS molecules.
Dehydration is one factor that increases MCHC, thereby facilitating sickling and occlusion of small blood vessels. Concurrent diseases that reduce MCHC (thalassemias) lessen sickling severity |
|
196. Consequences of sickling
|
1. Chronic hemolysis
2. Microvascular oclusions |
|
197. Morphology of sickle cell disease
|
1. The spleen is enlarged in early childhood due to sickled cell trapping in splenic cords.
2. Bone marrow shows normoblastic hyperplasia; if severe enough, can cause bone resorption 3. Microvascular occlusions produce tissue damage and infarction in several organs |
|
198. Clinical features of sickle cell anemia
|
1. Chronic hemolytic anemia
-propensity for gallstones, hyperbilirubinism 2. Vaso-occlusive crises 3. Aplastic crisis due to transient suppression of erythropoiesis 4. Progressive splenic fibrosis and impairment of the alternate complement pathway predispose to infections |
|
199. Thalassemia major
|
Homozygotes for β-thalessemia genes have sever, tranfusion-dependent anemia
This form is the most common in Mediterranean countries, parts of Africa, and Southeast Asia. RBCs are microcytic, hypochromic and are stipled or fragmented. Clinical course is generally brief; without transfusions, death occurs at an early age from profound anemia. Blood transfusions lessen the anemia and suppress the secondary changes related to excessive erythropoiesis (bone deformities). |
|
200. Talassemia minor
|
Heterozygotes for β-thalessemia genes are usually asymptomatic due to sufficient β-globin synthesis.
This form is more common and affects the same ethnic groups. RBC's show hypochromia, microcytosis, basophilic stippling and target cells. Recognition of β-thalassemia trait is important for genetic counseling |
|
201. Thalassemia intermedia
|
Clinical features and severity are intermediate between the major and minor forms.
This patients are genetically heterogeneous. |
|
202. α-thalassemia
|
Classification and the severity of the anemia is related to the number of α-globin genes deleted.
|
|
203. Silent carrier state in α-thalassemia
|
This type is completely asymptomatic; resulting from a single α-globin gene deletion
Reduction in α-globin synthesis is barely detectable |
|
204. α-thalassemia trait
|
Either one chromosome has both α-globin genes or each chromosome has a deletion of one gene.
The clinical picture is comparable to β-thalessemia. Although these two genotypes are clinically identical, they differ in whether offspring are at risk for severe α-thalassemia (> three α-chains deleted) |
|
205. HbH disease
|
Deletion of three α-globin genes causes marked suppression of α-chain synthesis, and formation of unstable tetramers of excess β-globin HbH.
Clinically, HbH disease resembles β-thalassemia intermedia |
|
206. Hydrops fetalis
|
Deletion of all four α-globin genes.
In the fetus, excess gamma-globin chains form tetramers (HbBarts) with extremely high oxygen affinity and inability to release O2 to tissues. Not compatible with life. |
|
207. Paroxysmal nocturnal hemoglobinuria (PNH)
|
Is a rare disorder characterized by chronic intravascular hemolysis.
It is the only hemolytic anemia resulting from an acquired (rather than inherited) membrane defect. RBCs have an increased sensitivity to complement-mediated lysis due to deficient expression of a family of proteins normally anchored to the cell membrane via GPI. Their deficiency renders RBC hypersensitive to complement, which is activated spontaneously at low rates. May arise due to an autoimmune response to GPI-linked proteins on hematopoietic stem cells. Aplastic anemia sometimes precedes the development of PNH; it also rarely transforms to acute leukemia. |
|
208. Warm antibody hemolytic anemia
|
This anemia is idiopathic in 60% of cases.
IgG anti-red blood cell antibodies coat the RBCs; they do not fix complement but do act as opsonins. RBCs are speherocytic due to membrane fragment loss thru macrophage phagocytosis; they are eventually sequestered and destroyed in the spleen. Thus, splenomegaly is a characteristic. |
|
209. Mechanism of antibody formation in drug induced hemolytic anemias
|
1. Hapten model
-Drugs bind to the RBC surface; antibodies then interact with the drug or the RBC-drug complex 2. Autoantibody model -Drugs initiate production of antibodies directed against intrinsic RBC antigens |
|
210. Cold agglutinin immune hemolytic anemia
|
Anemia is caused by IgM antibodies that agglutinate RBCs at low temperatures.
Acute hemolysis occurs during recovery from certain infections (EBV). It is usually self-limited and rarely induces significant hemolysis Chronic hemolysis occurs w/lymphoproliferative disorders or may be idiopathic. Clinical symptoms result form RBC agglutination and complement fixation in areas of the body that are 30˚ or lower |
|
211. Cold hemolysin hemolytic anemia
|
This anemia occurs in paroxysmal cold hemoglobinuria, manifesting as acute intermittent massive intravascular hemolysis after exposure to cold.
Autoantibodies are IgG directed against the P blood group antigen. They attach to the RBCs and fix complement at low temps; when the temp is elevated, hemolysis occurs. Most cases follow infections |
|
212. Megaloblastic anemias
|
Most commonly due to deficiency of vitamin B12 or folate
|
|
213. Morphology of megaloblastic anemias
|
1. Abnormally large erythroid precursors (megaolblasts) in which nuclear maturation labs behind cytoplasmic maturation
2. Ineffective erythropoieses with compensatory megaloblastic hyperplasia 3. Prominent anisocytosis 3. Abnormal granulopoiesis with giant megamyelocytes and hypersegmented neutrophils |
|
214. Pathophysiology of megaloblastic anemias
|
Vitamin B12 and folate are essential for the production of thymidine, a building block of DNA
Deficiency results in deranged or inadequate DNA synthesis, but normal RNA and protein synthesis. Anemia results from a combination of ineffective erythropoiesis and abnormal red cells that are unusually susceptible to premature removal by phagocytes. These deficiencies also affect all rapidly dividing cells, including myeloid precursors and GI epithelium. Ineffective granulopoiesis and thrombopoiesis often results in pancytopenia. |
|
215. Vitamin B12 deficiencies
|
Anemias of vitamin B12 deficiency
Can result from impaired absorption, which has several causes: 1. Achlorhydria, which impairs viatamin B12 release from teh R protein bound form 2. Gastrectomy, which leads to the loss of intrinsic factor 3. Pernicious anemias 4. Resection of the distal ileum, which prevents absorption of intrinsic factor-B12 complex 5. Malabsorption syndromes 6. Increased requirements (i.e. pregnancy) 7. Inadequate diet (very uncommon) |
|
216. Pernicious anemia
|
Likely due to an autoimmune response to gastric parietal cells resulting in chronic atrophic gastritis and marked parietal cell loss, followed b deficient intrinsic factor production.
Gastric injury is probably initiated by autoreactive T cells, secondarily generated autoantibodies to various components of the vitamin B12 uptake pathway are also present in the serum and gastric secretions of most patients. |
|
217. What are some of the autoantibodies involved in pernicious anemia?
|
1. Type I antibodies block the binding of vitamin B12 to intrinsic factor (IF)
2. Type II antibodies prevent IF or IF-B12 complex from binding to the ileal receptor. 3. Antibodies against the gastric proton pump bind to parietal cells and affect acid secretion. There is significant association of pernicious anemia with other autoimmune disorders of the adrenal and thyroid glands. |
|
218. Morphology of pernicious anemia
|
1. Bone marrow changes including megaloblastic erythroid hyperplasia, giant myelocytes and metamyelocytes, hypersegmented neutrophils, large multilobed nuclei in megakaryocytes
2. Alimentary canal; includes atrophic glossitis; the tongue is shiny, glazed and red 3. CNS: lesions are found in 75% of cases. They are characterized by demyelination of dorsal and lateral spinal cord tracts, and, if advanced, result in spastic paresis and sensory ataxia. |
|
219. Clinical features of pernicious anemia
|
Onset is insidious; patients are usually 40-60 w/symptoms due to anemia and posterolateral spinal tract involvement.
There is an increased risk of gastric cancer. Dx is based on serum vitamin B12 levels, the detection of anti-IF antibodies, and hematologic responses (reticulocytosis) after parenteral vitamin administration |
|
220. Anemia of folate deficiency
|
Induces a megaloblastic anemia clinically and hematologically indistinguishable from that seen in vitamin B12 deficiency
EXCEPT that gastric atrophy and the neurologic changes of vitamin B12 deficiency do not occur. Dx requires demonstration of reduced serum or RBC folate levels. |
|
221. Causes of folate deficiency
|
1. Inadequate intake, usually in those living on marginal diets (i.e.chronic alcoholics, elderly, and the indigent)
2. Malabsorption syndromes 3. Increased demand (pregnancy) 4. Admin of folate antagonists such as methotrexate, a chemotherapeutic agent. |
|
222. Etiology of iron deficiency anemia
|
Negative iron balance and consequent anemia can result from:
1. Low dietary intake (rarely the cause of iron deficiency by itself in the US b/c the avg daily intake is more than enough for men and adequate for most women) malabsorption, excessive demand, and chronic blood loss. 2. Malabsorption caused by sprue and celiac disease or after gastrectomy 3. Increased demands 4. Chronic blood loss; this is the most important cause of iron deficiency in the western world. |
|
223. Clinical features of iron deficiency anemia
|
1. Peripheral blood: RBCs are hypochromic and microcytic, and variable in shape
2. Marrow: There is mild hyperplasia of normoblasts, but stainable iron in marrow macropahges are absent 3. Other organs: if severe enough, depletion of essential iron containing enzymes can cause allopecia, koilonychia (nail disease), and atrophy of the tongue and gastric mucosa. Plummer-Vinson triad may occur |
|
224. Please inform me; what the f*ck is the Plummer-Vinson triad?!?
|
1. Hypochromic, microcytic anemia
2. Atrophic glossitis 3. Espophageal webs |
|
225. Aplastic anemia
|
Characterized by a failure or suppression of multipotent myeloid stem cells; neutropenia, anemia, and thrombocytopenia (pancytopenia) result.
|
|
226. Causes of aplastic anemia
|
Idiopathic in 60% of cases
Known causes are: 1. Myelotoxic drugs or chemicals 2. Total body irradiation 3. Infections 4. Inherited diseases (e.g. Fanconi anemia) |
|
227. Pathogenesis of aplastic anemia
|
Stem cell alterations may be due to environmental insults, drug exposure, or infections. In idiopathic cases, stem cell failure may be due to:
1. Primary defect in the number or function of stem cells; in some case due to mutagen exposure. Occasionally, genetically damaged stem cells can transform to acute leukemias. 2. Suppression of antigenically altered stem cells by T cell mediated immune mechanisms. |
|
228. Morphology and clinical features of aplastic anemia
|
Hypocellular marrow (hematopoietic cells replaced by fat cells) with secondary effects due to granulocytopenia and thrombocytopenia.
Onset is insidious w/symptoms related to loss of RBCs, neutrophils, and platelets. Splenomegaly is absent. More commonly, bone marrow transplantation or immunosuppression is required. |
|
229. Pure red blood cell aplasia
|
A form of marrow failure due to absence of RBC precursors; this type of anemia may appear acutely and transiently in chronic hemolytic states due to parvovirus infection.
|
|
230. Myelophthisic anemia
|
Space occupying lesions that destroy or distort the marrow architecture depress productive capacity
Associated w/pancytopenia and frequently w/the appearance of white and red blood cell precursors in the peripheral blood. Most common cause is metastatic cancer. |
|
231. Diffuse liver disease (toxic, infectious or cirrhotic) anemia
|
The anemia is primarily due to bone marrow failure; often exacerbated by variceal bleeding or folate deficiency
|
|
232. Chronic renal failure and anemia
|
Chronic renal failure is almost always associated w/anemia.
The basis is multifactorial, but inadequate erythropoietin production is most important. Treatment w/recombinant erythropoietin usually yields significant improvement. |
|
233. Polycythemia
|
A relative or absolute increase in teh concentration of RBCs in the peripheral blood.
Relative increases may be due to decreased plasma volumes associated with dehydration or due to stress polycythemia, an obscure condition of unknown cause also called Gaisbock syndrome. Absolute increases may be primary or secondary. |
|
234. Primary polycythemia
|
Increased RBC mass is due to a myeloid neoplasm, polycythemia vera, in which red blood cell precursors proliferate in an erythropoietin independent fashion
|
|
235. Secondary polycythemia
|
Increased RBC mass is due to increased erythropoietin, which may be physiologic (lung disease, high altitude living) or pathophysiologic (erythropoietin-secreting tumors).
|
|
236. What conditions caused increased vascular fragility?
|
1. Infections, esp meningoccus and rickettsia
2. Drug reactions 3. Poor vascular support (Ehlers-Danlos syndrome, Cushing syndrome) 4. Henoch-Schönlein purpura |
|
237. Henoch-Schönlein purpura
|
Systemic hypersensitivity reaction of unknown cause characterized by purpuric rash, abdominal pain, polyarthralgia, and acute glomerulonephritis
Associated with vascular and glomerular mesangial deposition of immune complexes |
|
238. Causes of thrombocytopenia?
|
1. Decreased production
2. Decreased survival 3. Sequestration (by spleen) 4. Dilution 5. HIV |
|
239. Immune thombocytopenia purpura (ITP)
|
Two forms:
1. Acute ITP: this self limited disorder is seen most often in children after a viral infection. Platelet destruction is due to transient antiplatelet autoantibodies 2. Chronic ITP: Platelet autoantibodies are usually directed toward one of two platelet antigens. Destruction of antibody-coated platelets occurs in the spleen. Splenectomy benefits 75-80% of cases. |
|
240. Clinical features of ITP
|
Typically occurs in adults, particularly women of childbearing age.
Usually a long history of easy bruising or nosebleeds but sometimes onset can be sudden, with a shower of petechial hemorrhages or internal bleeding. Subarachnoid or intracerebral hemorrhage is rare but serious. The iodiopathic form must be distinguished fom that occurring in the context of SLE, AIDS, drug exposure, and lymphoid neoplasms. |
|
241. Morphology of ITP
|
The spleen is normal in size but shows sinusoidal congestion and prominent germinal centers.
Bone marrow megakaryocyte numbers are increased. |
|
242. Dx of ITP
|
Based largely on clinical features, such as petechiae and thrombocytopenia
Bone marrow biopsy can be performed to confirm increased megakaryocyte numbers. The bleeding time is prolonged, while the PT and PTT times are normal. If splenomegaly and lymphadenopathy are present, a lymphoid neoplasm should be suspected. |
|
242. Drug induced thrombocytopenia
|
A wide variety of drugs can cause immune mediate platelet destruction by acting as haptens or participating in the formation of immune complexes that deposit on platelet membranes.
In most instances, drug induced antibodies cause rapid removal of platelets via the reticuloendothelial system and result in bleeding symptoms. |
|
243. Thrombotic thrombocytopenic purpure (TTP)
|
Usually affects women. Thrombocytopenia, microangiopathic hemolyic anemia, fever, and transient neurologic defects.
Associated with inherited or acquired defiencies in AADAMTS13, a serum metalloprotease that limtites the size of vWF multimers int eh plasma. In its absence, very high molecular weight vWF multimers accumulate that are capable of promoting platelet aggreation throughout the circulation. The the case of acquired TTP, patients often have antibodies against ADAMTS13. |
|
244. Hemolytic uremic syndrome (HUS)
|
Often occurs in young children and the elderly during outbreaks of food poisoning.
Thrombocytopenia, microangiopathic hemolyic anemia, fever, renal failure. Most commonly follows GI infections with E. coli. |
|
245. Similarities between HUS and TTP
|
In some patients, there are overlapping symptoms.
Most of the clinical manifestations are due to widespread hyaline microthrombi in arterioles and capillaries composed of dense aggregate of platelets and fibrin. |