I. PLASMA is the fluid portion of blood that contains many different proteins, such as albumin, which maintains blood colloidal osmotic (oncotic) pressure; gamma globulins; beta globulins, which participate in the transport of hormones, metal ions, and lipids; and fibrinogen, which participates in blood clotting. Plasma without fibrinogen is called serum.
II. RED BLOOD CELLS (RBCs or erythrocytes)
1. RBCs do not contain a nucleus or mitochondria.
2. RBCs use glucose as the primary fuel source (i.e., glycolysis or hexose monophosphate shunt during stress).
3. RBCs arc biconcave-shaped disks (shape maintained by spectrin) and contain both hemoglobin and carbonic anhydrase.
B. Layers. If blood is centrifuged (and clotting is prevented), three layers are separated: 1.. Top layer: plasma
2. Middle layer: buffy coat containing leukocytes and platelets
3. Bottom layer: RBCs
C. Hematocrit is the percent volume of a blood sample occupied by RBCs. A normal hematocrit value is 45%. Hematocrit values less than 45% may indicate anemia.
1. A hypotonic environment causes RBCs to swell, rupture (thereby forming ghosts), and release hemoglobin. This process is called hemolysis.
2. A hypertonic environment causes RBCs to shrink so that spiny projections protrude from the surface. This process is called crenation.
E. Blood group antigens. The A, B, and O blood group antigens are carbohydrates linked to lipids of the RBC membrane. Because these carbohydrate antigens are genetically determined, an individual who receives mismatched blood will mount an immune reaction.
1. Type O blood is the universal donor.
F. The Rh factor is clinically important in pregnancy. If the mother isRh —, she will produce Rh antibodies if the fetus is Rh+. This situation will not affect the first pregnancy, but will affect the second pregnancy with an Rh+ fetus.
1. In the second pregnancy with an Rh+ fetus, a hemolytic condition of RBCs occurs known as erythroblastosis fetalis.
2. Kernicterus, which is a pathologic deposition of bilirubin in the basal ganglia, may develop due to the jaundice from the RBC hemolysis.
III. HEMOGLOBIN (Hb)
1. Hb is a globular protein consisting of four subunits.
a. Adult Hb (HbA) consists of two alpha-globin subunits and two beta-globin subunits designated Hb oi2P2.
b. Fetal Hb (HbF) consists of two alpha-globin subunits and two gamma-globin subunits designated Hb at7y2- HbF is the major form of Hb during pregnancy because the oxygen affinity of 1 IbF is higher than the oxygen affinity of HbA and thereby pulls oxygen from the maternal blood into feral blood. The higher oxygen affinity of HbF is explained by 2,3-bisphosphoglycerate (BPG). When 2,3-BPG binds HbA, the oxygen affinity of HbA is lowered. However, 2,3-BPG does not bind HbF, and therefore, the oxygen affinity of HbF is higher.
2. Hb contains a heme moiety, which is an iron (Fe)-containing porphyrin. Fe2+ (ferrous state) binds oxygen, forming oxyhemoglobin. Fe5+ (ferric state) does not hind oxygen, forming deoxyhemoglobin. The heme moiety is synthesized partially in mitochondria and partially in cytoplasm.
3. The Hb-02 dissociation curve is sigmoid shaped because each successive oxygen that binds to Hb increases the affinity for the next oxygen (i.e., binding is cooperative). Therefore, the affinity for the fourth oxygen is the highest.
4. Concentration of Hb a. In men and boys, the concentration of Hb is 15 g/100 ml blood.
b. In women and girls, the concentration of Hb is 13.5 g/100 ml blood.
1. Thalassemia syndromes arc a heterogeneous group of genetic defects characterized by the lack of or decreased synthesis of either ot-globin (ot-thalassemia) or (3-globin (p-thalassemia).
a. Hydrops fetalis is the most severe form of «-thalassemia and causes severe pallor, generalized edema, and massive hepatosplenomegaly, and invariably leads to intrauterine fetal death.
b. p-Thalassemia major is the most severe form of ^-thalassemia and causes a severe, transfusion-dependent anemia. It is most common in Mediterranean countries and parts of Africa and southeast Asia.
2. Types 1 and 2 diabetes. The amount of glycosylated Hb is an indicator of blood glucose normalization over the previous .3 months (because the half-life of RBCs is 3 months) in patients with type 1 and type 2 diabetes. Long periods of elevated blood glucose levels result in a glycosylated Hb (i.e., HbAlc) of 12%-20%, whereas normal levels are approximately 5%.
IV. BLOOD GAS EXCHANGE (Figure 9-1)
1. Oxygen is not soluble in plasma, so it is transported by Hb.
2. Approximately 90% of C02 is transported as HCOj in plasma.
Chloride i shift oxyHb ^-deoxyHb ^vdeoxyHb 'H+
HCO3" in plasma
PO2=40 mm Hg
P02=100 mm Hg
Figure 9-1. (A) Hemoglobin (Hb)-oxygen (02) dissociation curve. Note the sigmoid shape of the curve. At a P02 of 100 mm Hg found in arterial blood and lung alveoli, Hb is 100% saturated. At a P02of 40 mm Hg found in mixed venous blood and tissues, Hb is 75% saturated. At a Po2 of 25 mm Hg, Hb is 50% saturated (P50). At high altitudes, the curve is shifted to the right, which facilitates unloading of 02 to tissues. In carbon monoxide poisoning, the curve is shifted to the left and plateaus. (B) Blood gas exchange in tissues and lung alveoli. In tissues, carbon dioxide is generated and freely diffuses into RBCs. In RBCs, carbon dioxide combines with water to form hydrogen ions (H+) and bicarbonate (HCOj ) in a reaction catalyzed by carbonic anhydrase (CA). Bicarbonate leaves the RBC in exchange for chloride ion (called the chloride shift) using band III protein (solid black dot). Carbon dioxide is transported to the lung as bicarbonate in the plasma. The P02 within tissues is 40 mm Hg and favors oxygen dissociation from oxyHb to form deoxyHb. The oxygen freely diffuses to tissues. The H+ is buffered by combining with deoxyHb to form deoxyHb-H"1. In the lung, bicarbonate enters the RBC and combines with H+ from deoxyHb-H+ to form carbon dioxide and water in a reaction catalyzed by CA. Carbon dioxide diffuses to lung alveoli and is exhaled. The Po2 within lung alveoli is 100 mm Hg and favors saturation of deoxyHb with oxygen to form oxyHb.
3. The rate-limiting step in the utilization of oxygen hy a cell is the adenosine diphosphate (ADP) level.
1. High-altitude living. The adaptation to chronic hypoxemia is due in part to increased synthesis of 2,3-BPG. When 2,3-BPG hinds Hb, the oxygen affinity of Hb is lowered, thereby facilitating unloading of oxygen to tissues. This shifts the Hb-02 dissociation curve to the right.
2. Carbon monoxide (CO) poisoning. CO competes for oxygen-binding sites on Hb because Hb has a higher affinity for CO than for oxygen. This shifts the Hb-02 dissociation curve to the left and plateaus the curve below saturation.
V. WHITE BLOOD CELLS (WBCs or leukocytes)
1. Neutrophils are the most abundant leukocyte in the peripheral circulation (40%-75%).
2. They have a multilobed nucleus.
3. They have primary (azurophilic) granules, which are lysosomes that contain acid hydrolases and myeloperoxidase (produces hypochlorite ions).
4. Neutrophils have secondary granules that contain lysozyme, lactoferrin, alkaline phosphatase, and other bacteriostatic and bacteriocidal substances.
5. They have respiratory burst oxidase (a membrane enzyme), which produces hydrogen peroxide and superoxide, which kill bacteria.
6. Neutrophils are the first to arrive at an area of tissue damage (within 30 minutes; acute inflammation), being attracted to the site by complement C5a and leukotriene B4.
7. They are highly adapted for anaerobic glycolysis with large amounts of glycogen to function in a devascularized area.
8. Neutrophils play an important role in phagocytosis of bacteria and dead cells by using antibody receptors (Fc portion), complement factors, and bacterial polysaccharides to bind to the foreign material. Neutrophils must bind to the foreign material to begin phagocytosis.
9. They impart natural (or innate) immunity along with macrophages and natural killer (NK) cells.
1. Eosinophils comprise 5% of the leukocytes in the peripheral circulation.
2. They have a bi-lobed nucleus.
3. They have highly eosinophilic granules that contain major basic protein, acid hydrolases, and peroxidase.
4. Eosinophils have immunoglobulin E (IgE) antibody receptors.
5. They play a role in parasitic infection (e.g., schistosomiasis, ascariasis, trichinosis).
6. They play a role in reducing the severity of allergic reactions by secreting hista-minase and prostaglandins El and E2, which degrade histamine (secreted by mast cells) and inhibit mast cell secretion, respectively.
1. Basophils comprise 0.5% of the leukocytes in the peripheral circulation (i.e., the least abundant leukocyte).
2. They have highly basophilic granules that contain heparin, histamine, 5-hy-droxytryptamine, and sulfated proteoglycans.
1. Monocytes comprise 1%—5% of the leukocytes in the peripheral circulation.
2. They are members of the monocyte-macrophage system, which includes Kupffer cells in liver, alveolar macrophages, histiocytes in connective tissue, microglia in brain, Langerhans cells in skin, osteoclasts in bone, and dendritic antigen-presenting cells.
3. Monocytes have granules that are lysosomes that contain acid hydrolases, aryl sulfatase, acid phosphatase, and peroxidase.
4. They respond to dead cells, microorganisms, and inflammation by leaving the peripheral circulation to enter tissues and are then called macrophages.
5. Monocytes impart natural (innate) immunity along with neutrophils and NK cells.
E. B lymphocytes and plasma cells
1. Development before exposure to antigen a. During fetal development, B-cell differentiation occurs in the bone marrow.
b. Pro-B cells and pre-B cells undergo heavy-chain gene rearrangement.
C. Immature B cells begin light-chain rearrangement and express antigen-specific IgM on the cell surface.
d. Mature (or virgin) B cells express antigen-specific IgM and IgD on the cell surface.
e. Mature B cells migrate to spleen, lymph node, and gut-associated tissue and lie in wait for antigen exposure.
2. Development after exposure to antigen a. Mature B cells bind antigen using IgM and IgD. As a consequence, CD79a and CD79b function as signal transducers and cause proliferation and differentiation of B cells into plasma cells that secrete IgM or IgD.
b. Later in the immune response, mature B cells internalize the antigen-IgM or antigen-IgD complex, and the complex undergoes degradation in endosomal acid vesicles.
C. Some of the antigen peptide fragments become associated with class II major histocompatibility complex (MHC) and are exposed on the cell surface of the mature B cell.
d. The antigen peptide-class 11 MHC is recognized by CD4+ helper T cells, which secrete interleukin-2 (IL-2).
e. Under the influence of CD4+ helper T cclls and IL-2, mature B cells undergo isotype switching, which allows B cells to differentiate into plasma cells that secrete IgG, IgE, or IgA, and hypermutation, which produces antibodies that bind with greater affinity.
3. B cells, plasma cells, and immunoglobulins are the basis of humoral response.
4. B memory cells arc programmed to reacr to the same antigen upon re-exposure to that antigen, resulting in a faster immune response called the secondary immune response. The immunoglobulin secreted by B memory cells has a higher affinity for the antigen that the immunoglobulin produced during the initial exposure due to hypermutation. This is the basis of immunization.
F. T lymphocytes
1. Development before exposure to antigen a. In fetal development, T-cell differentiation occurs in the thymus.
b. Pre-T cells begin T-cell receptor (TcR) gene rearrangement.
C. Immature T cells express antigen-specific TcR, CD4, and CD8 on the cell surface.
d. Immature T cells undergo the following processes:
(1) Positive selection, whereby only those T cells that bind with a certain affinity to MHC proteins on thymic epitheliocytes survive (all other T cells undergo apoptosis)
(2) Negative selection, whereby T cells that rccognized "self" antigens undergo apoptosis, leaving T cclls that recognize only foreign antigens e. Mature T cells downregulate either CD4 or CD8 and leave the thymus. Mature T cells are never both CD4+ and CD8+.
f. Mature T cells migrate to the thymic-dependent zone of lymph nodes and to the periarterial lymphatic sheath in the spleen, where they lie in wait for antigen exposure.
2. Development after exposure to antigen a. Exogenous antigens circulating in the bloodstream arc phagocytosed by antigen-presenting cells and undergo degradation in endosomal acid vesicles. Antigen proteins are degraded into antigen peptide fragments, which arc presented on the cell surface in conjunction with class II MHC. CD4+ helper T cells with antigen-specific TcR on their cell surfaces recognize the antigen peptide fragment.
b. Endogenous antigens (virus or bacteria with a cell) are processed within the rough endoplasmic reticulum into antigen peptide fragments, which arc presented on the cell surface in conjunction with class 1 MHC. CD8+ cytotoxic T cells with antigen-specific TcR on its ccll surface recognize the antigen peptide fragment.
3. CD4+ helper T cells promote B-cell differentiation and are depleted in patients with AIDS.
4. CD8+ cytotoxic T cells are the basis of cell-mediated immune response.
5. Suppressor T cells are either CD4 + or CD8+ and inhibit the activity of cytotoxic T cells and helper T cells.
6. Memory T cells are programmed to react to the same antigen upon re-exposure to that antigen, resulting in a faster cell-mediated immune response.
G. NK cells play an important role in the elimination of virus-infected cells and tumor cells not previously encountered. They impart natural (innate) immunity along with neutrophils and macrophages.
VI. HYPERSENSITIVITY REACTIONS. In addition to providing protection, the immune system may produce deleterious reactions called hypersensitivity or allergic reactions, which include the following:
A. Type I anaphylactic reactions are mediated by IgE (i.e., antibody-mediated), which binds to antibody receptors on basophils and mast cells. When cross-linked by antigens, IgE triggers basophils and mast cells to release their contents. Reaction occurs within minutes. Clinically, this type of reaction occurs in a wide spectrum ranging from rashes and wheal-and-flare reactions to anaphylactic shock.
B. Type II cytotoxic reactions are mediated by IgG or IgM (i.e., antibody-mediated), which bind to antigen on the surface of a cell and kill the cell through complement activation. Clinically, this type of reaction occurs in blood transfusion reactions, Rh incompatibility, transplant rejection via antibodies, drug-induced thrombocytopenia purpura, hemolytic anemia, and autoimmune diseases.
C. Type III immune complex reactions are mediated by antigen-antibody complexes (i.e., antibody-mediated) that activate complement, which in turn activates neutrophils and macrophages to cause tissue damage. Reaction occurs within hours. Clinically, this type of reaction occurs in serum sickness, chronic glomerulonephritis, poststreptococcal glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa, Farmer's lung, and the Arthus reaction.
D. Type IV delayed-type reactions are mediated by T cells (i.e., cell-mediated). This type of reaction takes longer to mount (1-2 days) than antibody-mediated reactions (types I-I1I) due to the time it takes to mobilize T cells through a cascade of activation events. Clinically, this type of reaction occurs in poison ivy dermatitis (contact sensitivity), whereby Langerhans cells (antigen-presenting cells) in the skin respond to urushiol (an oil); transplant rejection via cells; tuberculin reaction (Mycobacterium tuberculosis; purified protein derivative skin test); sarcoidosis; Crohn's disease; and ulcerative colitis.
1. Platelets are cell fragments derived from megakaryocytes.
2. They are involved in hemostasis (blood clotting).
3. They have a-granulcs that contain platelet factor 4, platelet-derived growth factor (PDGF), factor V, and fibrinogen.
4. They have S-granules that contain serotonin, ADP, and calcium.
1. Platelet activation by either collagen or thrombin causes release of arachidonic acid from the cell membrane, which is converted to thromboxane A2. Thromboxane A2 stimulates platelet secretion.
2. A severe reduction in the number of circulating platelets is called thrombocytopenia, which causes spontaneous bleeding and manifests in skin as small reddish-purple blotches called purpura.
VIII. HEMOSTASIS (Figure 9-2) A. Two pathways
1. Extrinsic pathway a. Damaged tissue releases thromboplastin.
b. Thromboplastin initiates a cascade involving factors VII, X, V, and prothrombin activator.
C. Prothrombin activator converts prothrombin to thrombin.
Lysis of blood clot or thrombus
Lysis of blood clot or thrombus
Damaged tissue releases thromboplastin
RBC trauma or
Figure 9-2. Diagram of hemostasis. The extrinsic and intrinsic pathways are depicted, both of which lead to the production of prothrombin activator. Prothrombin activator converts prothrombin to thrombin. Thrombin subsequently converts fibrinogen to fibrin. Vitamin K is essential for hemostasis. The shaded box indicates the mechanism for lysis of the blood clot or thrombus. Tissue plasminogen activator (TPA) converts plasminogen to plasmin. Plasmin initiates lysis.
d. Thrombin converts fibrinogen to fibrin.
e. Fibrin, along with RBCs, platelets, and plasma, forms a blood clot, or thrombus.
2. Intrinsic pathway a. RBC trauma or RBC contact with subendothelial collagen initiates a cascade involving factors XII, XI, IX, VIII, X, V, and prothrombin activator.
b. Prothrombin activator converts prothrombin to thrombin. C. Thrombin converts fibrinogen to fibrin.
d. Fibrin, along with RBCs, platelets, and plasma, forms a blood clot, or thrombus.
B. Vitamin K is essential for hcmostasis becausc it acts as a cofactor for an enzyme that forms 7-carboxyglutamate residues in certain blood factor proteins. This allows factor proteins to bind to cell membranes because 7-carboxyglutamate residues have a high affinity for calcium.
1. Vitamin K deficiency can result in hemorrhage. However, adult vitamin K deficiency is rare because intestinal bacteria produce 50% of the required vitamin K.
2. Dicumarol and warfarin are vitamin K analogues that inhibit hemostasis.
1. In patients with hemophilia A (the most common type of hemophilia), factor VIII is absent.
2. In patients with hemophilia B, factor IX is absent.
IX. SELECTED PHOTOMICROGRAPHS
A. Hereditary spherocytosis, thalassemia major, sickle cell disease, and G6PD deficiency (Figure 9-3)
Figure 9-3. (A) Hereditary spherocytosis, a genetic disease characterized by a deficiency in the spectrin protein that helps stabilize the RBC membrane, usually is caused by a mutation of the ankyrin gene. This results in aniso-cytosis (variation in size ol RBCs) and spherocytes with no central pallor zone. The osmotic fragility tesr is the confirmatory test for hereditary spherocytosis. (Reprinted with permission from Stiene-Martin EA, Lotspeich-Steininger CA, Koepke JA: Clinical Hematology, 2nd ed. Philadelphia, Lippincott, 1998, p 91.) (B) ^-thalassemia major is shown with some large, polychromatic RBCs that are newly released from the bone marrow in response to the anemia. 1 lowever, most RBCs are small (microcytic) and colorless (hypochromic). Also apparent are many irregular-shaped RBCs (poikilocytes) that have been traumatized or damaged during passage through the spleen. (Courtesy of Jean Shafer; Department of Medicine; University of Rochester from web site [email protected], Carden Jennings Publishing Co. Ltd.) (C) Sickle cell anemia is shown with sickle RBCs (depranocytes) due to the rod-shaped polymers of the inherited abnormal hemoglobin S (HbS). The RBC does not become sickled until it has lost its nucleus and has its full complement of HbS. Sickle cells are thin, elongated, and well-filled with HbS. The main clinical manifestations of sickle cell disease are chronic hemolytic anemia and occlusion of microvascu-lature (called vaso-occlusive disease). Vaso-occlusive crisis may occur in the brain, liver, lung, or spleen. Factors that induce sickling are Po2 (e.g., high altitude) or a concentration of 60% FlbS or greater in RBCs. (Reprinted with permission from Stiene-Martin EA, Lotspeich-Sreininger CA, Koepke JA: Clinical Hematology, 2nd ed. Philadelphia, Lippincott, 1998, p 96.) (D) Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic disease in which the deficiency reduces the ability of RBCs to protect themselves from oxidative injury. This leads to a denaturation ofHb, which forms Hb precipitates within the RBC (see inset) called Heinz bodies. As rhese RBCs percolate through the spleen, splenic macrophages "chew" the Heinz bodies so that RBCs have a "bite" of cytoplasm removed and arc called bite cells. However, the majority of RBCs are normocytic and normochromatic. (Courtesy of Jean Shafer; Department of Medicine; University of Rochester from web site [email protected], Carden Jennings Publishing Co. Ltd. Inset reprinted with permission from Stiene-Martin EA, Lotspeich-Steininger CA, Koepke JA: Clinical Hematology, 2nd ed. Philadelphia, Lippincott, 1998, p 99.)
B. Vitamin B,2 deficiency, lead poisoning, iron deficiency, Howell-Jolly bodies (Figure 9-4)
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