Vascular spasms Vascular spasm is the immediate response to blood vessel injury, which involves constriction of the damaged blood vessel (vasoconstriction).
Platelet plug formation Serotonin enhances the vascular response. ADP is a potent aggregating agent that attracts more platelets to the area and causes them to release their contents.
Thromboxane A2 is a short livedprostaglandin derivative that is generatedand released by platelets, that stimulatesboth events.PGI2 (prostacyclin) is a prostaglandinproduced by the endothelial cells that islimited to the immediate area.
Coagulation Coagulation (blood clotting) is a three phase process during which blood is transformed from a liquid to a gel. Factors that enhance clot formation are called coagulation factors (procoagulants). Factors that inhibit clotting are called anticoagulants.
Clotting may be initiated by either theintrinsic pathway or the extrinsic pathway,and both are triggered by the same tissuedamaging events.PF3 is a phospholipid associated with theexternal surfaces of aggregated platelets,that is a pivotal molecule in bothmechanisms.
When blood is exposed to an additionalfactor released by injured cells, called tissuefactor (tissue thromboplastin), the extrinsicmechanism is triggered.
When factor X (an intermediate) has beenactivated, it complexes with tissue factor orPF3 and calcium ions to form prothrombinactivator.Prothrombin activator catalyzes thetransformation of the plasma proteinprothrombin to the active enzyme thrombin.
Thrombin catalyzes the polymerization offibrinogen.Fibrin strands are long, hair-like insolubleproteins that are formed from fibrinogen.Factor XIII (fibrin stabilizing factor) is anenzyme that binds the fibrin strands tightlytogether and strengthens and stabilizes theclot, in the presence of calcium ions.
Clot retraction and repair Clot retraction is a platelet-induced process that causes the clot to be stabilized further. Serum is plasma minus the clotting proteins,which gets squeezed from the clot as the platelets contract. Platelet-derived growth factor (PDGF) stimulates smooth muscle and fibroblasts to divide and rebuild the wall.
Fibrinolysis Fibrinolysis is a process that removes unneeded clots when healing has occurred. Plasmin is a fibrin-digesting enzyme that dissolves clots, produced upon the activation of plasminogen.
The presence of a clot in and around theblood vessel causes the endothelial cells tosecrete tissue plasminogen activator (tPA).
Factors limiting Clot growth orformation Thrombin not adsorbed to fibrin is quickly inactivated by antithrombin III, which is an alpha-globulin protein present in plasma. Protein C is another protein produced in the liver, that also inhibits the activity of other intrinsic pathway procoagulants.
Heparin is a natural anticoagulant containedin the granules of basophils, mast cells andendothelial cells that inhibits thrombin byenhancing the activity of antithrombin III.
Disorders of hemostasis A clot that develops and persists in an unbroken blood vessel is called a thrombus. If a thrombus breaks away from the vessel wall and floats freely in the bloodstream, it becomes an embolus.
Aspirin is an antiprostaglandin drug thatinhibits thromboxane A2 formation, andtherefore blocks platelet aggregation andplatelet plug formation.Warfarin (Coumadin) is an anticoagulant byinterfering with the action of vitamin K.
Thrombocytopenia is a condition in whichthe number of circulating platelets isdeficient, causing spontaneous bleedingfrom small blood vessels.
Hemophilia is a term that refers to severaldifferent sex-linked, hereditary bleedingdisorders that have similar symptoms.Classical hemophilia results from adeficiency of factor VIII (antihemophilicfactor).
Origin Substance Primary EffectsPlatelets Serotonin Enhance vascular spasmPlatelets ADP Aggregating agentPlatelets Thromboxane A2 Vascular spasm and aggregationPlatelets Platelet-derived growth factor (PDGF) Stimulates smooth muscle and fibroblasts to rebuild vessel wallEndothelium PGI2 (prostacyclin) Inhibitor of platelet aggregationEndothelium Tissue Plasminogen activator (tPA) Converts plasminogen into plasmin, which digests fibrinEndothelium Tissue Thromboplastin (TF) Activates extrinsic pathwayEndothelium, Basophils & Mast Cells Heparin Enhances activitiy of antithrombin IIIPlasma Protein Antithrombin III Inactivation of thrombinPlasma Protein (produced in liver) Protein C Inhibits activity of intrinsic pathway procoagulantsSynthetic Aspirin Inhibits thromboxane A2 formationSynthetic Warfarin (Coumadin) Inhibits action of vitamin K
Transfusion and bloodreplacement
Transfusion of whole blood Whole blood transfusion are performed when blood loss is substantial and when treating thrombocytopenia. Whole blood from which most of the plasma has been removed, called packed red cells, are used for infusions to treat anemia.
Red blood cell antigens that promoteagglutination are called agglutinogens.ABO blood groups are based on thepresence or absence of two agglutinogens,type A and type B.
Agglutinins are preformed antibodies thatact against RBCs carrying ABO antigensthat are not present on a person’s own redblood cells.
There are at least eight different types of Rhagglutinogens, each of which is called anRh factor.Pregnant Rh- women who carry Rh+ babieswill form anti-Rh antibodies, which, duringthe second pregnancy, will destroy thebaby’s RBCs in a condition known aserythroblastosis fetalis.
When mismatched blood is infused, atransfusion reaction occurs in which thedonor’s red blood cells are avidly attackedby the recipient’s plasma agglutinins.Groups O blood cells have neither the A notthe B antigen, so the blood group is knownas the universal donor.
Group AB plasma is devoid of antibodies toboth A and B antigens, so the blood groupknown as the universal recipient.When a patient predonates their own blood,and has it stored so that it is immediatelyavailable if needed during or after anoperation, it is known as an autologoustransfusion.
Plasma and blood volumeexpanders When plasma is not available, various colliodal solutions, or plasma expanders, can be infused.
Diagnostic blood tests
A differential white blood cell count is adiagnostic tool used to determine therelative proportion of individual leukocytetypes.The amount of prothrombin present inblood is assessed by determining theprothrombin time.
A platelet count is performed whenthrombocytopenia is suspected.A complete blood count (CBC), whichincludes counts of the different types offormed elements, a hematocrit, and tests forclotting factors, is performed duringphysical examinations and before hospitaladmissions.
Nonspecific body defenses
Skin and mucosae A pathogen is a harmful or disease causing microorganism. Lysozyme is an enzyme, found in saliva and lacrimal fluid, that destroys bacteria.
Phagocytes Macrophages are the primary phagocytes, and are derived from monocytes. Neutrophils are the most abundant type of white blood cell, and become phagocytic when they encounter infectious material in the tissues.
Natural killer cells Natural killer cells are defensive cells that can lyse and kill cancer cells and virus- infected body cells before the immune system is activated. NKs are part of a large group of lymphocytes called third population cells, which recognize glycolipids on the membrane of infected cells.
Inflammation The purpose of the inflammatory response is to prevent the spread of damaging agents to nearby tissues, and dispose of cell debris. Important inflammatory chemicals released into the extracelluar fluid by injured tissue cells include histamines, kinins, prostaglandins, complement and lymphokines.
Hyperemia is congestion of the affectedarea with blood.Exudate is fluid containing proteins thatseeps from the bloodstream into tissuespaces, due to the effect of theinflammatory chemicals on the capillaries.
Phagocyte mobilization Chemicals called leukocytosis-inducing factors released by injured cells promote rapid release of neutrophils from red bone marrow. Chemotactic agents are inflammatory chemicals that attract neutrophils to the site of the injury.
Margination is the binding of neutrophils toeach other when complementary CAMSconnect, which concentrates neutrophilsalong the inflamed capillary walls.Diapedesis is the squeezing of neutrophilsthrough the capillary walls en route to theinfection site.
Pus is a mixture of dead or dyingneutrophils, broken down tissue cells, andliving and dead pathogens.
Antimicrobial proteins Antimicrobial proteins, such as complement and interferon, attack microorganisms directly or hinder their ability to reproduce. Complement refers to a group of about 20 plasma proteins that provide a mechanism for destroying foreign substances in the body by enhancing the effectiveness of the body’s defenses.
The classical pathway is a method ofactivating complement, that is linked to theimmune system due to the binding of C1 tothe antigen-antibody complex, in a stepcalled complement fixation.
The alternative pathway to the activation ofcomplement is triggered by interaction ofcertain plasma proteins withpolysaccharides in the cell wall ofpathogenic microorganisms.
When C3b complement binds to the targetscell’s surface, it triggers the insertion ofcomplement proteins called membraneattack complex (MAC) into the cell’smembrane, which opens a hole in themembrane.
Interferons are molecules that diffuse tonearby cells where they stimulate synthesisof PKR, which inhibits protein synthesis ininfected cells.
Fever is abnormally high body temperaturein a systemic response to infection.Pyrogens are chemicals secreted byleukocytes and macrophages that raise thebody’s thermostat in response to infection.
Specific body defenses:Immunity
The immune system is the body’s built inspecific defense system, which stalks andeliminates almost any type of pathogen thatenters the body.Humoral immunity is provided byantibodies present in the fluids, whereascellular immunity is provided by thelymphocytes themselves.
Complete antigens and haptens Antigens are substances that can mobilize the immune system and provoke an immune response, and are considered intruders, or nonself.
Complete antigens exhibit immunogenicity,which is the ability to stimulateproliferation of specific lymphocytes, andreactivity, which is the ability to react withthe products of these reactions (antibodies).
A hapten is an incomplete antigen that isnot immunogenic unless it combines withthe body’s own proteins, in which case animmune response is initiated.
Antigenic determinants Antigenic determinants are active sites on antigens on which antibodies can bind.
MHC proteins Self-antigens are proteins that line the surface of all body cells, and are therefore not considered foreign to the immune system. MHC proteins (class I and II) are glycoproteins that mark a cell as self.
Lymphocytes Immunocompetence is the ability of lymphocytes to recognize a specific antigen by binding to it, and is determined by where in the body the lymphocytes mature. Self-tolerance is the relative lack of responsiveness of lymphocytes to self- antigens.
Antigen-presenting cells Antigen-presenting cells engulf foreign particles and present fragments of these antigens on their own membranes, where they can be recognized by T cells.
Clonal selection anddifferentiation of B cells Clonal selection is the stimulation of B cells, by cross-linked receptor/antigen complexes, to grow and multiply rapidly. A clone is one of many cells that are derived from the same ancestor cell by clonal selection.
Plasma cells are the antibody-secretingeffector cells of the humoral response.Memory cells are long-lived clone cells thatdo not differentiate into plasma cells, butcan mount an almost immediate humoralresponse if the same antigen is encounteredagain.
Immunological memory The primary immune response is the cellular proliferation and differentiation which occurs on the first exposure to a particular antigen.
A secondary immune response occurs whensomeone is re-exposed to the same antigen,and is faster, more prolonged, and moreeffective than the primary response.Memory cells that initiate the secondaryresponse provide immunological memory.
Active and passive humoralimmunity Active humoral immunity is the production of antibodies against encountered antigens. Vaccines induce artificially acquired active immunity, because antigens from weak or dead pathogens are artificially injected into the body.
In passive humoral immunity, the acquiredantibodies are obtained from the serum ofan immune human or animal donor.
Antibodies Antibodies (immunoglobulins) are soluble proteins secreted by activated B cells or by plasma cells in response to an antigen, and are capable of binding specifically with that antigen.
When the four polypeptide chains of anantibody are combined, they form anantibody monomer with two identicalhalves consisting of heavy and light chains,and having a T or Y shape.
A variable and constant region exists oneach of the four chains.Antibodies responding to different antigenshave different variable regions, but theirconstant regions are the same in allantibodies of a given class.
The variable regions of antibodies allcombine to form an antigen-binding siteshaped to fit a specific antigen, whereas theconstant regions determine how theantibody will function in antigenelimination.
Secretory IgA is one of five classes ofimmunoglobulins, and is responsible forpreventing pathogens from gaining entryinto the body.
Somatic recombination is the process ofrecombining gene segments when a B cellbecome immunocompetent, in order to codefor antibodies that are specific to the vastnumber of antigens the body mayencounter.
Antigen-antibody complexes are the resultof the binding of antibodies with theirspecific antigens, and serve to inactivate theinvaders for later destruction by other cells.Complement fixation occurs as a result ofthe binding of antibodies to the antigens oncells, which exposes complement bindingsites on their constant regions.
Neutralization occurs when antibodiesblock specific binding sites on viruses orbacterial exotoxins.Agglutination is clumping of cells as aresult of cross-linking of antibody-antigencomplexes.
Precipitation is the cross-linking of solublemolecules into large complexes thatprecipitate out of solution.Monoclonal antibodies are produced bydescendants of a single cell, and are pureantibody preparations specific for a singleantigenic determinant.
Clonal selection anddifferentiation of T cells Class 1 MHC proteins display fragments of proteins synthesized in the cell from endogenous antigens. Endogenous antigens are foreign proteins that are synthesized within a body cell
Class II MHC proteins are found only onthe surfaces of mature B cells, some T cells,and antigen presenting cells, and are fromexogenous proteins.Exogenous proteins are foreign proteins.
TCRs are T cell antigen receptors.MHC restriction reflects the preference fora specific class of MHC proteins by helperand cytotoxic T cells.The process in which the T cells adhere toand crawl over the surface of other cellsexamining them for antigens is calledimmunologic surveillance.
Costimulatory signals, such as the bindingof macrophage proteins, are required for theproliferation of T cells.Anergy is a state of T cell unresponsivenessto antigens due to binding withoutcostimulatory signals.
Cytokines are chemical mediators involvedin cellular immunity.Lymphokines are soluble glycoproteincytokines released by activated T cells.
Monokines are cytokines secreted bymonokinesT cell proliferation is enhanced by twocytokines that act as costimulators:interleukin 1 is released by macrophagescostimulates bound T cells to liberateinterleukin 2, which is a key growth factor.
Helper T cells are regulatory cells that playa central role in the immune response bystimulating the proliferation of other T cellsand B cell already bound to antigens.
T cell-independent antigens activate B cellswithout the help of the T cells themselves.Most antigens, (T cell-dependent antigens),require T cell costimulation to activate Bcells.
Cytotoxic T cells (killer T cells) are theonly T cells that can directly attack and killother cells.
When a cytotoxic T cell performs a lethalhit, it binds tightly t the target cell andinserts the cytotoxic chemical perforin intothe plasma membrane of the target cell.Some cytotoxic T cells producelymphotoxin, which causes fragmentationof the target cell’s DNA.
Some Tc cells release tumor necrosis factor,which slowly kills the target cell.Another secretion of Tc cells is gammainterferon, which stimulates macrophages tokiller status and indirectly enhances thekilling process.
Suppressor T cells are regulatory cells thatrelease lymphokines to suppress the activityof both T and B cells.Delayed-type hypersensitivity cells appearto promote allergic reactions called delayedhypersensitivity reactions.
Organ transplants andprevention of rejection Autografts are tissue grates transplanted from one body site to another in the same person. Isografts are grafts donated by genetically identical individuals, the only example being identical twins.
Allografts are grafts transplanted fromindividuals that are not genetically identicalby belong to the same species.Xenografts are grafts taken from anotheranimal species.