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Factors V and VIII serve as procofactors purchase zestril 10mg mastercard, which purchase zestril 5 mg with visa, when activated by will reduce blood flow to the damaged area. Platelet-derived growth factor, which stimu- Two additional proteins that are considered part of the blood coagulation cas- lates proliferation of vascular cells, is also cade, protein S and protein C, are regulatory proteins. Only protein C is regulated released into the environment surrounding by proteolytic cleavage, and when activated, is itself a serine protease. The Process of Blood Coagulation Activation of the blood coagulation cascade is triggered by the reaction of plasma The utilization of an active site ser- proteins with the subendothelium at the same time that platelets are adhering to the ine to cleave a peptide bond is subendothelial layer. Historically, two different pathways were discovered, one common to a variety of enzymes dependent on external stimuli (such as blunt trauma, which initiates the extrinsic referred to as serine proteases. Serine pro- pathway) and one using internal stimuli (the intrinsic pathway). As our understand- teases are essential for activating the forma- ing of blood clotting has expanded, it has become obvious that these distinctions are tion of a blood clot from fibrin. Fibrin and no longer correct, because there is overlap between the pathways, but the terms have many of the other proteins involved in blood persisted in the description of the pathways. Thrombin, the serine protease that converts fibrinogen culating Factor VII binds to tissue factor, which autocatalyzes its own activation to to fibrin, has the same aspartate-histidine- Factor VIIa. Factor VIIa then activates Factor X (to Xa) in the extrinsic pathway and serine catalytic triad found in chymotrypsin Factor IX (to IXa) in the intrinsic pathway. Factor IXa, as part of the intrinsic path- and trypsin. Therefore, activation of both the extrinsic and intrin- Thrombin is activated by proteolytic sic pathways result in the conversion of Factor X to Factor Xa. All of these conver- cleavage of its precursor protein, prothrom- sions require access to membranes and calcium; the platelet membrane, which had bin. The sequence of proteolytic cleavages adhered to the damaged site, is used as a scaffold for the activation reactions to leading to thrombin activation requires Fac- occur. The -carboxylated clotting proteins are chelated to membrane surfaces via tor VIII, the blood-clotting protein deficient in electrostatic interactions with calcium and negatively charged phospholipids of the Sloe Klotter. The protein cofactors VIIIa and Va serve as sites for assembling enzyme–cofactor complexes on the platelet surface, thereby accelerating and local- izing the reaction. The result is thrombin formation, which augments its own formation by converting Factors V, VIII, and XI into activated cofactors and CHAPTER 45 / BLOOD PLASMA PROTEINS, COAGULATION AND FIBRINOLYSIS 833 Intrinsic pathway Damaged tissue surface Kallikrein Prekallikrein Extrinsic pathway Trauma XII XIIa XI XIa HMWK PL, Ca PL, Ca IX VIIa VII Tissue factor (III) IXa VIII VIIIa PL, Ca PL, Ca X Xa V a PL, Ca II Prothrombin IIa Thrombin Final common pathway I Ia Fibrinogen Fibrin aggregate (soft clot) XIII XIIIa Cross-linked clot (hard clot) Fig. Activation of clot formation occurs through two separate but interlocking pathways, termed the intrinsic and extrinsic pathways. The intrinsic pathway is activated when plasma proteins react with the exposed subendothelium of the damaged blood vessel. Platelets and vWF bind to the exposed subendothelium, and the platelets, in turn, bind fibrinogen. The extrinsic pathway is activated by tissue factor. The reactions designated by “PL, Ca” are occurring through cofactors bound to phospholipids (PL) on the cell surface in a Ca2 - coordination complex. Factors XIIa, XIa, IXa, VIIa, Xa, and thrombin are serine proteases. Note the positive feedback regulation of thrombin on the activation of proteases earlier in the cascade sequence. Proteins of Blood Coagulation Coagulation Factors Factor Descriptive Name Function/Active Form I Fibrinogen Fibrin II Prothrombin Serine protease III Tissue factor Receptor and cofactor IV Ca 2 Cofactor V Proaccelerin, labile factor Cofactor VII Proconvertin Serine protease VIII Antihemophilia factor A Cofactor IX Antihemophilia factor B, Christmas factor Serine protease X Stuart-Prower factor Serine protease XI Plasma thromboplastin antecedent Serine protease XII Hageman (contact) factor Serine protease XIII Fibrin stabilizing factor Ca2 -dependent transglutaminase Prekallikrein Serine protease High-molecular-weight kininogen Cofactor Regulatory Proteins Thrombomodulin Endothelial cell receptor, binds thrombin Protein C Activated by thrombomodulin-bound thrombin; is a serine protease Protein S cofactor; binds activated protein C 834 SECTION EIGHT / TISSUE METABOLISM The initial activation of prothrom- stimulating platelet degranulation. Note that these factors are in the intrinsic path- bin to thrombin is slow, because way. The intrinsic pathway is thought to sustain the coagulation response initiated the activator cofactors, Factors by the extrinsic pathway. The major substrate of thrombin is fibrinogen, which is VIIIa and Va, are only present in small hydrolyzed to form fibrin monomers that undergo spontaneous polymerization to amounts. However, once a small amount of form the fibrin clot. This is considered a “soft” clot because the fibrin monomers thrombin is activated, it will accelerate its are not cross-linked. Cross-linking requires Factor XIIIa, which is activated by own production by cleaving Factors V and VIII to their active forms.

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Pyruvate is then oxi- dized completely to CO2 by pyruvate dehydrogenase and the TCA cycle order zestril 10mg without prescription. Complete aerobic oxidation of glucose to CO2 can generate approximately 30 to 32 moles of ATP per mole of glucose buy zestril 10mg lowest price. In anaerobic glycolysis, lactate dehydroge- nase oxidizes the NADH generated from glycolysis by reducing pyruvate to lactate (Fig. Because O2 is not required to reoxidize the NADH, the pathway is referred to as anaerobic. The energy yield from anaerobic glycolysis (2 moles of ATP per mole of glucose) is much lower than the yield from aerobic oxidation. The lactate (lactic acid) is released into the blood. Under pathologic conditions that cause hypoxia, tissues may generate enough lactic acid to cause lactic acidemia. In each cell, glycolysis is regulated to ensure that ATP homeostasis is maintained, without using more glucose than necessary. In most cell types, hexokinase (HK), the first enzyme of glycolysis, is inhibited by glucose 6-phosphate (see Fig. Thus, glucose is not taken up and phosphorylated For glucose 6-phosphate and other by a cell unless glucose-6-P enters a metabolic pathway, such as glycolysis or sugar phosphoesters, the phos- glycogen synthesis. The control of glucose-6-P entry into glycolysis occurs at phate group will be denoted with phosphofructokinase-1(PFK-1), the rate-limiting enzyme of the pathway. PFK-1 is allosterically inhibited by ATP and allosterically activated by AMP. AMP increases in the cytosol as ATP is hydrolyzed by energy-requiring reactions. Glycolysis has functions in addition to ATP production. For example, in liver and adipose tissue, this pathway generates pyruvate as a precursor for fatty acid biosynthesis. Glycolysis also provides precursors for the synthesis of compounds such as amino acids and 5-carbon sugar phosphates. Glucose ATP NADH Pyruvate THE WAITING ROOM NADH Lactate Acetyl CoA Lopa Fusor is a 68-year-old woman who is admitted to the hospital emergency room with very low blood pressure (80/40 mm Hg) caused Anaerobic TCA by an acute hemorrhage from a previously diagnosed ulcer of the stom- glycolysis cycle ach. Lopa’s bleeding stomach ulcer has reduced her effective blood volume severely enough to compromise her ability to perfuse (deliver blood to) her tis- Fig. Because there is no net generation of packs of cigarettes per day. Her respiratory rate is rapid and labored, her skin is NADH, there is no need for O2, and, thus, the cold and clammy, and her lips are slightly blue (cyanotic). CHAPTER 22 / GENERATION OF ATP FROM GLUCOSE: GLYCOLYSIS 401 As appropriate emergency measures are taken to stabilize her and elevate her The hematocrit (the percentage of blood pressure, blood is sent for immediate blood typing and cross-matching, so the volume of blood occupied by that blood transfusions can be started. A battery of laboratory tests are ordered, packed red blood cells) and hemo- globin content (g hemoglobin in 100 mL including venous hemoglobin, hematocrit, and lactate levels, and arterial blood pH, blood) are measured to determine whether partial pressures of oxygen (pO2) and carbon dioxide (pCO2), bicarbonate, and oxy- the oxygen-carrying capacity of the blood is gen saturation. Results show that the hemorrhaging and COPD have resulted in adequate. They can be decreased by condi- hypoxemia, with decreased oxygen delivery to her tissues, and both a respiratory tions that interfere with erythropoiesis (syn- and metabolic acidosis. They also can be Otto Shape, a 26-year-old medical student, had gained weight during his decreased during chronic bleeding, but not first sedentary year in medical school. During his second year, he began during immediate acute hemorrhage, if watching his diet, jogging for an hour 4 times each week, and playing ten- interstitial fluid replaces the lost blood vol- nis twice a week. To prepare for the race, ume and dilutes out the red blood cells. The he begins training with wind sprints, bouts of alternately running and walking. The pO2 and oxy- gen saturation determine whether adequate Ivan Applebod is a 56-year-old morbidly obese accountant (see Chapters oxygen is available for tissues. He decided to see his dentist because he felt excruciating pain in his ment of the pCO2 and bicarbonate can dis- teeth when he ate ice cream. He really likes sweets and keeps hard candy tinguish between a metabolic and a respira- in his pocket.

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It has three branches that trans- port general sense impulses (e discount zestril 10mg with visa. Motor fibers dents to use mnemonics (ne-MON-iks) zestril 2.5mg otc, or memory de- to the muscles of mastication (chewing) join the third vices, to remember anatomical lists. It is branches of the trigeminal nerve that a dentist the tradition was that these devices be bawdy. The orig- anesthetizes to work on the teeth without causing pain. The abducens (ab-DU-senz) nerve is another nerve send- longer applies, as a few of the names have been changed. The muscles of facial ex- phrase using the first letter of each cranial nerve? You pression are all supplied by branches from the facial nerve. This nerve also includes special sensory fibers for taste (an- can also check the Internet for sites where medical terior two-thirds of the tongue), and it contains secretory mnemonics are shared. Checkpoint 10-11 How many pairs of cranial nerves are there? The vestibulocochlear (ves-tib-u-lo-KOK-le-ar) nerve car- ries sensory impulses for hearing and equilibrium from the Checkpoint 10-12 The cranial nerves are classified as being inner ear. This nerve was formerly called the auditory or sensory, motor, or mixed. The glossopharyngeal (glos-o-fah-RIN-je-al) nerve con- tains general sensory fibers from the back of the tongue and the pharynx (throat). This nerve also contains sensory Disorders Involving the Cranial fibers for taste from the posterior third of the tongue, se- Nerves cretory fibers that supply the largest salivary gland (parotid), and motor nerve fibers to control the swallow- Destruction of optic nerve (II) fibers may result from in- ing muscles in the pharynx. Certain medications, when used in high doses over long periods, can damage the branch of the vestibu- The nervous system is one of the first systems to develop locochlear nerve responsible for hearing. By the beginning of the third week of de- Injury to a nerve that contains motor fibers causes velopment, the rudiments of the central nervous system paralysis of the muscles supplied by these fibers. Beginning with maturity, the nervous sys- lomotor nerve (III) may be damaged by certain infections tem begins to undergo changes. The brain begins to de- or various poisonous substances. Because this nerve sup- crease in size and weight due to a loss of cells, especially in plies so many muscles connected with the eye, including the cerebral cortex, accompanied by decreases in synapses the levator, which raises the eyelid, injury to it causes a and neurotransmitters. The speed of processing informa- paralysis that usually interferes with eye function. Memory di- Bell palsy is a facial paralysis caused by damage to the minishes, especially for recent events. Changes in the vas- facial nerve (VII), usually on one side of the face. This in- cular system throughout the body with a narrowing of the jury results in distortion of the face because of one-sided arteries (atherosclerosis) reduce blood flow to the brain. Degeneration of vessels increases the likelihood of stroke. Neuralgia (nu-RAL-je-ah) in general means “nerve Much individual variation is possible, however, with pain. Although age nerve is known as trigeminal neuralgia or tic douloureux might make it harder to acquire new skills, tests have (tik du-lu-RU). At first, the pain comes at relatively long shown that practice enhances skill retention. As with intervals, but as time goes on, intervals usually shorten other body systems, the nervous system has vast reserves, 10 while durations lengthen. Treatments include micro- and most elderly people are able to cope with life’s surgery and high-frequency current. Word Anatomy Medical terms are built from standardized word parts (prefixes, roots, and suffixes).

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