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Pathology_Robbins. Cell proliferation is driven by signals provided by growth factors and from the extracellular matrix. Many different growth factors have been described, some of which act on multiple cell types, while others are cell-type specific (Chapter 1). Growth factors are typically produced by cells near the site of damage. The most important sources of these growth factors are macrophages that are activated by the tissue injury, but epithelial and stromal cells also produce some of these factors. Several growth factors bind to ECM proteins and are displayed at the site of tissue injury at high concentrations. All growth factors activate signaling pathways that ultimately induce changes in gene expression that drive cells through the cell cycle and support the biosynthesis of molecules and organelles that are needed for cell division (Chapter 1). In addition to responding to growth factors, cells use integrins to bind to ECM proteins, and signals from the integrins can also stimulate cell


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Pathology_Robbins. that are needed for cell division (Chapter 1). In addition to responding to growth factors, cells use integrins to bind to ECM proteins, and signals from the integrins can also stimulate cell proliferation.


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Pathology_Robbins. In the process of regeneration, proliferation of residual cells is supplemented by development of mature cells from stem cells. In Chapter 1 we introduced the major types of stem cells. In adults, the most important stem cells for regeneration after injury are tissue stem cells. These stem cells live in specialized niches, and it is believed that injury triggers signals in these niches that activate quiescent stem cells to proliferate and differentiate into mature cells that repopulate the injured tissue. Mechanisms of Tissue Regeneration The importance of regeneration in the replacement of injured tissues varies in different types of tissues and with the severity of injury.


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Pathology_Robbins. Mechanisms of Tissue Regeneration The importance of regeneration in the replacement of injured tissues varies in different types of tissues and with the severity of injury. • In epithelia of the intestinal tract and skin, injured cells are rapidly replaced by proliferation of residual cells and differentiation of cells derived from tissue stem cells, providing the underlying basement membrane is intact. The residual epithelial cells produce the growth factors involved in these processes. The newly generated cells migrate to fill the defect created by the injury, and tissue integrity is restored (


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Pathology_Robbins. Fig. 3.23 http://ebooksmedicine.net • Tissue regeneration can occur in parenchymal organs whose cells are capable of proliferation, but with the exception of the liver, this is usually a limited process. Pancreas, adrenal, thyroid, and lung have some regenerative capacity. The surgical removal of a kidney elicits in the remaining kidney a compensatory response that consists of both hypertrophy and hyperplasia of proximal duct cells. The mechanisms underlying this response are not understood, but they likely involve local production of growth factors and interactions of cells with the ECM. The extraordinary capacity of the liver to regenerate has made it a valuable model for studying this process, as described below.


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Pathology_Robbins. Restoration of normal tissue architecture can occur only if the residual tissue is structurally intact, for example after partial surgical resection of the liver. By contrast, if the entire tissue is damaged by infection or inflammation, regeneration is incomplete and is accompanied by scarring. For example, extensive destruction of the liver with collapse of the reticulin framework, as occurs in a liver abscess, leads to scar formation even though the remaining liver cells have the capacity to regenerate. The human liver has a remarkable capacity to regenerate, as demonstrated by its growth after partial hepatectomy, which may be performed for tumor resection or for living-donor hepatic transplantation. The mythologic image of liver regeneration is the regrowth of the liver of Prometheus, which was eaten every day by an eagle sent by Zeus as punishment for stealing the secret of fire, and regrew every night. The reality, although less dramatic, is still quite impressive.


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Pathology_Robbins. Regeneration of the liver occurs by two major mechanisms: proliferation of remaining hepatocytes and repopulation from progenitor cells. Which mechanism plays the dominant role depends on the nature of the injury. Proliferation of hepatocytes following partial hepatectomy. In humans, resection of up to 90% of the liver can be corrected by proliferation of the residual hepatocytes. This process is driven by cytokines such as IL-6 produced by Kupffer cells, and by growth factors such as hepatocyte growth factor (HGF) produced by many cell types.


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Pathology_Robbins. Liver regeneration from progenitor cells. In situations in which the proliferative capacity of hepatocytes is impaired, such as after chronic liver injury or inflammation, progenitor cells in the liver contribute to repopulation. In rodents, these progenitor cells have been called oval cells because of the shape of their nuclei. Some of these progenitor cells reside in specialized niches called canals of Hering, where bile canaliculi connect with larger bile ducts. The signals that drive proliferation of progenitor cells and their differentiation into mature hepatocytes are topics of active investigation. Different tissues consist of continuously dividing cells (epithelia, hematopoietic tissues), normally quiescent cells that are capable of proliferation (most parenchymal organs), and non-dividing cells (neurons, skeletal and cardiac muscle).The regenerative capacity of a tissue depends on the proliferative potential of its constituent cells.


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Pathology_Robbins. Cell proliferation is controlled by the cell cycle, and is stimulated by growth factors and interactions of cells with the extracellular matrix. Regeneration of the liver is a classic example of repair by regeneration. It is triggered by cytokines and growth factors produced in response to loss of liver mass and inflammation. In different situations, regeneration may occur by proliferation of surviving hepatocytes or repopulation from progenitor cells.


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Pathology_Robbins. If repair cannot be accomplished by regeneration alone, it occurs by replacement of the injured cells with connective tissue, leading to the formation of a scar, or by a combination of regeneration of some residual cells and scar formation. As discussed earlier, scarring may happen if the tissue injury is severe or chronic and results in damage to parenchymal cells and epithelia as well as to the connective tissue framework, or if nondividing cells are injured. In contrast to regeneration, which involves the restitution of tissue components, scar formation is a response that “patches” rather than restores the tissue. The term scar is most often used in connection to wound healing in the skin, but also may be used to describe the replacement of parenchymal cells in any tissue by collagen, as in the heart after myocardial infarction. Repair by connective tissue deposition consists of a series of sequential steps that follow tissue injury ( Fig. 3.24


Pathology_Robbins

Pathology_Robbins. Repair by connective tissue deposition consists of a series of sequential steps that follow tissue injury ( Fig. 3.24 Within minutes after injury, a hemostatic plug comprised of platelets (Chapter 4) is formed, which stops bleeding and provides a scaffold for infiltrating inflammatory cells.


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Pathology_Robbins. Inflammation. This step is comprised of the typical acute and chronic inflammatory responses. Breakdown products of complement activation, chemokines released from activated platelets, and other mediators produced at the site of injury function as chemotactic agents to recruit neutrophils and then monocytes during the next 6 to 48 hours. As described earlier, these inflammatory cells eliminate the offending agents, such as microbes that may have entered through the wound, and clear the debris. Macrophages are the central cellular players in the repair process—M1 macrophages clear microbes and necrotic tissue and promote inflammation in a positive feedback loop, and M2 macrophages produce growth factors that stimulate the proliferation of many cell types in the next stage of repair. As the injurious agents and necrotic cells are cleared, the http://ebooksmedicine.net


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Pathology_Robbins. Fig. 3.24 Steps in repair by scar formation: healing of a large wound in the skin. This is an example of healing by second intention. (A) Hemostatic plug and inflammation. (B) Proliferation of epithelial cells; formation of granulation tissue by vessel growth and proliferating fibroblasts. (C) Remodeling to produce the fibrous scar. inflammation resolves; how this inflammatory flame is extinguished in most situations of injury is still not well defined. Cell proliferation. In the next stage, which takes up to 10 days, several cell types, including epithelial cells, endothelial and other vascular cells, and fibroblasts, proliferate and migrate to close the now-clean wound. Each cell type serves unique functions. Epithelial cells respond to locally produced growth factors and migrate over the wound to cover it.


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Pathology_Robbins. Epithelial cells respond to locally produced growth factors and migrate over the wound to cover it. Endothelial and other vascular cells proliferate to form new blood vessels, a process known as angiogenesis. Because of the importance of this process in physiologic host responses and in many pathologic conditions, it is described in more detail later. Fibroblasts proliferate and migrate into the site of injury and lay down collagen fibers that form the scar. The combination of proliferating fibroblasts, loose connective tissue, new blood vessels and scattered chronic inflammatory cells, forms a type of tissue that is unique to healing wounds and is called granulation tissue. This term derives from its pink, soft, granular gross appearance, such as that seen beneath the scab of a skin wound.


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Pathology_Robbins. Remodeling. The connective tissue that has been deposited by fibroblasts is reorganized to produce the stable fibrous scar. This process begins 2 to 3 weeks after injury and may continue for months or years. Healing of skin wounds can be classified into healing by first intention (primary union), referring to epithelial regeneration with minimal scarring, as in well-apposed surgical incisions, and healing by second intention (secondary union), referring to larger wounds that heal by a combination of regeneration and scarring. Because the fundamental processes involved in both types of wound healing represent a continuum from regeneration to scarring, we do not make this distinction in our discussion of the key events in tissue repair.


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Pathology_Robbins. Angiogenesis is the process of new blood vessel development from existing vessels. It is critical in healing at sites of injury, in the development of collateral circulations at sites of ischemia, and in allowing tumors to increase in size beyond the constraints of their original blood supply. Much work has been done to understand the mechanisms of angiogenesis, and therapies have been developed either to augment the process (e.g., to improve blood flow to a heart ravaged by coronary atherosclerosis) or to inhibit it (to frustrate tumor growth or block pathologic vessel growth, as in wet macular degeneration of the eye). Angiogenesis involves sprouting of new vessels from existing ones, and consists of the following steps ( Fig. 3.25 Vasodilation in response to NO and increased permeability induced by VEGF Separation of pericytes from the abluminal surface and breakdown of the basement membrane to allow formation of a vessel sprout


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Pathology_Robbins. Separation of pericytes from the abluminal surface and breakdown of the basement membrane to allow formation of a vessel sprout Migration of endothelial cells toward the area of tissue injury Proliferation of endothelial cells just behind the leading front (“tip”) of migrating cells Recruitment of periendothelial cells (pericytes for small capillaries and smooth muscle cells for larger vessels) to form the mature vessel Suppression of endothelial proliferation and migration and deposition of the basement membrane It has been suggested that endothelial progenitor cells are present in the bone marrow and can be recruited to promote new vessel formation. However, these cells likely play a minor, if any, role in the angiogenesis associated with the healing of most wounds. Leading (”tip”) cell (VEGF, Notch Formation of new vessel ECM Pericyte recruitment Elongation of vascular stalk


Pathology_Robbins

Pathology_Robbins. Leading (”tip”) cell (VEGF, Notch Formation of new vessel ECM Pericyte recruitment Elongation of vascular stalk Fig. 3.25 Angiogenesis. In tissue repair, angiogenesis occurs mainly by the sprouting of new vessels. The steps in the process, and the major signals involved, are illustrated.The newly formed vessel joins up with other vessels (not shown) to form the new vascular bed. The process of angiogenesis involves several signaling pathways, cell–cell interactions, ECM proteins, and tissue enzymes.


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Pathology_Robbins. • Growth factors. VEGFs, mainly VEGF-A (Chapter 1), stimulates both migration and proliferation of endothelial cells, thus initiating the process of capillary sprouting in angiogenesis. It promotes vasodilation by stimulating the production of NO and contributes to the formation of the vascular lumen. Fibroblast growth factors (FGFs), mainly FGF-2, stimulate the proliferation of endothelial cells. They also promote the migration of macrophages and fibroblasts to the damaged area, and stimulate epithelial cell migration to cover epidermal wounds. Newly formed vessels need to be stabilized by the recruitment of pericytes and smooth muscle cells and by the deposition of connective tissue. Multiple growth factors, including PDGF and TGF-β, likely participate in the stabilization process: PDGF recruits smooth muscle cells and TGF-β suppresses endothelial proliferation and migration, and enhances the production of ECM proteins.


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Pathology_Robbins. Notch signaling. Through “cross talk” with VEGF, the Notch signaling pathway regulates the sprouting and branching of new vessels and thus ensures that the new vessels that are formed have the proper spacing to effectively supply the healing tissue with blood. ECM proteins participate in the process of vessel sprouting in angiogenesis, largely through interactions with integrin receptors of endothelial cells and by providing the scaffold for vessel growth. Enzymes in the ECM, notably the matrix metalloproteinases (MMPs), degrade the ECM to permit remodeling and extension of the vascular tube. Newly formed vessels are leaky because of incomplete interendothelial junctions and because VEGF, the growth factor that drives angiogenesis, increases vascular permeability. This leakiness accounts in part for the edema that may persist in healing wounds long after the acute inflammatory response has resolved. Activation of Fibroblasts and Deposition of Connective Tissue


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Pathology_Robbins. Activation of Fibroblasts and Deposition of Connective Tissue The laying down of connective tissue occurs in two steps: (1) migration and proliferation of fibroblasts into the site of injury and (2) deposition of ECM proteins produced by these cells. These processes are orchestrated by locally produced cytokines and growth factors, including PDGF, FGF-2, and TGF-β. The major sources of these factors are inflammatory cells, particularly alternatively activated (M2) macrophages that infiltrate sites of injury.


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Pathology_Robbins. In response to cytokines and growth factors, fibroblasts enter the wound from the edges and migrate toward the center. Some of these cells may differentiate into cells called myofibroblasts, which contain smooth muscle actin and have increased contractile activity, and serve to close the wound by pulling its margins toward the center. Activated fibroblasts and myofibroblasts also increase their synthetic activity and produce connective tissue proteins, mainly collagen, which is the major component of the fully developed scar.


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Pathology_Robbins. TGF-β is the most important cytokine for the synthesis and deposition of connective tissue proteins. It is produced by most of the cells in granulation tissue, including alternatively activated macrophages. The levels of TGF-β in tissues are primarily regulated not by the transcription of the gene but by the post-transcriptional activation of latent TGF-β, the rate of secretion of the active molecule, and factors in the ECM, notably integrins, that enhance or diminish TGF-β activity. In addition, microfibrils made up of fibrillin also regulate the bioavailability of TGF-β (Chapter 6). TGF-β stimulates fibroblast migration and proliferation, increases the synthesis of collagen and fibronectin, and decreases the degradation of ECM by inhibiting metalloproteinases. TGF-β is involved not only in scar formation after injury but also in the development of fibrosis in lung, liver, and kidneys that follows chronic inflammation. TGF-β also has anti-inflammatory effects that serve to limit and


Pathology_Robbins

Pathology_Robbins. in scar formation after injury but also in the development of fibrosis in lung, liver, and kidneys that follows chronic inflammation. TGF-β also has anti-inflammatory effects that serve to limit and terminate inflammatory responses. It does this by inhibiting lymphocyte proliferation and the activity of other leukocytes.


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Pathology_Robbins. As healing progresses, the number of proliferating fibroblasts and new vessels decreases, but the fibroblasts progressively assume a more synthetic phenotype, and hence there is increased deposition of ECM. Collagen synthesis, in particular, is necessary for the healing wound to become strong and mechanically stable. Collagen synthesis by fibroblasts begins early in wound healing (days 3–5) and continues for several weeks, depending on the size of the wound. Net collagen accumulation depends not only on increased synthesis but also on diminished collagen degradation (discussed later). As the scar matures, there is progressive vascular regression, which eventually transforms the highly vascularized granulation tissue into a pale, largely avascular scar. http://ebooksmedicine.net Remodeling of Connective Tissue


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Remodeling of Connective Tissue After the scar is formed, it is remodeled to increase its strength and contract it. Wound strength increases because of cross-linking of collagen and increased size of collagen fibers. In addition, there is a shift of the type of collagen deposited, from type III collagen early in repair to more resilient type I collagen. In well-sutured skin wounds, strength may recover to 70% to 80% of normal skin by 3 months. Wound contraction is initially caused by myofibroblasts and later by cross-linking of collagen fibers.


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Pathology_Robbins. With time, the connective tissue is degraded and the scar shrinks. The degradation of collagens and other ECM components is accomplished by a family of matrix metalloproteinases (MMPs), so called because they are dependent on metal ions (e.g., zinc) for their enzymatic activity. MMPs are produced by a variety of cell types (fibroblasts, macrophages, neutrophils, synovial cells, and some epithelial cells), and their synthesis and secretion are regulated by growth factors, cytokines, and other agents. They include interstitial collagenases, which cleave fibrillar collagen (MMP-1, -2, and -3); gelatinases (MMP-2 and 9), which degrade amorphous collagen and fibronectin; and stromelysins (MMP-3, -10, and -11), which degrade a variety of ECM constituents, including proteoglycans, laminin, fibronectin, and amorphous collagen. Neutrophil elastase, cathepsin G, plasmin, and other serine proteinases can also degrade ECM but are less important in wound remodeling than the MMPs. In addition,


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Pathology_Robbins. and amorphous collagen. Neutrophil elastase, cathepsin G, plasmin, and other serine proteinases can also degrade ECM but are less important in wound remodeling than the MMPs. In addition, activated collagenases can be rapidly inhibited by specific tissue inhibitors of metalloproteinases (TIMPs), produced by most mesenchymal cells. Thus, a balance of MMPs and TIMPs regulates the size and nature of the scar.


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Pathology_Robbins. Granulation tissue is characterized by proliferation of fibroblasts and new thin-walled, delicate capillaries in a loose extracellular matrix, often with admixed inflammatory cells, mainly macrophages ( Fig.3.26A ).This tissue progressively invades the site of injury; the amount of granulation tissue that is formed depends on the size of the tissue deficit created by the wound and the intensity of inflammation. scar or fibrosis in tissues is composed of largely inactive, spindle-shaped fibroblasts, dense collagen, fragments of elastic tissue, and other ECM components (


Pathology_Robbins

Pathology_Robbins. scar or fibrosis in tissues is composed of largely inactive, spindle-shaped fibroblasts, dense collagen, fragments of elastic tissue, and other ECM components ( Fig. 3.26B ). Pathologists often use special stains to identify different protein constituents of scars and fibrotic tissues.The trichrome stain detects collagen fibers, and the elastin stain identifies delicate fibers of elastin, which is the major component of pliable elastic tissue. (The trichrome actually contains three stains—hence its name—that stain red cells orange, muscle red, and collagen blue.) Another extracellular matrix protein that makes up the connective tissue stroma of normal organs and is present in early scars is reticulin, which is composed of type III collagen, and it too can be identified with a special stain.


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Pathology_Robbins. REPAIR BY SCAR FORMATION progressively assume a more synthetic phenotype, and hence there is increased deposition of ECM. Collagen synprogressively assume a more synthetic phenotype, and hence there is increased deposition of ECM. Collagen syn • Repair occurs by deposition of connective tissue and scar formation if the injured tissue is not capable of regeneration or if the structural framework is damaged and cannot support regeneration. Fig. 3.26 (A) Granulation tissue showing numerous blood vessels, edema, and a loose extracellular matrix containing occasional inflammatory cells. Collagen is stained blue by the trichrome stain; minimal mature collagen can be seen at this point. (B) Trichrome stain of mature scar, showing dense collagen (stained blue) and scattered vascular channels. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The main steps in repair by scarring are clot formation, inflammation, angiogenesis and formation of granulation tissue, migration and proliferation of fibroblasts, collagen synthesis, and connective tissue remodeling. Macrophages are critical for orchestrating the repair process, by eliminating offending agents and producing cytokines and growth factors that stimulate the proliferation of the cell types involved in repair. TGF-β is a potent fibrogenic agent; ECM deposition depends on the balance among fibrogenic agents, matrix metalloproteinases (MMPs) that digest ECM, and the tissue inhibitors of MMPs (TIMPs). Tissue repair may be impaired by a variety of factors that reduce the quality or adequacy of the reparative process. Factors that interfere with healing may be extrinsic (e.g., infection) or intrinsic to the injured tissue, and systemic or local:


Pathology_Robbins

Pathology_Robbins. Infection is one of the most important causes of delayed healing; it prolongs inflammation and potentially increases the local tissue injury. Diabetes is a metabolic disease that compromises tissue repair for many reasons (Chapter 24), and is an important systemic cause of abnormal wound healing. Nutritional status has profound effects on repair; protein malnutrition and vitamin C deficiency, for example, inhibit collagen synthesis and retard healing. Glucocorticoids (steroids) have well-documented anti-inflammatory effects, and their administration may result in weak scars because they inhibit TGF-β production and diminish fibrosis. In some instances, however, the anti-inflammatory effects of glucocorticoids are desirable. For example, in corneal infections, glucocorticoids may be prescribed (along with antibiotics) to reduce the likelihood of opacity due to collagen deposition.


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Pathology_Robbins. Mechanical factors such as increased local pressure or torsion may cause wounds to pull apart (dehisce). Poor perfusion, resulting either from arteriosclerosis and diabetes or from obstructed venous drainage (e.g., in varicose veins), also impairs healing. Foreign bodies such as fragments of steel, glass, or even bone impede healing. The type and extent of tissue injury affects the subsequent repair. Complete restoration can occur only in tissues composed of cells capable of proliferating; even then, extensive injury will probably result in incomplete tissue regeneration and at least partial loss of function. Injury to tissues composed of nondividing cells must inevitably result in scarring; such is the case with healing of a myocardial infarct.


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Pathology_Robbins. The location of the injury and the character of the tissue in which the injury occurs also are important. For example, in inflammation arising in tissue spaces (e.g., pleural, peritoneal, synovial cavities), small exudates may be resorbed and digested by the proteolytic enzymes of leukocytes, resulting in resolution of the inflammation and restoration of normal tissue architecture. However, when the exudate is too large to be fully resorbed it undergoes organization, a process during which granulation tissue grows into the exudate, and a fibrous scar ultimately forms. Clinical Examples of Abnormal Wound Healing and Scarring Complications in tissue repair can arise from abnormalities in any of the basic components of the process, including deficient scar formation, excessive formation of the repair components, and formation of contractures. Defects in Healing: Chronic Wounds


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Pathology_Robbins. Defects in Healing: Chronic Wounds These are seen in numerous clinical situations, as a result of local and systemic factors. The following are some common examples. Fig. 3.27A ) develop most often in elderly people as a result of chronic venous hypertension, which may be caused by severe varicose veins or congestive heart failure. Deposits of iron pigment (hemosiderin) are common, resulting from red cell breakdown, and there may be accompanying chronic inflammation. These ulcers fail to heal because of poor delivery of oxygen to the site of the ulcer. Fig. 3.27B ) develop in individuals with atherosclerosis of peripheral arteries, especially associated with diabetes. The ischemia results in atrophy and then necrosis of the skin and underlying tissues. These lesions can be quite painful.


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Pathology_Robbins. Fig. 3.27C ) are areas of skin ulceration and necrosis of underlying tissues caused by prolonged compression of tissues against a bone, for example, in bedridden, immobile elderly individuals with numerous morbidities. The lesions are caused by mechanical pressure and local ischemia. Fig. 3.27D ) affect the lower extremities, particularly the feet. Tissue necrosis and failure to heal are the result of small vessel disease causing ischemia, neuropathy, systemic metabolic abnormalities, and secondary infections. Histologically, these lesions are characterized by epithelial ulceration ( Fig. 3.27E ) and extensive granulation tissue in the underlying dermis ( Fig. 3.27F In some cases failure of healing may lead to dehiscence (wound rupture). Although not common, this occurs most frequently after abdominal surgery and is a result of increased abdominal pressure, such as may occur with vomiting, coughing, or ileus.


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Pathology_Robbins. Excessive formation of the components of the repair process can give rise to hypertrophic scars and keloids. The accumulation of excessive amounts of collagen may result in a raised scar known as a hypertrophic scar. These often grow rapidly and contain abundant myofibroblasts, but they tend to regress over several months ( Fig. 3.28A ). Hypertrophic scars generally develop after thermal or traumatic injury that involves the deep layers of the dermis. If the scar tissue grows beyond the boundaries of the http://ebooksmedicine.net


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Pathology_Robbins. Fig. 3.27 Chronic wounds illustrating defects in wound healing. (A–D) External appearance of skin ulcers. repair and regeneration: mechanisms, signaling, and translation, Sci Transl Med 6:265, 2014.) (A) Venous leg ulcer; (B) arterial ulcer, with more extensive tissue necrosis; (C) diabetic ulcer; and (D) pressure sore. (E–F) Histologic appearance of a diabetic ulcer. (E) ulcer crater; (F) chronic inflammation and granulation (From Eming SA, Margin P, Tomic-Canic M: Wound tissue. original wound and does not regress, it is called a keloid ( Fig. 3.28B ). Certain individuals seem to be predisposed to keloid formation, particularly those of African descent.


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Pathology_Robbins. original wound and does not regress, it is called a keloid ( Fig. 3.28B ). Certain individuals seem to be predisposed to keloid formation, particularly those of African descent. Exuberant granulation is another deviation in wound healing characterized by the formation of excessive amounts of granulation tissue, which protrudes above the level of the surrounding skin and blocks reepithelialization (this process has been called, with more literary fervor, proud flesh). Excessive granulation must be removed by cautery or surgical excision to permit restoration of epithelial continuity. Rarely, incisional scars or traumatic injuries may be followed by exuberant proliferation of fibroblasts and other connective tissue elements that may, in fact, recur after excision. Called desmoids, or aggressive fibromatoses, these neoplasms lie at the gray zone of benign and malignant low-grade tumors.


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Pathology_Robbins. Wound contraction is an important part of the normal healing process. An exaggeration of this process gives rise to contracture and results in deformities of the wound and the surrounding tissues. Contractures are particularly prone to develop on the palms, the soles, and the anterior aspect of the thorax. Contractures are commonly seen after serious burns and can compromise the movement of joints. The term fibrosis is used to denote the excessive deposition of collagen and other ECM components in a tissue. The terms scar and fibrosis may be used interchangeably, but fibrosis most often refers to the abnormal deposition of collagen that occurs in internal organs in chronic diseases. The basic mechanisms of fibrosis are the same as those of scar formation in the skin during tissue repair. Fibrosis is a pathologic process induced by persistent injurious stimuli such as chronic infections and immunologic reactions, and is typically associated with loss of tissue ( Fig.


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Pathology_Robbins. Fig. 3.29 ). It may be responsible for substantial organ dysfunction and even organ failure. As discussed earlier, the major cytokine involved in fibrosis is TGF-β. The mechanisms that lead to increased TGF-β activity in fibrosis are not precisely known, but cell death by necrosis or apoptosis and the production of ROS seem to be important triggers, regardless of the tissue. The cells that produce collagen in response to TGF-β stimulation may vary depending on the tissue. In most organs, such as in the lung and kidney, myofibroblasts are the main source of collagen, but stellate cells are the major collagen producers in liver cirrhosis. http://ebooksmedicine.net Fig. 3.28 Clinical examples of excessive scarring and collagen deposition.


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Pathology_Robbins. http://ebooksmedicine.net Fig. 3.28 Clinical examples of excessive scarring and collagen deposition. (A) Hypertrophic scar. (B) Keloid. (C) Microscopic appearance of a keloid. Note the thick connective tissue deposition in the dermis. (A–B from Eming SA, Margin P, Tomic-Canic M: Wound repair and regeneration: mechanisms, signaling, and translation, Sci Transl Med 6:265, 2014, p. 2.) Fibrotic disorders include diverse chronic and debilitating diseases such as liver cirrhosis, systemic sclerosis (scleroderma), fibrosing diseases of the lung (idiopathic pulmonary fibrosis, pneumoconioses, and drug-or radiation-induced pulmonary fibrosis), end-stage kidney disease, and constrictive pericarditis. These conditions are discussed in the relevant chapters later in the book. Because fibrosis is the major cause of morbidity and death in these conditions, there is great interest in the development of anti-fibrotic drugs.


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Pathology_Robbins. The main phases of cutaneous wound healing are inflammation, formation of granulation tissue, and ECM remodeling. Cutaneous wounds can heal by primary union (first intention) or secondary union (secondary intention); secondary healing involves more extensive scarring and wound contraction. Tissue injury, loss of epithelial integrity Fig. 3.29 Mechanisms of fibrosis. Persistent tissue injury leads to chronic inflammation and loss of tissue architecture. Cytokines produced by macrophages and other leukocytes stimulate the migration and proliferation of fibroblasts and myofibroblasts and the deposition of collagen and other extracellular matrix proteins. The net result is replacement of normal tissue by fibrosis. Wound healing can be altered by many conditions, particularly infection and diabetes; the type, volume, and location of the injury are important factors that influence the healing process. Excessive production of ECM can cause keloids in the skin.


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Pathology_Robbins. Excessive production of ECM can cause keloids in the skin. Persistent stimulation of collagen synthesis in chronic inflammatory diseases leads to tissue fibrosis, often with extensive loss of the tissue and functional impairment. Alitalo K: The lymphatic vasculature in disease, Nat Med 17:1371– 1380, 2011. [An excellent review of the cell biology of lymphatic vessels, their functions in immune and inflammatory reactions, and their roles in inflammatory, neoplastic, and other diseases.] Dennis EA, Norris PC: Eicosanoid storm in infection and inflammation, Nat Rev Immunol 15:511, 2015. [A review of the proand antiinflammatory activities of eicosanoids.] Duffield JS, Lupher M, Thannickal VJ, et al: Host responses in tissue repair and fibrosis, Ann Rev Pathol Mech Dis 8:241, 2013. [An overview of the cellular mechanisms of fibrosis, with an emphasis on the role of the immune system in fibrotic reactions to chronic infections.]


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Pathology_Robbins. Eming SA, Martin P, Tomic-Canic M: Wound repair and regeneration: mechanisms, signaling, and translation, Sci Transl Med 6:265r6, 2014. [A modern review of host responses that contribute to tissue repair.] Flannagan RS, Jaumouillé V, Grinstein S: The cell biology of phagocytosis, Ann Rev Pathol Mech Dis 7:61–98, 2012. [A modern discussion of the receptors involved in phagocytosis, the molecular control of the process, and the biology and functions of phagosomes.] Friedman SL, Sheppard D, Duffield JS, et al: Therapy for fibrotic diseases: nearing the starting line, Sci Transl Med 5:167sr1, 2013. [An excellent review of the current concepts of the pathogenesis of fibrosis, emphasizing the roles of different cell populations and the extracellular matrix, and the potential for translating basic knowledge to the development of new therapies.]


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Pathology_Robbins. Gabay C, Lamacchia C, Palmer G: IL-1 pathways in inflammation and human diseases, Nat Rev Rheumatol 6:232, 2010. [An excellent review of the biology of IL-1 and the therapeutic targeting of this cytokine in inflammatory diseases.] Hubmacher D, Apte SS: The biology of the extracellular matrix: novel insights, Curr Opin Rheumatol 25:65–70, 2013. [A brief review of the structural and biochemical properties of the ECM.] Kalliolias GD, Ivashkiv LB: TNF biology, pathogenic mechanisms and emerging therapeutic strategies, Nat Rev Rheumatol 12:49, 2016. [An excellent review of TNF and its signaling pathways, and the development and clinical efficacy of TNF inhibitors.] Khanapure SP, Garvey DS, Janero DR, et al: Eicosanoids in inflammation: biosynthesis, pharmacology, and therapeutic frontiers, Curr Top Med Chem 7:311, 2007. [A summary of the properties of this important class of inflammatory mediators.]


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Pathology_Robbins. Kolaczkowska E, Kubes P: Neutrophil recruitment and function in health and inflammation, Nat Rev Immunol 13:159–175, 2013. [An excellent review of neutrophil generation, recruitment, functions and fates, and their roles in different types of inflammatory reactions.] Kopp JL, Grompe M, Sander M: Stem cell versus plasticity in liver and pancreas regeneration, Nat Cell Biol 18:238, 2016. [An excellent review of the relative contributions of parenchymal cells and stem cells to organ regeneration.] Mayadas TN, Cullere X, Lowell CA: The multifaceted functions of neutrophils, Ann Rev Pathol Mech Dis 9:181, 2014. [An excellent review of neutrophil biology.] McAnully RJ: Fibroblasts and myofibroblasts: their source, function, and role in disease, Int J Biochem Cell Biol 39:666, 2007. [A discussion of the two major types of stroma cells and their roles in tissue repair and fibrosis.]


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Pathology_Robbins. Nathan C, Ding A: Nonresolving inflammation, Cell 140:871, 2010. [A discussion of the abnormalities that lead to chronic inflammation.] Okin D, Medzhitov R: Evolution of inflammatory diseases, Curr Biol 22:R733–R740, 2012. [An interesting conceptual discussion of the balance between the high potential cost and benefit of the inflammatory response and how this balance may be disturbed by environmental changes, accounting for the association between inflammation and many of the diseases of the modern world.] Page-McCaw A, Ewald AJ, Werb Z: Matrix metalloproteinases and the regulation of tissue remodelling, Nat Rev Mol Cell Biol 8:221, 2007. [A review of the function of matrix modifying enzymes in tissue repair.]


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Pathology_Robbins. Ricklin D, Lambris JD: Complement in immune and inflammatory disorders, J Immunol 190:3831–3838, 3839–3847, 2013. [Two companion articles on the biochemistry and biology of the complement system, and the development of therapeutic agents to alter complement activity in disease.] Rock KL, Latz E, Ontiveros F, et al: The sterile inflammatory response, Annu Rev Immunol 28:321–342, 2010. [An excellent discussion of how the immune system recognizes necrotic cells and other noninfectious harmful agents.] Romito A, Cobellis G: Pluripotent stem cells: current understanding and future directions, Stem Cells Int 2016. [Epub 2015] [A cogent summary of endogenous and induced pluripotent stem cells.] Schmidt S, Moser M, Sperandio M: The molecular basis of leukocyte recruitment and its deficiencies, Mol Immunol 55:49–58, 2013. [A review of the mechanisms of leukocyte recruitment and leukocyte adhesion deficiencies.]


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Pathology_Robbins. Sica A, Mantovani A: Macrophage plasticity and polarization: in vivo veritas, J Clin Invest 122:787–795, 2012. [An excellent review of macrophage subpopulations, their generation, and their roles in inflammation, infections, cancer, and metabolic disorders.] Stappenbeck TS, Miyoshi H: The role of stromal stem cells in tissue regeneration and wound repair, Science 324:1666, 2009. [An excellent review of the role of tissue stem cells in repair.] Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, et al: The pathogenesis of sepsis, Ann Rev Pathol Mech Dis 6:19, 2011. [A discussion of the current concepts of pathogenic mechanisms in sepsis and septic shock.] Welti J, Loges S, Dimmeler S, et al: Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer, J Clin Invest 123:3190, 2013. [A review of new advances in elucidating the stimuli and control of angiogenesis, and the development of therapies targeting the process.]


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Pathology_Robbins. Zlotnik A, Yoshie O: The chemokine superfamily revisited, Immunity 36:705–716, 2012. [An excellent update on the classification, functions, and clinical relevance of chemokines and their receptors.] http://ebooksmedicine.net studentconsult.com Hemodynamic Disorders, Thromboembolism, and Shock Pathogenesis of Septic Shock Stages of Shock


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Pathology_Robbins. Pathogenesis of Septic Shock Stages of Shock The health of cells and tissues depends on the circulation of blood, which delivers oxygen and nutrients and removes wastes generated by cellular metabolism. Under normal conditions, as blood passes through capillary beds, proteins in the plasma are retained within the vasculature and there is little net movement of water and electrolytes into the tissues. This balance is often disturbed by pathologic conditions that alter endothelial function, increase vascular hydrostatic pressure, or decrease plasma protein content, all of which promote edema—the accumulation of fluid in tissues resulting from a net movement of water into extravascular spaces. Depending on its severity and location, edema may have minimal or profound effects. In the lower extremities, it may only make one’s shoes feel snugger after a long sedentary day; in the lungs, however, edema fluid can fill alveoli, causing life-threatening hypoxia.


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Pathology_Robbins. The structural integrity of blood vessels is frequently compromised by trauma. Hemostasis is the process of blood clotting that prevents excessive bleeding after blood-vessel damage. Inadequate hemostasis may result in hemorrhage, which can compromise regional tissue perfusion and, if massive and rapid, may lead to hypotension, shock, and death. Conversely, inappropriate clotting (thrombosis) or migration of clots (embolism) can obstruct blood vessels, potentially causing ischemic cell death (infarction). Indeed, thromboembolism lies at the heart of three major causes of morbidity and death in developed countries: myocardial infarction, pulmonary embolism (PE), and cerebrovascular accident (stroke). With this as a preface, we begin our discussion of hemodynamic disorders with conditions that increase tissue blood volumes.


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Pathology_Robbins. Hyperemia and congestion both refer to an increase in blood volume within a tissue, but have different underlying mechanisms. Hyperemia is an active process resulting from arteriolar dilation and increased blood inflow, as occurs at sites of inflammation or in exercising skeletal muscle. Hyperemic tissues are redder than normal because of engorgement with oxygenated blood. Congestion is a passive process resulting from impaired outflow of venous blood from a tissue. It can occur systemically, as in cardiac failure, or locally as a consequence of an isolated venous obstruction. Congested tissues have an abnormal blue-red color (cyanosis) that stems from the accumulation of deoxygenated hemoglobin in the affected area. In long-standing chronic congestion, inadequate tissue perfusion and persistent hypoxia may lead to parenchymal cell death and secondary tissue fibrosis, and the elevated intravascular pressures may cause edema or sometimes rupture capillaries, producing focal


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Pathology_Robbins. and persistent hypoxia may lead to parenchymal cell death and secondary tissue fibrosis, and the elevated intravascular pressures may cause edema or sometimes rupture capillaries, producing focal hemorrhages.


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Pathology_Robbins. MORPHOLOGYCutsurfacesofhyperemicorcongestedtissuesfeelwetandtypicallyoozeblood.Onmicroscopicexamination,acute pulmonary congestion ismarkedbyblood-engorgedalveolarcapillariesandvariabledegreesofalveolarseptaledemaandintraalveolarhemorrhage.Inchronic pulmonary congestion, theseptabecomethickenedandfibrotic,andthealveolarspacescontainnumerousmacrophagesladenwithhemosiderin(“heartfailurecells”)derivedfromphagocytosedredcells.Inacute http://ebooksmedicine.net Fig. 4.1 Liverwithchronicpassivecongestionandhemorrhagicnecrosis.


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Pathology_Robbins. Fig. 4.1 Liverwithchronicpassivecongestionandhemorrhagicnecrosis. (A)Inthisautopsyspecimen,centralareasareredandslightlydepressedcomparedwiththesurroundingtanviableparenchyma,creating“nutmegliver”(socalledbecauseitresemblesthecutsurfaceofanutmeg).(B)Microscopicpreparationshowscentrilobularhepaticnecrosiswithhemorrhageandscatteredinflammatorycells.(Courtesy of Dr. James Crawford.) hepatic congestion, thecentralveinandsinusoidsaredistendedwithblood,andtheremayevenbenecrosisofcentrallylocatedhepatocytes.Theperiportalhepatocytes,betteroxygenatedbecauseoftheirproximitytohepaticarterioles,experiencelessseverehypoxiaandmaydeveloponlyreversiblefattychange.Inchronic passive congestion of the liver, thecentralregionsofthehepaticlobules,viewedongrossexamination,arered-brownandslightlydepressed(owingtocellloss)andareaccentuatedagainstthesurroundingzonesofuncongestedtan,sometimesfatty,liver(nutmeg liver) (


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Pathology_Robbins. Fig.4.1A ).Microscopicfindingsincludecentrilobularhepatocytenecrosis,hemorrhage,andhemosiderin-ladenmacrophages( Fig.4.1B Approximately 60% of lean body weight is water, two-thirds of which is intracellular. Most of the remaining water is found in extracellular compartments in the form of interstitial fluid; only 5% of the body’s water is in blood plasma. As noted earlier, edema is an accumulation of interstitial fluid within tissues. Extravascular fluid can also collect in body cavities and such accumulations are often referred to collectively as effusions. Examples include effusions in the pleural cavity (hydrothorax), the pericardial cavity (hydropericardium), or the peritoneal cavity (hydroperitoneum, or ascites). Anasarca is severe, generalized edema marked by profound swelling of subcutaneous tissues and accumulation of fluid in body cavities.


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Pathology_Robbins. Table 4.1 lists the major causes of edema. The mechanisms of inflammatory edema are largely related to increased vascular permeability and are discussed in Chapter 3; the noninflammatory causes are described in the following discussion. Fluid movement between the vascular and interstitial spaces is governed mainly by two opposing forces—the vascular hydrostatic pressure and the colloid osmotic pressure produced by plasma proteins. Normally, the outflow of fluid produced by hydrostatic pressure at the arteriolar end of the microcirculation is nearly balanced by inflow at the venular end owing to slightly elevated osmotic pressure; hence there is only a small net outflow of fluid into the interstitial space, which is drained by lymphatic vessels. Either increased hydrostatic pressure or diminished colloid osmotic pressure causes increased movement of water into the interstitium (


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Pathology_Robbins. Fig. 4.2 ). This in turn increases the tissue’s hydrostatic pressure, and eventually a new equilibrium is achieved. Excess edema fluid is removed by lymphatic drainage and is returned to the bloodstream by way of the thoracic duct ( Fig. 4.2 The edema fluid that accumulates in the setting of increased hydrostatic pressure or reduced intravascular Table 4.1 Causes of Edema CongestiveheartfailureConstrictivepericarditisAscites(livercirrhosis)VenousobstructionorcompressionThrombosisExternalpressure(e.g.,mass)Lowerextremityinactivitywithprolongeddependency DatafromLeafA,CotranRS:Renal pathophysiology, ed3,NewYork,1985,OxfordUniversityPress,p146. http://ebooksmedicine.net


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Pathology_Robbins. DatafromLeafA,CotranRS:Renal pathophysiology, ed3,NewYork,1985,OxfordUniversityPress,p146. http://ebooksmedicine.net Fig. 4.2 Factorsinfluencingfluidmovementacrosscapillarywalls.Capillaryhydrostaticandosmoticforcesarenormallybalancedsothereislittlenetmovementoffluidintotheinterstitium.However,increasedhydrostaticpressureordiminishedplasmaosmoticpressureleadstoextravascularfluidaccumulation(edema).Tissuelymphaticsdrainmuchoftheexcessfluidbacktothecirculationbywayofthethoracicduct;however,ifthecapacityforlymphaticdrainageisexceeded,tissueedemaresults. colloid typically is a protein-poor transudate; by contrast, because of increased vascular permeability, inflammatory edema fluid is a protein-rich exudate with a high specific gravity. The usual cutoffs for specific gravity (<1.012 for transudates and >1.020 for exudates) illustrate the point but are not clinically useful. We will now discuss the various causes of edema.


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Pathology_Robbins. Increases in hydrostatic pressure are mainly caused by disorders that impair venous return. Local increases in intravascular pressure caused, for example, by deep venous thrombosis in the lower extremity can cause edema restricted to the distal portion of the affected leg. Generalized increases in venous pressure, with resultant systemic edema, occur most commonly in congestive heart failure (Chapter 11). Fig. 4.3 illustrates the interlocking mechanisms that underlie generalized edema resulting from cardiac, renal, and hepatic failure. Several factors increase venous hydrostatic pressure in patients with congestive heart failure (


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Pathology_Robbins. Fig. 4.3 ). The reduced cardiac output leads to systemic venous congestion and resultant increase in capillary hydrostatic pressure. At the same time reduction in cardiac output results in hypoperfusion of the kidneys, triggering the renin-angiotensin-aldosterone axis and inducing sodium and water retention (secondary hyperaldosteronism). In patients with normal heart function, this adaptation increases cardiac filling and cardiac output, thereby improving renal perfusion. However, the failing heart often cannot increase its cardiac output in response to the compensatory increases in blood volume. Instead, a vicious cycle of fluid retention, increased venous hydrostatic pressures, and worsening edema ensues. Unless cardiac output is restored or renal water retention is reduced (e.g., by salt restriction or treatment with diuretics or aldosterone antagonists), this downward spiral continues. Because secondary hyperaldosteronism is a common feature of generalized edema, salt


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Pathology_Robbins. (e.g., by salt restriction or treatment with diuretics or aldosterone antagonists), this downward spiral continues. Because secondary hyperaldosteronism is a common feature of generalized edema, salt restriction, diuretics, and aldosterone antagonists also are of value in the management of generalized edema resulting from non-cardiac causes.


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Pathology_Robbins. Reduction of plasma albumin concentrations leads to decreased colloid osmotic pressure of the blood and loss of fluid from the circulation. Under normal circumstances, albumin accounts for almost half of the total plasma protein. Therefore, conditions in which albumin is either lost from the circulation or synthesized in inadequate amounts are common causes of reduced plasma osmotic pressure. Nephrotic syndrome is the most important cause of albumin loss from the blood. In diseases that are characterized by nephrotic syndrome (Chapter 14), the glomerular capillaries become leaky, leading to the loss of albumin (and other plasma proteins) in the urine and the development of generalized edema. Reduced albumin synthesis occurs in the setting of severe liver disease (e.g., cirrhosis) (Chapter 16) and protein malnutrition (Chapter 8). Regardless of cause, low albumin levels lead in a stepwise fashion to edema, reduced intravascular volume, renal hypo-perfusion, and secondary


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Pathology_Robbins. (Chapter 16) and protein malnutrition (Chapter 8). Regardless of cause, low albumin levels lead in a stepwise fashion to edema, reduced intravascular volume, renal hypo-perfusion, and secondary hyperaldosteronism. Unfortunately, increased salt and water retention by the kidney not only fails to correct the plasma volume deficit but also exacerbates the edema, because the primary defect—low serum protein—persists.


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Pathology_Robbins. Edema may result from lymphatic obstruction that compromises resorption of fluid from interstitial spaces. Impaired lymphatic drainage and consequent lymph-edema usually results from a localized obstruction caused by an inflammatory or neoplastic condition. For example, the parasitic infection filariasis can cause massive edema of the lower extremity and external genitalia (so-called “elephantiasis”) by producing inguinal lymphatic and lymph node fibrosis. Infiltration and obstruction of superficial lymphatics by breast cancer may cause edema of the overlying skin; the characteristic finely pitted appearance of the skin of the affected breast is called peau d’orange (orange peel). Lymphedema also may occur as a complication of therapy. One relatively common setting for this clinical entity is in women with breast cancer who undergo axillary lymph node resection and/or irradiation, both of which can disrupt and obstruct lymphatic drainage, resulting in severe lymphedema of the arm.


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Pathology_Robbins. HEART FAILURE RENAL FAILURE MALNUTRITION, HEPATIC SYNTHESIS, NEPHROTIC SYNDROME Capillary hydrostatic pressure Renal blood flow Activation of the renin-angiotensin-aldosterone system Retention of Na+ and H2O EDEMA Blood volume Plasma albumin Plasma osmotic pressure Fig. 4.3 Pathwaysleadingtosystemicedemaresultingfromheartfailure,renalfailure,orreducedplasmaosmoticpressure. http://ebooksmedicine.net Excessive retention of salt (and its obligate associated water) can lead to edema by increasing hydrostatic pressure (because of expansion of the intravascular volume) and reducing plasma osmotic pressure. Excessive salt and water retention are seen in a wide variety of diseases that compromise renal function, including poststreptococcal glomerulonephritis and acute renal failure (Chapter 14).


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Pathology_Robbins. The effects of edema vary, ranging from merely annoying to rapidly fatal. Subcutaneous edema is important to recognize primarily because it signals potential underlying cardiac or renal disease; however, when significant, it also can impair wound healing and the clearance of infections. Pulmonary edema is a common clinical problem. It is seen most frequently in the setting of left ventricular failure, but also may occur in renal failure, acute respiratory distress syndrome (Chapter 11), and inflammatory and infectious disorders of the lung. It can cause death by interfering with normal ventilatory function; besides impeding oxygen diffusion, alveolar edema fluid also creates a favorable environment for infections. Brain edema is life threatening; if the swelling is severe, the brain can herniate (extrude) through the foramen magnum. With increased intracranial


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Pathology_Robbins. Edemaresultsfromthemovementoffluidfromthevasculatureintotheinterstitialspaces;thefluidmaybeproteinpoor(transudate)orproteinrich(exudate). Edemamaybecausedby: Increasedhydrostaticpressure(e.g.,heartfailure) Increasedvascularpermeability(e.g.,inflammation) Decreasedsynthesis(e.g.,liverdisease,proteinmalnutrition) Increasedloss(e.g.,nephroticsyndrome) Lymphaticobstruction(e.g.,inflammationorneoplasia) Sodiumretention(e.g.,renalfailure) pressure, the brain stem vascular supply can be compressed, leading to death due to injury to the medullary centers controlling respiration and other vital functions (Chapter 23).


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Pathology_Robbins. Hemorrhage, defined as the extravasation of blood from vessels, is most often the result of damage to blood vessels or defective clot formation. As described earlier, capillary bleeding can occur in chronically congested tissues. Trauma, atherosclerosis, or inflammatory or neoplastic erosion of a vessel wall also may lead to hemorrhage, which may be extensive if the affected vessel is a large vein or artery. The risk of hemorrhage (often after a seemingly insignificant injury) is increased in a wide variety of clinical disorders collectively called hemorrhagic diatheses. These have diverse causes, including inherited or acquired defects in vessel walls, platelets, or coagulation factors, all of which must function properly to ensure homeostasis. These are discussed in the next section. Here we focus on clinical features of hemorrhages, regardless of the cause. Hemorrhage may be manifested by different appearances and clinical consequences.


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Pathology_Robbins. Hemorrhage may be manifested by different appearances and clinical consequences. • Hemorrhage may be external or accumulate within a tissue as a hematoma, which ranges in significance from trivial (e.g., a bruise) to fatal (e.g., a massive retroperitoneal hematoma resulting from rupture of a dissecting aortic aneurysm) (Chapter 10). Large bleeds into body cavities are described variously according to location— hemothorax, hemopericardium, hemoperitoneum, or hemarthrosis(in joints). Extensive hemorrhages can occasionally result in jaundice from the massive breakdown of red cells and hemoglobin. http://ebooksmedicine.net Fig. 4.4 (A)Punctatepetechialhemorrhagesofthecolonicmucosa,aconsequenceofthrombocytopenia.(B)Fatalintracerebralhemorrhage. Petechiae are minute (1 to 2 mm in diameter) hemorrhages into skin, mucous membranes, or serosal surfaces (


Pathology_Robbins

Pathology_Robbins. Petechiae are minute (1 to 2 mm in diameter) hemorrhages into skin, mucous membranes, or serosal surfaces ( Fig. 4.4A ); causes include low platelet counts (thrombocytopenia), defective platelet function, and loss of vascular wall support, as in vitamin C deficiency (Chapter 8). Purpura are slightly larger (3 to 5 mm) hemorrhages. Purpura can result from the same disorders that cause petechiae, as well as trauma, vascular inflammation (vasculitis), and increased vascular fragility. Ecchymoses are larger (1 to 2 cm) subcutaneous hematomas (colloquially called bruises). Extravasated red cells are phagocytosed and degraded by macrophages; the characteristic color changes of a bruise result from the enzymatic conversion of hemoglobin (red-blue color) to bilirubin (blue-green color) and eventually hemosiderin (golden-brown).


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Pathology_Robbins. The clinical significance of any particular hemorrhage depends on the volume of blood that is lost and the rate of bleeding. Rapid loss of up to 20% of the blood volume, or slow losses of even larger amounts, may have little impact in healthy adults; greater losses, however, can cause hemorrhagic (hypovolemic) shock (discussed later). The site of hemorrhage also is important; bleeding that would be trivial in the subcutaneous tissues can cause death if located in the brain ( Fig. 4.4B ). Finally, chronic or recurrent external blood loss (e.g., due to peptic ulcer or menstrual bleeding) frequently culminates in iron deficiency anemia as a consequence of a loss of iron in hemoglobin. By contrast, iron is efficiently recycled from phagocytosed red cells, so internal bleeding (e.g., a hematoma) does not lead to iron deficiency.


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Pathology_Robbins. Normal hemostasis comprises a series of regulated processes that culminate in the formation of a blood clot that limits bleeding from an injured vessel. The pathologic counterpart of hemostasis is thrombosis, the formation of blood clot (thrombus) within non-traumatized, intact vessels. This discussion begins with normal hemostasis and its regulation, to be followed by causes and consequences of thrombosis. Hemostasis is a precisely orchestrated process involving platelets, clotting factors, and endothelium that occurs at the site of vascular injury and culminates in the formation of a blood clot, which serves to prevent or limit the extent of bleeding. The general sequence of events leading to hemostasis at a site of vascular injury is shown in Fig. 4.5 Arteriolar vasoconstriction occurs immediately and markedly reduces blood flow to the injured area (


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Pathology_Robbins. Fig. 4.5 Arteriolar vasoconstriction occurs immediately and markedly reduces blood flow to the injured area ( Fig. 4.5A ). It is mediated by reflex neurogenic mechanisms and augmented by the local secretion of factors such as endothelin, a potent endothelium-derived vasoconstrictor. This effect is transient, however, and bleeding would resume if not for activation of platelets and coagulation factors. Primary hemostasis: the formation of the platelet plug. Disruption of the endothelium exposes subendothelial von Willebrand factor (vWF) and collagen, which promote platelet adherence and activation. Activation of platelets results in a dramatic shape change (from small rounded discs to flat plates with spiky protrusions that markedly increased surface area), as well as the release of secretory granules. Within minutes the secreted products recruit additional platelets, which undergo aggregation to form a primary hemostatic plug ( Fig. 4.5B


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Pathology_Robbins. Fig. 4.5B Secondary hemostasis: deposition of fibrin. Vascular injury exposes tissue factor at the site of injury. Tissue factor is a membrane-bound procoagulant glycoprotein that is normally expressed by subendothelial cells in the vessel wall, such as smooth muscle cells and fibroblasts. Tissue factor binds and activates factor VII (see later), setting in motion a cascade of reactions that culiminates in thrombin generation. Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork, and also is a potent activator of platelets, leading to additional platelet aggregation at the site of injury. This sequence, referred to as secondary hemostasis, consolidates the initial platelet plug ( Fig. 4.5C


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Pathology_Robbins. Fig. 4.5C Clot stabilization and resorption. Polymerized fibrin and platelet aggregates undergo contraction to form a solid, permanent plug that prevents further hemorrhage. At this stage, counterregulatory mechanisms (e.g., tissue plasminogen activator, t-PA made by endothelial cells) are set into motion that limit clotting to the site of injury ( Fig. 4.5D ) and eventually lead to clot resorption and tissue repair. http://ebooksmedicine.net 102CHAPTER 4 Hemodynamic Disorders, Thromboembolism, and Shock A. VASOCONSTRICTION Site of injury B. PLATELET ACTIVATION AND AGGREGATION 2 Shape change 4 Recruitment 3 Granule release (ADP, TXA2) C. ACTIVATION OF CLOTTING FACTORS AND FORMATION OF FIBRIN D. CLOT RESORPTION Trapped neutrophilExpression of:


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Pathology_Robbins. C. ACTIVATION OF CLOTTING FACTORS AND FORMATION OF FIBRIN D. CLOT RESORPTION Trapped neutrophilExpression of: Fig. 4.5 Normal hemostasis. (A) After vascular injury, local neurohumoral factors induce a transient vasoconstriction. (B) Platelets bind via glycoprotein Ib (GpIb) receptors to von Willebrand factor (VWF) on exposed ECM and are activated, undergoing a shape change and granule release. Released ADP and thromboxane A2 (TXA2) induce additional platelet aggregation through platelet GpIIb-IIIa receptor binding to fibrinogen, and form the primary hemostatic plug. (C) Local activation of the coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin polymerization, “cementing” the platelets into a definitive secondary hemostatic plug. (D) Counterregulatory mechanisms, mediated by tissue plasminogen activator (t-PA, a fibrinolytic product) and thrombomodulin, confine the hemostatic process to the site of injury.


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Pathology_Robbins. It should be emphasized that endothelial cells are central regulators of hemostasis; the balance between the anti-thrombic and prothrombotic activities of endothelium determines whether thrombus formation, propagation, or dissolution occurs. Normal endothelial cells express a variety of anticoagulant factors that inhibit platelet aggregation and coagulation and promote fibrinolysis; after injury or activation, however, this balance shifts, and endothelial cells acquire numerous procoagulant activities (activation of platelets and clotting factor, described above, see also Fig. 4.11 ). Besides trauma, endothelium can be activated by microbial pathogens, hemodynamic forces, and a number of pro-inflammatory mediators. We will return to the pro-coagulant and anti-coagulant roles of endothelium after a detailed discussion of the role of platelets and coagulation factors in hemostasis since endothelium modulates the functions of platelets and can trigger coagulation.


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Pathology_Robbins. The following sections describe roles of platelets, coagulation factors and endothelium in hemostasis in greater detail, following the scheme illustrated in Fig. 4.5


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Pathology_Robbins. Fig. 4.5 Platelets play a critical role in hemostasis by forming the primary plug that initially seals vascular defects and by providing a surface that binds and concentrates activated coagulation factors. Platelets are disc-shaped anucleate cell fragments that are shed from megakaryocytes in the bone marrow into the bloodstream. Their function depends on several glycoprotein receptors, a contractile cytoskeleton, and two types of cytoplasmic granules. α-Granules have the adhesion molecule P-selectin on their membranes (Chapter 3) and contain proteins involved in coagulation, such as fibrinogen, coagulation factor V, and vWF, as well as protein factors that may be involved in wound healing, such as fibronectin, platelet factor 4 (a heparin-binding chemokine), platelet-derived growth factor (PDGF), and transforming growth factor-β. Dense (or δ) granules contain adenosine diphosphate (ADP) and adenosine triphosphate, ionized calcium, serotonin, and epinephrine.


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Pathology_Robbins. After a traumatic vascular injury, platelets encounter constituents of the subendothelial connective tissue, such as vWF and collagen. On contact with these proteins, platelets undergo a sequence of reactions that culminate in the formation of a platelet plug ( Fig. 4.5B • Platelet adhesion is mediated largely via interactions with vWF, which acts as a bridge between the platelet surface receptor glycoprotein Ib (GpIb) and exposed collagen ( Fig. 4.6 ). Notably, genetic deficiencies of vWF (von Willebrand disease, Chapter 14) or GpIb (Bernard-Soulier syndrome) result in bleeding disorders, attesting to the importance of these factors.


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Pathology_Robbins. Fig. 4.6 ). Notably, genetic deficiencies of vWF (von Willebrand disease, Chapter 14) or GpIb (Bernard-Soulier syndrome) result in bleeding disorders, attesting to the importance of these factors. Fig. 4.6 Plateletadhesionandaggregation.VWFfunctionsasanadhesionbridgebetweensubendothelialcollagenandtheglycoproteinIb(GpIb)plate-letreceptor.PlateletaggregationisaccomplishedbyfibrinogenbindingtoplateletGpIIb-IIIareceptorsondifferentplatelets.Congenitaldeficienciesinthevariousreceptorsorbridgingmoleculesleadtothediseasesindicatedinthecoloredboxes.ADP, Adenosinediphosphate.Deficiency:Bernard-SouliersyndromeEndothelium GpIIb-IIIa complex Fibrinogen von Willebrand factor Deficiency: von Willebrand disease ADP induces conformational change GpIb GpIb Platelet Deficiency: Glanzmann thrombasthenia Subendothelium


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Pathology_Robbins. Platelets rapidly change shape following adhesion, being converted from smooth discs to spiky “sea urchins” with greatly increased surface area. This change is accompanied by alterations in glycoprotein IIb/IIIa that increase its affinity for fibrinogen (see later), and by the translocation of negatively charged phospholipids (particularly phosphatidylserine) to the platelet surface. These phospholipids bind calcium and serve as nucleation sites for the assembly of coagulation factor complexes.


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Pathology_Robbins. Secretion (release reaction) of granule contents occurs along with changes in shape; these two events are often referred to together as platelet activation. Platelet activation is triggered by a number of factors, including he coagulation factor thrombin and ADP. Thrombin activates platelets through a special type of G-protein– coupled receptor referred to as a protease-activated receptor (PAR), which is switched on by a proteolytic cleavage carried out by thrombin. ADP is a component of dense-body granules; thus, platelet activation and ADP release begets additional rounds of platelet activation, a phenomenon referred to as recruitment. Activated platelets also produce the prostaglandin thromboxane A2 (TXA2), a potent inducer of platelet aggregation. Aspirin inhibits platelet aggregation and produces a mild bleeding defect by inhibiting cyclooxygenase, a platelet enzyme that is required for TXA2 synthesis. Although the phenomenon is less well characterized, it is also suspected that


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Pathology_Robbins. and produces a mild bleeding defect by inhibiting cyclooxygenase, a platelet enzyme that is required for TXA2 synthesis. Although the phenomenon is less well characterized, it is also suspected that growth factors released from platelets contribute to the repair of the vessel wall following injury.


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Pathology_Robbins. • Platelet aggregation follows their activation. The conformational change in glycoprotein IIb/IIIa that occurs with platelet activation allows binding of fibrinogen, a large bivalent plasma polypeptide that forms bridges between adjacent platelets, leading to their aggregation. Predictably, inherited deficiency of GpIIb-IIIa results in a bleeding disorder called Glanzmann thrombasthenia. The initial wave of aggregation is reversible, but concurrent activation of thrombin stabilizes the platelet plug by causing further platelet activation and aggregation, and by promoting irreversible platelet contraction. Platelet contraction is dependent on the cytoskeleton and consolidates the aggregated platelets. In parallel, thrombin also converts fibrinogen into insoluble fibrin, cementing the platelets in place and creating the definitive secondary hemostatic plug. Entrapped red cells and leukocytes are also found in hemostatic plugs, in part due to adherence of leukocytes to P-selectin


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Pathology_Robbins. platelets in place and creating the definitive secondary hemostatic plug. Entrapped red cells and leukocytes are also found in hemostatic plugs, in part due to adherence of leukocytes to P-selectin expressed on activated platelets.


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Pathology_Robbins. PLATELETADHESION,ACTIVATION,ANDAGGREGATION EndothelialinjuryexposestheunderlyingbasementmembraneECM;plateletsadheretotheECMprimarilythroughthebindingofplateletGpIbreceptorstoVWF. Adhesionleadstoplateletactivation,aneventassociatedwithsecretionofplateletgranulecontents,includingcalcium(acofactorforseveralcoagulationproteins)andADP(amediatoroffurtherplateletactivation);dramaticchangesinshapeandmembranecomposition;andactivationofGpIIb/IIIareceptors. TheGpIIb/IIIareceptorsonactivatedplateletsformbridgingcrosslinkswithfibrinogen,leadingtoplateletaggregation. Concomitantactivationofthrombinpromotesfibrindeposition,cementingtheplateletpluginplace. The coagulation cascade is a series of amplifying enzymatic reactions that lead to the deposition of an insoluble fibrin clot. As discussed later, the dependency of clot formation on various factors differs in the laboratory test tube and in blood vessels in vivo (


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Pathology_Robbins. Fig. 4.7 ). However, clotting in vitro and in vivo both follow the same general principles, as follows. The cascade of reactions in the pathway can be likened to a “dance,” in which coagulation factors are passed from one partner to the next ( Fig. 4.8 ). Each reaction step involves an enzyme (an activated coagulation factor), a substrate (an inactive proenzyme form of a coagulation factor), and a cofactor (a reaction accelerator). These components are assembled on a negatively charged phospholipid surface, which is provided by activated platelets. Assembly of reaction complexes also depends on calcium, which binds to γ-carboxylated glutamic acid residues that are present in factors II, VII, IX, and X. The enzymatic reactions that produce γ-carboxylated glutamic acid use vitamin K as a cofactor and are antagonized by drugs such as Coumadin, a widely used anti-coagulant. http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net Fig. 4.7 Thecoagulationcascadeinthelaboratoryandinvivo.(A)Clottingisinitiatedinthelaboratorybyaddingphospholipids,calcium,andeitheranegative-chargedsubstancesuchasglassbeads(intrinsicpathway)orasourceoftissuefactor(extrinsicpathway).(B)Invivo,tissuefactoristhemajorinitiatorofcoagulation,whichisamplifiedbyfeedbackloopsinvolvingthrombin(dotted lines).Thered polypeptidesareinactivefactors,thedark green polypeptides areactivefactors,whereasthelight green polypeptidescorrespondtocofactors. Based on assays performed in clinical laboratories, the coagulation cascade has traditionally been divided into the extrinsic and intrinsic pathways ( Fig. 4.7A • The prothrombin time (PT) assay assesses the function of the proteins in the extrinsic pathway (factors VII, X, V, II (prothrombin), and fibrinogen). In brief, tissue factor, phospholipids, and calcium are added to plasma and the time for a fibrin clot to form is recorded.


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Pathology_Robbins. • The partial thromboplastin time (PTT) assay screens the function of the proteins in the intrinsic pathway (factors XII, XI, IX, VIII, X, V, II, and fibrinogen). In this assay, clotting of plasma is initiated by the addition of negative-charged particles (e.g., ground glass) that activate factor XII (Hageman factor) together with phospholipids and calcium, and the time to fibrin clot formation is recorded. Fig. 4.8 SequentialconversionoffactorXtofactorXabywayoftheextrinsicpathway,followedbyconversionoffactorII(prothrombin)tofactorIIa(throm-bin).Theinitialreactioncomplexconsistsofaprotease(factorVIIa),asubstrate(factorX),andareactionaccelerator(tissuefactor)assembledonaplateletphospholipidsurface.Calciumionsholdtheassembledcomponentstogetherandareessentialforthereaction.ActivatedfactorXathenbecomestheproteasecomponentofthenextcomplexinthecascade,convertingprothrombintothrombin(factorIIa)inthepresenceofadifferentreactionaccelerator,factorVa. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Although the PT and PTT assays are of great utility in evaluating coagulation factor function in patients, they do not recapitulate the events that lead to coagulation in vivo. This point is most clearly made by considering the clinical effects of deficiencies of various coagulation factors. Deficiencies of factors V, VII, VIII, IX, and X are associated with moderate to severe bleeding disorders, and prothrombin deficiency is likely incompatible with life. In contrast, factor XI deficiency is only associated with mild bleeding, and individuals with factor XII deficiency do not bleed and in fact may be susceptible to thrombosis. The paradoxical effect of factor XII deficiency may be explained by involvement of factor XII in the fibrinolysis pathway (discussed later); although there is also some evidence from experimental models suggesting that factor XII may promote thrombosis under certain circumstances, the relevance of these observations to human thrombotic disease remains to be


Pathology_Robbins

Pathology_Robbins. some evidence from experimental models suggesting that factor XII may promote thrombosis under certain circumstances, the relevance of these observations to human thrombotic disease remains to be determined.


Pathology_Robbins

Pathology_Robbins. Based on the effects of various factor deficiencies in humans, it is believed that, in vivo, factor VIIa/tissue factor complex is the most important activator of factor IX and that factor IXa/factor VIIIa complex is the most important activator of factor X (Fig. 4.7B ). The mild bleeding tendency seen in patients with factor XI deficiency is likely explained by the ability of thrombin to activate factor XI (as well as factors V and VIII), a feedback mechanism that amplifies the coagulation cascade. Among the coagulation factors, thrombin is the most important, because its various enzymatic activities control diverse aspects of hemostasis and link clotting to inflammation and repair. Among thrombin’s most important activities are the following:


Pathology_Robbins

Pathology_Robbins. Conversion of fibrinogen into crosslinked fibrin. Thrombin directly converts soluble fibrinogen into fibrin monomers that polymerize into an insoluble fibril, and also amplifies the coagulation process, not only by activating factor XI, but also by activating two critical cofactors: factors V and VIII. It also stabilizes the secondary hemostatic plug by activating factor XIII, which covalently crosslinks fibrin. Platelet activation. Thrombin is a potent inducer of platelet activation and aggregation through its ability to activate PARs, thereby linking platelet function to coagulation. Proinflammatory effects. PARs also are expressed on inflammatory cells, endothelium, and other cell types ( Fig. 4.9 ), and activation of these receptors by thrombin is believed to mediate proinflammatory effects that contribute to tissue repair and angiogenesis.


Pathology_Robbins

Pathology_Robbins. Fig. 4.9 ), and activation of these receptors by thrombin is believed to mediate proinflammatory effects that contribute to tissue repair and angiogenesis. Anti-coagulant effects. Remarkably, through mechanisms described later, on encountering normal endothelium, thrombin changes from a procoagulant to an anticoagulant; this reversal in function prevents clots from extending beyond the site of the vascular injury. Factors That Limit Coagulation. Once initiated, coagulation must be restricted to the site of vascular injury to prevent deleterious consequences. One limiting factor is simple dilution; blood flowing past the site of injury washes out activated coagulation factors, which are rapidly removed by the liver. A second is the requirement for negatively charged phospholipids, which, as mentioned, are mainly provided by platelets that have been


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig.4.11 foranticoagulantactivitiesmediatedbythrombinviathrombomodulin.(Courtesy of Shaun Coughlin, MD, PhD, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California.) activated by contact with subendothelial matrix at sites of vascular injury. However, the most important counter-regulatory mechanisms involve factors that are expressed by intact endothelium adjacent to the site of injury (described later). Activation of the coagulation cascade also sets into motion a fibrinolytic cascade that limits the size of the clot and contributes to its later dissolution (


Pathology_Robbins

Pathology_Robbins. Fig. 4.10 ). Fibrinolysis is largely accomplished through the enzymatic activity of plasmin, which breaks down fibrin and interferes with its polymerization. An elevated level of breakdown products of fibrinogen (often called fibrin split products), most notably fibrin-derived D-dimers, are a useful clinical markers of several thrombotic states (described later). Plasmin is generated by enzymatic catabolism of the inactive circulating precursor plasminogen, either by a factor XII–dependent pathway (possibly explaining the association of factor XII deficiency and thrombosis) or by plasminogen activators. The most important plasminogen activator is t-PA; it is synthesized principally by endothelium and is most active when bound to fibrin. This characteristic makes t-PA a useful therapeutic agent, since its fibrinolytic activity is largely confined to sites of recent thrombosis. Once activated, plasmin is in turn tightly controlled by counterregulatory factors such as α2-plasmin


Pathology_Robbins

Pathology_Robbins. agent, since its fibrinolytic activity is largely confined to sites of recent thrombosis. Once activated, plasmin is in turn tightly controlled by counterregulatory factors such as α2-plasmin inhibitor, a plasma protein that binds and rapidly inhibits free plasmin.


Pathology_Robbins

Pathology_Robbins. The balance between the anticoagulant and procoagulant activities of endothelium often determines whether clot formation, propagation, or dissolution occurs ( Fig. 4.11 ). Normal endothelial cells express a multitude of factors that inhibit the procoagulant activities of platelets and coagulation factors and that augment fibrinolysis. These factors act in concert to prevent thrombosis and to limit clotting to sites of vascular damage. However, if injured or exposed to proinflammatory factors, endothelial cells lose many of their antithrombotic properties. Here, we complete the discussion of hemostasis by focusing on the antithrombotic activities of normal endothelium; we return to the “dark side” of endothelial cells later when discussing thrombosis. The antithrombotic properties of endothelium can be divided into activities directed at platelets, coagulation factors, and fibrinolysis.


Pathology_Robbins

Pathology_Robbins. The antithrombotic properties of endothelium can be divided into activities directed at platelets, coagulation factors, and fibrinolysis. Platelet inhibitory effects. An obvious effect of intact endothelium is to serve as a barrier that shields platelets from subendothelial vWF and collagen. However, normal endothelium also releases a number of factors that inhibit platelet activation and aggregation. Among the most important are prostacyclin (PGI2), nitric oxide (NO), and adenosine diphosphatase; the latter degrades ADP, already discussed as a potent activator of platelet aggregation. Finally, endothelial cells bind and alter the activity of thrombin, which is one of the most potent activators of platelets.


Pathology_Robbins

Pathology_Robbins. Anticoagulant effects. Normal endothelium shields coagulation factors from tissue factor in vessel walls and expresses multiple factors that actively oppose coagulation, most notably thrombomodulin, endothelial protein C receptor, heparin-like molecules, and tissue factor pathway inhibitor. Thrombomodulin and endothelial protein C receptor bind thrombin and protein C, respectively, in a complex on the endothelial cell surface. When bound in this complex, thrombin loses its ability to activate coagulation factors and platelets, and instead cleaves and activates protein C, a vitamin K–dependent protease that requires a cofactor, protein S. Activated protein C/protein S complex is a potent inhibitor of coagulation factors Va and VIIIa. Heparin-like molecules on the surface of endothelium bind and activate antithrombin III, which then inhibits thrombin and factors IXa, Xa, XIa, and XIIa. The clinical utility of heparin and related drugs is based on their ability to stimulate antithrombin


Pathology_Robbins

Pathology_Robbins. and activate antithrombin III, which then inhibits thrombin and factors IXa, Xa, XIa, and XIIa. The clinical utility of heparin and related drugs is based on their ability to stimulate antithrombin III activity. Tissue factor pathway inhibitor (TFPI), like protein C, requires protein S as a cofactor and, as the name implies, binds and inhibits tissue factor/factor VIIa complexes.


Pathology_Robbins

Pathology_Robbins. Fibrinolytic effects. Normal endothelial cells synthesize t-PA, already discussed, as a key component of the fibrinolytic pathway. The primary abnormalities that lead to intravascular thrombosis are (1) endothelial injury, (2) stasis or turbulent blood flow, and (3) hypercoagulability of the blood (the so-called “Virchow triad”) ( Fig. 4.12 ). Thrombosis is http://ebooksmedicine.net THROMBOSISInactivates tissue factor-VIIa complexes molecule Anti-thrombin III Thrombin Thrombin t-PA Inactivates thrombin (also factors IXa and Xa) Inhibits platelet aggregation Activates fibrinolysis Endothelial effects PGI2, NO, and adenosine diphosphatase Inactivates factors Va and VIIIa Active protein CProtein C (requires protein S) receptorpathway inhibitor THROMBOSISVWF Extrinsic coagulation sequence Exposure of membrane-bound tissue factor Platelet adhesion (held together by fibrinogen)


Pathology_Robbins

Pathology_Robbins. THROMBOSISVWF Extrinsic coagulation sequence Exposure of membrane-bound tissue factor Platelet adhesion (held together by fibrinogen) Fig. 4.11 Anti-coagulantpropertiesofnormalendothelium(top)andprocoagulantpropertiesofinjuredoractivatedendothelium(bottom).NO, Nitricoxide;PGI2, prostaglandinI2(prostacyclin);t-PA, tissueplasminogenactivator;VWF, vonWillebrandfactor.Thrombinreceptorsarealsocalledprotease-activatedreceptors(PARs). Fig. 4.12 Virchow’striadinthrombosis.Endothelialintegrityisthemostimportantfactor.Abnormalitiesofprocoagulantsoranti-coagulantscantipthebalanceinfavorofthrombosis.Abnormalbloodflow(stasisorturbulence)canleadtohypercoagulabilitydirectlyandalsoindirectlythroughendothelialdysfunction. one of the scourges of modern man, because it underlies the most serious and common forms of cardiovascular disease. Here, the focus is on its causes and consequences; its role in cardiovascular disorders is discussed in detail in Chapters 10 and 11.


Pathology_Robbins

Pathology_Robbins. Endothelial injury leading to platelet activation almost inevitably underlies thrombus formation in the heart and the arterial circulation, where the high rates of blood flow impede clot formation. Notably, cardiac and arterial clots are typically rich in platelets, and it is believed that platelet adherence and activation is a necessary prerequisite for thrombus formation under high shear stress, such as exists in arteries. This insight provides part of the reasoning behind the use of aspirin and other platelet inhibitors in coronary artery disease and acute myocardial infarction.


Pathology_Robbins

Pathology_Robbins. Obviously, severe endothelial injury may trigger thrombosis by exposing VWF and tissue factor. However, inflammation and other noxious stimuli also promote thrombosis by shifting the pattern of gene expression in endothelium to one that is “prothrombotic.” This change is sometimes referred to as endothelial activation or dysfunction and can be produced by diverse exposures, including physical injury, infectious agents, abnormal blood flow, inflammatory mediators, metabolic abnormalities, such as hypercholesterolemia or homocystinemia, and toxins absorbed from cigarette smoke. Endothelial activation is believed to have an important role in triggering arterial thrombotic events. http://ebooksmedicine.net The role of endothelial cell activation and dysfunction in arterial thrombosis is also discussed in Chapters 10 and 11. Here it suffices to mention several of the major pro-thrombotic alterations:


Pathology_Robbins

Pathology_Robbins. The role of endothelial cell activation and dysfunction in arterial thrombosis is also discussed in Chapters 10 and 11. Here it suffices to mention several of the major pro-thrombotic alterations: Procoagulant changes. Endothelial cells activated by cytokines downregulate the expression of thrombomodulin, already described as a key modulator of thrombin activity. This may result in sustained activation of thrombin, which can in turn stimulate platelets and augment inflammation through PARs expressed on platelets and inflammatory cells. In addition, inflamed endothelium also downregulates the expression of other anticoagulants, such as protein C and tissue factor protein inhibitor, changes that further promote a procoagulant state. Anti-fibrinolytic effects. Activated endothelial cells secrete Plasminogen activator inhibitors (PAI), which limit fibrinolysis and downregulate the expression of t-PA, alterations that also favor the development of thrombi.


Pathology_Robbins

Pathology_Robbins. Turbulence (chaotic blood flow) contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, as well as by forming countercurrents and local pockets of stasis. Stasis is a major factor in the development of venous thrombi. Under conditions of normal laminar blood flow, platelets (and other blood cells) are found mainly in the center of the vessel lumen, separated from the endothelium by a slower-moving layer of plasma. By contrast, stasis and turbulence have the following deleterious effects: Both promote endothelial cell activation and enhanced procoagulant activity, in part through flow-induced changes in endothelial gene expression. Stasis allows platelets and leukocytes to come into contact with the endothelium when the flow is sluggish. Stasis also slows the washout of activated clotting factors and impedes the inflow of clotting factor inhibitors.


Pathology_Robbins

Pathology_Robbins. Turbulent and static blood flow contributes to thrombosis in a number of clinical settings. Ulcerated atherosclerotic plaques not only expose subendothelial ECM but also cause turbulence. Abnormal aortic and arterial dilations called aneurysms create local stasis and consequently are fertile sites for thrombosis (Chapter 9). Acute myocardial infarction results in focally noncontractile myocardium. Ventricular remodeling after more remote infarction can lead to aneurysm formation. In both cases, cardiac mural thrombi are more easily formed because of the local blood stasis (Chapter 11). Mitral valve stenosis (e.g., after rheumatic heart disease) results in left atrial dilation. In conjunction with atrial fibrillation, a dilated atrium also produces stasis and is a prime location for the development of thrombi. Hyperviscosity syndromes (such as polycythemia vera, Chapter 12) increase resistance to flow and cause small vessel stasis; the deformed red cells in sickle cell anemia (Chapter


Pathology_Robbins

Pathology_Robbins. of thrombi. Hyperviscosity syndromes (such as polycythemia vera, Chapter 12) increase resistance to flow and cause small vessel stasis; the deformed red cells in sickle cell anemia (Chapter 12) cause vascular occlusions, and the resultant stasis also predisposes to thrombosis.


Pathology_Robbins

Pathology_Robbins. Hypercoagulability refers to an abnormally high tendency of the blood to clot, and is typically caused by alterations in coagulation factors. It contributes infrequently to arterial or intracardiac thrombosis but is an important underlying risk factor for venous thrombosis. The alterations of the coagulation pathways that predispose affected persons to thrombosis can be divided into primary (genetic) and secondary (acquired) disorders ( Table 4.2 Primary (inherited) hypercoagulability is most often caused by mutations in the factor V and prothrombin genes: • Approximately 2% to 15% of whites carry a specific factor V mutation (called the Leiden mutation, after the Dutch city where it was first described). Among those with recurrent deep venous thrombosis (DVT), the frequency of this mutation approaches 60%. The mutation alters an amino acid residue in factor V and renders it Table 4.2 Hypercoagulable States


Pathology_Robbins

Pathology_Robbins. Table 4.2 Hypercoagulable States FactorVmutation(G1691Amutation;factorVLeiden)Prothrombinmutation(G20210Avariant)IncreasedlevelsoffactorVIII,IX,orXIorfibrinogen ProlongedbedrestorimmobilizationMyocardialinfarctionAtrialfibrillationTissueinjury(surgery,fracture,burn)CancerProstheticcardiacvalvesDisseminatedintravascularcoagulationHeparin-inducedthrombocytopeniaAnti-phospholipidantibodysyndrome http://ebooksmedicine.net resistant to proteolysis by protein C. Thus, an important anti-thrombotic counterregulatory mechanism is lost. Heterozygotes carry a fivefold increased risk for venous thrombosis, with homozygotes having a 50-fold increased risk. A single-nucleotide substitution (G to A) in the 3′-untranslated region of the prothrombin gene is a fairly common allele (found in 1%–2% of the general population). This variant results in increased prothrombin transcription and is associated with a nearly threefold increased risk for venous thromboses.


Pathology_Robbins

Pathology_Robbins. Elevated levels of homocysteine contribute to arterial and venous thrombosis, as well as to the development of atherosclerosis (Chapter 10). The prothrombotic effects of homocysteine may be due to thioester linkages formed between homocysteine metabolites and a variety of proteins, including fibrinogen. Marked elevations of homocysteine may be caused by an inherited deficiency of cystathione β-synthetase. Less common primary hypercoagulable states include inherited deficiencies of anti-coagulants such as antithrombin III, protein C, or protein S; affected patients typically present with venous thrombosis and recurrent thromboembolism in adolescence or in early adult life.


Pathology_Robbins

Pathology_Robbins. Although the risk of thrombosis is only mildly increased in heterozygous carriers of factor V Leiden and the prothrombin gene variant, these genetic factors carry added significance for two reasons. First, both abnormal alleles are sufficiently frequent that homozygous and compound heterozygous persons are not uncommon, and these individuals are at much higher risk for thrombosis. More importantly, heterozygous individuals are at higher risk for venous thrombosis in the setting of other acquired risk factors, such as pregnancy, prolonged bed rest, and lengthy airplane flights. Consequently, inherited causes of hypercoagulability should be considered in young patients (<50 years of age), even when other acquired risk factors are present. Secondary (acquired) hypercoagulability is seen in many settings (


Pathology_Robbins

Pathology_Robbins. Secondary (acquired) hypercoagulability is seen in many settings ( Table 4.2 ). In some situations (e.g., cardiac failure or trauma), stasis or vascular injury may be the most important factor. The hypercoagulability associated with oral contraceptive use and the hyperestrogenic state of pregnancy may be related to increased hepatic synthesis of coagulation factors and reduced synthesis of anti-thrombin III. In disseminated cancers, release of procoagulant tumor products (e.g., mucin from adenocarcinoma) predisposes to thrombosis. The hypercoagulability seen with advancing age has been attributed to increased platelet aggregation and reduced release of PGI2 from endothelium. Smoking and obesity promote hypercoagulability by unknown mechanisms.


Pathology_Robbins

Pathology_Robbins. Among the acquired thrombophilic states, two are particularly important clinical problems and deserve special mention: • Heparin-induced thrombocytopenia (HIT) syndrome. This syndrome occurs in up to 5% of patients treated with unfractionated heparin (for therapeutic anti-coagulation). It is marked by the development of autoantibodies that bind complexes of heparin and platelet membrane protein (platelet factor-4) (Chapter 12). Although the mechanism is unclear, it appears that these antibodies may also bind similar complexes present on platelet and endothelial surfaces, resulting in platelet activation, aggregation, and consumption (hence thrombocytopenia), as well as causing endothelial cell injury. The overall result is a prothrombotic state, even in the face of heparin administration and low platelet counts. Newer low-molecular-weight fractionated heparin preparations induce autoantibodies less frequently but can still cause thrombosis if antibodies have already formed.


Pathology_Robbins

Pathology_Robbins. • Anti-phospholipid antibody syndrome. This syndrome (previously called the lupus anti-coagulant syndrome) has protean clinical manifestations, including recurrent thromboses, repeated miscarriages, cardiac valve vegetations, and thrombocytopenia. Depending on the vascular bed involved, the clinical presentations can include pulmonary embolism (following lower extremity venous thrombosis), pulmonary hypertension (from recurrent subclinical pulmonary emboli), stroke, bowel infarction, or renovascular hypertension. Fetal loss does not appear to be explained by thrombosis, but rather seems to stem from antibody-mediated interference with the growth and differentiation of trophoblasts, leading to a failure of placentation. Anti-phospholipid antibody syndrome is also a cause of renal microangiopathy, resulting in renal failure associated with multiple capillary and arterial thromboses (Chapter 14).


Pathology_Robbins

Pathology_Robbins. The name anti-phospholipid antibody syndrome came from the detection in patients of circulating antibodies that bind to phospholipids. But this name is misleading, as it is believed that the most important pathologic effects are mediated through binding of the antibodies to epitopes on proteins that are somehow induced or “unveiled” by phospholipids. Suspected antibody targets include β2-glycoprotein I, a plasma protein that associates with the surfaces of endothelial cells and trophoblasts, and prothrombin. In vivo, it is suspected that these antibodies bind to these and perhaps other proteins, thereby inducing a hypercoagulable state through uncertain mechanisms. However, in vitro, the antibodies interfere with phospholipids and thus inhibit coagulation (hence the name lupus anticoagulant, also a misnomer). The antibodies also frequently provide a false-positive serologic test for syphilis because the antigen in the standard assay for syphilis is embedded in cardiolipin.