Vascular Disorders and Thrombosis

CHAPTER 2


Vascular Disorders and Thrombosis



Free-living unicellular organisms obtain nutrients and eliminate metabolic waste products directly into the external environment. Multicellular organisms require a circulatory system to deliver nutrients to and remove waste products from cells. The movement of fluid and cells through the circulatory system maintains homeostasis and integrates functions of cells and tissues in complex, multicellular organisms. In this chapter, the basic abnormalities that affect fluid circulation and balance within an animal are described.



Circulatory System


The circulatory system consists of blood, a central pump (heart), blood distribution (arterial) and collection (venous) networks, and a system for exchange of nutrients and waste products between blood and extravascular tissue (microcirculation) (Fig. 2-1). A network of lymphatic vessels that parallel the veins also contributes to circulation by draining fluid from extravascular spaces into the blood vascular system.



The heart provides the driving force for blood distribution. Equal volumes of blood are normally distributed to the pulmonary circulation by the right side of the heart and the systemic circulation by the left side of the heart. The volume of blood pumped by each half of the heart per minute (cardiac output) is determined by the beats per minute (heart rate) and the volume of blood pumped per beat by the ventricle (stroke volume). Typically, each half of the heart pumps the equivalent of the entire blood volume of the animal per minute.


Arteries have relatively large diameter lumens to facilitate rapid blood flow with minimal resistance. Artery walls are thick and consist predominantly of smooth muscle fibers for tensile strength and elastic fibers for elasticity (Web Fig. 2-1). Elastic fibers allow arteries to act as pressure reservoirs, expanding to hold blood ejected from the heart during contraction and passively recoiling to provide continuous flow and pressure to arterioles between heart contractions.




Arterioles are the major resistance vessels within the circulatory system; intravascular pressure can fall by nearly half after blood passes through an arteriole. Arterioles have relatively narrow lumens, the diameter of which is controlled by the smooth muscle cells that are the major component of their walls. Extrinsic sympathetic innervation and local intrinsic stimuli regulate the degree of arteriolar smooth muscle contraction, causing arterioles to dilate or constrict to selectively distribute blood to the areas of greatest need.


Capillaries are the site of nutrient and waste product exchange between the blood and tissue. Capillaries are the most numerous vessel in the circulatory system, with a total cross-sectional area nearly 1300 times that of the aorta. However, they normally contain only about 5% of the total blood volume. The velocity of blood flow through the capillaries is very slow, and red blood cells generally move through a capillary in single file to further facilitate the diffusion of nutrients and wastes. Capillaries have narrow lumens (approximately 8 µm) and thin walls (approximately 1 µm) consisting of a single epithelial cell layer (endothelium). At the junctions between capillary endothelia are interendothelial pores, which make the capillary semipermeable to facilitate diffusion of nutrients and waste products between the blood and tissues. There are three types of capillaries: continuous, fenestrated, and discontinuous. The basic functions and tissue locations of these types of capillaries are illustrated in Fig. 2-2. They are discussed in greater detail in the chapters covering the diseases of organ systems.



The return trip of blood to the heart begins in the postcapillary venules. Venules have a composition similar to capillaries but may have thin layers of muscle as they become more distant from the capillary bed. Veins are composed mainly of collagen with smaller amounts of elastin and smooth muscle (Web Fig. 2-2). Venules and veins provide a low resistance pathway for the return of blood to the heart. Because of their distensibility, they can store large amounts of blood; nearly 65% of total blood volume is normally present within the systemic veins. Pressure and velocity of flow are low within venules and veins. Therefore other factors are necessary to help move venous blood toward the heart such as venous valves to prevent backflow of blood, skeletal muscle contraction, venous vasoconstriction, an increased pressure gradient due to decreased pressure in the heart during filling (cardiac-suction effect), and decreased pressure in the thoracic veins due to negative pressure within the thoracic cavity (respiratory pump).




The lymphatic system originates as blind-ended lymphatic capillaries, which permeate the tissue surrounding the microcirculation (arterioles, metarterioles, capillaries, and postcapillary venules [Fig. 2-3]).Lymphatic capillaries have overlapping endothelial cells and large interendothelial gaps so that external pressure allows movement of fluid and molecules into the vessel. However, intravascular lymphatic pressure forces these overlapping edges together to prevent the flow of lymph out of the vessel. Lymphatic capillary gaps are much larger than those between blood capillary endothelium, so they can accommodate movement of larger particles and substances. Lymphatic capillaries converge into progressively larger lymph vessels that drain into lymph nodes and then ultimately empty into the venous system. Similar to venous vessels, lymphatics are distensible, low-pressure vessels that require lymphatic valves and contraction of surrounding muscles to facilitate return of fluid to the blood.



All components of the circulatory system are lined by a single layer of endothelium. Endothelium forms a dynamic interface between blood and tissue and is a critical participant in fluid distribution, inflammation, immunity, angiogenesis, and hemostasis (Fig. 2-4). Normal endothelium is antithrombotic and profibrinolytic and helps maintain blood in a fluid state, but when injured, endothelium becomes prothrombotic and antifibrinolytic. Endothelial activation by oxidative stress, hypoxia, inflammation, infectious agents, tissue injury, or similar events results in the production and release of numerous substances with wide-ranging roles in physiology and pathology (Fig. 2-5 and Box 2-1). Endothelial activation is typically localized to restrict a host response to a specific area, while not affecting the normal function of endothelium and flow of blood in other parts of the body.



BOX 2-1   Endothelial Properties in Health and Disease


Endothelial Products










Microcirculation, Interstitium, and Cells


The exchange of fluid, nutrients, and waste products between blood and cells takes place through the interstitium, the space between cells, and the microcirculation. The interstitium is composed of structural, adhesive, and absorptive components collectively referred to as the extracellular matrix (ECM). Type I collagen is the major structural component of the ECM and forms the framework in which cells reside. This is intimately associated with type IV collagen of cell basement membranes. Adhesive glycoproteins provide sites of attachment for structural components and also serve as receptors for cells, such as phagocytes and lymphocytes, which move through the interstitium. Absorptive disaccharide complexes (glycosaminoglycans) and protein-disaccharide polymer complexes (proteoglycans) are hydrophilic and can bind large amounts of water and other soluble molecules. In most cases, no more than 1.0 mm of interstitial space separates a cell from a capillary.



Fluid Distribution and Homeostasis


Water comprises approximately 60% of body weight, of which about image is intracellular and image is extracellular (80% of which is in the interstitium and 20% is in the plasma). The distribution of fluid-nutrients, and waste products between the blood, interstitium, and cells is controlled by physical barriers, as well as pressure and concentration gradients between each compartment. The cell’s plasma membrane is a selective barrier that separates interstitial and intracellular compartments. Nonpolar (uncharged) lipid-soluble substances, such as O2, CO2, and fatty acids, move relatively freely across the plasma membrane based on concentration gradients. Polar (charged) lipid-insoluble particles and molecules, such as electrolytes, calcium, glucose, and amino acids, enter the cell by carrier-mediated transport. Water readily moves across the plasma membrane down its concentration gradient. Although approximately 100 times the volume of water in a cell crosses the plasma membrane in 1 second, cell fluid content remains relatively stable because of the activity of energy-dependent membrane pumps (e.g., Na+/K+-adenosine triphosphatase [ATPase] pump) and the balance between osmotic pressures exerted by interstitial and intracellular solutes.


The capillary wall is a semipermeable barrier that influences the movement of fluid, nutrients, and waste products between the blood and interstitium. Lipid-soluble substances can pass through capillary endothelium by dissolving in the membrane lipid bilayer, and large proteins can move through the cell by transport within vesicles. Most importantly, water and polar molecules move through interendothelial pores. Normally, these pores are large enough to allow the passage of water, small nutrients (ions, glucose, amino acids), and waste products, yet small enough to prevent the movement of cells and large proteins (albumin and other plasma proteins such as complement, kinin, and coagulation proteins). Local stimuli, such as inflammation, can cause endothelial cells to contract to widen interendothelial pores and allow the passage of larger molecules. Under normal conditions, the composition of plasma and interstitial fluid is very similar, with the exception of the large plasma proteins.


Movement of substances through interendothelial pores and cell membranes is generally passive in response to concentration and pressure gradients. Nutrient-rich arterial blood contains O2, glucose, and amino acids that move down their concentration gradients into the interstitium, where they are available for use by cells. CO2 and waste products generated by cells accumulate in the interstitium and move down their gradient into the venous blood. These gradients become larger in areas where cells are metabolically active.


Water distribution between the plasma and interstitium is determined mainly by osmotic and hydrostatic pressure differentials between the compartments and is described by the following formula (Fig. 2-6):


image




Although sodium and chloride account for approximately 84% of the total osmolality of plasma, free movement of these electrolytes through interendothelial pores balances their concentrations in the plasma and interstitium, so their contribution to differences in osmotic pressure between these compartments is minimal. In contrast, nonpermeable, suspended plasma proteins make up less than 1% of the total osmolality of plasma. However, because these proteins (particularly albumin) do not readily move through interendothelial pores, they exert a colloidal osmotic pressure that is responsible for the majority of the difference in osmotic pressure between the plasma and interstitium.


In the microcirculation, intravascular and interstitial osmotic pressures and interstitial hydrostatic forces remain relatively constant and favor intravascular retention of fluid. However, high hydrostatic pressures within the arteriolar end of the capillary bed result in a net filtration of fluid into the interstitium. Lower hydrostatic pressures in the venular end of the capillary bed result in a net absorption pressure and reentry of fluid into the microvasculature. Alternatively, filtration and absorption may not occur because of a drop in hydrostatic pressure across individual capillary beds. Instead, filtration may occur across the entire length of capillary beds with open precapillary sphincters and high rates of blood flow, whereas absorption may occur across the entire length of capillary beds with closed precapillary sphincters and low blood flow rates. The slight excess of fluid that is retained in the interstitium and any plasma proteins that have escaped the vasculature enter lymphatic capillaries to be drained from the area.


The constant flow of fluid between the microcirculation and interstitium allows exchange of nutrients and waste products between these two fluid compartments to support cell functions. Additionally, the interstitium provides a fluid buffer to either increase or decrease the plasma volume to assure effective circulatory function. Excessive fluid intake will expand plasma volume and increase hydrostatic pressure, resulting in greater filtration into the interstitium to maintain a relatively constant plasma volume. Reduced fluid intake will decrease plasma volume, shifting the movement of water from the interstitium into the plasma to increase circulating fluid volume.



Abnormal Fluid Distribution


Alteration in any of the factors that regulate normal fluid distribution between the plasma, interstitium, and cells can lead to pathologic imbalances between these compartments.



Imbalance Between Intracellular and Interstitial Compartments


Distribution of fluid between the interstitium and cells is generally dynamic but stable. This stability is necessary to maintain a relatively constant intracellular environment for cell function. Generalized conditions (e.g., alterations in plasma volume) and local stimuli (e.g., inflammation) can result in slight and usually transient shifts in fluid distribution between the interstitium and cells. Excess plasma volume (hypervolemia) results in movement of additional water into the interstitium and ultimately into the cell along both osmotic and hydrostatic gradients, causing cell swelling. In contrast, reduced plasma volume (hypovolemia) can result in a flow of water in the opposite direction resulting in cell shrinkage and decreased interstitial volume. Increased interstitial volume will also cause a slight flow of fluid into cells in the affected region.


Disruption of any of the mechanisms that maintain proper fluid distribution between the cell and interstitium can have serious consequences for the cell. Failure to maintain proper osmotic balance as a result of cell membrane damage or failure of the energy-dependent plasma membrane pumps results in cell swelling, which if not quickly corrected can lead to cell death by osmotic lysis.



Imbalance Between Intravascular and Interstitial Compartments (EDEMA)


Changes in distribution of fluid between the plasma and interstitium are most commonly manifested as edema, which is an accumulation of excess interstitial fluid. Edema occurs by four major mechanisms: (1) increased microvascular permeability, (2) increased intravascular hydrostatic pressure, (3) decreased intravascular osmotic pressure, and (4) decreased lymphatic drainage (Box 2-2).



BOX 2-2   Causes of Edema



Increased Vascular Permeability



Vascular leakage associated with inflammation



Neovascularization


Anaphylaxis (e.g., type I hypersensitivity to vaccines, venoms, and other allergens)


Toxins (e.g., endotoxin, paraquat, noxious gases, zootoxins)


Clotting abnormalities (e.g., pulmonary embolism, disseminated intravascular coagulation)


Metabolic abnormalities (e.g., microangiopathy caused by diabetes mellitus, encephalomalacia caused by thiamine deficiency)






Mechanisms of Edema Formation



Increased Microvascular Permeability


Increased microvascular permeability is most commonly associated with the initial microvascular reaction to inflammatory or immunologic stimuli. These stimuli induce localized release of mediators that cause vasodilation and increased microvascular permeability. Immediate increases in permeability are induced by mediators such as histamine, bradykinin, leukotrienes, and substance P, which cause endothelial cell contraction and widening of interendothelial gaps. Subsequent release of cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and γ-interferon induces cytoskeletal rearrangements within endothelial cells that result in endothelial cell retraction and more persistent widening of interendothelial gaps. Movement of intravascular fluid through these gaps into the interstitium results in localized edema that can dilute an inflammatory agent. The reaction terminates as localized edema and regresses when the stimulus is mild. However, most cases progress to the leakage of plasma proteins and emigration of leukocytes as early events in the formation of an acute inflammatory exudate.



Increased Intravascular Hydrostatic Pressure


Increased intravascular hydrostatic pressure is most often due to increased blood volume in the microvasculature. This can be the result of an active increased flow of blood into the microvasculature (hyperemia), such as occurs with acute inflammation. But more commonly, it results from passive accumulation of blood (congestion), often caused by heart failure or localized venous compression or obstruction. Increased microvascular volume and pressure cause increased filtration and reduced or even reversed fluid absorption back into the vessel. When increased hydrostatic pressure affects a localized portion of microvasculature, the edema is localized. In the case of heart failure, congestion and increased hydrostatic pressure can occur in the portal venous system (right heart failure) causing ascites; in the pulmonary venous system (left heart failure) causing pulmonary edema; or in both venous systems (generalized heart failure) causing generalized edema. Generalized edema can result in a reduction of circulating plasma volume and renal hypoperfusion, which activate a variety of volume-regulating compensatory responses. Plasma volume is increased through sodium retention induced by activation of the renin-angiotensin-aldosterone pathways, and water retention mediated by antidiuretic hormone (ADH) release following activation of intravascular volume and pressure receptors. The resulting intravascular volume overload further complicates the dynamics of fluid distribution that accompany heart failure.



Decreased Intravascular Osmotic Pressure


Decreased intravascular osmotic pressure most commonly results from decreased concentrations of plasma proteins, particularly albumin. Hypoalbuminemia reduces the intravascular colloidal osmotic pressure, resulting in increased fluid filtration and decreased absorption and culminating in edema. Hypoalbuminemia is caused by either decreased production of albumin by the liver or excessive loss from the plasma. Decreased hepatic production most commonly occurs because of a lack of adequate protein for the synthetic pathway as a result of malnutrition or intestinal malabsorption of protein. Less often, severe liver disease with decreased hepatocyte mass or impaired hepatocyte function can result in inadequate albumin production. Loss of albumin from the plasma can occur in gastrointestinal diseases characterized by severe blood loss, such as that caused by parasitism. Renal disease, in which glomerular and/or tubular function is impaired, can result in loss of albumin into the urine and dilution of remaining albumin caused by sodium retention and expanded intravascular fluid volume (e.g., nephrotic syndrome). Plasma exudation accompanying severe burns is a less frequent cause of albumin loss. Because of the systemic nature of hypoalbuminemia, edema caused by decreased intravascular osmotic pressure tends to be generalized.




Morphologic Characteristics of Edema


Edema is morphologically characterized by clear to slightly yellow fluid that generally contains a small amount of protein (transudate), which thickens and expands affected interstitium (Fig. 2-7). When edema occurs in tissues adjacent to body cavities or open spaces, such as alveolar lumens, the increased interstitial pressure often forces fluid into these cavities and spaces. The result can be fluid within alveolar lumens (pulmonary edema; Fig. 2-8), the thoracic cavity (hydrothorax), the pericardial sac (hydropericardium), or the abdominal cavity (ascites or hydroperitoneum; Fig. 2-9). Histologically, edema is an amorphous, pale eosinophilic fluid (hematoxylin and eosin [H&E] stain) because of its protein content (Fig. 2-10). The clinical significance of edema is variable, depending mainly on its location. Subcutaneous edema results in doughy to fluctuant skin and subcutis that is often cooler than adjacent unaffected tissue, but alone has minimal clinical impact (Fig. 2-11). Likewise, ascites does not generally have an impact on the function of abdominal organs. In contrast, edema of a tissue within a confined space, such as the brain in the cranial vault, can result in pressure within the organ that results in serious organ dysfunction. Similarly, filling a confined space with fluid, such as in hydrothorax or hydropericardium, can have a substantial impact on the function of the lungs and heart, respectively. In these situations, edema can have immediate and life-threatening implications.








Hemostasis


Hemostasis is the arrest of bleeding. It is a physiologic response to vascular damage and provides a mechanism to seal an injured vessel to prevent blood loss (hemo = blood, stasis = halt, slow). Hemostasis is a finely regulated process that predominantly involves interactions between endothelium, platelets, and coagulation factors. It normally occurs only at the site of vascular injury, without affecting fluidity and flow of blood in normal undamaged vasculature. Disruption of the delicate balance of hemostasis can result in the pathologic states of blood loss (hemorrhage) or inappropriate thrombus formation (thrombosis).


Normal endothelium provides a surface that promotes the smooth, nonturbulent flow of blood. It produces and responds to mediators that enhance vasodilation, and inhibit platelet activation and coagulation. In contrast, after injury or activation, endothelium produces or responds to mediators that induce vasoconstriction, enhance platelet adhesion and aggregation, and stimulate coagulation (Box 2-3).



BOX 2-3   Endothelial Mediators of Hemostasis



Anticoagulant













Platelets are anucleate cell fragments derived from megakaryocytes. Their major role in hemostasis is to form the initial plug that covers and seals a small area of vascular damage. After vascular damage, platelets adhere to subendothelial collagen and other ECM components (e.g., fibronectin, adhesive glycoproteins, and proteoglycans). Adhered platelets express receptors that promote aggregation of additional platelets and become activated to release the products of their cytoplasmic granules and produce other mediators of coagulation (e.g., thromboxane; Box 2-4). The phospholipid surfaces of aggregated platelet membranes also provide a surface to concentrate activated coagulation factors to promote coagulation.



BOX 2-4   Platelet Mediators in Hemostasis



Procoagulant
















Coagulation factors are plasma proteins produced mainly by the liver. Their purpose in hemostasis is to form fibrin. Coagulation factors are divided into (1) a structurally related and functionally interdependent contact group (prekallikrein, high molecular weight kininogen [HMWK], and factors XII and XI); (2) a vitamin K–dependent group (factors II, VII, IX, and X); and (3) a highly labile fibrinogen group (factors I, V, VIII, and XIII). Circulating coagulation factors are activated in a cascade fashion by hydrolysis of arginine- or lysine-containing peptides to convert them to enzymatically active serine proteases (except for factor XIII, which has cysteine-rich active sites). The contact group factors are activated by contact with collagen or subendothelial components to initiate coagulation by the intrinsic pathway. The extrinsic pathway of coagulation is activated by release of tissue factor (TF, factor III) from damaged cells. The vitamin K–dependent coagulation factors play an important role in localizing coagulation by γ-carboxylating glutamic acid residues of N-terminal ends of precursor factors, so they can bind calcium to form calcium bridges with platelet phospholipids.



Hemostatic Process


The sequence of events that contribute to hemostasis are (1) transient vasoconstriction and platelet aggregation to form a platelet plug at the site of damage (primary hemostasis), (2) coagulation to form a meshwork of fibrin (secondary hemostasis), (3) fibrinolysis to remove the platelet/fibrin plug (thrombus retraction), and (4) tissue repair at the damaged site (Fig. 2-12).




Primary Hemostasis


Primary hemostasis includes the initial vascular and platelet response to injury. Neurogenic stimuli and mediators released locally by endothelium and platelets cause vasoconstriction immediately after damage (Fig. 2-12, A). The nature and effectiveness of vasoconstriction is partially determined by the size of the affected vessel, the amount of smooth muscle it contains, and endothelial integrity. Narrowing of the vessel lumen allows opposing endothelial surfaces to come into contact with and sometimes adhere to each other to reduce the volume of blood flowing through the damaged area. Platelets can directly adhere to the exposed subendothelial matrix of collagen, fibronectin, and other glycoproteins and proteoglycans (Fig. 2-12, B). However, more efficient adhesion occurs when von Willebrand’s factor released by local activated endothelium coats subendothelial collagen to form a specific bridge between collagen and the glycoprotein platelet receptor GPIb. At this stage and without further stimulation, adhered and aggregated platelets may disaggregate. Otherwise, platelets within the aggregate secrete the contents of their dense bodies and α-granules and produce substances such as thromboxane to accelerate hemostasis. Adenosine diphosphate (ADP) released from dense granules triggers the binding of fibrinogen to platelet receptor GPIIb-IIIa, resulting in the formation of fibrinogen bridges that link platelets into a loose aggregate. Platelet contraction consolidates this loose aggregate into a dense plug, which covers the damaged area. When vascular injury is minimal, platelet plugs alone may resolve the damage. If not, the exposed collagen and aggregated platelet phospholipids promote secondary hemostasis at the site.

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Sep 17, 2016 | Posted by in GENERAL | Comments Off on Vascular Disorders and Thrombosis
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