Vascular Disorders and Thrombosis

K = Capillary endothelial permeability constant

P = Hydrostatic pressure

σ = Reflection coefficient

π = Colloid osmotic pressure

cap = capillary

int = interstitium

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).

Mechanisms of Edema Formation

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.

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).

Thrombus Dissolution

The purpose of a fibrin-platelet thrombus is to form a temporary patch that is dissolved after healing of the vessel (thrombolysis). The rate of dissolution must be balanced so that it does not occur so quickly that bleeding returns but is not prolonged so that vessel occlusion may occur (Fig. 2-16). Fibrin dissolution (fibrinolysis) is initiated immediately on vessel injury by the cleavage of the plasma protein plasminogen into plasmin (Fig. 2-17). Plasminogen is activated by a wide variety of proteases, including activated contact group coagulation factors, plasminogen activators present within endothelium and other tissues (tissue plasminogen activator [tPA]), and activators present in secretions and fluids. Plasminogen adsorbs to fibrin within a thrombus, so that on activation the plasmin is localized to the site of the thrombus. The presence of fibrin increases the efficiency of tPA-dependent plasmin generation by nearly twofold. Additionally, by binding to fibrin, plasmin is protected from its major inhibitor (α₂-antiplasmin). The bound plasmin restricts thrombus size by degrading both cross-linked (insoluble) fibrin within the thrombus and fibrinogen, so that additional fibrin formation is inhibited. Dissolution of insoluble, but not soluble, fibrin by plasmin results in the formation of fibrin degradation products (FDPs). FDPs are various-sized fragments of fibrin and fibrinogen that can impair hemostasis. Collectively, FDPs inhibit thrombin, interfere with fibrin polymerization, and can coat platelet membranes to inhibit platelet aggregation.

Regulation of Hemostasis

The potent biologic effects of hemostatic products must be finely regulated to achieve appropriate hemostasis, without creating detrimental effects associated with too little or too much activity. Coagulation factors are continuously activated at a low, basal level to keep the system primed for a rapid response to an injurious stimulus. Proteins that inhibit or degrade activated hemostatic products are present in the plasma or are locally produced at the site of hemostasis (see Fig. 2-17). These products help confine hemostasis to a site of vascular damage and inhibit hemostatic reactions in normal vasculature. Regulation is also achieved by simple dilution of activated agents as blood removes them from the area, and the factors are removed from the circulation by the liver and spleen.

Hemostasis and Other Host Responses

Hemostatic pathways are highly integrated, and many factors within the pathways have multiple roles. Thrombin has a major procoagulant role to cleave factor I to yield fibrin monomers. Thrombin also activates factors V, VIII, XI, and XIII and is a potent activator of platelets. In contrast, high concentrations of thrombin destroy, rather than activate, factors V and VIII. When thrombin binds to thrombomodulin on endothelial surfaces, it activates protein C, a potent anticoagulant.

An important link between intrinsic and extrinsic pathways is the TF/factor VIIa complex. This complex is the major component of extrinsic coagulation, but it can also activate factor IX to allow a bypass of the contact phase of intrinsic coagulation. In turn, intrinsic factors XIIa, XIIf, and IXa and kallikrein can activate factor VII, which greatly increases the efficiency of extrinsic coagulation. These features give the TF/factor VIIa complex a central role in efficient hemostasis. Extrinsic coagulation and the TF/factor VIIa complex are probably the most important mechanisms for in vivo hemostasis because bleeding tendencies are not usually associated with factor XII, prekallikrein, and HMWK deficiencies and some factor XI deficiencies in humans and animals. Although the intrinsic pathway does not appear to be essential for in vivo hemostasis, it does appear to play an essential role in the formation of pathologic thrombi in response to major vascular damage.

Hemostasis is closely tied to inflammation and other host responses. A prothrombotic environment is also proinflammatory. Inflammatory stimuli, such as IL-1 and TNF, activate endothelium to produce TF and to increase their expression of leukocyte adhesion molecules. Thrombin and histamine released by degranulating mast cells also stimulate the expression of the adhesin P-selectin. In early stages of inflammation, leukocytes can loosely attach and roll along endothelium or adhered platelets by interacting with endothelial or platelet P-selectin. During this interaction, the neutrophil α_Mβ₂ integrin may localize neutrophils to fibrinogen on the surface of activated platelets to promote the conversion of fibrinogen into fibrin. An enhanced prothrombotic environment during inflammation also occurs because of decreased thrombomodulin function in response to inflammatory products such as endotoxin, IL-1, TNF, and TGF-β. Additionally, adhered or migrating neutrophils and platelets can release lysosomal proteases (e.g., elastase, collagenase, and acid hydrolases), which cleave many products on endothelial or platelet surfaces. The conversion of prekallikrein to kallikrein during the contact phase of intrinsic coagulation is another source of integration between hemostatic, fibrinolytic, and inflammatory pathways. Kallikrein is chemotactic, can directly cleave C5 to C5a and C5b, can cleave HMWK to form bradykinin, and can convert plasminogen into plasmin. Plasmin also influences other host responses by cleaving C3 to generate C3a and C3b. Mitogenic factors produced by activated endothelium and platelets (e.g., platelet-derived growth factor [PDGF], TGF-β, and vascular endothelial growth factor [VEGF]) contribute to healing of damaged tissue. Some hemostatic reactions initiate pathways that have multiple and sometimes opposite outcomes. Intrinsic pathway factors XIIa, XIIf, and XIa and kallikrein not only initiate the formation of fibrin but also initiate fibrinolysis by cleaving plasminogen into plasmin. Factor XIIa not only participates directly in intrinsic coagulation and fibrinolysis but also indirectly initiates kinin formation and complement activation by converting prekallikrein to kallikrein. Additionally, both kallikrein and plasmin can directly activate factor XII to result in autoamplification of all factor XIIa pathways. Not all stimuli that activate factor XII lead to fibrin formation. Certain stimuli (e.g., misfolded proteins such as amyloid) activate inflammatory factor XII pathways (kallikrein-kinin) without concurrent activation of coagulation (via subsequent activation of factor XI). Other hemostatic products that influence other host systems include factor Xa, thrombin, and fibrinopeptides, all of which have inflammatory and coagulation functions. These interactions indicate the fine balance within the hemostatic system and the interrelatedness of hemostasis, inflammation, and other host responses.

Hemorrhage

Hemorrhage occurs because of abnormal function or integrity of one or more of the major factors that influence hemostasis—the endothelium and blood vessels, platelets, or coagulation factors.

Abnormalities in blood vessels can result from various inherited or acquired problems. Trauma can physically disrupt a vessel and cause hemorrhage by rhexis (rhexis = breaking forth, bursting). Hemorrhage by rhexis can also occur following vascular erosion by inflammatory reactions or invasive neoplasms. Certain fungi commonly invade and damage blood vessels to cause extensive local hemorrhage (e.g., internal carotid artery erosion secondary to guttural pouch mycosis in horses). More commonly, minor defects in otherwise intact blood vessels allow small numbers of erythrocytes to escape by diapedesis (dia = through, pedian = leap). Endotoxemia is a common cause of endothelial injury that results in small widespread hemorrhages (Fig. 2-18). Infectious agents, such as canine adenovirus-1, or chemicals, such as uremic toxins, can also damage endothelium. Similarly, immune complexes can become entrapped between endothelial cells and activate complement and neutrophil influx to result in damage to the endothelium and vessel wall (type III hypersensitivity reaction). Developmental collagen disorders, such as the Ehlers-Danlos syndrome, are sometimes accompanied by hemorrhage. Affected blood vessels contain abnormal collagen in their basement membranes and surrounding supportive tissue, resulting in vascular fragility and predisposition to leakage or damage. Similar hemorrhages occur due to collagen defects in guinea pigs or primates with vitamin C deficiency.

Decreased platelet numbers (thrombocytopenia) or abnormal platelet function (thrombocytopathy) can cause hemorrhage. Thrombocytopenia can result from decreased production, increased destruction, or increased use of platelets. Decreased production generally occurs following megakaryocyte damage or destruction as a result of causes such as radiation injury, estrogen toxicity, cytotoxic drugs, and viral or other infectious diseases (e.g., feline and canine parvoviruses). Increased platelet destruction is often immune-mediated. Autoimmune destruction due to antibody production against platelet membrane components, such as GPIIb and GPIIIa, can occur after immune dysregulation (e.g., systemic lupus erythematosus). Alteration of platelet membranes by drugs or infectious agents may also stimulate immune-mediated destruction or removal of platelets from the circulation. Isoimmune destruction of platelets in neonatal pigs has occurred after ingestion of colostrum-containing antiplatelet antibodies. Viral diseases (e.g., equine infectious anemia and feline immunodeficiency syndrome) and arthropod-borne agents are often associated with platelet destruction and their removal by the spleen. The most common cause of increased platelet use is diffuse endothelial damage or generalized platelet activation, which initiates disseminated intravascular coagulation (DIC). With DIC there is widespread intravascular coagulation and platelet activation, which rapidly results in consumption of platelets and coagulation factors (see section on Thrombosis). This results in progressive thrombocytopenia and hemorrhage as the syndrome escalates. Another platelet consumption disease that is not accompanied by coagulation is thrombotic thrombocytopenic purpura. In this condition, platelet aggregates form in the microvasculature, possibly the result of increased release of proagglutinating substances by normal or damaged endothelium.

Decreased platelet function is usually associated with an inability to adhere or aggregate at a site of vascular injury. Inherited problems of platelet function in humans include deficiency of GPIb on the platelet surface (Bernard-Soulier syndrome), deficient or defective GPIIb and GPIIIa on the platelet surface (Glanzmann’s thrombasthenia), and deficient release of platelet granule content (“storage pool disease”). Glanzmann’s thrombasthenia is a rare disease that has been reported in Otterhound and Great Pyrenees dogs. In these dogs, there is prolonged bleeding and hematoma formation from minor injury and spontaneous epistaxis because of a mutation affecting a Ca²⁺-binding domain of the extracellular portion of GPIIb. Abnormal synthesis or release of platelet granule content has been reported in Simmental cattle, dogs (Spitz, Basset hound, and American foxhounds), cats, and fawn-hooded rats. Defective platelet storage of ADP occurs in the Chédiak-Higashi syndrome (Aleutian mink, cattle, Persian cats, and killer whales). Acquired platelet inhibition and dysfunction is most often associated with administration of nonsteroidal antiinflammatory drugs such as aspirin. Aspirin inhibits the cyclooxygenase pathway of arachidonic acid metabolism, thus decreasing thromboxane production to result in reduced platelet aggregation. Platelet function is also inhibited by uremia because of renal failure. Secondary platelet dysfunction can also occur because of deficiencies of factors necessary for normal platelet function. In von Willebrand’s disease, or in autoimmune or myeloproliferative disorders in which autoantibodies against von Willebrand’s factor are produced, the amount of functional von Willebrand’s factor is decreased. This results in decreased platelet adhesion following vascular damage with either subclinical or severe hemorrhage.

Decreased concentrations or function of coagulation factors can also result in hemorrhage. Inherited deficiencies in coagulation factors have been recognized in many different breeds of dogs and less often other species (Box 2-5). These conditions are characterized by hemorrhage that can range from subclinical to severe. In many cases, the coagulation factor deficiency is recognized because of prolonged bleeding after venipuncture or surgery, but otherwise has minimal significance to the animal. Other inherited deficiencies are characterized by severe episodes of hemorrhage that begin soon after birth.

Acquired defects in coagulation can be caused by decreased production or increased use of coagulation factors. Severe liver disease results in decreased synthesis of most coagulation factors. Production of coagulation factors II, VII, IX, X and proteins C and S is reduced by vitamin K deficiency. Decreased vitamin K production, absorption, or function will reduce conversion of glutamic acid residues into γ-carboxyglutamic acid on these factors. Common substances that competitively inhibit this conversion include dicumarol in moldy sweet clover (Melilotus alba), warfarin-containing rodenticides, and sulfaquinoxaline (Fig. 2-19). An inherited deficiency of binding of γ-glutamyl-carboxylase with vitamin K has been reported in British Devon Rex cats. The most common acquired cause of decreased coagulation factors is increased consumption associated with DIC.

The appearance of hemorrhage depends on its cause, location, and severity. Hemorrhage within tissue is often characterized based on size. A petechia (pl. petechiae) is a pinpoint (1 to 2 mm) hemorrhage that occurs mainly because of diapedesis associated with minor vascular damage (see Fig. 2-18). An ecchymosis (pl. ecchymoses) is a larger (up to 2 to 3 cm in diameter) hemorrhage that occurs with more extensive vascular damage (Fig. 2-20), whereas suffusive hemorrhage affects larger contiguous areas of tissue than the other two types (Fig. 2-21). Hemorrhage that occurs in a focal, confined space forms a hematoma. Hematomas are most common in the ears of long-eared dogs or pigs and in the spleen after trauma to the vasculature (Fig. 2-22). The hematoma grows in size until the pressure exerted by the extravascular blood matches that within the injured vessel or the vessel seals internally by hemostasis. Hemorrhage into body cavities results in pooling of coagulated or noncoagulated blood within the cavity and is classified by terms such as hemoperitoneum (blood in the peritoneal cavity), hemothorax (blood in the thoracic cavity), and hemopericardium (blood in the pericardial sac) (Fig. 2-23).

The significance of hemorrhage depends mainly on the amount, rate, and location of the blood loss. In most cases, blood loss occurs locally and is quickly stopped by hemostatic processes that seal the damaged vessel. In more severe cases, blood loss continues until local tissue pressure matches intravascular pressure and ends the hemorrhage (such as occurs with hematoma formation). When these mechanisms fail to stop blood loss, significant hemorrhage can occur externally or internally into body cavities. Rapid loss of substantial amounts of blood, such as occurs because of traumatic injury of a large vessel, can lead to hypovolemia, decreased tissue perfusion, and hypovolemic shock (see later discussion in this chapter). In contrast, slow rates of blood loss can be totally or partially compensated for by increased hematopoiesis. Many cases of gastric ulceration and hemorrhage are characterized by persistent but slow rates of blood loss. Some hemorrhages can create pressure that interferes with tissue function. This is most significant in vital organs or in tissue with little room to expand in response to the pressure, such as the brain and heart.

Thrombosis

Thrombosis is characterized by the formation of an inappropriate clot of fibrin and/or platelets along with other blood elements (thrombus; pl. thrombi) on the wall of a blood or lymphatic vessel or heart (mural thrombus), or free in their lumens (thromboembolus). Major determinants of thrombosis are historically referred to as Virchow’s triad and include the endothelium and blood vessels (vascular injury), coagulation factor and platelet activity (coagulability), and the dynamics of blood flow (stasis or turbulence) (Fig. 2-24 and Box 2-6).

Alterations in the endothelium are the most important factor in thrombosis and can result in increased production of procoagulant substances and decreased production of anticoagulant substances. Endothelial injury and exposure of TF and subendothelial components, such as collagen and fibronectin, are potent stimuli for platelet aggregation and coagulation. Causes of injury are widely varied in their severity and cause and include trauma, vasculitis caused by infection or immunologic reactions, metabolic disorders, neoplasia, and toxins. Additionally, loss of anticoagulant properties of normal endothelium combined with local release of procoagulant substances can result in fibrin formation. Platelets may also adhere to intact endothelium by interacting with altered proteoglycans in the endothelial glycocalyx. Reduced prostacyclin synthesis may also increase platelet adhesion to endothelium.

Abnormal blood flow increases the risk of thrombosis. Reduced blood flow may occur systemically with heart failure or in a local region of congestion caused by vascular obstruction or vascular dilation. Reduced blood flow is most important in veins, in which the slow flow rate favors accumulation of activated coagulation factors and contact of platelets with the endothelium. Venous thrombosis is common in horses with occlusion of intestinal veins secondary to intestinal torsion. Inactivity can also lead to venous stasis and thrombosis in the limbs, a common problem in humans but not in animals. Dilated heart chambers (e.g., dilatative cardiomyopathy) or dilated vessels (e.g., aneurysms) are also areas in which reduced blood flow predisposes to thrombosis.

Turbulent blood flow also enhances the potential for thrombosis. Turbulence disrupts laminar blood flow so the thin layer of plasma that normally separates the endothelium from cellular elements, particularly platelets, is disrupted, and platelets interact more readily with the endothelium. Similarly, turbulence results in mixing of the blood, which provides greater opportunity for interactions between coagulation factors. Turbulence can also physically damage endothelium, creating a strong stimulus for platelet adhesion and coagulation. Turbulence, along with increased risk of thrombosis, is usually greatest in areas in which vessels branch, there is narrowing of the vessel lumen, or at sites of venous or lymphatic valves.

Increased coagulability of blood (hypercoagulability) is another factor that predisposes to thrombosis. Hypercoagulability usually reflects an increase or decrease in the concentration of activated hemostatic proteins (e.g., coagulation factors and coagulation or fibrinolytic inhibitors) caused by enhanced activation or decreased degradation of these proteins. Less often, an alteration in hemostatic protein function may influence coagulability. Activity of coagulation and fibrinolytic proteins can increase in certain conditions such as inflammation, stress, surgery, neoplasia, pregnancy, and renal disease (e.g., the nephrotic syndrome). Inflammation is the most common cause of hypercoagulability, resulting in a variety of changes such as increased TF, increased platelet reactivity, increased fibrinogen, increased levels of phosphatidylserine, increased PAI-1, and decreased thrombomodulin. Transient increases in fibrinogen can also occur with stress and tissue necrosis. Factor I and factor VIII are elevated by trauma, acute illness, surgery, and increased metabolism that accompanies hyperthyroidism. Deficiency of ATIII, a major inhibitor of thrombin, occurs relatively often in dogs with the nephrotic syndrome. In this syndrome, ATIII is depleted because of loss through damaged glomeruli. In affected dogs, there is an increased incidence of venous thrombosis and pulmonary embolism. Increased platelet activation (e.g., heartworm disease, nephrotic syndrome, and neoplasia) can also contribute to hypercoagulability of blood.

The appearance of a thrombus depends on its underlying cause, location, and composition (relative proportions of platelets, fibrin, and erythrocytes). Thrombi composed predominantly of platelets and fibrin tend to be pale, whereas those containing many erythrocytes are red. Cardiac and arterial thrombi are usually initiated by endothelial damage. This damage provides a site for firm platelet attachment and subsequent incorporation of fibrin. Rapid blood flow in these arteries and arterioles inhibits passive incorporation of erythrocytes into the thrombus (Fig. 2-25). Cardiac and arterial thrombi are dull, usually firmly attached to the vessel wall, and red-gray (pale thrombi) (Fig. 2-26). The thrombus may or may not occlude the vessel lumen, and large thrombi tend to have tails that extend downstream from the point of endothelial attachment. Cardiac and larger arterial thrombi often have a laminated appearance created by rapid blood flow and characterized by alternating layers of platelets, interspersed by fibrin intermixed with erythrocytes and leukocytes (lines of Zahn) (Fig. 2-27).

Venous thrombi often occur in areas of stasis. Because of the slow blood flow and reduced clearance rate of activated clotting factors in these areas, erythrocytes are commonly incorporated into a loose meshwork of fibrin and platelets (Fig. 2-28). Venous thrombi are typically gelatinous, soft, glistening, and dark red (red thrombi) (Fig. 2-29). They are almost always occlusive and molded to the vessel lumen and often extend for a considerable distance upstream from their point of origin. They commonly have points of attachment to the vessel wall, but these are often very loose and difficult to discern. Venous thrombi are morphologically similar to postmortem clots (see Fig. 1-24). Compared with venous thrombi, postmortem clots are softer and do not have a point of vascular attachment. In larger vessels or in the heart, erythrocytes may settle to the bottom of the clot, leaving a yellow upper layer (chicken fat clot) indicative of postmortem formation. The presence or absence of associated lesions is often a major factor in distinguishing between an antemortem venous thrombus and a postmortem clot.

The significance of a thrombus is determined by its location and its ability to disrupt perfusion in a dependent tissue. Disruption of tissue perfusion is influenced mainly by the size of the thrombus, its rate of formation, and its method of resolution or repair. In general, thrombi that rapidly develop are more detrimental than those that slowly develop. A slowly developing thrombus creates progressive narrowing of the vessel lumen, but the slow rate of development provides opportunity for collateral blood flow to increase into the affected area. Small thrombi are usually less damaging than large thrombi. Small thrombi are more easily removed by thrombolysis with little residual vessel damage or tissue compromise. In contrast, large thrombi substantially narrow the vessel lumen to restrict blood flow, are often occlusive, and are less readily dissolved by thrombolysis (Fig. 2-30). Occlusive thrombi block blood flow either into (occlusive arterial thrombus) or out of (occlusive venous thrombus) an area and often result in ischemia (decreased oxygenation of tissue) or infarction (necrosis of tissue caused by lack of oxygen).

Under most circumstances and after removal of the injurious stimulus, the well-regulated cascade of events in thrombosis results in the return to normal function of the endothelium and subendothelial collagen (Fig. 2-31, A). However, blood flow through a vessel containing a chronic large or occlusive thrombus can change over time. The thrombus provides an ongoing stimulus for platelet adhesion and coagulation, so thrombus propagation can result in progressive narrowing and possible occlusion of the vessel lumen. A thrombus can also be incorporated into the wall of the vessel by a process similar to that used to replace irreversibly damaged tissue. Products of the aggregated platelets stimulate permanent healing of the damaged area by recruiting fibroblasts to the damaged area. Thrombotic debris is removed by macrophages, and granulation tissue and subsequent fibrosis (organization) occur at the site of the thrombus. Concurrently, there is regrowth of endothelium over the surface of the scar. Although there is a permanent narrowing of the vessel lumen, the regrowth of endothelium over the healed thrombus decreases the stimulus for continued thrombosis (Fig. 2-31, B). In occlusive and some large thrombi, this healing process may be accompanied by invasion and growth of endothelial-lined blood channels through the fibrosed area (recanalization) (Fig. 2-31, C, and Fig. 2-32). This provides alternate routes for blood flow to reestablish through or around the original thrombus. Although reestablishment of blood flow increases tissue perfusion, the permanent vascular narrowing and altered, more turbulent blood flow at the site of a healed thrombus result in an increased risk for subsequent thrombosis at the site.

In some cases, a thrombus or portions of a thrombus can break loose and enter the circulation as an embolus (pl. emboli), a piece of free-floating foreign material within the blood. Thromboemboli (emboli derived from fragments of a thrombus) eventually become lodged in a smaller-sized vessel as the vessel diameter reaches a size that prevents the passage of the embolus, a process called embolization. Venous thromboemboli typically lodge in the pulmonary circulation where they can cause pulmonary infarcts or right-sided heart failure. Arterial thromboemboli typically lodge within a smaller artery downstream from the site of the thrombus, often near sites of vascular bifurcation. Arterial emboli frequently result in infarction of dependent tissue, depending on the tissue and nature of its vascular supply. Cardiac thromboemboli usually lodge at the bifurcation of the external iliac arteries with a portion of the thromboembolus entering each iliac vessel to form a saddle thrombus (Fig. 2-33).

Emboli can also originate from substances other than thrombi. Fat from the bone marrow can be released into the circulation after a fracture of a long bone. Most fat emboli lodge in the pulmonary circulation. Fibrocartilaginous emboli consist of portions of an intervertebral disk, which are released after rupture of a degenerative disk. These can result in occlusion of local vessels and sometimes cause localized spinal cord infarction. Bacteria from inflammatory lesions, such as vegetative valvular endocarditis, or abscesses can enter the blood to form bacterial emboli. When these lodge within vessels, they may cause infarction and secondary sites of infection. Intravascular parasites, such as heartworms (e.g., Dirofilaria), or flukes (e.g., schistosomes) can form parasitic emboli. Malignant neoplasms that invade a vessel result in the formation of neoplastic emboli composed of neoplastic cells. Less common sources of emboli include hematopoietic cells from the bone marrow, amniotic fluid, agglutinated erythrocytes, or clumps of other cells, such as hepatocytes, released after tissue trauma. In any case, the significance of these emboli is their potential to occlude a vessel and inhibit blood flow to dependent tissue.

A serious manifestation of abnormal coagulation is DIC. This is a severe dyshomeostasis caused by the generation of excess thrombin. There are many causes, including diffuse vascular damage (e.g., trauma, vasculitis, and burns), which results in exposure of blood to TF. Intravascular generation of TF by endothelial cells and monocytes can also occur in response to bacteremia, other systemic infections, or any other stimuli that activate the release of inflammatory mediators. The result is TF-induced activation of extrinsic coagulation to produce thrombin. Thrombin causes platelet aggregation and activation of coagulation factors V, VIII, and I to form fibrin, resulting in widespread microvascular clots. Concurrently, the high levels of thrombin stimulate clot dissolution by binding to thrombomodulin to activate protein C, by converting plasminogen into plasmin, and by binding to ATIII to become inactivated. The widespread nature of the coagulation response results in the consumption of these and other factors, resulting in widespread hemorrhages. This combination of microthrombosis with concurrent or rapidly sequential hemorrhage represents one of the most profound and dramatic examples of dyshomeostasis in animals.

Increased Blood Flow

Hyperemia is an active engorgement of vascular beds with a normal or decreased outflow of blood. It occurs because of increased metabolic activity of tissue that results in localized increased concentrations of CO₂, acid, and other metabolites. These cause a local stimulus for vasodilation and increased flow (hyperemia). Hyperemia can occur as a physiologic mechanism within the skin to dissipate heat. It also occurs because of increased need such as increased blood flow to the gastrointestinal tract after a meal. Hyperemia is also one of the first vascular changes that occur in response to an inflammatory stimulus (Fig. 2-34). Neurogenic reflexes and release of vasoactive substances, such as histamine and prostaglandins, mediate the change to promote delivery of inflammatory mediators to the site. Tissues with hyperemic vessels are bright red and warm, and there is engorgement of the arterioles and capillaries.

Decreased Blood Flow

Congestion is the passive engorgement of a vascular bed generally caused by a decreased outflow with a normal or increased inflow of blood (see Fig. 2-34). Passive congestion can occur acutely (acute passive congestion) or chronically (chronic passive congestion). Acute passive congestion can occur in the liver and lungs in response to acute heart failure (Fig. 2-35), after euthanasia, or in organs in which relaxation of smooth muscle from barbiturate anesthesia/euthanasia results in dilation of the vasculature and vascular sinusoids such as in the spleen. Most passive congestion is recognized clinically as chronic passive congestion. It can occur locally because of the obstruction of venous outflow caused by a neoplastic or inflammatory mass, displacement of an organ, or fibrosis resulting from healed injury. Generalized passive congestion occurs because of decreased passage of blood either through the heart or the lungs. This is most often caused by heart failure or conditions (e.g., pulmonary fibrosis) that inhibit the flow of blood through the lungs. Right-sided heart failure causes portal vein and hepatic congestion (Fig. 2-36). Left-sided heart failure results in pulmonary congestion (Fig. 2-37). Chronically, there may be fibrosis caused by the hypoxia and cell injury that accompanies congestion (e.g., chronic hepatic congestion). Congested tissues are dark red, swollen (edema), and cooler than normal. The microvasculature is engorged with blood, and there is often surrounding edema and sometimes hemorrhage caused by diapedesis.

Decreased Tissue Perfusion

Reduced blood flow to an area is usually caused by a local obstruction of a vessel, local congestion, or decreased cardiac output. Local obstruction results in either reduced blood flow into an area or inadequate blood flow out of an area. Ischemia occurs when the perfusion of tissue in the affected area becomes inadequate to meet the metabolic needs of the tissue. Ischemia caused by arterial disease is most commonly the result of incomplete luminal blockage by a thrombus or embolus. The result is a decreased flow of oxygenated blood into the area. Arteriolar vasoconstriction, if prolonged, can also result in ischemia. Ischemia resulting from venous lesions can be caused by intraluminal obstruction such as a venous thrombus. However, external pressure that occludes the vein, such as inflammatory or neoplastic masses, is a common cause. Venous obstruction leads to congestion characterized by slowing and stagnation of blood flow, with loss of tissue oxygenation, local increased hydrostatic pressure, and leakage of fluid into the interstitium (edema). Increased interstitial pressure may partially inhibit arterial inflow into the area to compound the problem. Capillaries can also become occluded by thrombi or external pressure. The severity of ischemia is determined by the local vascular anatomy and degree of anastomoses and collateral circulation, the number of microcirculatory vessels and degree of resistance of the arteriole supplying the capillaries, the extent of the decreased perfusion, the rate at which the occlusion occurred, and the metabolic needs of the tissue. Ischemia can be tolerated to different levels by different tissues. The brain and heart are most susceptible because of a high need for O₂ and nutrients, combined with poor collateral circulation. In contrast, organs that recondition blood (e.g., lungs, gastrointestinal tract, kidneys, and skin) can tolerate substantial reductions in flow because they already receive more blood than necessary for their metabolic needs. Other tissues receive blood based on their immediate needs (e.g., skeletal muscle during physical activity). Rapid and complete occlusion that affects large areas of tissue is generally more severe because collateral circulation may not be able to reestablish flow to certain areas quickly enough to prevent tissue injury.

In tissue in which there has been a return of blood flow after brief ischemia, the tissue often returns to normal. The ATP of ischemic tissue is degraded to adenosine, a potent vasodilator, which relieves the ischemia and allows ATP production to resume. However, after prolonged ischemia, the return of blood flow can result in a variety of detrimental effects. Reflow results in fluid loss to the interstitium, resulting in high tissue pressure, which compresses veins and inhibits local venous return. The congested capillaries hemorrhage, TF is released, and vessels are occluded by thrombi. In ischemic cells, a breakdown product of ATP is hypoxanthine. In the absence of oxygen, this is nonreactive. However, on the return of oxygen, xanthine oxidase converts hypoxanthine into urates, hydrogen peroxide, and superoxide anions. Subsequent reaction of superoxide results in the formation of additional reactive oxygen species such as hydroxyl radicals. Collectively, these oxygen-free radicals formed during reperfusion can induce damage, in addition to that caused by ischemia and energy depletion of the cell.

An infarct is a local area of peracute ischemia that undergoes coagulative necrosis. Infarction is caused by the same events that result in ischemia and is most common secondary to thrombosis or thromboembolism. The characteristics of an infarct are variable based on the type and size of vessel that was occluded (artery or vein), the duration of the occlusion, the tissue in which it occurs, and the prior perfusion and vitality of the tissue. Complete arterial blockage usually results in immediate infarction (Fig. 2-38). In contrast, when venous obstruction occurs, such as from torsions or displacements of the bowel, there is extensive congestion and edema of the affected bowel that precedes and promotes infarction. Concurrent disease, decreased cardiovascular function, anemia, or decreased tissue vitality will increase the likelihood of localized areas of ischemia progressing to infarction. In tissue with a single blood supply and minimal anastomoses (e.g., brain, heart, kidney, and spleen), occlusion of nearly any sized vessel typically results in infarction of the dependent tissue (Fig. 2-39). In tissue with parallel blood supplies that have numerous anastomoses (e.g., skeletal muscle and gastrointestinal tract), occlusion is less serious unless it occurs in a large vessel. Tissues with dual blood supplies (e.g., liver and lung) are not commonly susceptible to infarction unless concurrent underlying disease compromises the overall blood supply.

Most infarcts are dark red soon after their occurrence because of hemorrhage from damaged vessels in the infarcted area and backflow of blood into the area from surrounding vessels (see Fig. 2-39). As cells undergo necrosis, there is swelling of the affected area, which can force blood out of the infarcted region, giving it a pale appearance (Fig. 2-40). Additionally, hemolysis of erythrocytes and degradation and diffusion of hemoglobin give the infarct a progressively paler appearance. This change in color can occur within 1 to 5 days depending on the tissue and extent of the infarction. Certain types of tissue that have a loose (spongy) consistency, such as the lungs and storage-type spleens (e.g., dogs and pigs), usually remain red because the interstitial areas are expandable and necrosis-induced pressure does not build up to force blood out of the infarcted region (Figs. 2-41 and 2-42). Parenchymal tissues with a less expansible interstitium (e.g., kidney) generally become pale over time because of the pressure that forces blood from the necrotic area. Inflammation occurs at the periphery of the dead tissue so that leukocytes, then macrophages, enter the area to clear the necrotic debris, and subsequently neovascularization and granulation occur to replace the necrotic region with fibrous tissue. This process can occur over a period of weeks or months depending on the extent of the damage. In contrast to the coagulative necrosis caused by infarction in most tissue, infarction in the brain and nervous tissue is characterized by liquefactive necrosis. Subsequently, there is glial cell removal of damaged tissue and astrocytic production of glial fibers (astrogliosis) to replace the affected area.

Cardiogenic Shock

Cardiogenic shock results from failure of the heart to adequately pump blood. Cardiac failure can occur due to myocardial infarction, ventricular tachycardia, fibrillation or other arrhythmias, dilatative or hypertrophic cardiomyopathy, obstruction of blood flow from the heart (e.g., pulmonary embolism and pulmonary or aortic stenosis), or other cardiac dysfunctions. In all cases, there is a decrease in both stroke volume and cardiac output. Major compensatory mechanisms (e.g., sympathetic stimulation of the heart), which increase heart contractility, stroke volume, total cardiac output, and heart rate, are only variably successful depending on the nature of the cardiac damage and the ability of the damaged heart to respond. Unsuccessful compensation leads to stagnation of blood and progressive tissue hypoperfusion.

Hypovolemic Shock

Hypovolemic shock arises from reduced circulating blood volume as the result of blood loss caused by hemorrhage or the result of fluid loss secondary to vomiting, diarrhea, or burns. Reduced circulating blood volume leads to decreased vascular pressure and tissue hypoperfusion. Immediate compensatory mechanisms (e.g., peripheral vasoconstriction and fluid movement into the plasma) act to increase vascular pressure and maintain blood flow to critical tissues such as the heart, brain, and kidney. Increased pressure provides an adequate driving force on which local mechanisms can draw on to increase blood flow based on their needs. When the insult is mild, compensation is generally successful and the animal returns to homeostasis. Loss of about 10% of blood volume can occur without a decrease in blood pressure or cardiac output. However, if greater volumes are lost, adequate pressure and perfusion cannot be maintained and there is insufficient blood flow to meet the needs of the tissues. When blood loss approaches 35% to 45%, blood pressure and cardiac output can fall dramatically.

Blood Maldistribution

Blood maldistribution is characterized by decreased peripheral vascular resistance and pooling of blood in peripheral tissues. This is caused by neural or cytokine-induced vasodilation that can result from situations such as trauma, emotional stress, systemic hypersensitivity to allergens, or endotoxemia. Systemic vasodilation results in a dramatically increased microvascular area, and although the blood volume is normal, the effective circulating blood volume is decreased. Unless compensatory mechanisms can override the stimulus for vasodilation, there is pooling and stagnation of blood with subsequent tissue hypoperfusion. The three major types of shock caused by blood maldistribution are anaphylactic, neurogenic, and septic shock.

Anaphylactic shock is a generalized type I hypersensitivity. Common causes include exposure to insect or plant allergens, drugs, or vaccines. The interaction of the inciting substance with immunoglobulin E bound to mast cells results in widespread mast cell degranulation and the release of histamine and other vasoactive mediators. Subsequently, there is systemic vasodilation and increased vascular permeability, causing hypotension and tissue hypoperfusion.

Neurogenic shock may be induced by trauma, particularly trauma to the nervous system; electrocution, such as by lightning strike; fear; or emotional stress. In contrast to anaphylactic and endotoxic shock, cytokine release is not a major factor in the initial peripheral vasodilation. Instead, there are autonomic discharges that result in peripheral vasodilation, followed by venous pooling of blood and tissue hypoperfusion.

Septic shock is the most common type of shock associated with blood maldistribution. In septic shock, peripheral vasodilation is caused by components of bacteria or fungi that induce the release of excessive amounts of vascular and inflammatory mediators. The most common cause of septic shock is endotoxin, a lipopolysaccharide (LPS) complex within the cell wall of Gram-negative bacteria. Less often, peptidoglycans and lipoteichoic acids of Gram-positive organisms initiate shock. Local release of LPS from degenerating bacteria is a potent stimulus for many of the host responses induced by the infectious agent. LPS often gains entry from microflora of the bowel, entering the circulation into the reticuloendothelial system, then accumulating in the liver, spleen, alveoli, and leukocytes. LPS activates cells (mainly endothelium and leukocytes) through a series of reactions involving LPS-binding protein (an acute phase protein), CD14 (a cell membrane protein and soluble plasma protein) and Toll-like receptor 4 (TLR4, a signal-transducing protein). Endothelial activation by LPS inhibits production of anticoagulant substances (e.g., TFPI and thrombomodulin). Activation of monocytes and macrophages by LPS induces the direct or indirect release of TNF and IL-1 and other cytokines (e.g., IL-6, IL-8, chemokines). LPS directly activates factor XII to initiate intrinsic coagulation and other factor XIIa–related pathways (kinins, fibrinolysis, complement). LPS can also directly activate the complement cascade to generate the anaphylatoxins C3a and C5a. Although these events are important for enhancing the inflammatory response to control localized infections associated with relatively low concentrations of LPS, they can be detrimental if the response becomes more pronounced. This may occur with overwhelming infections by bacteria (generating large concentrations of LPS), or when prolonged intestinal ischemia as the result of other types of shock results in breakdown of the mucosal integrity and leakage of bacteria and toxins into the blood. These higher concentrations of LPS induce even more production of TNF, IL-1, and other cytokines, and the secondary effects of these cytokines become more prominent. TNF and IL-1 induce TF expression and endothelial activation of extrinsic coagulation and enhance the expression of endothelial leukocyte adhesion molecules. IL-1 also stimulates the release of platelet-activating factor (PAF) and PAI to enhance platelet aggregation and coagulation. PAF released from leukocytes, platelets, and endothelium can cause platelet aggregation and thrombosis, increased vascular permeability, and similar to TNF and IL-1, stimulation of arachidonic acid metabolite production (particularly prostacyclin [PGI₂] and thromboxane). TNF and IL-1 induce nitric oxide production, which also contributes to vasodilation and hypotension. Neutrophils become activated by TNF and IL-1 to enhance their adhesion to endothelium, which further interferes with blood flow through the microvasculature. The end result of the activation of these myriad vascular, proinflammatory, and procoagulant alterations is the profound systemic vasodilation, hypotension, and tissue hypoperfusion characteristic of septic shock.

Stages and Progression of Shock

Regardless of the underlying cause, shock generally progresses through three different stages: (1) a nonprogressive stage, (2) a progressive stage, and (3) an irreversible stage.

Nonprogressive shock is characterized by compensatory mechanisms that counteract reduced functional circulating blood volume and decreased vascular pressure. Baroreceptors respond to decreased pressure by increasing medullary sympathetic nervous output and epinephrine/norepinephrine release, which increases cardiac output and causes arteriolar vasoconstriction (increased peripheral resistance) in most tissues in an attempt to raise vascular pressure. Notable exceptions are critical tissues, such as the heart, brain, and kidney, to which the blood flow is preserved. Left atrial volume receptors and hypothalamic osmoreceptors help regulate pressure by altering water and sodium balance. Reduced plasma volume stimulates ADH release and water retention and activates angiotensin II production by the renin-angiotensin system to result in aldosterone release and sodium retention. ADH and angiotensin II are also vasoconstrictors and help contribute to increased peripheral resistance. Vasoconstriction also results from endothelial release of endothelin, cold, increased O₂, or decreased CO₂. Decreased microvascular pressure results in a shift in fluid movement from the interstitium into the plasma to also help increase blood volume. The results of these and other responses are increased heart rate and cardiac output, as well as increased vascular pressure. This provides an adequate driving force on which local mechanisms can draw on to increase blood flow based on their needs. When the insult is mild, compensation is generally successful and the animal returns to homeostasis.

In the case of severe or prolonged hypovolemia or cardiac damage that inhibits the ability of the heart to increase output, compensatory mechanisms are inadequate and shock enters the progressive stage. In this stage, there is blood pooling, tissue hypoperfusion, and progressive cell injury. Cellular metabolism becomes less efficient and shifts from aerobic to anaerobic with pyruvate converted to lactate without entering the Krebs cycle. The deficient production of ATP and overproduction of lactic acid inhibits normal cell functions and results in cellular and systemic acidosis. Metabolic products (e.g., adenosine and potassium), increased local osmolarity, local hypoxia, and increased CO₂ eventually result in arteriolar relaxation and dilation. In the case of septic shock, these events exacerbate preexisting cytokine- and mediator-induced vasodilation of the microvasculature. In hypovolemic and cardiogenic shock, the decreased vascular resistance initiates pooling and stagnation of blood within previously closed vascular beds. Widespread arteriolar dilation caused by local influences overrides systemic controls and dramatically contributes to further decreases in vascular plasma volume and pressure. When oxygen and energy stores of the cell are depleted, membrane transport mechanisms are impaired, lysosomal enzymes are released, structural integrity is lost, and cell necrosis occurs. In addition to the detrimental metabolic effects of deficient oxygenation, cell and tissue injury occur in response to the dramatic accumulation of mediators that is characteristic of progressive shock, regardless of its underlying cause. These include histamine, kinins, PAF, complement fragments, and a wide variety of cytokines (e.g., TNF, IL-1, IL-8). These mediators are associated with inappropriate systemic inflammation and systemic activation of complement, coagulation, fibrinolysis, and kinin pathways.

The exact point in which shock enters the irreversible stage is not clear. At the cellular level, metabolic acidosis that results from anaerobic metabolism inhibits enzyme systems needed for energy production. Decreased metabolic efficiency allows vasodilatory substances to accumulate in the ischemic cells and tissues. Once these local products and reflexes override centrally mediated vasoconstriction to produce vasodilation, it is unlikely that shock will be reversed. The fall in peripheral resistance as the result of widespread peripheral vasodilation decreases vascular pressure even more. Irreversibility is generally assured when shock progresses into the syndrome of multiple organ dysfunction. As each organ system fails, particularly the lung, liver, intestine, kidney, and heart, there is a reduction in the metabolic support each system provides to the others. Vicious cycles occur in which the failing function of one organ or tissue contributes to the failure of another (e.g., decreased cardiac output causes renal and pancreatic ischemia; electrolyte imbalances caused by renal ischemia then result in cardiac arrhythmias and myocardial depressant factor released by the ischemic pancreas contribute to even greater reductions in cardiac output). The endpoint of irreversible shock is often manifested as DIC, which is the profound and paradoxic dysfunction of hemostasis.

Clinical and Morphologic Features of Shock

Clinical features of shock are rapidly progressive and include hypotension, weak pulse, tachycardia, hyperventilation with pulmonary rales, reduced urine output, and hypothermia. Organ and system failure occurs in later stages, each manifesting with signs specific to that organ or tissue.

The lesions of shock are variable and depend on the nature and severity of the initiating stimulus and the stage of progression of shock. Characteristically, there are vascular changes accompanied by cell degeneration and necrosis. Generalized congestion and pooling of blood are present in most cases, unless there has been substantial blood loss. Edema, hemorrhage (petechial and ecchymotic), and thrombosis may be present as reflections of the vascular deterioration that accompanies shock. Thrombosis and platelet plugging of capillaries can be prominent in septic shock. Vascular abnormalities are most obvious in those cases that progress to DIC. Cell degeneration and necrosis are most prominent in those cells that are most susceptible to hypoxia, such as neurons and cardiac myocytes, and cells that do not obtain adequate preferential blood flow during shock. Hepatocytes, renal tubular epithelium, adrenal cortical epithelium, and gastrointestinal epithelium are often affected. With the exception of loss of neurons and myocytes, virtually all of these tissue changes can revert to normal if the animal survives. Specific changes may include severe pulmonary congestion, edema, and hemorrhage with alveolar epithelial necrosis, fibrin exudation, and hyaline membrane formation. Passive congestion and centrilobular hepatic necrosis, as well as renal tubular necrosis, are often present in these metabolically important organs. Intestinal congestion, edema, and hemorrhage with mucosal necrosis may occur. In the heart, myofibril coagulation is caused by hypercontraction of sarcomeres and is most likely a response to high sarcoplasmic calcium levels as the result of lack of energy and membrane damage. Cerebral edema and in some cases cerebrocortical laminar necrosis as a result of cerebral ischemia may be present.

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