Chapter 4 - Hemodynamic Disorders, Thromboembolism, and Shock

#INFARCTION: #Morphology: Red infarcts

(1) as a result of venous occlusions (such as in ovarian torsion); (2) in loose tissues (e.g., lung) where blood can collect in infarcted zones; (3) in tissues with dual circulations such as lung and small intestine (4) in previously congested tissues (as a consequence of sluggish venous outflow); and (5) when flow is reestablished after infarction has occurred (e.g., after angioplasty of an arterial obstruction).

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: 4 Sequence of events leading to hemostasis at a site of vascular injury

1. Arteriolar vasoconstriction 2. Primary hemostasis: the formation of the platelet plug 3. Secondary hemostasis: deposition of fibrin 4. Clot stabilization and resorption

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: Factors That Limit Coagulation.

1. Dilution: Blood flowing over the site of injury washes out activated coagulation factors, which are rapidly removed by the liver. 2. The requirement for negatively charged phospholipids: Mainly provided by platelets that have been activated by contact with subendothelial matrix at sites of vascular injury. However, the most important counterregulatory mechanisms involve factors that are expressed by intact endothelium adjacent to the site of injury

#Edema: Major causes of edema

1. Increased Hydrostatic Pressure 2. Reduced Plasma Osmotic Pressure (Hypoproteinemia) 3. Lymphatic Obstruction 4. Sodium Retention 5. Inflammation

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: Fibrinolytic cascade:

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. 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.

#HYPEREMIA AND CONGESTION: Acute Pulmonary Congestion: Morphology

Acute pulmonary congestion is marked by blood-engorged alveolar capillaries and variable degrees of alveolar septal edema and interalveolar hemorrhage.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Platelets Mechanism of action

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 • Platelet adhesion • Platelets rapidly change shape • Secretion (release reaction) of granule contents • Platelet aggregation

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: #Primary abnormalities that lead to intravascular thrombosis: Endothelial Injury:

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.

#HYPEREMIA AND CONGESTION: Congestion - Definition

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 hemorrhages.

#EMBOLISM: Pulmonary Thromboembolism

Pulmonary emboli originate from deep venous thromboses and are responsible for the most common form of thromboembolic disease. In more than 95% of cases, venous emboli originate from thrombi within deep leg veins proximal to the popliteal fossa. Frequently, multiple emboli occur, either sequentially or as a shower of smaller emboli from a single large thrombus; a patient who has had one pulmonary embolus is at increased risk for having more . Rarely, an embolus passes through an atrial or ventricular defect and enters the systemic circulation (paradoxical embolism)

#Edema: #Major causes of edema: 2. Reduced Plasma Osmotic Pressure

Reduction of plasma albumin concentrations leads to decreased colloid osmotic pressure of the blood and loss of fluid from the circulation. Nephrotic syndrome - is the most important cause of albumin loss from the blood. In diseases that are characterized by nephrotic syndrome, the glomerular capillaries become leaky, leading to the loss of albumin (and other plasma proteins) in the urine and the development of generalized edema. 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.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: #Thrombin functions: • Anti-coagulant effects.

Remarkably, 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.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Platelets: #Mechanism of action: • Secretion (release reaction) of granule contents

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 the 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 causes 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 growth factors released from platelets contribute to the repair of the vessel wall following injury.

#SHOCK: Pathogenesis of Septic Shock:

Septic shock is most frequently triggered by gram-positive bacterial infections, followed by gram-negative bacteria and fungi. After activation of innate immunity, these cells and factors initiate a number of inflammatory responses that interact in a complex, incompletely understood fashion to produce septic shock and multiorgan dysfunction.

#SHOCK 3 Types of Shock • Septic shock

Septic shock is triggered by microbial infections and is associated with severe systemic inflammatory response syndrome (SIRS). In addition to microbes, SIRS may be triggered by a variety of insults, including burns, trauma, and/or pancreatitis. The common pathogenic mechanism is a massive outpouring of inflammatory mediators from innate and adaptive immune cells that produce arterial vasodilation, vascular leakage, and venous blood pooling. These cardiovascular abnormalities result in tissue hypoperfusion, cellular hypoxia, and metabolic derangements that lead to organ dysfunction and, if severe and persistent, organ failure and death.

#SHOCK Definition

Shock is a state in which diminished cardiac output or reduced effective circulating blood volume impairs tissue perfusion and leads to cellular hypoxia. At the outset, the cellular injury is reversible; however, prolonged shock eventually leads to irreversible tissue injury and is often fatal

#SHOCK 3 Types of Shock

Shock may complicate severe hemorrhage, extensive trauma or burns, myocardial infarction, pulmonary embolism, and microbial sepsis. Its causes fall into three general categories: • Cardiogenic shock • Hypovolemic shock • Septic shock

#INFARCTION: Factors That Influence Infarct Development: • Rate of occlusion

Slowly developing occlusions are less likely to cause infarction because they allow time for the development of collateral blood supplies. For example, small interarteriolar anastomoses, which normally carry minimal blood flow, interconnect the three major coronary arteries. If one coronary artery is slowly occluded (e.g., by encroaching atherosclerotic plaque), flow in this collateral circulation may increase sufficiently to prevent infarction—even if the original artery becomes completely occluded.

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: #Primary abnormalities that lead to intravascular thrombosis: Abnormal Blood Flow Definition

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 (=a slowing or stoppage of the normal flow of a bodily fluid or semifluid). *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.

#INFARCTION: #Morphology: Septic infarctis

occur when infected cardiac valve vegetations embolize, or when microbes seed necrotic tissue. In these cases the infarct is converted into an abscess, with a correspondingly greater inflammatory response and healing by organization and fibrosis.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #4 Sequence of events leading to hemostasis at a site of vascular injury: 1. Arteriolar vasoconstriction

• Arteriolar vasoconstriction occurs immediately and markedly reduces blood flow to the injured area. It is mediated by reflex neurogenic mechanisms and intensified by the local secretion of factors such as endothelin, a potent endothelium-derived vasoconstrictor. This effect is transient (not permanent) , however, and bleeding would resume if not for activation of platelets and coagulation factors.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #4 Sequence of events leading to hemostasis at a site of vascular injury: 4. Clot stabilization and resorption

• 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 and eventually lead to clot resorption and tissue repair.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: Thrombin functions

• Conversion of fibrinogen into crosslinked fibrin. • Platelet activation. • Proinflammatory effects • Anti-coagulant effects.

#HEMORRHAGE: #Clinical Features: Ecchymoses

• 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).

#HEMORRHAGE: #Clinical Features: Hematoma

• 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). 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.

#SHOCK: Pathogenesis of Septic Shock: Factors play major roles in the pathophysiology of septic shock:

• Inflammatory and counterinflammatory responses. • Endothelial activation and injury. • Induction of a procoagulant state. • Metabolic abnormalities. • Organ dysfunction.

#EMBOLISM: #Pulmonary Thromboembolism Major clinical and pathologic features

• Most pulmonary emboli (60%-80%) are small and clinically silent. With time, they undergo organization and become incorporated into the vascular wall; in some cases, organization of thromboemboli leaves behind bridging fibrous webs. • At the other end of the spectrum, a large embolus that blocks a major pulmonary artery can cause sudden death. • Embolic obstruction of medium-sized arteries and subsequent rupture of downstream capillaries that became anoxic can cause pulmonary hemorrhage. Such emboli do not usually cause pulmonary infarction because the area also receives blood through an intact bronchial circulation (dual circulation). However, a similar embolus in the setting of left-sided cardiac failure (and diminished bronchial artery perfusion) can lead to a pulmonary infarct. • Embolism to small end-arteriolar pulmonary branches usually causes infarction. • Multiple emboli occurring through time can cause pulmonary hypertension and right ventricular failure (cor pulmonale).

#HEMORRHAGE: #Clinical Features: Petechiae

• Petechiae are minute (1 to 2 mm in diameter) hemorrhages into skin, mucous membranes, or serosal surfaces (Fig. 4.4A); Causes include : 1. Low platelet counts (thrombocytopenia) 2. Defective platelet function 3. Loss of vascular wall support, as in vitamin C deficiency. Petechiae are pinpoint-sized spots of bleeding under the skin or mucous membranes.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: #Endothelium: Antithrombotic activities of normal endothelium

• Platelet inhibitory effects. • Anticoagulant effects. • Fibrinolytic effects.

#EMBOLISM: Amniotic Fluid Embolism

Amniotic fluid embolism is an uncommon, grave complication of labor (צירים) and the immediate postpartum period occurring in 1 in 40,000 deliveries. Onset is characterized by sudden severe dyspnea, cyanosis, and hypotensive shock, followed by seizures and coma. If the patient survives the initial crisis, pulmonary edema typically develops, along with (in about half the patients) disseminated intravascular coagulation secondary to release of thrombogenic substances from amniotic fluid. Indeed it is thought that morbidity and mortality in such cases results not from mechanical obstruction of pulmonary vessels but from biochemical activation of the coagulation system and the innate immune system caused by substances in the amniotic fluid. The underlying cause is the entry of amniotic fluid (and its contents) into the maternal circulation via tears in the placental membranes and/or uterine vein rupture. Histologic analysis shows squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa, and mucin derived from the fetal respiratory or gastrointestinal tracts in the maternal pulmonary microcirculation.

#EMBOLISM: Definition

An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by the blood from its point of origin to a distant site, where it often causes tissue dysfunction or infarction. Emboli can arrest anywhere in the vascular tree. The primary consequence of systemic embolization is ischemic necrosis (infarction) of downstream tissues, whereas embolization in the pulmonary circulation leads to hypoxia, hypotension, and right-sided heart failure.

#INFARCTION: Definition and causes

An infarct is an area of ischemic necrosis caused by occlusion of the vascular supply to the affected tissue. Arterial thrombosis or arterial embolism underlies the vast majority of infarctions. Less common causes of arterial obstruction include vasospasm, expansion of an atheroma secondary to intraplaque hemorrhage, and extrinsic compression of a vessel, such as by tumor, a dissecting aortic aneurysm, or edema within a confined space.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: #Endothelium: #Antithrombotic activities of normal endothelium: • Platelet inhibitory effects

An obvious effect of intact endothelium is to serve as a barrier that protect platelets from subendothelial vWF and collagen. However, normal endothelium also releases a number of factors that inhibit platelet activation and aggregation. 1. Prostacyclin (PGI2) 2. Nitric oxide (NO) 3. Adenosine diphosphatase; which degrades ADP (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.

#Edema: Anasarca - Definition

Anasarca is severe, generalized edema marked by profound swelling of subcutaneous tissues and accumulation of fluid in body cavities.

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: Arterial and Cardiac Thrombosis

Atherosclerosis is a major cause of arterial thromboses because it is associated with the loss of endothelial integrity and with abnormal blood flow (Fig. 4.13B). Myocardial infarction can predispose to cardiac mural thrombi by causing dyskinetic myocardial contraction and endocardial injury (Fig. 4.13A), and rheumatic heart disease may engender atrial mural thrombi by causing atrial dilation and fibrillation. Both cardiac and aortic mural thrombi are prone to embolization. Although any tissue can be affected, the brain, kidneys, and spleen are particularly likely targets because of their rich blood supply.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: Coagulation Cascade: Extrinsic and Intrinsic pathways

Based on assays performed in clinical laboratories, the coagulation cascade has traditionally been divided into the extrinsic and intrinsic pathways. • 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. • 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.

#HEMORRHAGE: Hemorrhagic diatheses - Definition

Bleeding diathesis refers to the increased tendency to bleed or bruise 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.

#SHOCK 3 Types of Shock • Cardiogenic shock

Cardiogenic shock results from low cardiac output as a result of myocardial pump failure. It may be caused by myocardial damage (infarction), ventricular arrhythmias, extrinsic compression (cardiac tamponade), or outflow obstruction (e.g., pulmonary embolism).

#HEMORRHAGE: Definition

Hemorrhage, defined as the extravasation (=the leakage from the vein into the surrounding tissue) of blood from vessels, is most often the result of damage to blood vessels or defective clot formation.

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: Disseminated Intravascular Coagulation (DIC)

DIC is widespread thrombosis within the microcirculation that may be of sudden or insidious onset. It may be seen in disorders ranging from obstetric complications to advanced malignancy. To complicate matters, the widespread microvascular thrombosis consumes platelets and coagulation proteins (hence the synonym consumptive coagulopathy), and at the same time, fibrinolytic mechanisms are activated. The net result is that excessive clotting and bleeding may co-exist in the same patient

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: Factors deficiency:

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. 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. 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.

#HYPEREMIA AND CONGESTION: Chronic Pulmonary Congestion: Morphology

In chronic pulmonary congestion, the septa become thickened and fibrotic, and the alveolar spaces contain numerous macrophages consist a lot of hemosiderin ("heart failure cells" = Brown granules of hemosiderin from break down of RBC's appear in the macrophage cytoplasm) derived from phagocytosed red cells.

#HYPEREMIA AND CONGESTION: Acute hepatic Congestion: Morphology

In hepatic congestion, the central vein and sinusoids are distended with blood, and there may even be necrosis of centrally located hepatocytes. The periportal hepatocytes, better oxygenated because of their proximity to hepatic arterioles, experience less severe hypoxia and may develop only reversible fatty change

#Edema: #Major causes of edema: MORPHOLOGY

Edema is easily recognized on gross test; microscopic examination shows Clearing and separation of the extracellular matrix (ECM) elements. Although any tissue can be involved, edema most commonly is encountered in subcutaneous tissues, lungs, and brain. Subcutaneous edema can be diffuse but usually accumulates preferentially in parts of the body positioned the greatest distance below the heart, where hydrostatic pressures are highest. Thus, edema typically is most pronounced in the legs with standing and the sacrum with recumbency, a relationship termed dependent edema. 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. Edema resulting from renal dysfunction or nephrotic syndrome often manifests first in loose connective tissues (e.g., the eyelids, causing periorbital edema). With pulmonary edema, the lungs often are two to three times their normal weight, and sectioning shows frothy, sometimes blood-tinged fluid consisting of a mixture of air, edema fluid, and extravasated red cells. Brain edema can be localized (e.g., because of abscess or tumor) or generalized, depending on the nature and extent of the pathologic process or injury. With generalized edema, the sulci are narrowed as the gyri swell and become flattened against the skull.

#Edema: #Major causes of edema: 3. Lymphatic Obstruction

Edema may result from lymphatic obstruction that compromises resorption of fluid from interstitial spaces

#Edema: #Major causes of edema: 3. Sodium and Water Retention

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

#Edema: #Major causes of edema: MORPHOLOGY pitting edema

Finger pressure over edematous subcutaneous tissue displaces the interstitial fluid, leaving a finger-shaped depression; this appearance is called pitting edema.

#EMBOLISM: Air Embolism

Gas bubbles within the circulation can mix and obstruct vascular flow and cause distal ischemic injury. Thus, a small volume of air trapped in a coronary artery during bypass surgery or introduced into the cerebral arterial circulation by neurosurgery performed in an upright "sitting position" can occlude flow. Small venous gas emboli generally have no deleterious effects, but sufficient air can enter the pulmonary circulation during obstetric or laparoscopic procedures or as a consequence of a chest wall injury to cause hypoxia, and very large venous emboli may arrest in the heart and cause death. A particular form of gas embolism called decompression sickness is caused by sudden changes in atmospheric pressure. Scuba divers, underwater construction workers, and persons in unpressurized aircraft who undergo rapid ascent are at risk. When air is breathed at high pressure (e.g., during a deep sea dive), increased amounts of gas (particularly nitrogen) become dissolved in the blood and tissues. If the diver then ascends (depressurizes) too rapidly, the nitrogen expands in the tissues and bubbles out of solution in the blood to form gas emboli, which cause tissue ischemia. Rapid formation of gas bubbles within skeletal muscles and supporting tissues in and about joints is responsible for the painful condition called the bends. Gas bubbles in the pulmonary vasculature cause edema, hemorrhages, and focal atelectasis (a complete or partial collapse of the entire lung or area (lobe) of the lung) or emphysema, leading to respiratory distress, the so-called "chokes". Bubbles in the central nervous system can cause mental impairment and even sudden onset of coma. A more chronic form of decompression sickness is called caisson disease, in which recurrent or persistent gas emboli in the bones lead to multifocal ischemic necrosis; the heads of the femurs, tibiae, and humerus are most commonly affected. Placing affected persons in a high-pressure chamber, to force the gas back into solution, treats acute decompression sickness. Subsequent slow decompression permits gradual gas resorption and exhalation so that obstructive bubbles do not re-form.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: Definition

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. 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. After injury or activation, the balance in endothelium bw procoagulant factors to anticoagulant factors shifts, and endothelial cells acquire numerous procoagulant activities (activation of platelets and clotting factor).

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: #Primary abnormalities that lead to intravascular thrombosis: Hypercoagulability - Definition

Hypercoagulability refers to an abnormally high tendency of the blood to clot, and is typically caused by alterations in coagulation factors. The alterations of the coagulation pathways that predispose (גרם לרגישות למחלה) affected persons to thrombosis can be divided into: Primary (genetic) and Secondary (acquired) disorders

#HYPEREMIA AND CONGESTION: Definition

Hyperemia and congestion both refer to an increase in blood volume within a tissue, but have different underlying mechanisms.

#HYPEREMIA AND CONGESTION: Hyperemia - Definition

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.

#SHOCK 3 Types of Shock • Hypovolemic shock

Hypovolemic shock results from low cardiac output due to loss of blood or plasma volume (e.g., resulting from hemorrhage or fluid loss from severe burns).

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: Fate of the Thrombus

If a patient survives an initial thrombotic event, during the ensuing days to weeks the thrombus evolves through some combination of the following four processes: • Propagation: The thrombus enlarges through the accumulation of additional platelets and fibrin, increasing the odds of vascular occlusion or embolization. • Embolization: Part or all of the thrombus is dislodged (נעקר ממקומו) and transported elsewhere in the vasculature. • Dissolution: If a thrombus is newly formed, activation of fibrinolytic factors may lead to its rapid shrinkage and complete dissolution. With older thrombi, extensive fibrin polymerization makes the thrombus substantially more resistant to plasmin-induced proteolysis, and lysis is ineffectual (לא יעיל). This acquisition of resistance to lysis has clinical significance, as therapeutic administration of fibrinolytic agents (e.g., t-PA in the setting of acute coronary thrombosis) generally is not effective unless administered within a few hours of thrombus formation. • Organization and recanalization: Older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts. In time, capillary channels are formed that—to a limited extent—create canals along the length of the thrombus, thereby reestablishing the continuity of the original lumen. Further recanalization can sometimes convert a thrombus into a vascularized mass of connective tissue that is eventually incorporated into the wall of the remodeled vessel. Occasionally, instead of organizing, the center of a thrombus undergoes enzymatic digestion, presumably because of the release of lysosomal enzymes from entrapped leukocytes. If bacterial seeding occurs, the contents of degraded thrombi serve as an ideal culture medium, and the resulting infection may weaken the vessel wall, leading to the formation of a mycotic aneurysm.

#HYPEREMIA AND CONGESTION: Chronic hepatic Congestion: Morphology

In chronic passive congestion of the liver, the central regions of the hepatic lobules, viewed on gross examination, are red-brown and slightly depressed (due to cell loss) and are accentuated against the surrounding zones of uncongested tan, sometimes fatty, liver (nutmeg liver) (Fig. 4.1A). Microscopic findings include centrilobular hepatocyte necrosis, hemorrhage, and hemosiderin-laden macrophages (Fig. 4.1B).

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: #Hypercoagulability: Secondary (acquired) disorders - Causes

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 (אמצעי מניעה דרך הפה) and the hypoestrogenic 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. Among the acquired thrombophilic states, two are particularly important clinical problems: • Heparin-induced thrombocytopenia (HIT) syndrome • Anti-phospholipid antibody syndrome.

#Edema: #Major causes of edema: 1. Increased Hydrostatic Pressure Mechanism

Increases in hydrostatic pressure are mainly caused by disorders that impair venous return. 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 hypo perfusion 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 defective cycle of fluid retention, increased venous hydrostatic pressures, and worsening edema ensues.

#INFARCTION: Morphology

Infarcts are classified based on their color (reflecting the amount of hemorrhage) and the presence or absence of microbial infection. Thus, infarcts may be either red (hemorrhagic) or white (anemic) and may be either septic or bland.

#Edema: #Major causes of edema: 3. Lymphatic Obstruction: peau d`orange

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).

#EMBOLISM: Systemic Thromboembolism

Most systemic emboli (80%) arise from intracardiac mural thrombi; two-thirds of these are associated with left ventricular infarcts and another 25% with dilated left atria (e.g., secondary to mitral valve disease) By contrast with venous emboli, which lodge primarily in the lung, arterial emboli can travel virtually anywhere; their final resting place understandably depends on their point of origin and the relative flow rates of blood to the downstream tissues. Common arteriolar embolization sites include the lower extremities (75%) and central nervous system (10%); intestines, kidneys, and spleen are less common targets.

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: Venous Thrombosis (Phlebothrombosis)

Most venous thrombi occur in the superficial or the deep veins of the leg. Deep venous thromboses (DVTs) in the larger leg veins at or above the knee joint (e.g., popliteal, femoral, and iliac veins) are more serious because they are prone to embolize. Although such DVTs may cause local pain and edema, collateral channels often circumvent the venous obstruction. Consequently, DVTs are entirely asymptomatic in approximately 50% of patients and are recognized only after they have embolized to the lungs. Lower-extremity DVTs are associated with stasis and hypercoagulable states Thus, common predisposing factors include congestive heart failure, bed rest, and immobilization; the latter two factors reduce the milking action by leg muscles and thus slow venous return.

#INFARCTION: Factors That Influence Infarct Development: • Tissue vulnerability to hypoxia.

Neurons undergo irreversible damage when deprived of their blood supply for only 3 to 4 minutes. Myocardial cells, although hardier than neurons, still die after only 20 to 30 minutes of ischemia. By contrast, fibroblasts within myocardium remain viable after many hours of ischemia

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: #Endothelium: #Antithrombotic activities of normal endothelium: • Fibrinolytic effects.

Normal endothelial cells synthesize t-PA, a key component of the fibrinolytic pathway.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: #Endothelium: #Antithrombotic activities of normal endothelium: • Anticoagulant effects.

Normal endothelium protects 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 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

#HEMOSTASIS AND THROMBOSIS: Normal and Pathological hemostasis - Definition

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 hemostasis is thrombosis, the formation of blood clot (thrombus) within non-traumatized, intact vessels.

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: #Primary abnormalities that lead to intravascular thrombosis: #Endothelial Injury: Mechanism

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.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: #Thrombin functions: • 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.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: #Fibrinolytic cascade: Plasmin generation

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 inhibitor, a plasma protein that binds and rapidly inhibits free plasmin.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Platelets: #Mechanism of action: • Platelet adhesion

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. Notably, genetic deficiencies of vWF (von Willebrand disease) or GpIb (Bernard-Soulier syndrome) result in bleeding disorders, attesting to the importance of these factors.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Platelets: #Mechanism of action: • Platelet aggregation

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, thus, fibrinogen 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 (הפעלה במקביל של טרומבין) 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 expressed on activated platelets.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Platelets Structure and Function

Platelets are disc-shaped anucleate (Lacking of cell nucleus) 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 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.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Platelets Definition

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.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Platelets: #Mechanism of action: • Platelets rapidly change shape

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, 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.

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: #Primary abnormalities that lead to intravascular thrombosis: #Hypercoagulability: Primary (genetic) alterations of coagulation pathway: Causes

Primary (inherited) hypercoagulability is most often caused by mutations in the factor V and prothrombin genes The mutation alters an amino acid residue in factor V and makes it 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. • Elevated levels of homocysteine contribute to arterial and venous thrombosis, as well as to the development of atherosclerosis. 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 cystathionin 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.

#Edema: #Major causes of edema: #Clinical Features: Pulmonary edema

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, and inflammatory and infectious disorders of the lung. Besides impeding oxygen diffusion, alveolar edema fluid also creates a favorable environment for infections.

#EMBOLISM: Fat Embolism

Soft tissue crush injury or rupture of marrow vascular sinusoids (eg, due to a long bone fracture) release microscopic fat globules into the circulation. The pathogenesis of fat emboli syndrome involves both mechanical obstruction and biochemical injury. Fat microemboli occlude pulmonary and cerebral microvasculature, both directly and by triggering platelet aggregation. This deleterious effect is exacerbated by fatty acid release from lipid globules, which causes local toxic endothelial injury. Platelet activation and granulocyte recruitment (with free radical, protease, and eicosanoid release) complete the vascular assault. Because lipids are dissolved by the solvents used during tissue processing, microscopic demonstration of fat microglobules (i.e., in the absence of accompanying marrow elements) requires specialized techniques (frozen sections and fat stains)

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: #Primary abnormalities that lead to intravascular thrombosis: #Abnormal Blood Flow: Stasis and turbulence effects :

Stasis = A slowing or stoppage of the normal flow of a bodily fluid or semifluid: such as. a : slowing of the current of circulating blood. • 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 slows the inflow of clotting factor inhibitors

Edema - Definition

The accumulation of interstitial fluids in tissues resulting from a net movement of water into extravascular spaces.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: #Endothelium: The balance between Pro\Anti coagulant activity

The balance between the anticoagulant and procoagulant activities of endothelium often determines whether clot formation, propagation, or dissolution occurs. Normal endothelial cells express a multitude of factors that inhibit the procoagulant activities of platelets and coagulation factors and that promotes 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.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: Coagulation Cascade: Definition

The coagulation cascade is a series of amplifying enzymatic reactions that lead to the deposition of an insoluble fibrin clot. 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. 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.

#Edema: #Major causes of edema: #Clinical Features: Exudate vs Transudate

The edema fluid that accumulates in the setting of increased hydrostatic pressure or reduced intravascular colloid typically is a protein-poor transudate; Bxy contrast, because of increased vascular permeability, inflammatory edema fluid is a protein-rich exudate with a high specific gravity

#INFARCTION: Factors That Influence Infarct Development:

The effects of vascular occlusion range from inconsequential to tissue necrosis leading to organ dysfunction and sometimes death. The range of outcomes is influenced by the following three variables: • Anatomy of the vascular supply • Rate of occlusion • Tissue vulnerability to hypoxia.

#SHOCK: Pathogenesis of Septic Shock: Factors play major roles in the pathophysiology of septic shock: • Inflammatory and counterinflammatory responses.

The elevation in CRP & procalcitonin is a clinically useful indicator of septic shock. Microbial components can activate coagulation directly through factor XII and indirectly through altered endothelial function. The hyperinflammatory state, initiated by sepsis, triggers counterregulatory immunosuppressive mechanisms, which may involve both innate and adaptive immune cells. As a result, septic patients may oscillate between hyperinflammatory and immunosuppressed states during their clinical course. Proposed mechanisms for the immune suppression include a shift from proinflammatory (TH1) to anti-inflammatory (TH2) cytokines, production of anti-inflammatory mediators (e.g., soluble TNF receptor, IL-1 receptor antagonist, and IL-10), lymphocyte apoptosis, the immunosuppressive effects of apoptotic cells, and the induction of cellular anergy. In some patients the counterregulatory mechanisms overshoot the inflammatory responses and the resultant immune suppression renders such patients susceptible to superinfections.

#Edema: #Major causes of edema: 3. Lymphatic Obstruction: Parasitic infection - filariasis

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.

#INFARCTION: Factors That Influence Infarct Development: • Anatomy of the vascular supply

The presence or absence of an alternative blood supply is the most important factor in determining whether occlusion of an individual vessel causes damage. The dual supply of the lung by the pulmonary and bronchial arteries means that obstruction of the pulmonary arterioles does not cause lung infarction unless the bronchial circulation also is compromised. Similarly, the liver, which receives blood from the hepatic artery and the portal vein, and the hand and forearm, with its parallel radial and ulnar arterial supply, are resistant to infarction. By contrast, the kidney and the spleen both have end-arterial circulations, and arterial obstruction generally leads to infarction in these tissues

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: Primary abnormalities that lead to intravascular thrombosis: (the so-called Virchow triad)

The primary abnormalities that lead to intravascular thrombosis are (1) endothelial injury, (2) stasis or turbulent blood flow, (3) hypercoagulability of the blood

Hemostasis - Definition

The process of blood clotting that prevents excessive bleeding after blood-vessel damage.

#HEMORRHAGE: #Clinical Features: Basics

The site of hemorrhage is important; bleeding that would be trivial in the subcutaneous tissues can cause death if located in the brain. 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.

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: #Hypercoagulability: #Secondary (acquired) disorders - Causes: • Anti-phospholipid antibody syndrome.

This syndrome (previously called the lupus anti-coagulant syndrome) has protean clinical manifestations, including recurrent thromboses, repeated miscarriages (הפלות), 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. Anti-phospholipid antibody syndrome is also a cause of renal microangiopathy, resulting in renal failure associated with multiple capillary and arterial thromboses. 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. Anti-phospholipid antibody syndrome has primary and secondary forms. Individuals with a well-defined autoimmune disease, such as systemic lupus erythematosus, are designated as having secondary antiphospholipid syndrome (hence the earlier term lupus anticoagulant syndrome). In primary anti-phospholipid syndrome, patients exhibit only the manifestations of a hypercoagulable state and lack evidence of other autoimmune disorders; occasionally, it appears following exposure to certain drugs or infections. Therapy involves anticoagulation and immunosuppression. Although antiphospholipid antibodies are clearly associated with thrombotic diatheses, they have also been identified in 5% to 15% of apparently normal individuals, implying that they are necessary but not sufficient to cause the full-blown syndrome.

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: #Hypercoagulability: #Secondary (acquired) disorders - Causes: • 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), 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.

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: Clinical Features

Thrombi are significant because they cause obstruction of arteries and veins and may give rise to emboli. The effect that is of the greatest clinical importance depends on the site of thrombosis. Thus, although venous thrombi can cause congestion and edema in vascular beds distal to an obstruction, they are most worrisome because of their potential to embolize to the lungs and cause death. Conversely, whereas arterial thrombi can embolize and cause tissue infarction, their tendency to obstruct vessels (e.g., in coronary and cerebral vessels) is considerably more important.

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: Morphology

Thrombi can develop anywhere in the cardiovascular system. Arterial or cardiac thrombi typically arise at sites of endothelial injury or turbulence; venous thrombi characteristically occur at sites of stasis. Thrombi are focally attached to the underlying vascular surface and tend to propagate toward the heart; thus, arterial thrombi grow in a retrograde direction from the point of attachment, whereas venous thrombi extend in the direction of blood flow. The propagating portion of a thrombus tends to be poorly attached and therefore prone to fragmentation and migration through the blood as an embolus. Thrombi can have grossly (and microscopically) apparent laminations called lines of Zahn; these represent pale platelet and fibrin layers alternating with darker red cell-rich layers. Such lines are significant in that they are only found in thrombi that form in flowing blood; their presence can therefore usually distinguish antemortem(כאלה שגורמים מוות) thrombosis from the bland nonlaminated clots that form in the postmortem state (After death state). Thrombi occurring in heart chambers or in the aortic lumen are designated as mural thrombi. Abnormal myocardial contraction (arrhythmias, dilated cardiomyopathy, or myocardial infarction) or endomyocardial injury (myocarditis, catheter trauma) promote cardiac mural thrombi (are thrombi that attach to the wall of a blood vessel and cardiac chamber.) (Fig. 4.13A), whereas ulcerated atherosclerotic plaques and aneurysmal dilation promote aortic thrombosis (Fig. 4.13B). Arterial thrombi are frequently occlusive. They are typically rich in platelets, as the processes underlying their development (e.g., endothelial injury) lead to platelet activation. Although usually superimposed on a ruptured atherosclerotic plaque, other vascular injuries (vasculitis, trauma) can also be underlying causes. (Venous thrombosis has been associated with red blood cell and fibrin rich red clot while arterial thrombosis occur on atherosclerotic lesions with active inflammation, and are rich in platelets and give an appearance of white clot) Venous thrombi (phlebothrombosis) are almost invariably occlusive; they frequently propagate some distance toward the heart, forming a long cast within the vessel lumen that is prone to give rise to emboli. Because these thrombi form in the sluggish venous circulation, they tend to contain more enmeshed red cells, leading to the moniker red, or stasis, thrombi. At autopsy, postmortem clots can sometimes be mistaken for venous thrombi. However, the former are gelatinous and because of red cell settling they have a dark red dependent portion and a yellow "chicken fat" upper portion; they also are usually not attached to the underlying vessel wall. By contrast, red thrombi typically are firm, focally attached to vessel walls, and they contain gray strands of deposited fibrin. Thrombi on heart valves are called vegetations. Bacterial or fungal bloodborne infections can cause valve damage, leading to the development of large thrombotic masses (infective endocarditis) . Sterile vegetations also can develop on noninfected valves in hypercoagulable states—the lesions of so-called "nonbacterial thrombotic endocarditis" .Less commonly, sterile, verrucous endocarditis (Libman-Sacks endocarditis) can occur in the setting of systemic lupus erythematosus .

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: #Thrombin functions: • 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, by: 1. Activating factor XI 2. Activating factor V 3. Activating factor VIII. 4. Activating factor XII = stabilizes the secondary hemostatic plug which covalently crosslinks fibrin.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #Coagulation Cascade: #Thrombin functions: • Platelet activation.

Thrombin is a potent inducer of platelet activation and aggregation through its ability to activate PARs (protease-activated receptors), thereby linking platelet function to coagulation.

#INFARCTION: #Morphology: White infarcts

White infarcts occur with arterial occlusions in solid organs with end-arterial circulations (e.g., heart, spleen, and kidney), and where tissue density limits the infiltration of blood from adjoining patent vascular beds. Infarcts tend to be wedge-shaped, with the occluded vessel at the apex and the organ periphery forming the base; when the base is a serosal surface, there is often an overlying fibrinous exudate. Lateral margins may be irregular, reflecting flow from adjacent vessels. The margins of acute infarcts typically are indistinct and slightly hemorrhagic; with time, the edges become better defined by a narrow rim of hyperemia attributable to inflammation. Infarcts resulting from arterial occlusions in organs without a dual circulation typically become progressively paler and more sharply defined with time. By comparison, hemorrhagic infarcts are the rule in the lung and other spongy organs. Extravasated red cells in hemorrhagic infarcts are phagocytosed by macrophages, and the heme iron is converted to intracellular hemosiderin. Small amounts do not impart any appreciable color to the tissue, but extensive hemorrhages leave a firm, brown residue. In most tissues, the main histologic finding associated with infarcts is ischemic coagulative necrosis . An inflammatory response begins to develop along the margins of infarcts within a few hours and usually is well defined within 1 to 2 days. Eventually, inflammation is followed by repair, beginning in the preserved margins (Chapter 3). In some tissues, parenchymal regeneration can occur at the periphery of the infarct, where the underlying stromal architecture has been spared. Most infarcts, however, are ultimately replaced by scar (Fig. 4.18).The brain is an exception to these generalizations; ischemic tissue injury in the central nervous system results in liquefactive necrosis (Chapter 2).

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #4 Sequence of events leading to hemostasis at a site of vascular injury: 2. Primary hemostasis: the formation of the platelet plug

• 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 fat 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

#HEMOSTASIS AND THROMBOSIS: #Thrombosis: #Primary abnormalities that lead to intravascular thrombosis: #Endothelial Injury: The role of endothelial cell activation and dysfunction in arterial thrombosis:

• Procoagulant changes: Endothelial cells activated by cytokines downregulate the expression of thrombomodulin= TM, a key modulator of thrombin activity (Cofactor& TM directly inhibits most of the procoagulant functions of thrombin) This may result in prolonged activation of thrombin, which can in turn stimulate platelets and increase 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.

#HEMORRHAGE: #Clinical Features: Purpura

• 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.

#HEMOSTASIS AND THROMBOSIS: #Normal Hemostasis: #4 Sequence of events leading to hemostasis at a site of vascular injury: 3. Secondary hemostasis: deposition of fibrin

• 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, setting in motion a cascade of reactions that culminates 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