Lecture 6 Hemodynamic Pathology 2 PDF

Hemodynamic Pathology Part 2  Objectives Define hemostasis and explain its role in preventing excessive bleeding after vascular injury. Recognize the consequences of inadequate hemostasis. Explain the mechanisms and consequences of thrombosis and embolism. Differentiate the types...

Hemodynamic Pathology Part 2  Objectives Define hemostasis and explain its role in preventing excessive bleeding after vascular injury. Recognize the consequences of inadequate hemostasis. Explain the mechanisms and consequences of thrombosis and embolism. Differentiate the types of shock. Review of Normal Circulation Start at the Right Ventricle (1) and follow the numbers to (11) Watch this video to help simplify: Click this link https://www.youtube.com/watch?v=8C0ee yXQXiI HEMOSTASIS, HEMORRHAGIC DISORDERS AND THROMBOSIS NORMAL HEMOSTASIS - process by which blood clots form at sites of vascular injury Derangement from normal hemostasis results to hemorrhagic (excessive bleeding) thrombosis (excessive clotting) Normal Hemostasis A precisely orchestrated process involving Platelets Clotting factors Endothelium that occurs at the site of injury and culminates in the formation of a blood clot, which serves to prevent or limit the extent of bleeding. IMPORTANT Functions It maintain blood in a fluid, clot free state in normal vessels. It produces a localized Haemostatic Plug at the site of vascular injury. The pathologic opposite to hemostasis is Thrombosis  Arteriolar vasoconstriction Normal uninjured BV - collagen and tissue factor is not exposed. Injury: -Occurs immediately, transient -Reduced blood flow Mediated by reflex neurogenic mechanisms Augmented by endothelin - potent vasoconstrictor  Primary hemostasis The formation of platelet plug. 1. Exposure of vWF and collagen promote platelet adhesion. 2. Activation changes platelet shape (round -> flat). 3. Release secretory granules (ADP, TxA2 - thromboxane A2) 4. Recruit additional platelets 5. Form primary hemostatic plug  Secondary Hemostasis Deposition of fibrin. 1. Tissue factor exposed (from SM and fibroblasts) - procoagulant 2. TF complexes with FVII 3. Thrombin cleaves fibrinogen to fibrin. 4. Fibrin meshwork activates other platelets.  Clot stabilization and resorption Polymerized fibrin form a permanent plug. Counterregulatory mechanisms by the endothelial cells (t-PA) limit clotting -> clot resorption and tissue repair Endothelial cells - express procoagulant and anticoagulant factors. Platelets Platelets are anucleate cell fragments from megakaryocytes. Roles: forming the primary plug, surface to bind and activate coagulation factors Function depends on: 1. Glycoprotein receptors (vWF, collagen) 2. Contractile Cytoskeleton 3. Cytoplasmic granules a. a-Granules - P-selectin, fibrinogen, factor V, vWF, PF4, PDGF b. Dense granules - ADP, ATP, iCa, serotonin, epinephrine Platelet Action Platelet adhesion GpIb and vWF, Gp1a/IIa and collagen - vW disease and Bernard-Soulier syndrome Shape change “Spiky” - GpIIb/IIIa affinity for fibrinogen -negatively charged phospholipids to the surface -to bind calcium for coagulation factor complexes Secretion (Platelet activation) -Coagulation factor thrombin - PAR-1 -ADP - dense granules, with additional activation - recruitment Aspirin - COX inhibitor - prevents TxA2 - thromboxane A2 (TxA2) - induce production aggregation -treatment of coronary artery disease Platelet Action Platelet aggregation GpIIb/IIIa binds to fibrinogen - bridge between platelets -> aggregation -Def of GpIIb/IIIa - Glanzmann thrombasthenia Initial aggregation - reversible Platelet plug and further activation - irreversible Thrombin converts fibrinogen to insoluble fibrin (secondary hemostasis). Coagulation Cascade COAGULATION CASCADE * * * * * * Coagulation cascade Coagulation cascade - Enzymatic reactions that lead to the deposition of an insoluble fibrin clot. The coagulation cascade in the laboratory and in vivo shown above. (A) Clotting is initiated in the laboratory by adding phospholipids, calcium, and either a negatively charged substance such as glass beads (intrinsic pathway) or a source of tissue factor (extrinsic pathway). (B) In vivo, tissue factor is the major initiator of coagulation, which is amplified by feedback loops involving thrombin (dotted lines). The red polypeptides are inactive factors. the dark green polypeptides are active factors the light green polypeptides correspond to cofactors (reaction accelerators). Factors marked with an asterisk (*) are vitamin K dependent as are protein C and S (not depicted). Warfarin acts as an anticoagulant by inhibiting the γ-carboxylation of the vitamin K–dependent coagulation factors. Vitamin K is an essential cofactor for the synthesis of all of these vitamin K–dependent clotting factors. Coagulation Cascade Vitamin K dependent - factors II, VII, IX, X Antagonized by coumadin (warfarin) - anticoagulant Laboratory assays -Extrinsic - prothrombin time (PT) - Factors VII, X, V, II [prothrombin] and fibrinogen -Tissue factor, phospholipids, calcium added to plasma and record the time to clot formation (Normal: 10 to 13 seconds) - Intrinsic - partial thromboplastin time (PTT) - Factors XII, XI, IX, VIII, X, V, II, Fibrinogen -Initiated by adding negatively charged particle (i.e. ground glass), phospholipids, calcium to activate XII (Hageman Factor) and record the time to clot formation (Normal: 30 to 40 seconds) Coagulation Cascade Deficiencies of factors V, VII, VIII, IX, and X - moderate to severe bleeding disorders In severe hemophilia A (factor VIII) bleeding occurs spontaneously. In mild hemophilia A (factor VIII) bleeding occurs only after trauma. Prothrombin deficiency - likely incompatible to life Factor XI def - mild bleeding Factor XII def - do not bleed, susceptible to thrombosis Coagulation Cascade Factor deficiencies most important in vivo Factor VIIa/TF - most important activator of factor IX Factor IXa/factor VIIIa - most important activator of factor X Thrombin Thrombin is the most important 2 coagulation factor. 4 Important role: 1. Conversion of fibrinogen into 1 cross-linked fibrin - also amplifies coagulation -FIX, FV, FVIII (dotted line); 3 activating FXIII - stabilize secondary platelet plug Thrombin Thrombin is the most important 2 coagulation factor. 4 Important role: 1. Conversion of fibrinogen into 1 cross-linked fibrin 2. Platelet activation - PAR-1 3 3. Pro-inflammatory effects - PARs 4. Anticoagulant effects - when encountering normal endothelium Fibrinolytic Cascade Limiting coagulation is important to prevent deleterious consequences. 1. Blood dilution - washes out activated coagulation factors - removed by liver 2. Negatively charged phospholipids - present in intact endothelium adjacent to injury FIBRINOLYTIC cascade - plasmin breaks down fibrin by interfering with polymerization. -D-dimers - breakdown product of fibrinogen; important marker in thrombotic states.  Endothelium The balance between the anticoagulant and procoagulant activities of endothelium often determines whether clot formation, propagation, or dissolution occurs. Uninjured - inhibit procoagulant activities of platelets and coagulation factors Antithrombotic properties of intact endothelium: 1. Platelet inhibitory effects - barrier for vWF and collagen against platelets; prostacyclin (PGI2) from COX-1, nitric oxide (NO) from NO synthase, adenosine diphosphatase degrades ADP - platelet activator for aggregation 2. Anticoagulant effects - TF not exposed; thrombomodulin, Protein C, heparin-like molecules, tissue factor pathway inhibitor. 3. Fibrinolytic effects - synthesize t-PA Endothelium 2 2 2 1 3  Hemorrhagic Disorders Primary or secondary defects in vessel walls, Platelets Coagulation factors General Principles of abnormal bleeding  Hemorrhagic Disorders Defects of primary hemostasis (platelet defects or von Willibrand disease) ○ Small bleeds in skin or mucosal membranes; petechiae (1-2mm hemorrhages); purpura (>3mm) ○ Mucosal bleeding - epistaxis (nosebleeds), GI bleeding, excessive menstruation (menorrhagia) ○ Thrombocytopenia (very low platelet counts) complication -> intracerebral hemorrhage (fatal) Defects of secondary hemostasis (coagulation factor defects) ○ Bleed into soft tissues (muscle) or joints. Bleeding to joints (hemarthrosis) after minor trauma is characteristic of hemophilia. Generalized defects involving small vessels ○ Present with “palpable purpura” and echymoses (bruises) are hemorrhages of 1 to 2 cm ○ Hematoma - large enough volume of blood that is a palpable mass  Clinical significance depends on volume. Greater than 20% loss of blood may result to hemorrhagic (hypovolemic) shock). Small bleeding in the subcutaneous tissues in the brain is fatal because the skull can cause compress the brain, compromise the blood supply, and cause herniation of brain stem. Chronic or recurrent external blood loss (peptic ulcer or menstrual bleeding) - cause iron loss -> iron def anemia. Hemorrhage into body cavities or tissues -> iron is recycled Thrombosis ENDOTHELIAL INJURY ALTERATIONS IN NORMAL BLOOD FLOW HYPERCOAGULABILITY 1. Endothelial Injury Endothelial damage stimulates both platelet adhesion and activation of the coagulation cascade. Endothelial injury is frequently an initiating factor when thrombus occurs in the arterial circulation. Common causes of endothelial injury are: 1. In heart and arterial circulation the endothelial injury, under high shear stress 2. Toxins from inflammatory processes, metabolic abnormalities change gene expression to favor “prothombotic” - called endothelial dysfunction Prothrombotic alterations (endothelial dysfunction) - Procoagulant changes - downregulation of thrombomodulin, protein C, TFPi - Antifibrinolytic effects - secrete plasmin activator inhibitors - limit fibrinolysis; downregulate t-PA->favor thrombi 2. Alterations in Blood Flow The two factors which contributes to formation of thrombosis by altering the normal blood flow are: Turbulence in Blood Flow: Turbulence means deviation of the bloodstream which become distorted and abnormally hits the vascular and cardiac lining ; thus not only deviating the platelets towards the endothelium, but also lead to endothelial damage. It contributes to arterial and cardiac thrombosis Stasis in Blood Flow: It is the major factor in the development of venous thrombosis 2. Alterations in Blood Flow The normal blood flow is LAMINAR. In laminar blood flow the cellular elements flow centrally in the vessel lumen, separated from endothelium by a slower moving clear zone of plasma. Stasis and turbulence then leads to thrombosis in following manner: They disrupt laminar blood flow and bring platelets in contact with the endothelium. They prevent dilution of activated clotting factors by fresh flowing blood. They retard the inflow of clotting factors inhibitors and permit the build up of thrombi. Promote endothelial cell activation, predisposing to local thrombosis. 3. Hypercoagulability Hypercoagulability contributes less frequently to thrombotic states but it is an important component in thrombosis. It is defined as any alteration in the coagulation pathway that predisposes to thrombosis 3. Hypercoagulability (Genetic) Most common genetic cause: Factor V mutation and Prothrombin mutation Mutations in Factor V Leiden: There is a substitution for the normal arginine residue at position 506 of factor V. Due to this mutation, factor V cannot be inactivated by cleavage at the usual arginine residue and is therefore resistant to anticoagulant effect of activated protein C. The patients with this mutation usually present with recurrent thrombosis and recurrent Primary (Genetic) Prothrombin Gene Mutation - A single –nucleotide substitution (G to A) in the 3 ‘ – untranslated region of the prothrombin gene is a fairly common allele - This variant results in increased prothrombin transcription and is associated with a nearly three fold increased risk for venous thrombosis - Prothrombin (factor II) is the precursor of thrombin, the end-product of the coagulation cascade Heterozygous carriers have 30% higher plasma prothrombin levels than normals Heterozygous carriers have an increased risk of deep vein and cerebral vein thrombosis Primary (Genetic) RARE GENETIC CAUSES Antithrombin III, Protein C and S Deficiency: Patients with this deficiency usually present with deep venous thrombosis and recurrent thromboembolism in adolescence or early adult life. VERY RARE GENETIC CAUSES Homocystinuria - elevated levels of homocysteine, can be acquired or genetic. Genetic due to def of cystathione B-synthetase Acquired due to def of vitamin B6, B12, and folic acid 3. Hypercoagulability (Acquired) Acquired thrombophilia is usually multifactorial. >Most important - cardiac failure or trauma or tissue injury cause stasis or vascular injury >Cancer - procoagulant tumors = thrombosis >Advancing age - dec PGI2 (prostacyclin) >Oral contraceptive or hyperestrogenic state - due to inc hepatic synthesis of coagulation factors and reduced anticoagulant synthesis >HIT syndrome - antibodies bind to complex of heparin and PF4 -> activate platelets -> prothrombotic state. Usually due to unfractionated heparin >APAS - autoimmune disorder; cause venous or arterial thrombosis, pregnancy complications - recurrent miscarriages, unexplained fetal death Anti–β2-glycoprotein antibodies are suspected to and premature birth —----------> have a major role in APS by activating endothelial cells, monocytes, and platelets. Acquired (Secondary) Heparin Induced Thrombocytopenia with Thrombosis (HITT) - Occurs in 5% patients treated with unfractionated heparin (for therapeutic anticoagulation) - Antibodies are formed against heparin and platelet membrane protein (platelet factor 4) - 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 injury - Overall result is a prothrombotic state, even in the face of heparin administration and low platelet count Thrombosis Morphology A thrombus is easily recognized as a solid mass in the lumen of a blood vessel that is often attached to the vessel wall. PALE THORMBI RED THROMBI Thrombi in the fast flowing arterial Typically occurs in venous circulation, circulation are composed predominantly of where the slower blood flow fibrin and platelets, with few entrapped encourages entrapment of red cells. erythrocytes – hence the term Pale They are composed of platelets, fibrin Thrombus and large numbers of erythrocytes trapped in the fibrin mesh. Arterial Thrombosis Arterial thrombosis are frequently occlusive; most common site - coronary, cerebral, femoral arteries. Atherosclerosis is a major cause. Mural Thrombi: When arterial thrombi arise in heart chambers or in aortic lumen, they are usually adherent to the wall of underlying structure and are termed Mural Thrombi. (Picture A) Lines of Zahn: pale platelet and fibrin deposits alternating with darker red cell-rich layers; signify that a thrombus has formed in flowing blood - differentiated from postmortem non laminated clots. (Picture B) Venous Thrombosis PHLEBOTHROMBOSIS: Thrombi form in sluggish venous circulation - contain more red cells - red or stasis thrombi Deep venous thrombosis is common and has important medical implications because the large thrombi that form in these vein are often easily detached. They travel in the circulation to the heart and lung and lodge in the pulmonary arteries (Pulmonary Embolism) Vegetations Thrombi on heart valves - vegetations - can be infected or sterile. -Infected - Infective endocarditis - cause endothelial injury and disturb blood flow which induce formation of thrombotic mass -Sterile - nonbacterial thrombotic endocarditis - develop on non infected valves with hypercoagulable state Fate of the Thrombus If a patient survives the initial thrombosis, in the ensuing days to weeks thrombi undergo some combination of the following four events: Propagation - Thrombi accumulate additional platelets and fibrin Embolization - Thrombi dislodge and travel to other sites Dissolution - Result of fibrinolysis, depends on size and when it occurred Organization and recanalization - Capillary channels eventually form that reestablish the continuity of the original lumen Disseminated Intravascular Coagulation (DIC) DIC is widespread thrombosis within the microcirculation. It is not a specific disease but rather a complication of a large number of conditions associated with systemic activation of thrombin. To complicate matters, the runaway thrombosis “uses up” platelets and coagulation factors (hence the synonym consumptive coagulopathy) and often activates fibrinolytic mechanisms. Thus, symptoms initially related to thrombosis can evolve into a bleeding catastrophe, such as hemorrhagic stroke or hypovolemic shock. EMBOLISM 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. Virtually 99% of the emboli represent some part of a dislodged thrombus, hence the commonly used term Thromboembolism. Inevitably, emboli lodge in vessels too small to permit further passage, resulting in partial or complete vascular occlusion. The potential consequences of such thromboembolic events is the ischemic necrosis of distal tissue known as Infarction PULMONARY EMBOLISM Cause and Incidence: The most serious form of thromboembolism is pulmonary embolism, which may cause sudden death. It has an incidence of 100 to 200 per 100,000 hospitalized patients Over 95% of PE originate in the deep veins of the leg (phlebothrombosis). Saddle Embolus - an embolus straddling the bifurcation of pulmonary artery Paradoxical embolism - a venous embolus gains access to the arterial circulation through an interatrial or interventricular defect  Pulmonary Embolism In general, the patient who has had one PE is at high risk for more. Major functional consequences of PE Most PE (60-80%) are clinically silent because they are small Sudden death, acute right heart failure (cor pulmonale) or CV collapse when emboli obstruct >60% of pulmonary circulation Embolic obstruction of medium-sized arteries with subsequent vascular rupture can result in pulmonary hemorrhage Embolic obstruction of small end-arteriolar pulmonary branches often does produce hemorrhage or infarction. Multiple emboli overtime may cause pulmonary hypertension and right ventricular failure. Systemic Thromboembolism Causes:Thromboembolism occurs in systemic arteries when the detached thrombus originates in the left side of the heart or a large artery. Systemic arterial thromboembolism commonly occurs: 1. In patients who have infective endocarditic with vegetations on the mitral and aortic valves. 2. In patients who have suffered myocardial infarction in which mural thrombus has occurred. 3. In patients with mitral stenosis and arterial thrombosis. 4. In patients with aortic and ventricular aneurysms, which contain mural thrombi Systemic Thromboembolism Clinical Effects of Systemic Thromboembolism: In contrast to venous emboli, which tend to lodge primarily in one vascular bed (the lung), arterial emboli can travel to a wide variety of sites. The site of arrest depends on the point of origin of the thromboembolism and the volume of blood flow through the downstream tissues. The major sites for arterial embolization are the lower extremities (75%) and the brain (10%), with intestines, kidneys, spleen and upper extremities involved to a lesser extent. The consequences of systemic emboli depend on any collateral vascular supply in the affected tissue, the tissue vulnerability to ischemia, and the caliber of the vessel occluded. In general, however, arterial emboli cause infarction of tissues in the distribution of the obstructed vessel. FAT EMBOLISM Causes: Fat Embolism occurs when globules of fat enter the bloodstream, typically after fractures of large bones (eg, femur) have exposed the fatty bone marrow. Clinical Effects of Fat Embolism: Fat embolism syndrome typically begins 1 to 3 days after injury, with sudden onset of tachypnea, dyspnea and tachycardia. Besides pulmonary insufficiency, the syndrome is characterized by neurological symptoms,including irritability and restlessness, which can progress to delirium or coma. A diffuse petechial rash in non dependent areas occurring in the absence of thrombocytopenia is seen in 20 to 50% of cases and is useful in establishing a diagnosis. The typical clinical features of fat embolism include a Hemorrhagic skin rash, dyspnea, tachycardia, tachypnea, irritability and restlessness. FAT EMBOLISM Bone marrow embolism Cellular elements on the left side of the embolus are hematopoietic cells  AIR EMBOLISM CAUSES: a. Surgery of or Trauma to internal Jugular vein: In injuries to the internal jugular vein, the negative pressure in the thorax tends to suck air into the jugular vein. This phenomenon does not occur in injuries to other systemic veins because they are separated by valves from the negative pressure in the chest b. Child birth or Abortion: Air embolism may occur during childbirth or abortion, when air may be forced into ruptured placental venous sinuses by forceful contractions of uterus. c. Blood Transfusion: Air embolism during blood transfusion occurs only if positive pressure is used to transfuse the blood and only if the transfusion is not discontinued at its completion. Clinical Effects of Air Embolism: When air enters the bloodstream, it passes into the right ventricle, creating a frothy mixture that effectively obstructs the circulation and causes death. AIR EMBOLISM CAUSE: Decompression sickness is a form of embolism that occurs in Caisson workers and undersea divers if they ascend too rapidly after being submerged for long periods. This disorder is also called the Bends or Caisson Disease. (Caissons are high pressure underwater chambers used for deep water construction work) When air is breathed under high underwater pressure, an increased volume of air, mainly oxygen and nitrogen, goes into solution in the blood and equilibrates with the tissues. If decompression to sea level is too rapid, the gases that equilibrated in the tissues come out of solution. Oxygen is rapidly absorbed into the blood, but nitrogen gas coming out of solution can not be absorbed rapidly enough and forms bubbles in the tissues and blood stream that acts as emboli. NITROGEN GAS EMBOLISM Platelets adhere to nitrogen gas bubbles in the circulation an activate coagulation cascade. The resulting disseminated intravascular coagulation aggravates the ischemic state caused by impaction of gas bubbles in capillaries. Involvement of brain in severe cases may cause extensive necrosis and death. In less severe cases, nerve and muscle involvement causes severe muscle contractions with intense pain (the bends). Nitrogen gas emboli in lungs cause Severe difficulty in breathing (the chokes) that is associated with alveolar edema and haemorrhage. AMNIOTIC FLUID EMBOLISM CAUSE: The underlying cause is infusion of amniotic fluid into the maternal circulation via a tear in the placental membranes and rupture of uterine veins. CLINICAL EFFECTS: Amniotic Fluid Embolism is a grave but uncommon complication of labour and the immediate postpartum period. It has a mortality of over 80%. With the vastly increased pressures in the uterus during labour, amniotic fluid may be forced into the maternal uterine veins. These amniotic fluid emboli travel in the circulation and lodge in the lungs, causing respiratory distress. The onset is characterized by sudden severe dyspnea, cyanosis, and hypotensive shock, followed by seizures and coma.  AMNIOTIC FLUID EMBOLISM Two small pulmonary arterioles are packed with laminated swirls of fetal squamous cells.  INFARCTION Definition: An Infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or venous drainage in a particular tissue Nearly 99% of all infarcts result from thrombosis or embolic events and almost all result from arterial occlusion. More rarely, obstruction of venous drainage results in infarction. Tissue infarction is a common and extremely important cause of clinical illness. Important clinical entities which are attributable to infarction are: 1. Myocardial Infarction 2. Cerebral Infarction 3. Pulmonary Infarction 4. Intestinal Infarction 5. Ischemic Necrosis of Extremities (Gangrene) CLASSIFICATION OF INFARCT The appearance of infarcts varies with the site. Various classification schemes are used A. PALE Versus RED INFARCT B. SOLID Versus LIQUIFIED INFARCT C. STERILE Versus SEPTIC INFARCT A. PALE VS RED INFARCT Pale Infarct: Occur as a result of arterial obstruction in solid organs such as heart, kidney, spleen and brain. These organs lack significant collateral circulation, and the solidity of the tissue limits the amount of haemorrhage that can seep into the area of ischemic necrosis from adjoining capillary beds Red or Hemorrhagic Infarct: 1. In tissues that have a double blood supply , e.g., lung, intestines and liver permitting some continued flow into the area although the amount is not sufficient to prevent infarction. The infarct is red because of extravasation of blood in the infarcted area from necrotic small vessels. 2. With venous occlusion (such as in ovarian torsion) 3. In loose tissues (such as lung), which allow blood to collect in the infarcted zone. 4. In tissues that were previously congested because of sluggish venous outflow 5. When flow is reestablished to a site of previous arterial occlusion Red and White Infarct Red and white infarcts. (A) Hemorrhagic, roughly wedge- shaped pulmonary red infarct. (B) Sharply demarcated white infarct in the spleen. B. SOLID Versus LIQUEFIED INFARCT In all tissues other than brain, infarction usually produces coagulative necrosis of cells, leading to solid infarct. In brain, on the other hand, liquefactive necrosis of cells leads to the formation of a fluid mass in the area of infarction. The end result is a cystic cavity C. STERILE Versus SEPTIC INFARCT Most infarcts are sterile. Septic infarcts are characterized by secondary bacterial infection of the necrotic tissue. Septic infarcts are characterized by acute inflammation that frequently converts the infarcts to an abscess. Secondary bacterial infection of an infarct may also result in gangrene (e.g., intestine). Septic infarcts occur: 1. Due to presence of microorganisms, as in lesions of infective endocarditis 2. When infarction occurs in a tissue that normally contain bacteria , e.g., intestine Brain infarct Liquifactive necrosis Morphology of Infarcts Infarction occurs in tissue supplied by an artery that, when occluded leaves an insufficient collateral blood supply. Infarcts in kidney, spleen and lungs are Wedge Shaped, with the occluded artery situated near the apex of the wedge and the base of the infarct located on the surface of the organ. The cerebral and myocardial infarcts are irregular shaped and determined by the distribution of the occluded artery and the limits of collateral arterial supply. Development of an Infarct The consequences of a vascular occlusion can range from no or minimal effect, all the way up to death of a tissue or even death of the individual The major determinants include: -Anatomy of the vascular supply - important determinant of extent of damage -Rate of occlusion - slow rate = slow to no infarction -Tissue vulnerability to hypoxia - Neurons - only 2-5 minutes; Myocardial cells - 30 mins -Hypoxemia - partial flow obstruction will lead to tissue infarction compared to normal  SHOCK A state of circulatory failure that impaires tissue perfusion and leads to cellular hypoxia At first, it is reversible; prolonged shock leads to irreversible damage and is fatal. Types of Shock Sepsis, septic shock, and the systemic inflammatory response syndrome Neurogenic - Spinal cord injury Anaphylactic shock - IgE-mediated hypersensitivity reaction ○ Acute vasodilation leads to hypotension and tissue hypoperfusion  Pathogenesis of Shock 1 4 3 2 Pathogenesis of Shock Pathogenesis of Shock 1. HYPOVOLEMIC SHOCK: Hypovolemia may be due to : -Haemorrhage: Either External or Internal -Excessive Fluid Loss: As occurs in diarrhea, vomiting, burns, dehydration, or excessive sweating 2. CARDIOGENIC SHOCK: Cardiogenic Shock results from a severe reduction in cardiac output due to primary cardiac disease, for example: Acute Myocardial Infarction, Acute Myocarditis, Ventricular Rupture, Arrhythmias 3. OBSTRUCTIVE SHOCK: Obstruction to blood flow in the heart or main pulmonary artery, as occurs in massive pulmonary embolism Pathogenesis of Shock 4. NEUROGENIC SHOCK Shock due to neurogenic stimuli is seen: -During anesthesia, In spinal cord injury The underlying mechanism which leads to shock in these conditions is Peripheral Vasodilatation. Widespread vasodilatation in small vessels leads to excessive pooling of blood in peripheral capacitance vessels. The result is reduction of effective blood volume and therefore a decreased cardiac output (Peripheral Circulatory Failure). Septic Shock Components NF-kB Septic Shock OUTCOME -Depends on the extent, virulence of the infection -The immune status of the host -Presence of comorbid conditions -Pattern and level of mediator production - if they are lessened or becomes worse Difficulty is in the concurrent activation of pro-inflammatory and anti-inflammatory mediators. Stages of Shock Initial nonprogressive stage Progressive stage Irreversible stage Non-progressive Stage In this phase a variety of neurohumoral mechanisms (compensatory mechanisms) help to maintain cardiac output and blood pressure. These include: -Baro receptor reflexes -Release of catecholamine -Activation of renin- angiotensin axis -Antidiuretic hormone release -Generalized sympathetic stimulation. The net effect is tachycardia, peripheral vasoconstriction and renal conservation of fluid. Cutaneous (skin) vasoconstriction is responsible for the characteristic coolness and pallor of skin in well developed shock. Vasoconstriction in renal arterioles decreases the pressure and rate of glomerluar filtration with resulting decreased urine output (oliguria). Progressive Phase If the underlying causes are not corrected, shock passes imperceptibly to the progressive phase. During which there is widespread tissue hypoxia. In the this stage anaerobic respiration is replaced by anaerobic glycolysis with excessive production of lactic acid (Metabolic Acidosis). With widespread tissue hypoxia, vital organs are affected and begin to fail; clinically patient becomes confused and the urinary output declines. Irreversible Shock Unless there is intervention the process enters irreversible stage. Lysosomal enzymes release further worsens the shock state. At this stage patient develops complete renal shut down due to tubular necrosis. Despite all measures, the downward clinical spiral almost inevitably culminates in death Clinical Outcome The clinical manifestations depend on the precipitating insult. In hypovolemic and cardiogenic shock the patient presents with hypotension; a weak, rapid pulse, tachypnea, and cool, clammy skin, cyanotic skin. In septic shock, however, the skin may initially be warm and flushed because of peripheral vasodilatation. If the compensatory mechanisms fail then eventually electrolyte imbalances and metabolic acidosis also deteriorates the situation. Then patient enters into renal failure. If the cause of shock can be treated, e,g., hypovolemia, then patient will survive. But patients in whom cause can not be treated , e.g., massive myocardial infarction, the patient will die. Stages of Shock