Hemodynamic Disorders, Thromboembolic Disease, and Shock PDF

TRANS 4.1...

TRANS 4.1 9/15/24 HEMODYNAMIC DISORDERS, THROMBOEMBOLIC DISEASE, AND SHOCK Homeostasis Edema and Effusions - As blood passes through capillary beds, CHONs in the Cardiovascular, Renal, Hepatic Functions plasma are retained within the vascular, and there is little Edema Effusion net movement of water and electrolytes into the tissues Accumulation of Fluid in Accumulation of Fluid in Alteration of Homeostasis by Pathologic Conditions Tissues Body Cavities - Alteration of Endothelial Function Under Normal Circumstances - ↓ Vascular Hydrostatic Pressure - Hydrostatic Pressure (The tendency to push water & salts - ↑ Plasma CHON content out of capillaries into the interstitial space) is nearly *All of which promotes Edema balanced by Plasma Colloid Osmotic Pressure (the Edema tendency to pull water & salts back into vessels - Accumulation of fluid in tissues resulting from a net *there is usually a small net movement of fluid into the Interstitium, but this drains into lymphatic vessels & ultimately returns to the movement of water into extravascular spaces bloodstream via Thoracic Duct keeping the tissues “Dry” *Effects ranges from mild discomfort to life-threatening conditions Hemostasis In Pathologic Disorders *Disruption of the balance ↑ Hydrostatic Pressure or ↓ Colloid Osmotic Pressure - The process of blood clotting that prevents *results in excessive bleeding after blood-vessel damage. *Inadequate hemostasis may result in Hemorrhage, which can Extravasation of Fluid into Tissues (↑ Movement of fluid out of vessels) compromise regional tissue perfusion, & if massive & rapid, may lead to Hypotension, Shock & death NOTE: Lymphatic Vessels Thrombosis Embolism - Remove much of the excess fluid - If the Net Rate of fluid movement exceeds the rate Inappropriate Clotting Migration of Clots of lymphatic drainage, fluid accumulates NOTE: Infarction - Ischemic Cell death caused by obstruction of blood Edema fluids & Effusions may be: vessels Inflammatory Non-Inflammatory 3 major Causes of Morbidity & Mortality in High Exudates Transudates Income Countries CHON-rich CHON-poor - Myocardial Infarction (MI) accumulate due to ↑ in Are common in many - Pulmonary Embolism (PE) vascular permeability disorders like Heart failure, - Cerebrovascular Accident (Stroke) caused by inflammatory Liver failure, Renal disease, mediators Malnutrition Figure 4.1 Factors Influencing Fluid Movement Across Figure 4.2 Mechanisms of Systemic Edema Capillary Walls in Heart Failure, Renal Failure, Malnutrition, Hepatic Failure, Nephrotic Syndrome Table 4.1 Pathophysiologic Categories of Edema ↑ Hydrostatic Pressure ↓ Plasma Osmotic Pressure (Hypoproteinemia) Impaired Venous Return *Main cause - CHON-losing Glomerulopathies (Nephrotic Syndrome) - Congestive Heart Failure (Widespread) - Liver Cirrhosis - Constrictive Pericarditis - Malnutrition - Ascites (Liver Cirrhosis) - CHON-losing Gastroenteropathy - Venous Obstruction or Compression (Localized) o Thrombosis (Deep Venous Thrombosis / DVT) Lymphatic Obstruction o External Pressure (Mass) - Inflammatory - Postsurgical - Lower Extremity Inactivity with prolonged Dependency - Neoplastic - Postirradiation Arteriolar Dilation Sodium Retention - Heat - Neurohumoral Dysregulation - Excessive salt intake with Renal Insufficiency Inflammation - ↑ Tubular Reabsorption of Na2+ - Acute Inflammation - Angiogenesis o Renal Hypoperfusion - Chronic Inflammation o ↑ Renin-Angiotensin-Aldosterone Secretion MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Increased Hydrostatic Pressure Sodium and Water Retention Main Cause: Disorders that impair Venous Return Effect of ↑ Salt Retention – with obligate retention of associated water Localized Impairment Systemic Impairment - ↑ Hydrostatic Pressure (due to intravascular fluid volume expansion) Resulting Edema is Associated with more - ↓ Vascular Colloid Osmotic Pressure (due to Dilation) confined to the affected part widespread Edema *Salt retention occurs whenever Renal Function is DVT Congestive Heart Failure compromised (Primary Kidney Disorders & Cardiovascular Disorders) that decrease Renal Perfusion Reduced Plasma Osmotic Pressure Common Cause: Most important cause of Renal Hypoperfusion: - Conditions leading to inadequate synthesis or ↑ Congestive Heart Failure loss of Albumin from the Circulation *like Hypoproteinemia, results in Activation of RA-AS NOTE: Albumin NOTE: In early Heart Failure - Accounts for almost ½ of the total plasma CHON - This response is beneficial as the retention of Na2+ Reduced Albumin Synthesis Albumin Loss & H2O & other adaptations (including ↑ vascular tone & ↑ Severe Liver Disease Nephrotic Syndrome levels of ADH) improve Cardiac Output & Restore CHON Malnutrition Normal Renal Perfusion NOTE: Regardless of the cause, ↓ Plasma Osmotic As Heart Failure worsens & cardiac output diminishes Pressure leads in stepwise fashion to: The retained fluid merely ↑ the Hydrostatic Pressure, - Edema - Renal Hypoperfusion leading to Edema & Effusions - ↓ Intravascular Volume - Secondary Hyperaldosteronism Lymphatic Obstruction Factors that disrupt Lymphatic Vessels & impair the *Not only does the ensuing Salt & Water retention by the kidney fail to correct the plasma volume deficit, but also clearance of interstitial fluid: exacerbates the Edema - Trauma - Invasive Tumors (Because the Primary defect – a low plasma CHON level - persists) - Fibrosis - Infectious Agents Resulting in: Lymphedema in the affected part of the body Example: Filariasis Severe removal of the upper extremity may also complicate surgical removal and/or irradiation of the breast and associated axillary lymph nodes in patients with breast cancer Edema Morphology Gross Appearance Microscopic Appearance Swelling of an affected part Clearing & Separation of the ECM & subtle cell swelling Most commonly seen in: Subcutaneous Tissues Lung, Brain Subcutaneous Edema Pulmonary Edema - Can be diffuse or more conspicuous in regions with - The lungs are often 2 or 3x their normal weight, and high hydrostatic pressures sectioning yields frothy, blood-tinged fluid Dependent Edema - A mixture of Air, Edema, & Extravasated Red cells - Distribution is influenced by Gravity (appears in legs when standing & the sacrum when recumbent) Pitting Edema - Finger pressure over markedly edematous subcutaneous tissue displaces the interstitial fluid & leaves a depression Periorbital Edema Brain Edema - Characteristic finding in severe renal disease -Can be localized or generalized depending on the Edema resulting from Renal Dysfunction nature & extent of the pathologic process or injury - Often appears initially in parts of the body containing - The swollen brain exhibits narrowed sulci & distended Loose CT (eyelids) gyri, which are compressed by the unyielding skull NOTE: Effusion common in a wide range of clinical settings NOTE: Peritoneal Effusions caused by Lymphatic Blockage - Pleural Cavity (Hydrothorax) - Chylous Effusion - Pericardial Cavity (Hydropericardium) - Exceptions for Transudative Effusion - Peritoneal Cavity (Hydroperitoneum / Ascites) - May be milky due to the presence of Lipids absorbed Transudative Effusion Exudative Effusion from the Gut CHON-poor, Translucent, CHON-rich, & often cloudy Straw colored *due to the presence of WBC Clinical Features Subcutaneous Edema Peritoneal Effusion (Ascites) - Important primarily because it signals potential underlying Resulting most commonly from: Portal Hypertension cardiac or renal disease. - Are prone to seeding by bacteria, leading to serious and - When significant, it can also impair wound healing & the sometimes fatal infections clearance of infection Pulmonary Edema Brain Edema - A common clinical problem that is most frequently seen in - Life threatening the setting of Left Ventricular Failure If severe, brain substance can: It can also occur with: - Herniate (extrude) through the foramen magnum, or o Renal Failure o Pulmonary Inflammation - the brain stem vascular supply can be compressed o Acute Respiratory Distress Syndrome o Infection *Either condition can injure the medullary centers & cause Death NOTE: Edema in the pulmonary interstitium & the alveolar spaces - Impedes Gas exchange (leading to Hypoxemia) and also Creates a favorable environment for Bacterial Infection - Is often exacerbated by: Pleural Effusions which may further compromise gas exchange by compressing the underlying pulmonary parenchyma MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Hyperemia & Congestion Chronic Passive Congestion Similarities: Both stem from: ↑ Blood volumes within tissues - The associated Chronic Hypoxia may result in Differences: Have different underlying mechanisms & consequences Ischemic Tissue Injury & Scarring Hyperemia Congestion Active process Passive process Arteriolar dilation (at sites of resulting from ↓ Venous In Chronically Congested Tissues Inflammation or in Skeletal muscle Outflow of blood from a - Capillary rupture can also produce small during exercise) leads to ↑ Tissue hemorrhagic foci Blood Flow - Subsequent catabolism of extravasated red cells Affected tissues turn Red Can be Systemic (Cardiac can leave residual telltale clusters of Hemosiderin- (Erythema) Failure) laden macrophages *because of ↑ delivery of or Localized (Isolated Venous oxygenated blood Obstruction) NOTE: Congested tissues NOTE: Congestion commonly leads to Edema - Have an abnormal Blue-Red color (Cyanosis) that stems from - As a result of ↑ hydrostatic pressures, the accumulation of deoxygenated Hgb in the affected area Morphology of a Congested Tissue Macroscopic Appearance: Dusky Reddish-blue color (Cyanosis) due to red cell stasis & the presence of deoxygenated Hgb Microscopic Appearance in Acute Pulmonary Congestion in Chronic Pulmonary Congestion Is marked by: Engorged alveolar capillaries, alveolar septal Often caused by: Congestive Heart Failure edema, Focal Intra-alveolar Hemorrhage Septa are: Thickened & Fibrotic, Alveoli: often contain numerous macrophages laden with Hemosiderin (Heart Failure Cells) derived from phagocytosed Red Cells In Acute Hepatic Congestion Chronic Passive Hepatic Congestion Central Vein & Sinusoids: Distended Macroscopic Appearance of The Centrilobular Regions Centrilobular Hepatocytes Periportal Hepatocytes - Grossly red-brown & slightly depressed (because of Cell Death) Relationship with Hepatic Arteriole for Oxygen Supply - are Accentuate against the surrounding zone of Distal Proximal uncongested tan liver (Nutmeg Liver) *Less Oxygenated *More Oxygenated Microscopic Appearance: Cellular Change There is Centrilobular congestion & hemorrhage may undergo may only develop Hemosiderin-laden Macrophages Ischemic Necrosis Fatty Change variable degrees of Hepatocyte dropout & Necrosis Figure 4.3 Liver with Chronic Passive Congestion & Hemorrhagic Necrosis Central areas: Red & Slightly depressed Centrilobular Necrosis with degenerating Hepatocytes & Surrounding Areas: Tan viable parenchyma Hemorrhage forming a “Nutmeg Liver” Pattern (resemblance to a cut surface of a Nutmeg) Hemostasis, Hemorrhagic Disorders, & Thrombosis DIC: Generalized activation of clotting producing bleeding Hemostasis due to the consumption of Coagulation Factors - The process by which blood clots form at sites of Normal Hemostasis vascular injury A precisely orchestrated process involving: Hemorrhagic Disorder Thrombotic Disorder - Platelets Excessive bleeding Blood clots form - Clotting factors, and Hemostatic mechanisms are within intact blood vessels - Endothelium either blunted or insufficient or within the chambers of that occurs at the: Site of Vascular Injury to prevent blood loss the heart and culminates in: the Formation of a Blood Clot NOTE: Thrombosis *which serves to prevent or limit the extent of bleeding. - Has a central role in the most common & clinically important forms of cardiovascular disease MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 General Sequence of Events Leading to Hemostasis at a site of Vascular Injury Arteriolar Vasoconstriction Transient - Occurs immediately and markedly reduced blood flow to the injured area Mediated by: Reflex Neurogenic mechanisms Augmented by: Local Secretion of factors (Endothelin) *a potent Endothelium-derived Vasoconstrictor *Effect is transient & bleeding would resume if not for activation of Platelets and Coagulation Factors Primary Hemostasis Platelet Plug Formation - Disruption of the Endothelium exposes subendothelial vWF & Collagen, which promote PLT adherence & Activation. - Activation of PLT results in a dramatic shape change (from small rounded discs to flat plates with spiky protrusions that markedly increase surface area), as well as the release of secretory granules. - Within a few minutes, the secreted products recruit additional PLT that undergo aggregation to form a Primary Hemostatic Plug. *PLT bind via GpIb receptors to vWF on the exposed ECM & are activated, undergoing a shaped change & granule release. Released ADP & TxA2 induce additional PLT Aggregation through PLT GpIIb-IIIa receptor binding to fibrinogen, & form a Primary Hemostatic Plug Secondary Hemostasis Fibrin Deposition - Vascular injury exposes tissue factor at the site of injury Tissue Factor: A membrane-bound Procoagulant GP Normally expressed by: Subendothelial cells *in the vessel wall (such as Smooth muscle cells & Fibroblasts) - Tissue Factors binds & 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, & also is a potent activator of PLT, leading to additional PLT Aggregation at the site of Injury *Local activation of the coagulation cascade (involving tissue factor & PLT Phospholipids) results in Fibrin Polymerization, “cementing” the PLT into a definitive Secondary Hemostatic Plug Clot Stabilization & Resorption - Polymerized fibrin and Platelet aggregates undergo contraction to form a solid, permanent plug that prevents further hemorrhage. - At this stage, counterregulatory mechanisms (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 *Counterregulatory Mechanisms, mediated by tissue plasminogen activator (t-PA: A Fibrinolytic product) and Thrombomodulin, confine the Hemostatic process to the site of injury. NOTE: Endothelial Cells as Central Regulator of Hemostasis - The balance between the Antithrombotic and Prothrombotic activities of Endothelium determines whether Thrombus formation, Propagation, or Dissolution occur. - Normal Endothelial cells express a variety of Anticoagulant factors that inhibit Platelet Aggregation and coagulation and promote fibrinolysis - After injury or activation, this balance shifts, and Endothelial cells acquire numerous Procoagulant activities. Activators of Endothelium: Trauma, Microbial Pathogens, Hemodynamic Forces, Pro-inflammatory Mediators. MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Platelets - Endothelial cells activated by Inflammatory - cytokine downregulate the expression of Thrombomodulin (a key modulator of Thrombin Coagulation Cascade Activity, enhancing the Procoagulant & - Proinflammatory actions of Thrombin) Endothelium - In addition, inflamed Endothelium also - downregulates the expression of other anticoagulants (CHON-C & Tissue Factor CHON NOTE: - Inhibitor) changes that further promote a procoagulant state Hemorrhagic Disorders Antifibrinolytic Effects - Activated Endothelial Cells secrete Plasminogen NOTE: Activator Inhibitors (PAIs), which limit Fibrinolysis, - and downregulate the expression of t-PA, alterations that also favor development of Thrombi Thrombosis Alterations in No Blood Flow Primary Abnormalities that lead to Thrombosis Normal Blood Flow: Laminar 1. Endothelial Injury *PLT (and other blood cellular elements) flow centrally in 2. Stasis / Turbulent Blood Flow the vessel lumen, separated from the Endothelium by a 3. Hypercoagulability of the blood slow-moving layer of Plasma Turbulence - contributes to Arterial & Cardiac Thrombosis - by causing Endothelial injury or dysfunction as well as by forming countercurrents that contribute to local pockets of stasis, Stasis - A major contributor to the development of Venous Thrombi Turbulence & Stasis Promote Endothelial Activation - Enhancing procoagulant activity and leukocyte adhesion in part through flow-induced changes in the expression of adhesion molecules and pro- inflammatory factors Disrupt Laminar Flow - And bring PLT into contact with Endothelium Prevent Washout and Dilution of Activated Clotting Factors - By fresh flowing blood and the inflow of clotting Figure 4.12 The Virchow Triad of Thrombosis factors inhibitors Most important Factor: Endothelial Integrity In Ulcerated Atherosclerotic Plaques *Injury to Endothelial Cells can alter Local Blood Flow & affect - Not only expose Subendothelial vWF and tissue Coagulability factors but also cause Turbulence *Abnormal Blood Flow (Stasis / Turbulence) can cause Endothelial Injury In Aortic & Arterial Dilations (Aneurysms) These factors may promote Thrombosis Independently or in Combination - Result in local stasis and are therefore fertile sites Endothelial Injury for Thrombosis - Leading to PLT Activation almost inevitably In Acute Myocardial Infarction underlies Thrombus Formation in the Heart & - Results in areas of noncontractile myocardium and Arterial Circulation, where the high rates of blood sometimes in cardiac aneurysm; both are flow impede clot formation. associated with Stasis and Flow Abnormalities that - Cardiac and arterial clits are typically rich in PLT, promote the formation of Cardiac Mural Thrombi and it is believed that PLT Adherence & Activation Rheumatic Mitral Valve Stenosis is necessary prerequisite for Thrombus Formation - Results in Left Atrial dilation; in conjunction with under high shear stress (Arteries) Atrial Fibrillation, a dilated atrium is a site of profound Stasis and a prime location for *Aspirin & other PLT Inhibitors in Coronary Artery Disease Thrombosis & Acute MI Hyperviscosity (Polycythemia Vera) - Increases Resistance to flow and causes small Severe Endothelial Injury vessel stasis - May trigger Thrombosis by exposing vWF & Tissue Deformed red cells in Sickle Cell Anemia Factor. - Impede blood flow through small vessels, with the Inflammation & other Noxious Stimuli resulting stasis also predisposing to Thrombosis - Also promote Thrombosis by shifting the pattern of Hypercoagulability gene Expression in Endothelium to one that is Refers to an Abnormally high Tendency of blood to clot, & “Prothrombotic” is typically caused by Alteration in Coagulation Factors - This change is sometimes referred to as” Endothelial Activation or Dysfunction” and can be Important role in Venous Thrombosis produced by diverse exposures, including Physical Primary (Genetic) Secondary (Acquired) Injury, Infectious Agents, Abnormal Blood Flow, Most Common are: Inflammatory Mediators, Metabolic Abnormalities Point mutations in the (Hypercholesterolemia, Homocystinemia, Toxins Factor V gene & absorbed from Cigarette Smoke) Prothrombin gene Major Prothrombotic Alterations Fate of the Thrombus Procoagulant Changes MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Table 4.2 Hypercoagulable States Primary (Genetic) Secondary (Acquired) Common Strong Risk Factors for Thrombosis - Factor V Mutation (Most Common) - Prolonged bed rest or Immobilization *Arg to Gln substitution in AA residue 506 leading to resistance to activated Protein C - Myocardial Infarction - Prothrombin Mutation (Most Common) - Atrial Fibrillation *G202I0A noncoding sequence variant leading to increased Prothrombin levels - Tissue Injury (Surgery, Fracture. Burn) - Cancer - ↑ Levels of Factors VIII, IX, XI, or Fibrinogen *Genetics Unknown - Prosthetic Cardiac Valves - Disseminated Intravascular Coagulation Rare - Heparin-Induced Thrombocytopenia - Antithrombin III Deficiency - Antiphospholipid Antibody Syndrome - Protein C Deficiency Other Risk Factors for Thrombosis - Protein S Deficiency - Cardiomyopathy - Nephrotic Syndrome Very Rare - Hyperestrogenic States (Pregnancy & Postpartum) - Fibrinolysis Defects - Oral Contraceptive Use - Homozygous Homocystinuria - Sickle Cell Anemia *Deficiency of Cystathione B-synthetase - Smoking Factor V Leiden Prothrombin Gene Mutation Other Inherited Causes Homocysteinemia MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Morphology Thrombi *Can develop anywhere in the Cardiovascular System & vary in size & shape depending on the involved site & the underlying cause Feature Arterial / Cardiac Thrombi Venous Thrombi Primary Site of Formation Arteries (↑ Pressure Vessels) Veins (↓ Pressure Vessels) Mechanism of Formation Occurs at Sites of Endothelial Injury or Turbulence Occurs at Sites of Stasis (Sluggish blood flow) Direction of Propagation Retrograde (against blood flow direction) Anterograde (Extends in the Direction of blood flow) *both Propagate Toward the Heart Friable meshwork of PLT, Fibrin, Red Cells, & More enmeshed Red Cells, fewer PLT Composition *a.ka Red Thrombi / Stasis Thrombi degenerating Leukocytes Occlusiveness Frequently Occlusive Almost always Occlusive Veins of Lower Extremities (90% of Cases), Common Sites Coronary, Cerebral, & Femoral arteries Upper Extremities, Periprostatic Plexus, (in decreasing order of frequency) Ovarian & Periuterine Veins Under special circumstances, they can also occur in the dural sinuses, portal vein or hepatic vein Lines of Zahn Present Present (PLT & Fibrin deposits alternating with Red Cell layers) (but often more subtle than in Arterial Thrombi) Relationship with Commonly associated Not Typically Associated Atherosclerosis (with Ruptured Atherosclerotic Plaque) Although these are usually superimposed on a ruptured Atherosclerotic plaque. Other vascular injuries (Vasculitis, Trauma) may be the underlying cause MI, Arrhythmias, Dilated Cardiomyopathy, Hypercoagulable states, Sluggish blood flow, Associated Conditions Atherosclerosis Immobility Terminology May be called Mural Thrombi Known as Phlebothrombosis (when formed in Heart chambers or Aorta) Attachment to Vessel Wall Focally attached at the site of initiation Focally attached but often extends as a long cast Risk of Embolization High High (due to poorly attached propagating portion) especially with larger thrombi The propagating portion of a Thrombus is often poorly attached and therefore prone to fragmentation and Embolization NOTE: Mural Thrombi - Thrombi occurring in heart chambers or in the aortic lumen - Abnormal myocardial contraction (Arrhythmias, Dilated Cardiomyopathy, MI) or Endomyocardial Injury (Myocarditis or Catheter Trauma) promotes cardiac Mural Thrombi & Ulcerated Atherosclerotic Plaque and Aneurysmal Dilation underlie Aortic Thrombi Figure 4.14 Mural Thrombi Thrombus in the Left and Right Ventricular apices, overlying a White Fibrous Scar Laminated Thrombus in a dilated abdominal Aortic Aneurysm (*). Numerous friable mural thrombi are also superimposed on advanced atherosclerotic lesions of the more proximal aorta (Left side) Feature Antemortem Clots (Venous / Arterial) Postmortem Clots Time of Formation Forms before death Forms after death Laminated with Lines of Zahn Gelatinous, with two distinct portions: Appearance (Pale Platelet & Fibrin deposits alternating with darker red Dark-Red lower portion (due to settled red cells) cell-rich layers) Yellow upper portion ("chicken fat" appearance) Texture Firm & Dry Soft & Gelatinous Attachment to Vessel Wall Firmly or focally attached Usually Not attached More Homogeneous with alternating layers Dark-Red and Yellow Color (Lines of Zahn) (Dependent on gravity) Blood Flow Influence Forms in Flowing Blood Forms in Stagnant Blood (which leads to the creation of lines of Zahn) (after circulation stops) Clinical Significance Pathological No Clinical Significance (can lead to embolism or occlusion) (occurs as part of natural postmortem changes) Result of pathological processes like Due to settling of blood components by gravity Formation Mechanism turbulence, stasis, endothelial injury after death NOTE: Vegetations - Thrombi on Heart Valves - May be Infected or Sterile - Blood-borne bacteria or fungi can adhere to previously damaged valves (due to Rheumatic Heart Disease) or may cause valve damage directly; in either case, Endothelial Injury & disturbed blood flow can induce the formation of large thrombotic masses (Infective Endocarditis) - Sterile vegetations can also develop on noninfected valves in persons with Hypercoagulable states (Nonbacterial Thrombotic Endocarditis) - Less commonly, sterile verrucous endocarditis (Libman-Sacks Endocarditis) can occur in the setting of SLE MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Fate of the Thrombus MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Disseminated Intravascular Coagulation (DIC) A widespread Thrombosis within the Microcirculation that may be of sudden or insidious onset. It is not a specific disease but rather a complication of a large number of conditions associated with Systemic Activation of Thrombin. Disorders which can be complicated by DIC: - Ranging from Obstetric complications to advanced Malignancy - which leads to widespread formation of thrombi in the microcirculation. These microvascular thrombi can cause diffuse circulatory insufficiency & organ dysfunction, particularly of the Brain, Lungs, Heart, & Kidneys. Figure 4.16 Embolus from a lower extremity deep To complicate matters, the runaway thrombosis “uses up” venous thrombosis, lodged at a pulmonary artery platelets & coagulation factors (hence the synonym Consumptive branchpoint Coagulopathy) & often activates fibrinolytic mechanisms. Overview of the Major Functional Consequences of NOTE: Symptoms initially related to Thrombosis Pulmonary Emboli - Can evolve into a bleeding catastrophe, such as - Most PE (60 – 80%) are clinically silent because Hemorrhagic stroke or Hypovolemic shock they are small. With time they become organized Embolism and are incorporated into the vascular wall; in some cases organization of the thromboembolus Embolus: A detached intravascular solid, liquid, or leaves behind a delicate, bridging fibrous web gaseous mass that is carried by the blood from - Sudden death, acute right heart failure (cor its point of origin to a distant site, where it often pulmonale), or cardiovascular collapse occurs causes tissue dysfunction or infarction when emboli obstruct 60% or more of the Thromboembolism pulmonary circulation - Vast majority of emboli are dislodged thrombi - Embolic obstruction of medium-sized arteries with Other rare emboli are composed of: subsequent vascular rupture can result in - Fat Droplets - Tumor fragments pulmonary hemorrhage but usually does not cause - Nitrogen bubbles - Bone marrow pulmonary infarction. This is because the lung is - Atherosclerotic debris - Foreign bodies supplied by both the pulmonary arteries and the (Cholesterol emboli) bronchial arteries, and the intact bronchial Emboli travel through the blood until they encounter vessels too circulation is usually sufficient to perfuse the small to permit further passage, causing Partial or Complete affected area. Understandably, if the bronchial Vascular Occlusion arterial flow is compromised (by left-sided cardiac NOTE: Emboli can lodge anywhere in the vascular tree failure), infarction may occur - Depending on where they originate - Embolic obstruction of small end-arteriolar Clinical Consequences (dependent on) pulmonary branches often does produce - Size & the position of the lodged embolus hemorrhage or infarction - Vascular bed that is impacted - Multiple emboli over time may cause pulmonary hypertension and right ventricular failure. Pulmonary Embolism (PE) Origin: Deep Vein Thrombosis (DVT) Systemic Thromboembolism Most common form of Thromboembolic disease Most Systemic Emboli (80%) arise from Intracardiac Mural Thrombi A common and serious disorder. It is more common in 2/3 associated with Left Ventricular Wall Infarctions males than in females ¼ with Left Atrial Dilation and Fibrillation Fragmented thrombi from DVT are carried through The remainder originates from Aortic Aneurysms, progressively larger veins and the right side of the heart Atherosclerotic plaques, valvular vegetations, Venous before slamming into the pulmonary arterial vasculature. Thrombi (Paradoxical Emboli); 10 – 15% are of unknown origin Depending on the size of the embolus, it can occlude the main pulmonary artery, straddle the pulmonary artery In contrast to venous emboli, the vast majority of which bifurcation (Saddle Embolus), or pass out into the smaller, lodge in the lung, arterial emboli can travel to a wide variety branching arteries of sites; the point of arrest depends on the source and the relative amount of blood flow that downstream tissues Frequently there are multiple emboli, occurring either receive. sequentially or simultaneously as a shower of smaller emboli from a single large mass; in general, the patient who Most come to rest in the lower extremities (75%) or the has had one PE is at high risk for more. brain (10%) but other tissues, including the intestines, kidneys, spleen, and upper extremities, may be involved. NOTE: Paradoxical Embolism - A venous embolus passes through an interatrial or Consequences of systemic emboli depend on the interventricular defect and gains access to the vulnerability of the affected tissues to ischemia, the caliber systemic arterial circulation. of the occluded vessel, and whether a collateral blood supply exists; in general, however, the outcome is tissue infarction NOTE: MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Fat Embolism Air Embolism Refers to the presence of microscopic fat globules – Gas bubbles within the circulation can coalesce to form sometimes with associated hematopoietic bone marrow – Frothy masses that obstruct vascular flow & cause Distal in the vasculature after fractures of long bones or, rarely, in Ischemic Injury the setting of soft-tissue trauma and burns Can occur when there is communication between: Vasculature & Outside Air It is fairly common, occurring in some 90% of individuals and a Negative Pressure Gradient that “sucks” in the air with severe skeletal injuries. Presumably these injuries rupture vascular sinusoids in the marrow or small venules, Introduction of Air in the cerebral circulation along marrow or adipose tissue to herniate into the vascular By: Neurosurgery in the “Sitting Position” space and travel to the lung. Fat embolism syndrome is the (*creating Gravitational Gradient) term applied t the minority of patients who become Other Mechanisms of Air Introduction symptomatic. During Endovascular & Interventional procedures as well as during Mechanical ventilation Volume of Air necessary to produce a clinical effect in the pulmonary circulation: more than 100mL (generally) *unless care is taken, this volume of air can be inadvertently introduced during Obstetric or Laparoscopic procedures, or as a consequence of chest wall injury Volume of air with Fatal Effects: 300 – 500mL at 100mL/sec Consequences of Air Microemboli trapped in the pulmonary vasculature: - Blockage of perfusion of downstream region. - Induction of an intense Inflammatory response with release of cytokines that may injure the alveoli Figure 4.17 Bone Marrow Embolism in the Pulmonary Bubbles in the CNS: Circulation - Can cause mental impairment - The cellular elements on the Left side of the - & even sudden onset of coma embolus are hematopoietic cells, and the cleared NOTE: Decompression Sickness vacuoles represent marrow fat - A form of Gas Embolism - The relatively uniform red area on the right of the embolus is an early organizing thrombus Mechanism of Occurrence: - When individuals experience sudden ↓ in Atmospheric Pressure Fat Embolism Syndrome is characterized by: Pulmonary - When air is breath at High pressure (during a deep- Insufficiency, Neurologic Symptoms, Anemia, and sea dive), ↑ amount of gas (particularly Nitrogen) is Thrombocytopenia, and is Fatal in 5 – 15% of cases dissolved in the Blood & Tissues - If the diver then ascends (Depressurizes) too Typically, 1 – 3 days after injury there is a sudden onset of rapidly, the Nitrogen comes out of solution in the Tachypnea, Dyspnea, and Tachycardia; Irritability; and tissues & the blood restlessness that can progress to Delirium or Coma. People at risk Thrombocytopenia is attributed to platelet adhesion to fat - Scuba & Deep-Sea Divers globules and subsequent aggregation or splenic - Underwater construction workers sequestration; anemia can result from similar red cell Bends aggregation and / or Hemolysis. - Painful condition resulting from the rapid formation of gas bubbles within skeletal muscles & A diffuse petechial rash (seen in 20 – 50% of cases) is supporting tissues in and about joints related to rapid onset of Thrombocytopenia and can be a History: so named in the 1880s because it was noted that useful diagnostic clue those afflicted characteristically arched their backs in a manner reminiscent of a then-popular women’s The pathogenesis of fat embolism syndrome involves both fashion pose called the Grecian Bend) mechanical obstruction and biochemical injury. Chokes Fat Microemboli and associated red cell and platelet - A form of Respiratory Distress aggregates can occlude the pulmonary and cerebral - Resulting from gas bubbles in the vasculature microvasculature. causing Edema, Hemorrhage, & Focal Atelectasis or Emphysema Release of free fatty acids from the fat globules Caisson Disease exacerbates the situation by causing local toxic injury to - A more chronic form of decompression sickness endothelium, and platelet activation and granulocyte History: Named for the pressurized vessels used in bridge recruitment (with free radical, protease, and eicosanoid construction; workers in these vessels suffered both release) complete the vascular assault. acute & chronic forms of decompression sickness - Persistence of gas emboli in the skeletal muscle Because lipids are dissolved out of tissue preparations by system leads to multiple foci of ischemic necrosis solvents routinely used in paraffin embedding, the Common sites: Femoral heads, Tibia, Humeri microscopic demonstration of fat microglobules typically NOTE: Treatment for Acute Decompression Sickness requires specialized techniques, including frozen sections - Individuals affected are treated by being placed in and stains for fat a chamber under sufficiently high pressure to force NOTE: the gas bubbles back into solution. - - Subsequent slow decompression permits gradual resorption & exhalation of the gases, which prevents the obstructive bubbles from reforming. MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Amniotic Fluid Embolism 5th most common cause of maternal mortality worldwide Accounts for roughly 10% of maternal deaths and results in permanent neurologic deficit in as many as 85% of survivors. An ominous complication of labor and immediate postpartum period. The onset is characterized by: - Sudden severe Dyspnea, Cyanosis, Shock, followed by Neurologic Impairment ranging from headache to Seizures and Coma, and by DIC. Note that thee features differ from those observed with Pulmonary Embolism from DVT; in fact, much of the morbidity and mortality in amniotic fluid embolism stems Infarction from the biochemical activation of coagulation factors, Infarct components of the innate immune system, and release of - An area of ischemic Necrosis caused by occlusion vasoactive substances, rather than the mechanical of either the Arterial supply or the venous drainage obstruction of pulmonary vessels by amniotic debris. Arterial Thrombosis / Arterial Embolism - Underlies the vast majority of Infarction The vasoactive substances cause acute pulmonary hypertension and right heart failure, which causes Hypoxia, Less common causes of Arterial Obstruction leading Left Heart Failure, Pulmonary Edema, and Diffuse Alveolar to Infarction Damage - Local Vasospasm The underlying cause is the infusion of amniotic fluid or fetal - Hemorrhage into an atheromatous plaque tissue into the maternal circulation via a tear in the placental - Extrinsic vessel compression (Tumor) membranes or rupture of uterine veins Other uncommon causes of tissue Infarction - Torsion of a vessel (in Testicular torsion or bowel volvulus) Classic findings at autopsy include the presence of: - Traumatic vascular rupture - Squamous Cells shed from fetal skin - Vascular compromise by Edema (Anterior - Lanugo Hair Compartment syndrome of the leg) - Fat from Vernix caseosa - Entrapment in a Hernia Sac - Mucin derived from the Fetal Respiratory or Gastrointestinal Tract in the maternal pulmonary Venous Thrombosis microvasculature - Can also case infarction - The more common outcome is just Congestion - In this setting, bypass channels rapidly open & permit vascular outflow, which then improves arterial inflow - Infarcts caused by venous thrombosis are thus more likely in organs with a single efferent vein (Testis & Ovary) Figure 4.18 Amniotic Fluid Embolism - 2 small pulmonary arterioles are packed with laminated swirls of fetal squamous cells - There is marked edema and congestion - Elsewhere the lung contained small organizing thrombi consistent with disseminated intravascular coagulation NOTE: - MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Classification of Infarcts *according to color & the presence or absence of infection Figure 4.19 A. Hemorrhagic, roughly B. Sharply demarcated white wedge-shaped Pulmonary infarct in the spleen Red Infarct Red Infarcts White Infarcts Occur with: Venous Occlusions (Testicular Torsion) Occur with: Arterial Occlusions 1. In loose, spongy tissues (Lung) where blood can collect - in Solid organs with End-Arterial Circulation (Heart, in the infarcted zone Spleen, Kidney) 2. In Tissues with Dual Circulations (Lung, Small - And where tissue density limits the seepage of blood Intestine) that allow blood to flow from an unobstructed from adjoining capillary beds into the necrotic area parallel supply into a necrotic zone 3. In tissues previously congested by sluggish venous outflow 4. When flow is reestablished to a site of previous arterial occlusion & necrosis (Following Angioplasty of an Arterial Obstruction) Gross Appearance of an Infarct Dominant Histologic Characteristic of Infarction Tend to be Wedge-shaped Ischemic Coagulative Necrosis Occluded vessel at the Apex & the Periphery of the Organ forming *if the vascular occlusion has occurred shortly (minutes to the Base hours) before the death of the person, histologic changes may - When the base is a serosal surface, there may be an be absent; it takes 3 – 12 hours for the dead tissue to show overlying fibrinous exudate resulting from an acute microscopic evidence of necrosis inflammatory response to mediator release from injured and necrotic cells Acute inflammation is present along the margins of infarcts within a few hours and is usually well defined within 1 – 2 days. Fresh infarcts are poorly defined and slightly hemorrhagic, but over a few days the margins tend to become better defined by Eventually a reparative response begins in the preserved a narrow rim and congestion attributable to inflammation margins. In comparison, in the lung hemorrhagic infarcts are the rule If the tissue harbors tissue stem cells, parenchymal regeneration can occur at the periphery where underlying Extravasated red cells in hemorrhagic infarcts are stromal architecture is preserved. However, most infracts are phagocytosed by macrophages, which convert heme iron into ultimately replaced by scar Hemosiderin Small amounts do not grossly impart any appreciable color to Exception to the Generalization: Brain the tissue, but extensive hemorrhage can leave a firm, brown *in that CNS infarction results in Liquefactive Necrosis hemosiderin-rich residuum NOTE: Septic Infarction - Occur when infected cardiac valve vegetations embolize or when microbes seed necrotic tissue - In these cases, the infarct is converted to an abscess, with a correspondingly greater inflammatory response. MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Table 4.3 Major Types of Shock Shock Factors which Play Major roles in Pathophysiology of A state of Circulatory failure that impairs tissue perfusion Septic Shock and leads to cellular Hypoxia. Inflammatory & Counter- *at the outset, the cellular injury is Reversible, however, prolonged Inflammatory Responses shock eventually leads to Irreversible tissue injury & can be fatal - Various microbial cell wall constituents engage NOTE: Complications of Shock receptors on cells of the Innate Immune System, - Severe Hemorrhage - Pulmonary Embolism triggering Pro-inflammatory Responses - Extensive Trauma or Burns - Microbial Sepsis Initiators of Inflammation in Sepsis - Myocardial Infarction Toll-like Receptors TLRs 3 General Categories of Shock Recognize a host of microbe-derived substances containing: - Pathogen-associated Molecular Patterns (PAMPs) Cardiogenic Shock - Damage-associated Molecular Patterns (DAMPs) Results from: Low Cardiac Output due to Myocardial pump failure GPCR This can be due to: - Intrinsic myocardial damage (Infarction) - Detect Bacterial peptides - Ventricular Arrhythmias C-Type Lectin Receptors Dectins - Extrinsic Compression (Cardiac Tamponade) NOTE: Ligation of these receptors leads to: - Outflow Obstruction (Pulmonary Embolism) ↑ Expression of the Genes encoding Inflammatory mediators Hypovolemic Shock via: Activation, & Nuclear Translocation of the Transcription factor Results from: Low Cardiac Output due to Low blood volume Nuclear Factor-κB (NF-κB) Can occur with: - Massive Hemorrhage The Upregulated mediators include: Numerous cytokine TNF, IL-1, IL-12, IL-18, IFN-γ - Fluid loss from severe burns Sepsis, Septic Shock, Systemic as well as other inflammatory mediators such as: Inflammatory Response High-mobility group box 1 Protein (HMGB1) - Interrelated and somewhat overlapping conditions Markers of Acute Inflammation: CRP & Procalcitonin Sepsis ROS, and Lipid Mediators are also elaborated: - Defined as life-threatening organ dysfunction caused Prostaglandins & Platelet-activating Factor (PAF) by a dysregulated host response to infection *These effector molecules induce endothelial cells to upregulate Septic Shock adhesion molecule expression and further stimulate cytokine and - Defined as a subset of Sepsis in which particularly chemokine production. profound circulatory, cellular, & metabolic Activation of Complement Cascade abnormalities are associated with a greater risk of - Activated by microbial components mortality than with sepsis alone Direct Activation Indirect Activation Systemic Inflammatory Response Syndrome (SIRS) through Proteolytic activity of - A sepsis-like condition associated with Systemic Plasmin Inflammation that may be triggered by a variety of Resulting in the production of: nonmicrobial insults (Burns, Trauma, Pancreatitis) - Anaphylotoxins (C3b) NOTE: Pathogenic feature common to SIRS & Septic shock - Chemotactic Fragments (C5a) - Massive Outpouring of inflammatory mediators from - Opsonins (C3b) Innate & Adaptive Immune Cells that produce Arterial *all of which contribute to the pro-inflammatory state. Vasodilation, Vascular Leakage, & Venous Blood Activation of Coagulation Pooling. - Activated by Microbial components Cytokine Release Syndrome Direct Activation Indirect Activation - Observed in cancer patients through Chimeric through Factor XII through Altered Endothelial Function Antigen Receptor T-cell (CAR-T) Therapy The accompanying widespread activation of Thrombin may The cardiovascular abnormalities associated with further augment Inflammation by triggering Protease- SIRS results in: activated receptors on inflammatory cells - Tissue Hypoperfusion Hyperinflammatory State - Cellular Hypoxia - Initiated by: Sepsis - Metabolic Derangements that lead to organ dysfunction - Triggers counter-regulatory immunosuppressive - Organ Failure & Death (if severe and persistent) mechanisms, which may involve both Innate and Adaptive immune cells Less Common Categories of Shock - As a result, septic patients may oscillate between Neurogenic Shock Anaphylactic Shock Hyperinflammatory & Immunosuppressed states during Shock occurring in the An IgE-mediated their clinical course setting of a Spinal cord Injury Hypersensitivity reaction Proposed Mechanisms for the Immune Suppression: NOTE: In both forms of shock, Acute Vasodilation leads to - A shift from Pro-inflammatory (Th1) to Anti-inflammatory Hypotension & Tissue Hypoperfusion (Th2) cytokines - Production of Anti-inflammatory mediators (Soluble TNF Pathogenesis of Septic Shock receptor, IL-1 receptor Antagonist, IL-10), Septic Shock is most frequently triggered by: - Lymphocyte Apoptosis 1. Gram + bacteria 2. Gram – bacteria 3. Fungi - Immunosuppressive effects of Apoptotic cells - Induction of Cellular Anergy MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Figure 4.21 Major Pathogenic Pathways in Septic Shock Microbial Products (PAMPS / Pathogen-associated Molecular Patterns) activate Endothelial cells & Cellular & Humoral elements of the Innate Immune System, initiating a cascade of events that lead to end-stage multiorgan failure. - The vascular leak and tissue edema decrease Endothelial Activation & Injury blood flow at the level of small vessels, producing - The Pro-inflammatory state & Endothelial cell statis and diminishing the washout of activated Activation associated with Sepsis lead to coagulation factors Widespread vascular leakage & tissue Edema, - Acting in concert, these effects lead to systemic which have deleterious effects on both nutrient activation of thrombin and the deposition of fibrin- delivery and waste removal. rich thrombi in small vessels, often throughout the Effect of Inflammatory Cytokines body, further compromising tissue perfusion. - To loosen Endothelial cell Tight Junctions, making - In full-blown DIC, the consumption of coagulation vessels leaky & resulting in the accumulation of factors and platelets is so great that deficiencies of CHON-rich Edema fluid throughout the body these factors appear, leading to concomitant Result of the Alteration bleeding and hemorrhage - Impedes tissue perfusion & may be exacerbated by Metabolic Abnormalities attempts to support the patient w/ intravenous fluids Other effects of Activated Endothelium - Septic patients exhibit insulin resistance and - Upregulates production of NO & other vasoactive hyperglycemia. inflammatory mediators (C3a, C5a, & PAF), which - Cytokines such as TNF & IL-1, stress-induced may contribute to Vascular smooth muscle hormones (glucagon, GH, Glucocorticoids), and Relaxation & Systemic hypotension. catecholamines all drive Gluconeogenesis - Another feature of sepsis is Microvascular - At the same time, the pro-inflammatory cytokines Dysfunction suppress insulin release while simultaneously - There is an increase in capillaries with intermittent promoting insulin resistance in the liver and other flow, & Heterogeneity of flow in various capillary tissues, likely by impairing the surface expression beds, & the normal autoregulation of flow based on of Glucose Transporter-4 (GLUT-4) tissue metabolic environment is lost - Hyperglycemia decreases Neutrophil function – - These changes cause a mismatch in O2 needs & thereby suppressing bactericidal activity – and O2 Delivery causes increased adhesion molecule expression Induction of a Procoagulant State on endothelial cells - Although sepsis is initially associated with an acute - The derangement in coagulation is sufficient to surge in glucocorticoid production, this phase may produce the formidable complication of DIC in up be followed by adrenal insufficiency and a to ½ of septic patient. functional deficit of glucocorticoids. - Sepsis alters the expression of many factors so as - This may stem from depression of the synthetic to favor coagulation. capacity of intact adrenal glands or frank adrenal Pro-inflammatory cytokines necrosis resulting from DIC (Waterhouse- - ↑ Tissue Factor production by Monocytes & Friderichsen Syndrome) possibly Endothelial Cells as well, and - Finally, cellular hypoxia and diminished oxidative - ↓ the production of Endothelial Anticoagulant phosphorylation lead to increased lactate Factors, such as Tissue Factor Pathway Inhibitor, production and lactic acidosis Thrombomodulin, & Protein C. (Fig. 4.10) Organ dysfunction - They also dampen fibrinolysis by ↑ PAI-1 Expression (Fig. 4.10) - Systemic hypotension, interstitial edema, Neutrophil Extracellular Traps (NETs microvascular dysfunction, and small vessel - may also play a role in promoting the procoagulant thrombosis all decrease the delivery of Oxygen and state by stimulating both Intrinsic and Extrinsic nutrients to the tissues that, because of cellular Pathways of coagulation. hypoxia, fail to properly use those nutrients that are delivered. MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 - Mitochondrial damage resulting from oxidative anaerobic glycolysis with excessive production of stress impairs oxygen use lactic acid - High levels of cytokines and secondary mediators - The resultant metabolic lactic acidosis lowers the diminish myocardial contractility and cardiac tissue pH, which blunts the vasomotor response; output; increased vascular permeability and arterioles dilate, and blood begins to pool in the endothelial injury can lead to the acute respiratory microcirculation. distress syndrome. - Peripheral pooling not only worsens the cardiac - Ultimately, these factors may conspire to cause output but also puts endothelial cells at risk for the failure of multiple organs, particularly the kidneys, development of anoxic injury with subsequent DIC liver, lungs, and heart, culminating in death - With widespread tissue hypoxia, vital organs are NOTE: Severity and outcome of Septic Shock affected and begin to fail Is Dependent on: - Extent and Virulence of the Infection Irreversible Stage - Immune status of the Host *In the absence of appropriate intervention, or in severe cases - Presence of other comorbid conditions Widespread cell injury is reflected in Lysosomal enzyme - Pattern and level of mediator production leakage Standard of Care for Septic Shock - Further aggravating the shock state - Remains Antibiotics to treat the underlying - Myocardial contractile function worsens, in part Infection because of increased NO synthesis - IV Fluids - The ischemic bowel may allow intestinal flora to - Pressors enter the circulation, and thus bacteremic shock - Supplemental oxygen to maintain blood pressure may be superimposed and limit tissue Hypoxia - Commonly, further progression to renal failure occurs as a consequence of ischemic injury of the Superantigens kidney, and despite the best therapeutic - Secreted bacterial CHONs interventions, the downward spiral culminates in - Cause a syndrome similar to septic shock (Toxic death Shock Syndrome) - Are polyclonal T-Lymphocyte Activators that induce the release of high levels of Cytokines that result in a variety of clinical manifestations, ranging from a diffuse rash to vasodilation, Hypotension, Shock and Death 3 Stages of Shock *documented most clearly in Hypovolemic shock but are common to other forms as well Initial Nonprogressive Stage - Reflex compensatory mechanisms are activated & vital organ perfusion is maintained Progressive Stage - Characterized by tissue hypoperfusion and onset of worsening circulatory and metabolic derangement, including Acidosis Irreversible Stage - Cellular and tissue injury is so severe that even if the Hemodynamic defects are corrected, survival is not possible Early Nonprogressive Phase of Shock *Various Neurohumoral mechanisms help maintain Cardiac Output & Blood Pressure These mechanisms include: - Baroreceptor Reflexes - Release of Catecholamines & ADH - Activation of RA-AS - Generalized Sympathetic Stimulation Net effect: - Tachycardia - Renal Fluid Conservation - Peripheral Vasoconstriction NOTE: Cutaneous Vasoconstriction Causes the characteristic: “Shocky” Skin coolness & pallor *Notably Septic Shock can initially cause Cutaneous Vasodilation, so the patient may present with warm, flushed skin Coronary & Cerebral Vessels - Are less sensitive to Sympathetic signals - Maintain relatively normal caliber, blood flow, & O2 Delivery - Thus, Blood is shunted away from the skin to the Vital organs such as the Heart & the Brain Progressive Phase *If the underlying causes are not corrected NOTE: Characterized by: Widespread tissue Hypoxia - In the setting of persistent Oxygen deficit, intracellular aerobic respiration is replaced by