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HEMODYNAMIC DISORDERS Jv = ([Pc − Pi] − σ[πc − πi]) •Hemodynamic Disorders •Thromboembolic Disease •Shock Overview • • • • • • • • • Edema (increased fluid in the ECF) Hyperemia (INCREASED flow) Congestion (INCREASED backup) Hemorrhage (extravasation) Hemostasis (keeping blood as a fluid) Thrombosis (clotting blood) Embolism (downstream travel of a clot) Infarction (death of tissues w/o blood) Shock (circulatory failure/collapse) EDEMA • ONLY 4 POSSIBILITIES!!! –Increased Hydrostatic Pressure –Reduced Oncotic Pressure –Lymphatic Obstruction –Sodium/Water Retention WATER • 60% of body • 2/3 of body water is INTRA-cellular • The rest is INTERSTITIAL • Only 5% is INTRA-vascular • EDEMA is SHIFT to the INTERSTITIAL SPACE • HYDRO– -THORAX, -PERICARDIUM, -PERICARDIUM • EFFUSIONS, ASCITES, ANASARCA INCREASED HYDROSTATIC PRESSURE • • • • • • • • • • • Impaired venous return Congestive heart failure Constrictive pericarditis Ascites (liver cirrhosis) Venous obstruction or compression Thrombosis External pressure (e.g., mass) Lower extremity inactivity with prolonged dependency Arteriolar dilation Heat Neurohumoral dysregulation REDUCED PLASMA ONCOTIC PRESSURE (HYPOPROTEINEMIA) • Protein-losing glomerulopathies (nephrotic syndrome) • Liver cirrhosis (ascites) • Malnutrition • Protein-losing gastroenteropathy LYMPHATIC OBSTRUCTION (LYMPHEDEMA) • Inflammatory • Neoplastic • Postsurgical • Postirradiation Na+ RETENTION • Excessive salt intake with renal insufficiency • Increased tubular reabsorption of sodium • Renal hypoperfusionIncreased renin-angiotensin-aldosterone secretion INFLAMMATION • Acute inflammation • Chronic inflammation • Angiogenesis Jv = ([Pc − Pi] − σ[πc − πi]) CHF EDEMA • INCREASED VENOUS PRESSURE DUE TO FAILURE • DECREASED RENAL PERFUSION, triggering of RENINANGIOTENSION-ALDOSTERONE complex, resulting ultimately in SODIUM RETENTION HEPATIC ASCITES • PORTAL HYPERTENSION • HYPOALBUMINEMIA ASCITES RENAL EDEMA • SODIUM RETENTION • PROTEIN LOSING GLOMERULOPATHIES (NEPHROTIC SYNDROME) • • • • • • • EDEMA SUBCUTANEOUS (“PITTING”) “DEPENDENT” ANASARCA LEFT vs RIGHT HEART PERIORBITAL (RENAL) PULMONARY CEREBRAL (closed cavity, no expansion) – HERNIATION of cerebellar tonsils – HERNIATION of hippocampal uncus over tentorium – HERNIATION, subfalcine “Pitting” Edema Transudate vs Exudate • Transudate – results from disturbance of Starling forces – specific gravity < 1.012 – protein content < 3 g/dl, LDH LOW • Exudate – results from damage to the capillary wall – specific gravity > 1.012 – protein content > 3 g/dl, LDH HIGH HYPEREMIA/(CONGESTION) HYPEREMIA Active Process CONGESTION Passive Process Acute or Chronic CONGESTION • LUNG –ACUTE –CHRONIC • LIVER –ACUTE –CHRONIC • CEREBRAL ACUTE PASSIVE HYPEREMIA/CONGESTION, LUNG Kerley B Air Bronchogram CHRONIC PASSIVE HYPEREMIA/CONGESTION, LUNG Acute Passive Congestion, Liver Acute Passive Congestion, Liver CHRONIC PASSIVE HYPEREMIA/CONGESTION, LIVER HEMORRHAGE • EXTRAVASATION beyond vessel • • • • • • • “HEMORRHAGIC DIATHESIS” HEMATOMA (implies MASS effect) “DISSECTION” PETECHIAE (1-2mm) (PLATELETS) PURPURA <1cm ECCHYMOSES >1cm (BRUISE) HEMO-: -thorax, -pericardium, -peritoneum, HEMARTHROSIS • ACUTE, CHRONIC EVOLUTION of HEMORRHAGE • ACUTE CHRONIC • PURPLE GREEN BROWN • HGB BILIRUBIN HEMOSIDERIN HEMATOMA vs. “CLOT” HEMOSTASIS • OPPOSITE of THROMBOSIS –PRESERVE LIQUIDITY OF BLOOD –“PLUG” sites of vascular injury • THREE COMPONENTS –VASCULAR WALL, i.e., endoth/ECM –PLATELETS –COAGULATION CASCADE SEQUENCE of EVENTS following VASCULAR INJURY • ARTERIOLAR VASOCONSTRICTION – Reflex Neurogenic – Endothelin, from endothelial cells • THROMBOGENIC ECM at injury site – Adhere and activate platelets – Platelet aggregation (1˚ HEMOSTASIS) • TISSUE FACTOR released by endothelium, plats. – Activates coagulation cascadethrombinfibrin (2˚ HEMOSTASIS) • FIBRIN polymerizes, TPA limits plug PLAYERS •ENDOTHELIUM •PLATELETS •COAGULATION “CASCADE” ENDOTHELIUM • NORMALLY –ANTIPLATELET PROPERTIES –ANTICOAGULANT PROPERTIES –FIBRINOLYTIC PROPERTIES • IN INJURY –PRO-COAGULANT PROPERTIES ENDOTHELIUM • ANTI-Platelet PROPERTIES – Protection from the subendothelial ECM – Degrades ADP (inhib. Aggregation) • ANTI-Coagulant PROPERTIES – Membrane HEPARIN-like molecules – Makes THROMBOMODULIN Protein-C – TISSUE FACTOR PATHWAY INHIBITOR • FIBRINOLYTIC PROPERTIES (TPA) ENDOTHELIUM • PROTHROMBOTIC PROPERTIES –Makes vWF, which binds PlatsColl –Makes TISSUE FACTOR (with plats) –Makes Plasminogen inhibitors ENDOTHELIUM • ACTIVATED by INFECTIOUS AGENTS • ACTIVATED by HEMODYNAMICS • ACTIVATED by PLASMA PLATELETS • ALPHA GRANULES – Fibrinogen – Fibronectin – Factor-V, Factor-VIII – Platelet factor 4, TGF-beta • DELTA GRANULES (DENSE BODIES) – ADP/ATP, Ca+, Histamine, Serotonin, Epineph. • With endothelium, form TISSUE FACTOR NORMAL platelet on LEFT, “DEGRANULATING” ALPHA GRANULE ON RIGHT AT OPEN WHITE ARROW PLATELET PHASES • ADHESION • SECRETION (i.e., “release” or “activation” or “degranulation”) • AGGREGATION PLATELET ADHESION • Primarily to the subendothelial ECM • Regulated by vWF, which bridges platelet surface receptors to ECM collagen PLATELET SECRETION • BOTH granules, α and δ • Binding of agonists to platelet surface receptors AND intracellular protein PHOSPHORYLATION PLATELET AGGREGATION • ADP • TxA2 (Thromboxane A2) • THROMBIN from coagulation cascade also • FIBRIN further strengthens and hardens and contracts the platelet plug PLATELET EVENTS • ADHERENCE to ECM • SECRETION of ADP and TxA2 • EXPOSE phospholipid complexes • Express TISSUE FACTOR • PRIMARYSECONDARY PLUG • STRENGTHENED by FIBRIN COAGULATION “CASCADE” • • • • • INTRINSIC(contact)/EXTRINSIC(TissFac) ProenzymesEnzymes Prothrombin(II)Thrombin(IIa) Fibrinogen(I)Fibrin(Ia) Cofactors – Ca++ – Phospholipid (from platelet membranes) – Vit-K dep. factors: II, VII, IX, X, Prot. S, C, Z COAGULATION TESTS • • • • • • (a)PTT INTRINSIC (HEP Rx) PT (INR) EXTRINSIC (COUM Rx) BLEEDING TIME (PLATS) (2-9min) Platelet count (150,000-400,000/mm3) Fibrinogen Factor assays THROMBOSIS • Pathogenesis • • • • • • • • Endothelial Injury Alterations in Flow Hypercoagulability Morphology Fate Clinical Correlations Venous Arterial (Mural) THROMBOSIS • Virchow’s TRIANGLE ENDOTHELIAL INJURY ABNORMAL FLOW (NON-LAMINAR) HYPERCOAGULATION ENDOTHELIAL “INJURY” • Jekyll/Hyde disruption –any perturbation in the dynamic balance of the pro- and antithrombotic effects of endothelium, not only physical “damage” ENDOTHELIUM • ANTI-Platelet PROPERTIES – Protection from the subendothelial ECM – Degrades ADP (inhib. Aggregation) • ANTI-Coagulant PROPERTIES – Membrane HEPARIN-like molecules – Makes THROMBOMODULIN Protein-C – TISSUE FACTOR PATHWAY INHIBITOR • FIBRINOLYTIC PROPERTIES (TPA) ENDOTHELIUM • PROTHROMBOTIC PROPERTIES –Makes vWF, which binds PlatsColl –Makes TISSUE FACTOR (with plats) –Makes Plasminogen inhibitors ABNORMAL FLOW • NON-LAMINAR FLOW • TURBULENCE • EDDIES • STASIS • “DISRUPTED” ENDOTHELIUM ALL of these factors may bring platelets into contact with endothelium and/or ECF ˚ 1 HYPERCOAGULABILITY (INHERITED) • COMMONEST: Factor V and Prothrombin defects • Common: Mutation in prothrombin gene, Mutation in methyltetrahydrofolate gene • Rare: Antithrombin III deficiency, Protein C deficiency, Protein S deficiency • Very rare: Fibrinolysis defects ˚ 2 HYPERCOAGULABILITY (ACQUIRED) • • • • • • • • • Prolonged bed rest or immobilization Myocardial infarction Atrial fibrillation Tissue damage (surgery, fracture, burns) Cancer (TROUSSEAU syndrome, i.e., migratory thrombophlebitis) Prosthetic cardiac valves Disseminated intravascular coagulation Heparin-induced thrombocytopenia Antiphospholipid antibody syndrome (lupus anticoagulant syndrome) • Lower risk for thrombosis: – – – – – – Cardiomyopathy Nephrotic syndrome Hyperestrogenic states (pregnancy) Oral contraceptive use Sickle cell anemia Smoking, Obesity MORPHOLOGY • ADHERENCE TO VESSEL WALL – HEART (MURAL) – ARTERY (OCCLUSIVE/INFARCT) – VEIN • OBSTRUCTIVE vs. NON-OBSTRUCTIVE • RED, YELLOW, GREY/WHITE • ACUTE, ORGANIZING, OLD MURAL THROMBI, HEART FATE of THROMBI • PROPAGATION (Downstream) • EMBOLIZATION • DISSOLUTION • ORGANIZATION • RECANALIZATION OCCLUSIVE ARTERIAL THROMBUS D.V.T. • D. (CALF, THIGH, PELVIC) V.T. • CHF a huge factor • INACTIVITY!!! • • • • • • Trauma Surgery Burns Injury to vessels, Procoagulant substances from tissues Reduced t-PA activity ARTERIAL/CARDIAC THROMBI • ACUTE MYOCARDIAL INFARCTION = OLD ATHEROSCLEROSIS + FRESH THROMBOSIS • ARTERIAL THROMBI also may send fragments DOWNSTREAM, but these fragments may contain flecks of PLAQUE also • LODGING is PROPORTIONAL to the % of cardiac output the organ receives, i.e., brain, kidneys, spleen, legs, or the diameter of the downstream vessel ATHEROEMBOLI • “CHOLESTEROL” clefts are components of atherosclerotic plaques, NOT thrombi!!! Disseminated Intravascular Coagulation D.I.C. • OBSTETRIC COMPLICATIONS • ADVANCED MALIGNANCY • SHOCK NOT a primary disease CONSUMPTIVE coagulopathy, e.g., reduced platelets, fibrinogen, F-VIII and other consumable clotting factors, brain, heart, lungs, kidneys, MICROSCOPIC ONLY EMBOLISM •Pulmonary • Systemic (Mural Thrombi and Aneurysms) • Fat • Air • Amniotic Fluid PULMONARY EMBOLISM • USUALLY SILENT • CHEST PAIN, LOW PO2, S.O.B. • Sudden OCCLUSION of >60% of pulmonary vasculature, presents a HIGH risk for sudden death, i.e., acute cor pulmonale, ACUTE right heart failure • “SADDLE” embolism often/usually fatal • PRE vs. POST mortem blood clot: – PRE: Friable, adherent, lines of ZAHN – POST: Current jelly or chicken fat SYSTEMIC EMBOLI • “PARADOXICAL” EMBOLI • 80% cardiac/20% aortic • Embolization lodging site is proportional to the degree of flow (cardiac output) that area or organ gets, i.e., brain, kidneys, legs OTHER EMBOLI •FAT (long bone fx’s ) •AIR (SCUBA bends) •AMNIOTIC FLUID, very prolonged or difficult delivery, high mortality Amniotic Fluid Embolism INFARCTION • Defined as an area of necrosis* secondary to decreased blood flow • HEMORRHAGIC vs. ANEMIC • RED vs. WHITE – END ARTERIES vs. NO END ARTERIES • ACUTEORGANIZATIONFIBROSIS INFARCTION FACTORS • NATURE of VASCULAR SUPPLY • RATE of DEVELOPMENT –SLOW (BETTER) –FAST (WORSE) • VULNERABILITY to HYPOXIA –MYOCYTE vs. FIBROBLAST • CHF vs. NO CHF HEART SHOCK • Pathogenesis –Cardiac –Septic –Hypovolemic • Morphology • Clinical Course SHOCK • Definition: CARDIOVASCULAR COLLAPSE • Common pathophysiologic features: – INADEQUATE CARDIAC OUTPUT and/or – INADEQUATE BLOOD VOLUME GENERAL RESULTS • INADEQUATE TISSUE PERFUSION • CELLULAR HYPOXIA • UN-corrected, a FATAL outcome TYPES of SHOCK • CARDIOGENIC: (Acute, Chronic Heart Failure) • HYPOVOLEMIC: (Hemorrhage or Leakage) • SEPTIC: (“ENDOTOXIC” shock, #1 killer in ICU) • NEUROGENIC: (loss of vascular tone) • ANAPHYLACTIC: (IgE mediated systemic vasodilation and increased vascular permeability) CARDIOGENIC shock • • • • • MI VENTRICULAR RUPTURE ARRHYTHMIA CARDIAC TAMPONADE PULMONARY EMBOLISM (acute RIGHT heart failure or “cor pulmonale”) HYPOVOLEMIC shock • • • • HEMORRHAGE, Vasc. compartmentH2O VOMITING, Vasc. compartmentH2O DIARRHEA, Vasc. compartmentH2O BURNS, Vasc. compartmentH2O SEPTIC shock • • • • • OVERWHELMING INFECTION “ENDOTOXINS”, i.e., LPS (Usually Gm-) Gm+ FUNGAL “SUPERANTIGENS”, (Superantigens are polyclonal T-lymphocyte activators that induce systemic inflammatory cytokine cascades similar to those occurring downstream in septic shock, “toxic shock” antigents by staph are the prime example.) SEPTIC shock events* (overwhelming infection) • • • • Peripheral vasodilation Pooling Endothelial Activation DIC * Think of this as a TOTAL BODY inflammatory response ENDOTOXINS • Usually Gm• Degraded bacterial cell wall products • Also called “LPS”, because they are Lipo- Poly-Saccharides • Attach to a cell surface antigen known as CD-14 ENDOTOXINS SEPTIC shock events (linear sequence) • SYSTEMIC VASODILATION (hypotension) • ↓ MYOCARDIAL CONTRACTILITY • • • • • DIFFUSE ENDOTHELIAL ACTIVATION LEUKOCYTE ADHESION ALVEOLAR DAMAGE (ARDS) DIC VITAL ORGAN FAILURE CNS CLINICAL STAGES of shock •NON-PROGRESSIVE (compensatory mechanisms) •PROGRESSIVE (acidosis, early organ failure) •IRREVERSIBLE NON-PROGRESSIVE • COMPENSATORY MECHANISMS •CATECHOLAMINES • VITAL ORGANS PERFUSED PROGRESSIVE • HYPOPERFUSION • EARLY “VITAL” ORGAN FAILURE • OLIGURIA •ACIDOSIS IRREVERSIBLE •HEMODYNAMIC CORRECTIONS of no use PATHOLOGY • • • • • • • MULTIPLE ORGAN FAILURE SUBENDOCARDIAL HEMORRHAGE (why?) ACUTE TUBULAR NECROSIS (why?) DAD (Diffuse Alveolar Damage, lung) (why?) GI MUCOSAL HEMORRHAGES (why?) LIVER NECROSIS (why?) DIC (why?) ARDS/DAD MYOCARDIAL NECROSIS ATN DIC CLINICAL PROGRESSION of SYMPTOMS • • • • • • • Hypotension Tachycardia Tachypnea Warm skin Cool skin Cyanosis Renal insufficiency Obtundance Death
