HEMODYNAMIC DISORDERS. J v = ([Pc Pi] σ[πc πi])

HEMODYNAMIC DISORDERS J v = ([Pc Pi] σ[πc πi])

Hemodynamic Disorders Thromboembolic Disease Shock

Overview Edema Hyperemia Congestion Hemorrhage Hemostasis Thrombosis Embolism Infarction Shock

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 hypoperfusion Increased 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 RENIN- ANGIOTENSION-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 Exudate results from damage to the capillary wall specific gravity > 1.012 protein content > 3 g/dl

HYPEREMIA/(CONGESTION)

HYPEREMIA Active Process CONGESTION Passive Process Acute or Chronic

LUNG CONGESTION 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 Activates coagulation cascade thrombin fibrin (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 Plats Coll 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 PRIMARY SECONDARY PLUG STRENGTHENED by FIBRIN

COAGULATION CASCADE INTRINSIC(contact)/EXTRINSIC(TissFac) Proenzymes Enzymes 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) HYPER- COAGULATION

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 Plats Coll 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. (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 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

INFARCTION Defined as an area of necrosis* secondary to decreased blood flow HEMORRHAGIC vs. ANEMIC RED vs. WHITE END ARTERIES vs. NO END ARTERIES ACUTE ORGANIZATION FIBROSIS

INFARCTION FACTORS NATURE of VASCULAR SUPPLY RATE of DEVELOPMENT SLOW (BETTER) FAST (WORSE) VULNERABILITY to HYPOXIA MYOCYTE vs. FIBROBLAST CHF vs. NO CHF

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. compartment H2O VOMITING, Vasc. compartment H2O DIARRHEA, Vasc. compartment H2O BURNS, Vasc. compartment H2O

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 antigens 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 PROGRESSIVE 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