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 ONCOTICPRESSURE (HYPOPROTEINEMIA)• Protein-losing glomerulopathies
(nephrotic syndrome)• Liver cirrhosis (ascites)• Malnutrition• Protein-losing gastroenteropathy
Na+ RETENTION• Excessive salt intake with renal
insufficiency• Increased tubular reabsorption of
sodium
• Renal hypoperfusionIncreased renin-angiotensin-aldosterone secretion
CHF EDEMA•INCREASED VENOUS PRESSURE
DUE TO FAILURE
•DECREASED RENAL PERFUSION, triggering of RENIN-ANGIOTENSION-ALDOSTERONE complex, resulting ultimately in SODIUM RETENTION
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
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
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
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 EVENTSfollowing 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
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 THROMBOMODULINProtein-C– TISSUE FACTOR PATHWAY INHIBITOR
• FIBRINOLYTIC PROPERTIES (TPA)
ENDOTHELIUM•PROTHROMBOTIC PROPERTIES
– Makes vWF, which binds PlatsColl– Makes TISSUE FACTOR (with plats)– Makes Plasminogen inhibitors
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
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)
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 THROMBOMODULINProtein-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” ENDOTHELIUMALL 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
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
Disseminated Intravascular Coagulation
D.I.C.•OBSTETRIC COMPLICATIONS•ADVANCED MALIGNANCY•SHOCKNOT a primary diseaseCONSUMPTIVE coagulopathy, e.g., reduced platelets, fibrinogen, F-VIII and other consumable clotting factors, brain, heart, lungs, kidneys, MICROSCOPIC ONLY
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
• ACUTEORGANIZATIONFIBROSIS
INFARCTION FACTORS• NATURE of VASCULAR SUPPLY• RATE of DEVELOPMENT–SLOW (BETTER)–FAST (WORSE)
• VULNERABILITY to HYPOXIA–MYOCYTE vs. FIBROBLAST
• CHF vs. NO CHF
SHOCK•Definition: CARDIOVASCULAR COLLAPSE
•Common pathophysiologic features:– INADEQUATE CARDIAC OUTPUT and/or– INADEQUATE BLOOD VOLUME
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
SEPTIC shock events(linear sequence)
•SYSTEMIC VASODILATION (hypotension)
•↓ MYOCARDIAL CONTRACTILITY•DIFFUSE ENDOTHELIAL ACTIVATION•LEUKOCYTE ADHESION•ALVEOLAR DAMAGE(ARDS)•DIC•VITAL ORGAN FAILURECNS
CLINICAL STAGES of shock
•NON-PROGRESSIVE (compensatory mechanisms)
•PROGRESSIVE (acidosis, early organ failure)
•IRREVERSIBLE
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?)