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 ONCOTICPRESSURE (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 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, LDH LOW

• Exudate– results from damage to the capillary wall– specific gravity > 1.012– protein content > 3 g/dl, LDH HIGH

HYPEREMIA/(CONGESTION)

HYPEREMIAActive Process

CONGESTIONPassive ProcessAcute or Chronic

CONGESTION• LUNG

–ACUTE

–CHRONIC

• LIVER–ACUTE

–CHRONIC

• CEREBRAL

ACUTE PASSIVE HYPEREMIA/CONGESTION,

LUNG

Kerley B

Air Bronch-ogram

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

HEMATOMAvs.

“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 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

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)

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 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

• SHOCKNOT 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 PROGRESSIONof SYMPTOMS

• Hypotension • Tachycardia • Tachypnea • Warm skin Cool skin Cyanosis

• Renal insufficiency• Obtundance

• Death