Pathology Ch4 - Hemodynamic Disorders, Thromboembolic Disease, and Shock - pp113-134
Edema and Effusions
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Disorders of CV, renal, or hepatic fxn > accumulation of fluid in tissues (edema) or body cavities (effusions)
o Fluid movement into tissue greater than lymphatic drainage > edema/effusion
o Inflammatory = exudates (protein-rich)
o Non-inflammatory = transudates (protein-poor)
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Increased Hydrostatic Pressure
o Caused by disorders that impair venous return
o Localized impairment (ex. DVT in lower leg) > edema confined to affected part
o Systemic increase in venous pressure (ex. CHF) > widespread edema
Reduced Plasma Osmotic Pressure
o Albumin accounts for ~1/2 total plasma protein = greatest effect on plasma osmotic pressure
o Deficient synthesis in severe liver disease and protein malnutrition, or excess loss found in nephrotic syndrome
o Reduced plasma osmotic pressure > edema > reduced intravascular volume > renal hypoperfusion > secondary
hyperaldosteronism > salt and water retention fail to correct plasma volume + exacerbates edema
Sodium and Water Retention
o Increases hydrostatic pressure (volume expansion) and diminishes vascular colloid osmotic pressure (dilution)
o Occurs whenever renal function is compromised (ex. primary renal disorders, CV disorders > renal hypoperfusion)
o Ex. CHF > renal hypoperfusion > renin-ATII-aldosterone > edema and effusions as cardiac output diminishes
Lymphatic Obstruction
o Trauma, fibrosis, invasive tumors, infectious agents > disrupt lymphatic vessels/drainage > lymphedema
o Ex. filariasis parasite > fibrosis of lymph channels/nodes > edema of genitalia and lower limbs (elephantitis)
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Morphology
o Subcutaneous edema can be diffuse or localized to areas w/ high hydrostatic pressures
 Dependent edema = distribution influenced by gravity (legs when standing, sacrum when lying down)
 Pitting edema = pressure of edemantous tissue displaces fluid > leave depression
o Edema resulting from renal dysfunction initially appears in areas of loose CT
 Periorbital edema = characteristic of severe renal disease
o Pulmonary edema = lungs 2-3x normal weight
o Brain edema = narrowed sulci and distended gyri, compressed by skull
o Hydrothorax = effusion involving pleural cavity
o Hydropericardium = effusion involving pericardial cavity
o Hydroperitoneum aka ascites = effusion involving the peritoneal cavity
Clinical Features
o Subcutaneous edema suggests CV or renal disease, and can impair wound healing and clearance of infection
o Pulmonary edema associated w/ left ventricular failure (also w/ renal failure, ARDS, pulmonary inflammation)
o Pulmonary effusions often accompany edema in the lungs, further compressing them
o Peritoneal effusions (ascite) result from portal HTN, and can lead to seeding by bacteria
o Brain edema is life threatening due to possibility of herniation through the foramen magnum
Hyperemia and Congestion
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Both stem from increased blood volumes within tissues
Hyperemia = active process of arteriolar dilation leading to inc. blood flow
o Affected tissues turn red (erythema)
Congestion = passive process resulting from reduced outflow of blood from tissue
o Affected tissues turn reddish-blue (cyanosis)
o Chronic passive congestion > chronic hypoxia > ischemic injury/scarring
o Capillary rupture > small hemorrhagic foci > residual hemosiderin-laden macrophages
o Acute pulmonary congestion = enlarged alveolar capillaries, septal edema, and intraalveolar hemorrhage
o Chronic pulmonary congestion = septa thickened/fibrotic, alveoli contain hemosiderin-laden macrophages ("heart
failure cells" -- b/c commonly due to CHF)
o Acute hepatic congestion = central vein and sinusoids distended, centrilobular area may show necrosis
o Chronic passive hepatic congestion = centrilobular regions dead red/brown and hemorrhagic ("nutmeg liver"), w/
hemosiderin-laden macrophages
Hemostasis, Hemorrhagic Disorders, and Thrombosis
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Hemostasis
o Arteriolar vasoconstriction
 Occurs immediately > reduces blood flow to injured area
 Mediated by reflex neurogenic mechanisms + local secretions (ex. endothelin)
o Primary hemostasis: formation of platelet plug
 Disruption of endothelium > expose von Willebrand Factor (vWF) and collagen > activate platelets
 Activated platelets change shape and release secretory granules to recruit other platelets
o Secondary hemostasis: deposition of fibrin
 Tissue factor at site of injury binds/activates factor VII > cascade > thrombin generation
 Thrombin cleaves circulating fibrinogen > fibrin > forms meshwork
o Clot stabilization and resorption
 Polymerized fibrin + platelets contract > form solid, permanent plug
 Counterregulatory mechanisms (ex. tissue plasminogen activator, t-PA) limits clotting to site of injury
 Counterregulatory mechanisms eventually lead to clot resorption and tissue repair
o Platelets
 Anucleated cell fragments shed from megakaryocytes in bone marrow
 Form primary plug > provide surface to bind and concentrate activated coagulation factors
 Function depends on glycoprotein receptors, a contractile cytoskeleton, and 2 cytoplasmic granules
 α-granules =
o Adhesion molecule on membrane (P-selectin)
o Coagulation proteins (fibrinogen, factor V, and vWF)
o Wound healing proteins (fibronectin, platelet factor 4, PDGF, and TGF-β)
 Dense (δ-) granules =
o ADP and ATP
o Ionized Ca++, serotonin, and epinephrine
 Upon initial contact w/ vWF and collagen >
 Platelet adhesion
o Mediated by interaction w/ vWF + collagen + glycoprotein Ib (GpIb) on platelets
 Deficiency in vWF (von Willebrand disease) or GpIb (Bernard-Soulier syndrome)
 Platelets rapidly change shape
o Change from smooth discs to spiky balls
o Changes in glycoprotein IIb/IIIa > inc. affinity for fibrinogen
o Translocation of negatively charged phospholipids to platelet surface > bind Ca++ > site
for assembly of coagulation factor complexes
 Secretion of granule contents
o Occurs w/ change in shape ("platelet activation" = change shape + secrete)
o Triggered by thrombin and ADP
 Thrombin > G-protein-coupled receptor (protease-activated receptor PAR)
 ADP from δ-granules > cycle of activation ("recruitment")
o Activated platelets produce thromboxane A2 (TxA2) > induces platelet aggregation
 Platelet aggregation
o Glycoprotein IIb/IIIa allows binding of fibrinogen > bridges adjacent platelets
 Deficiency in GpIIb-IIIa (Glanzmann thrombasthenia)
o Concurrent activation of thrombin >
 Platelet contraction > stabilizes platelet plug
 Cleaves fibrinogen > fibrin > secondary hemostatic plug
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Coagulation Cascade
 PT - prothrombin time (extrinsic pathway)
 Assess factors VII, X, V, II, and fibrinogen
 Tissue factor + phospholipids + Ca added to plasma > record time for fibrin clot to form
o TF > activates VII > activates X > cleaves prothrombin > thrombin > cleaves fibrinogen
 PTT - partial thromboplastin time (intrinsic pathway)
 Assess factors XII, XI, IX, VIII, X, V, II, and fibrinogen
 Add negative-charged particles (ground glass) + phospholipids + Ca > record time to clot
o Negative-charged particles activate factor XII (Hageman factor)
o XIIa > activates XI > activates IX > combines w/ VIIIa > activates X > cleaves prothrombin
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Deficiencies
 V, VII, VIII, IX, X = moderate/severe bleeding disorders
 Prothrombin = incompatible w/ life
 XI = mild bleeding
 XII = don't bleed (may be susceptible to thrombosis)
In Vivo cascade
 TF complexes w/ VII > activates IX > complexes w/ VIIIa > activates X
Thrombin is the most important coagulation factor
 Conversion of fibrinogen into crosslinked fibrin
o Cleaves fibrinogen
o Activates XI, and co-factors V and VIII > amplifies coagulation cascade
o Activates XIII > cross-links fibrin > stabilizes secondary plug
 Platelet activation by activating PARs (protease-activated receptors) on platelets
 Pro-inflammatory effects by activating PARs on inflammatory cells and endothelium
 Anticoagulant effects upon encountering normal endothelium
Factors that limit coagulation
 Blood flowing past injury site washes out activated coagulation factors > removed by liver
 Requirement of negatively charged phospholipids only displayed on activated platelets
 Fibrinolytic cascade limits size of clot and contributes later to dissolution
o Factor XII or t-PA convert plasminogen > plasmin
o Plasmin breaks down fibrin + interferes w/ polymerization
Endothelium
 Normal endothelial cells express factors that inhibit procoagulant activities
 Platelet inhibitory effects =
o Shield platelets from subendothelial vWF and collagen
o Express prostacyclin (PGI2), nitric oxide (NO), and adenosine diphosphatase
o Bind and alter activity of thrombin
 Anticoagulant effects =
o Shields coagulation factors from tissue factor in vessel walls
o Express thrombomodulin & endothelial protein C receptor > bind thrombin and protein
C and directs thrombin's activity toward protein C instead (requires protein S cofactor)
o Express heparin-like molecules > activate antithrombin III > inhibit thrombin and IXa, Xa,
XIa, and XIIa
o Express tissue factor pathway inhibitor (TFPI) > inhibits TF/VIIa complex (also using
protein S cofactor)
 Fibrinolytic effects = synthesize t-PA
 Injured endothelium or exposure to proinflammatory factors > lose antithrombotic properties
Hemorrhagic Disorders
o Sudden, massive hemorrhage = aortic dissection (ex. Marfan syndrome), AAA, and MI
o Moderate bleeding disorders = coagulation factor deficiencies (ex. hemophilias)
o Mild bleeding disorders = vWF defects, aspirin use, and uremia (renal failure)
o General principles related to abnormal bleeding:
 Defects of primary hemostasis (platelet defects or von Willebrand disease)
 Present w/ small bleeds in skin or mucosal membranes
 Petechiae (1-2mm) or purpura (>3mm)
 Mucosal bleeding manifests as epistaxis, GI bleeding, or menorrhagia
 Fatal complication of thrombocytopenia = intracerebral hemorrhage
 Defects of secondary hemostasis (coagulation factor defects)
 Present w/ bleeds in soft tissues or joints (hemarthrosis)
 Hemarthorosis especially indicative of hemophilia
 Intracranial hemorrhage may also occur
 Generalized defects involving small vessels
 Present w/ palpable purpura and ecchymoses (bruises)
 Volume of extravasated blood sufficient to create palpable mass (hematoma)
 Characteristic of systemic disorders (ex. vasculitis or amyloidosis)
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Thrombosis
o Endothelial Injury
 Exposure of vWF and TF leads to platelet activation
 Underlies thrombus formation in heart and arteries (high rate of blood flow impedes clot formation)
 Can also be caused by noxious stimuli or inflammation that shifts endothelium to prothrombotic state
 Ex. physical injury, infectious agents, abnormal blood flow, inflammatory mediators, metabolic
abnormalities (hypercholesterolemia or homocystinemia) and toxins absorbed from cigarettes
 Procoagulant changes =
 Activated by cytokines > downregulate thrombomodulin expression
 Activated by inflammation > downregulate protein C and TFPI
 Antifibrinolytic effects =
 Activated endothelial cells > secrete plasminogen activator inhibitos (PAIs)
 Limit fibrinolysis and downregulate t-PA expression
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Alternations in Normal Blood Flow
 Turbulence > local packets of stasis
 Promote endothelial activation, enhance procoagulant activity, and leukocyte adhesion
 Disrupt laminar flow > bring platelets in contact w/ endothelium
 Prevent washout and dilution of activate clotting factors
 Aneurysms (dilations in aorta/arteries) > local stasis
 Acute MI > noncontractile myocardium + cardiac aneurysms > stasis > cardiac mural thrombi
 Rheumatic mitral valve stenosis > left atrial dilation > stasis
 Hyperviscosity > inc. resistance to flow > small vessel stasis
 Sickle cell anemia > deformed RBC > impede blood flow through small vessels > stasis
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Hypercoagulability (aka thrombophilia)
 Primary (genetic) disorders
 Common: Factor V mutation, prothrombin mutation, inc. levels of VIII, IX, XI, or fibrinogen
 Rare: antithrombin III deficiency, protein C deficiency, protein S deficiency
 Very rare: fibrinolysis defects, homozygous homocystinuria
 Secondary (acquired) disorders
 High risk: prolonged bed rest/immobilization, MI, AFib, tissue injury, cancer, prosthetic cardiac
valves, DIC, heparin-induced thrombocytopenia, antiphospholipid antibody syndrome
 Low risk: cardiomyopathy, nephrotic syndrome, hyperestrogenic states & oral contraceptives
(inc. hepatic synthesis of coagulation factors), sickle cell anemia, smoking
 Factor V Leiden
 Mutation in factor V affecting 2-15% Caucasians
 Found in 60% of pts w/ recurrent DVT
 Mutation renders factor V resistant to cleavage and inactivation by protein C > loss of
antithrombotic counterregulatory pathway
 Heterozygotes > 5x risk of venous thrombosis; Homozygotes > 50x risk
 Prothrombin Mutation (G20210A)
 Mutation in 1-2% of population
 Leads to elevated prothrombin levels > 3x risk of venous thrombosis
 Elevated Homocysteine
 Caused by mutation leading to deficiency of cystathione β-synthetase
 Thioester linkages formed between homocysteine metabolites and fibrinogen
 Heparin-Induced Thrombocytopenia (HIT) Syndrome
 Follows administration of unfractionated heparin
 Induce antibodies that recognize complexes of heparin:platelet factor 4 on platelet surfaces
 Results in activation, aggregation, and consumption of platelets (thrombocytopenia)
 Low-molecular-weight heparin preparations induce HIT less frequently
 Antiphospholipid Antibody Syndrome (aka Lupus Anticoagulant Syndrome)
 Recurrent thromboses, repeated miscarriages, cardiac valve vegetation, and thrombocytopenia
 Can also cause PE, pulmonary HTN, stroke, bowel infarction, and renovascular HTN
 Binding of antibodies to epitopes on proteins unveiled by phospholipids (β2-glycoprotein I)
 Rx: anticoagulation and immunosuppression
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Morphology
 Arterial thrombi begin at sites of turbulence or endothelial injury > grow retrograde
 Venous thrombi begin at sites of stasis > extend in direction of blood flow
 Laminations (lines of Zahn) = pale platelet/fibrin deposits alternating w/ darker RBC-rich layers
 Mural thrombi = occur in heart chambers or in aortic lumen
 Heart valve thrombi (vegetations) = from infectious endocarditis or nonbacterial thrombotic
endocarditis/Libman-Sacks endocarditis
 Arterial thrombi = frequently occlusive (common in coronary, cerebral, and femoral aa.)
 Venous thrombi (phlebothrombosis) = invariably occlusive
Fate of the Thrombus
 Propagation = thrombi accumulate platelets and fibrin
 Embolization = thrombi dislodge and travel to other sites
 Dissolution = fibrinolysis > shrinkage/disapperance of thrombi (older thrombi more resistant to t-PA)
 Organization and recanalization = older thrombi organized by ingrowths of endothelial cells, SM cells, and
fibroblasts > become incorproated into vessel wall
Clinical Features
 Venous thrombosis (phlebothrombosis)
 Most occur in superficial or deep veins of legs
 Superficial typically in saphenous vein in setting of varicosities > local congestion, swelling, pain,
and tenderness, but rarely embolize. May lead to infections and ulcers (varicose ulcers).
 Deep vein thrombosis (DVT) more often embolize to the lungs > pulmonary infarction
o Asymptomatic in 50% of pts > not recognized until embolization
o Associated w/ hypercoagulable states
o Predisposing factors = bed rest/immobilization, CHF, trauma/surgery/burns, pregnancy,
old age, and tumor-associated inflammation and coagulation factors (migratory
thrombophlebitis/Trousseau syndrome)
 Arterial and cardiac thrombosis
 Atherosclerosis associated w/ loss of endothelial integrity and abnormal blood flow
 MI and rheumatic heart disease can predispose to cardiac mural thrombi
 Cardiac and aortic mural thrombi are prone to embolization > brain, kidneys, spleen
Disseminated Intravascular Coagulation
o Complication of a large number of conditions associated w/ systemic activation of thrombin
o Leads to widespread formation of thrombi in the microcirculation
o Cause diffuse circulatory insufficiency and organ dysfunction (esp. brain, lungs, heart, and kidneys)
o Thrombosis uses up platelets and coag factors > bleeding catastrophe > hemorrhagic stroke or hypovolemic shock
Embolism
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Pulmonary Embolism
o Most common form of thromboembolic disease
o Pts who had one PE are at high risk for more
o 95% originate from DVT > right side of heart > lodge in pulmonary aa.
 Can occlude the main pulmonary artery, straddle the bifurcation (saddle embolus), or pass to smaller aa.
o Can rarely pass through atrial/ventricular defects > lodge in arterial circulation (paradoxical embolism)
o Major functional consequences of PE:
 60-80% are clinically silent due to small size
 Can lead to sudden death, right heart failure, or CV collapse when obstructing >60% of pulmonary circ.
 Obstruction of medium-sized aa. > vascular rupture > pulmonary hemorrhage (but no infarction)
 Obstruction of small end-arteriolar pulmonary branches > hemorrhage or infarction
 Multiple emboli over time > pulmonary HTN and right ventricular failure
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Systemic Thromboembolism
o 80% arise from intracardiac mural thrombi
 2/3 associated w/ L ventricular wall infarcts
 1/4 associated w/ L atrial dilation/fibrillation
o Remainder from aortic aneurysms, atherosclerotic plaques, valvular vegetations, or paradoxical emboli
o Most come to rest in lower extremities (75%) or brain (10%)
o Can also come to rest in intestines, kidneys, spleen, and upper extremities
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Outcome depends on size of emboli, diameter of vessel occluded, and collateral circulation
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Fat and Marrow Embolism
o Can be found in pulmonary vasculature after fractures of long bones
o Rupture of vascular sinusoids in marrow > release marrow or adipose tissue into vasculature
o Occur in 90% of severe skeletal injuries, but <10% have clinical findings
o Fat embolism syndrome = symptomatic 10%
 Pulmonary insufficiency, neurologic symptoms, anemia, thrombocytopenia, 5-15% fatality
 1-3 days after injury > onset of tachypnea, dyspnea, and tachycardia
 Irritability and restlessness can progress to delirium/coma
 Diffuse petechial rash (20-50%) related to thrombocytopenia = useful for diagnosis
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Air Embolism
o Gas bubbles in circulation can coalesce > frothy masses > obstruct vascular flow > distal ischemic injury
 Can be introduced into cardiac/cerebral circulation by surgery (only small amount of air required)
 Can be introduced into pulmonary circulation by laproscopic or chest wall surgery (>100cc required)
o Decompression sickness = sudden decrease in atmospheric pressure (scuba or deep sea divers coming up fast)
 Rapid depressurization > nitrogen comes out of solution in tissue and blood
 Caisson disease = chronic form of decompression sickness, persistence of gas emboli in skeletal system >
multiple points of ischemic necrosis (commonly femoral heads, tibia, and humeri)
 Rx: pts placed in high pressure chamber > get gasses back into solution > slow decompression
o "The bends" = formation of gas bubbles in skeletal muscle and supporting tissues of joints
o "The chokes" = formation of gas bubbles in lung vasculature > respiratory distress
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Amniotic Fluid Embolism
o 5th most common cause of maternal mortality worldwide
o 10% of pregnancy deaths in US > 85% of survivors have permanent neurologic deficit
o Infusion of amniotic fluid/fetal tissue into maternal circulation via tear in placenta or rupture of uterine veins
o Activation of coag factors and components of innate immune system by amniotic fluid (not a mechanical blockage)
o Onset sudden severe dyspnea, cyanosis, and shock > neurlogic impairment (headaches/seizures/coma)
o Survival of initial symptoms > pulmonary edema develops + DIC
Infarction
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Area of ischemic necrosis caused by occlusion of arterial supply or venous drainage
Arterial thrombosis or arterial embolism underlies majority of infarctions
Morphology
o Red infarcts (hemorrhagic) - venous occlusions
 Venous occlusions
 Loose/spongy tissues where blood can collect in the infarcted zone (eg. lung)
 Tissues w/ dual circulations that allow blood to flow into necrotic zone (eg. lung and small intestine)
 Tissues previously congested by sluggish venous outflow
 When flow is reestablished to site of previous arterial occlusion and necrosis
o White infarcts (anemic) - arterial occlusions
 Arterial occlusions in solid organs w/ end-arterial circulation (eg. heart, spleen, kidney)
 Where tissue density limits the seepage of blood from adjoining capillary beds into necrotic area
o Tend to be wedge-shaped, w/ occluded vessel at apex
o Dominant characteristic = ischemic coagulative necrosis (except in brain > liquefactive necrosis)
o Septic infarctions = infected cardiac valve vegetations embolize or microbes seed necrotic tissue > infarct
converted into abscess
Factors that influence development of an infarct
o Anatomy of the vascular supply = availability of alternative blood supply
o Rate of occlusion = slow occlusions less likely to cause infarction (time to develop collateral circulation)
o Tissue vulnerability to hypoxia = neurons (3-4 min), myocardial cells (20-30 min), fibroblasts (hours)
o Hypoxemia = abnormally low blood O2 increases likelihood and extent of infarction
Shock
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Diminished cardiac output or reduced effective circulating blood volume impairs tissue perfusion > cellular hypoxia
Reversible at onset, but prolonged shock leads to irreversible injury/death
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Cardiogenic shock
o Results from low cardiac output due to myocardial pump failure
o Due to MI, ventricular arrhythmias, extensive compression (cardiac tamponade), or outflow obstruction (PE)
Hypovolemic shock
o Results from low cardiac output due to low blood volume
o Due to massive hemorrhage or fluid loss from severe burns
Shock associated w/ systemic inflammation
o May be triggered by microbial infections, burns, trauma, or pancreatitis
o Leads to outpouring of inflammatory mediators > arterial vasodilation, vascular leakage, venous blood pooling
o Result in tissue hypoperfusion, cellular hypoxia, and metabolic derangements > organ dysfunction/failure/death
Septic shock = caused by microbial infection
Neurogenic shock = anesthetic accident or spinal cord injury
Anaphylactic shock = IgE-mediated hypersensitivity reaction
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Pathogenesis of Septic Shock
o Most common cause of death in ICUs (20% mortality rate)
o Most frequently triggered by gram-positive bacterial infections (followed by gram-negative, then fungi)
o Inflammatory and counter-inflammatory responses
 Microbial cell wall constituents (PAMPs) engage innate immune system > pro-inflammatory
 TNF, IL-1, IFN-γ, IL-12, IL-18, HMGB1, ROS, prostaglandins, PAF > endothelial cells upregulate
adhesion molecule expression > further stimulate cytokine and chemokine production
 Complement activation > anaphylotoxins (C3a, C5a), chemotactics (C5a), and opsonins (C3b)
 Activate coagulation directly via factor XII + indirectly through altered endothelial function
 Hyperinflammatory state activates counter-regulatory immunosuppressive state > pts oscillate between
hyperinflammatory and immunosuppressed states
 Shift from pro-inflammatory TH1 to anti-inflammatory TH2
 Production of anti-inflammatory mediators (TNF receptor, IL-1 receptor antagonist, IL-10)
 Lymphocyte apoptosis and induction of cellular anergy
o Endothelial activation and injury
 Leads to widespread vascular leakage and tissue edema > impedes tissue perfusion
 Upregulates production of nitric oxide (NO) and other vasoactive inflammatory mediators > vascular SM
relaxation > systemic hypotension
o Induction of a procoagulant state
 Produces complication of DIC in up to 1/2 of septic pts
 Leads to systemic activation of thrombin and deposition of fibrin-rich thrombi in small vessels > further
complicate tissue perfusion
o Metabolic abnormalities
 Septic pts exhibit insulin resistance and hyperglycemia > dec. neutrophil function
 Cellular hypoxia and diminished oxidative phosphorylation > inc. lactate production > lactic acidosis
o Organ dysfunction
 Systemic hypotension + interstitial edema + small vessel thrombosis > decrease O2/nutrient delivery
 High levels of cytokines and secondary mediators > diminish myocardial contractility and cardiac output
 Increased vascular permeability and endothelial injury > acute respiratory distress syndrome
 >>> Multiple organ failure (esp. kidneys, liver, lungs, heart) > death
o Rx: antibiotics, IV fluids, and supplemental oxygen
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Stages of Shock
o Nonprogressive phase = reflex compensatory mechanisms > perfusion of vital organs maintained
 Baroreceptor reflexes, catecholamine release, renin-angiotensin, ADH release, sympathetic stimulation
 Net effect = tachycardia, peripheral vasoconstriction, and renal conservation of fluid
o Progressive phase = tissue hypoperfusion + worsening circulatory and metabolic imbalances
 Widespread tissue hypoxia > shift to anaerobic glycolysis > excess lactic acid production
 Lactic acidosis > lower tissue pH > blunts vasomotor response > arterioles dilate > blood pools in
microcirculation > lowers cardiac output and raises risk of DIC
 Vital organs begin to fail
o Irreversible stage = cellular and tissue injury too severe to recover
 Lysosomal enzyme leakage > further aggravates shock state
 Ischemic bowel may allow intestinal flora to enter circulation > superimposed bacteremic septic shock
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Pt may develop anuria as a result of acute tubular necrosis and renal failure
Eventually results in death
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Morphology
o Cellular and tissue changes essentially those of hypoxic injury
o Changes particularly evident in brain, heart, lungs, kidneys, adrenals, and GI tract
 Adrenals = cortical cell lipid depletion
 Kidneys = acute tubular necrosis
 Lungs = diffuse alveolar damage when shock caused by sepsis or trauma (shock lung)
o Development of DIC > deposition of fibrin-rich microthrombin in brain, heart, lungs, kidney, adrenal glands, and GI
o Consumption of platelets and coag factors > petechial hemorrhages on serosal surface of skin
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Clinical Consequences
o Hypovolemic and cardiogenic shock = hypotension, weak/rapid pulse, tachypnea, coolclammy/cyanotic skin
o Septic shock = skin initially warm due to vasodilation > cardiac, cerebral, and pulmonary dysfunction > electrolyte
disturbances and metabolic acidosis > renal insufficiency > severe fluid and electrolyte imbalances