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Hemodynamic Disorders, Thromboembolic Disease, and Shock

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1. HYPEREMIA AND CONGESTION

• Acute pulmonary congestion: blood-engorged alveolar capillaries, alveolar septal edema, intraalveolar hemorrhage
• Chronic pulmonary congestion: thickened fibrotic septa; alveolar macrophages laden with hemosiderin = "heart failure cells"
• Acute hepatic congestion: central vein and sinusoids distended with blood; centrilobular hepatocyte necrosis
• Chronic passive liver congestion ("nutmeg liver"): congested red-brown central zones surrounded by tan, fatty periportal hepatocytes

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2. EDEMA

• ~60% of lean body weight is water; 2/3 intracellular, 1/3 interstitial; only 5% in plasma
• Cavity collections: hydrothorax (pleural), hydropericardium (pericardial), hydroperitoneum/ascites (peritoneal)
• Fluid types: transudate (protein-poor, low specific gravity, non-inflammatory) vs. exudate (protein-rich, inflammatory)

Causes of Non-Inflammatory Edema

• Left heart failure → pulmonary edema
• Right heart failure → peripheral and dependent edema (legs, presacral region when supine)
• Venous obstruction (DVT, hepatic vein obstruction in Budd-Chiari syndrome)

• Decreased synthesis: liver disease (cirrhosis), protein malnutrition (kwashiorkor)
• Increased loss: nephrotic syndrome (protein lost in urine), protein-losing enteropathy
• Result: generalized edema (anasarca)

• Causes: fibrosis (post-irradiation), tumors, parasitic infection (filariasis)
• Results in lymphedema - hard, non-pitting

• Activation of RAAS (low renal perfusion → aldosterone → Na+ retention)
• Occurs in heart failure, renal failure

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3. HEMORRHAGE

• Hematoma: blood accumulates within tissue
• Petechiae (<1-2 mm): tiny pin-point bleeds (e.g., thrombocytopenia, vitamin C deficiency)
• Purpura (3-5 mm): slightly larger
• Ecchymoses (>1-2 cm): larger subcutaneous bleeds ("bruises")
• Hemothorax, hemopericardium, hemarthrosis: blood in body cavities

• Loss of up to 20% blood volume: well tolerated in healthy adults
• Greater loss → hemorrhagic (hypovolemic) shock
• Location matters: minor subcutaneous bleed vs. fatal intracranial bleed
• Chronic external blood loss (e.g., peptic ulcer, menorrhagia) → iron deficiency anemia
• Internal bleeding (hematoma) does NOT cause iron deficiency - iron is recycled from phagocytosed RBCs

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4. HEMOSTASIS AND THROMBOSIS

Normal Hemostasis

• Immediate, mediated by neurogenic reflexes and local endothelin release
• Transient - bleeding resumes without platelet/coagulation activation

• Endothelial injury exposes subendothelial ECM (especially collagen and vWF)
• von Willebrand factor (vWF) bridges collagen and platelet GpIb receptors → platelet adhesion
• Adhesion triggers platelet activation: shape change, secretion of granules (ADP, TXA2, serotonin, fibronectin)
• Secreted ADP and TXA2 recruit more platelets → aggregation via conformational change in GpIIb-IIIa receptors that bind fibrinogen
• Result: primary hemostatic plug (loose)

• Tissue factor (TF/factor III) is exposed at injury site and initiates coagulation
• Most important factors: VII, IX, X, II (prothrombin), and fibrinogen; cofactors V and VIII
• Thrombin (factor IIa) is the central enzyme - it:
  • Converts fibrinogen → fibrin
  • Activates factor XIII (crosslinks fibrin)
  • Promotes platelet contraction
• Result: secondary hemostatic plug (solid, stable fibrin mesh)

• Washout of activated factors; hepatic removal
• Requirement for phospholipid surfaces (only on activated platelets)
• Antithrombin III: inhibits thrombin and factors IXa, Xa, XIa, XIIa (heparin enhances this)
• Proteins C and S: inactivate factors Va and VIIIa
• Tissue plasminogen activator (t-PA): activates plasminogen → plasmin, which degrades fibrin clots
• Thrombomodulin: on intact endothelium, binds thrombin and shifts it to activate protein C

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5. THROMBOSIS

Virchow's Triad

Hypercoagulable States

• Factor V Leiden (Arg506Glu): most common; factor V becomes resistant to protein C inactivation; ~3-fold increased venous thrombosis risk; heterozygous frequency >1% in USA
• Prothrombin G20210A variant: elevated prothrombin levels
• Antithrombin III, Protein C, Protein S deficiencies (rare; present in young adults with venous thromboembolism)
• Elevated homocysteine: associated with both arterial and venous thrombosis

• Prolonged bed rest / immobilization
• Myocardial infarction, atrial fibrillation
• Surgery, fracture, burns
• Cancer (especially mucinous adenocarcinomas - Trousseau syndrome)
• Prosthetic cardiac valves
• DIC, Heparin-induced thrombocytopenia (HIT)
• Antiphospholipid antibody syndrome (APS): antibodies against phospholipid-binding proteins → recurrent arterial/venous thrombosis, recurrent miscarriages; can be primary or secondary (e.g., in SLE)

• Cardiomyopathy, nephrotic syndrome
• Pregnancy, oral contraceptive use
• Sickle cell anemia, smoking

Morphology of Thrombi

• Lines of Zahn: pale platelet/fibrin layers alternating with darker RBC-rich layers (indicates thrombus formed in flowing blood - distinguishes antemortem from postmortem clot)
• Mural thrombi: attached to wall of vessels/heart chambers (e.g., post-MI left ventricular thrombus, aortic aneurysm thrombi)
• Occlusive thrombi: completely obstruct vessel lumen (common in smaller arteries and veins)
• Venous thrombi: form in areas of stasis; propagate toward heart; more prone to embolize

Fates of Thrombi

1. Propagation: enlargement by accumulation of more platelets/fibrin
2. Embolization: dislodgement and travel to distant sites
3. Dissolution: by fibrinolytic activity (most effective with fresh thrombi)
4. Organization and recanalization: fibroblasts and smooth muscle cells grow in; new capillary channels form over weeks, restoring some flow

DIC (Disseminated Intravascular Coagulation)

• Widespread simultaneous activation of coagulation throughout microvascular system
• Causes: obstetric complications (abruptio placentae, septic abortion), sepsis, malignancy, severe trauma, massive transfusions
• Paradoxical combination: thrombosis AND hemorrhage - clotting factors consumed ("consumption coagulopathy")
• Lab: elevated PT, PTT; elevated D-dimers; low fibrinogen, low platelets, fragmented RBCs (schistocytes)

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6. EMBOLISM

Pulmonary Thromboembolism (PTE)

• Source: >95% from deep veins of the leg (popliteal vein or above)
• Frequency: very common; 2-4 per 1000 hospital patients/year; underdiagnosed
• Most small emboli are clinically silent; 60-80% resolve through fibrinolysis
• Massive emboli (>60% of pulmonary circulation): sudden death, right heart failure
• Multiple smaller emboli over time: pulmonary hypertension, right heart strain
• Hemorrhagic pulmonary infarction: when emboli occur in patients with pulmonary congestion (underlying cardiac or respiratory disease); produces wedge-shaped hemorrhagic infarct

Systemic Thromboembolism

• Source: left heart (80%) - mural thrombi after MI, atrial thrombi in atrial fibrillation, valvular disease
• Also: aortic aneurysm thrombi, paradoxical embolism (through patent foramen ovale)
• Target organs: lower extremity arteries (75%), brain (also common), intestines, kidneys, spleen
• Most result in infarction

Fat Embolism

• Source: fat globules from bone marrow after fractures of long bones or pelvis; also after liposuction, burns
• Fat Embolism Syndrome (1-3% of severe fractures): 1-3 days after injury; triad of:
  • Pulmonary insufficiency (hypoxemia, tachypnea)
  • Neurological symptoms (confusion, irritability, coma)
  • Petechial rash (from thrombocytopenia/fat emboli in skin vessels)
• Mechanism: mechanical obstruction + free fatty acid release → toxic endothelial injury, platelet activation

Amniotic Fluid Embolism

• Rare but catastrophic (~1/40,000 deliveries); mortality ~60%
• Amniotic fluid enters maternal circulation via uterine vein tears at placental site
• Onset: sudden severe dyspnea, cyanosis, hypotension, neurological symptoms, DIC
• Pathology: fetal squamous cells, mucin, lanugo hair in pulmonary vasculature

Air Embolism

• Gas bubbles obstruct flow; 100 mL needed to cause cardiovascular compromise (small amounts tolerated)
• Decompression sickness: rapid pressure decrease (divers, aviators) - dissolved nitrogen forms bubbles
  • Joints/muscles: "the bends"
  • Pulmonary: "the chokes"
  • Chronic form: caisson disease - multifocal ischemic necrosis (especially femoral heads)
• Treatment: hyperbaric oxygen (re-compresses nitrogen bubbles)

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7. INFARCTION

Red (Hemorrhagic) vs. White (Anemic) Infarcts

Histology

• Main finding: ischemic coagulative necrosis (except brain → liquefactive)
• Inflammatory response at margins: 1-2 hours, well defined by 1-2 days
• Followed by repair: regeneration at periphery or scar formation
• Remote infarcts: replaced by scar tissue

Factors Influencing Infarct Development

1. Anatomy of vascular supply: dual supply (lung, liver) → more protected; end-arterial organs (heart, kidney, spleen) → more vulnerable
2. Rate of occlusion: slow occlusion → time for collaterals to develop (e.g., gradual coronary stenosis in atherosclerosis)
3. Tissue vulnerability to hypoxia:
   • Neurons: irreversible after 3-4 minutes
   • Myocardium: irreversible after 20-30 minutes
   • Fibroblasts: viable for many hours

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8. SHOCK

Types of Shock

Pathogenesis of Septic Shock

• Incidence: >750,000 cases/year in USA; 2% of all hospital admissions; 50% need ICU
• Mortality: 20-30% despite modern care
• Most common trigger: gram-positive bacteria > gram-negative > fungi

• Pattern recognition receptors (TLRs, NOD-like receptors) on macrophages, neutrophils, dendritic cells, endothelium recognize:
  • LPS (gram-negative endotoxin) + LPS-binding protein → CD14/TLR4 complex
  • Gram-positive cell wall components (peptidoglycan, lipoteichoic acid)
• Trigger massive release of: TNF, IL-1, IL-6, IL-12, IFN-γ, IL-17 and other mediators
• Result: widespread endothelial activation, vasodilation, increased vascular permeability, procoagulant state, metabolic derangements
• Severe septic shock → multi-organ failure → death

Stages of Shock

• Compensatory mechanisms maintain perfusion to vital organs
• Baroreceptor reflexes, catecholamine release, RAAS activation, ADH release
• Peripheral vasoconstriction, tachycardia, fluid conservation by kidneys

• Compensatory mechanisms fail
• Widespread tissue hypoxia → anaerobic glycolysis → lactic acidosis
• Acidosis blunts vasoconstriction response; decreased cardiac output
• Renal conservation fails (oliguria)
• Progressive organ dysfunction

• Severe cellular and tissue injury
• Myocardial depression, lysosomal enzyme leakage, gut microbe translocation
• Damage to vital organs becomes irreversible despite restoration of perfusion
• Multi-organ failure (kidney → renal tubular necrosis; lungs → ARDS; GI → ischemic enterocolitis)

Morphologic Changes in Shock

• Brain: ischemic encephalopathy
• Heart: foci of coagulative necrosis; subendocardial hemorrhage
• Kidneys: acute tubular necrosis (ATN) - most common cause of acute kidney injury in shock
• Lungs (in septic/traumatic shock): diffuse alveolar damage → ARDS
• Adrenals: lipid depletion (cortical cells secrete all stored lipid)
• GI: ischemic enterocolitis; stress ulcers

Clinical Features

• Hypotension, weak rapid pulse, tachypnea
• Cool, clammy, cyanotic skin (due to peripheral vasoconstriction)

• Skin may be warm and flushed early (vasodilation)
• Later stages mirror hypovolemic shock as decompensation occurs

• Hypovolemic shock in young healthy patients: >90% survival with appropriate treatment
• Septic or cardiogenic shock: substantially worse outcomes even with optimal care

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Summary Table: Rapid Review

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