Thrombosis

Virchow's Triad

1. Endothelial Injury

• Physical trauma, atherosclerotic plaque ulceration
• Infectious agents and cytokines
• Metabolic abnormalities: hypercholesterolemia, hyperhomocysteinemia
• Cigarette smoke toxins, hypertension
• Abnormal blood flow itself

• Procoagulant shift: downregulation of thrombomodulin, endothelial protein C receptor, and tissue factor pathway inhibitor (TFPI); upregulation of tissue factor
• Antifibrinolytic effects: increased secretion of PAI (plasminogen activator inhibitor), reducing t-PA activity

2. Abnormal Blood Flow (Stasis or Turbulence)

• Turbulence promotes arterial and cardiac thrombosis by causing endothelial dysfunction and creating local pockets of stasis
• Stasis is the dominant factor in venous thrombosis

• Platelets and leukocytes contact the endothelium
• Activated clotting factors accumulate (impaired washout)
• Clotting factor inhibitors are not replenished

3. Hypercoagulability

Primary (Genetic) Hypercoagulable States

Secondary (Acquired) Hypercoagulable States

• HIT syndrome: Autoantibodies bind heparin-platelet factor 4 (PF4) complexes → platelet activation → paradoxical thrombosis despite low platelet counts. Occurs in up to 5% of patients on unfractionated heparin.
• Antiphospholipid antibody syndrome (APS): Antibodies bind β2-glycoprotein I and phospholipid-associated proteins → recurrent arterial and venous thromboses, recurrent miscarriages, cardiac valve vegetations, thrombocytopenia. Paradoxically, these antibodies appear as anticoagulants in vitro but cause thrombosis in vivo.

Morphology of Thrombi

• Arterial thrombi: Attach to vessel wall, grow retrograde from attachment point; tend to be platelet-rich and pale ("white thrombi")
• Venous thrombi: Grow in the direction of blood flow (toward the heart); tend to be fibrin-rich and red ("red thrombi")
• Lines of Zahn: Pale layers of platelets + fibrin alternating with dark layers of red cells, seen in arterial thrombi and cardiac chambers - confirms ante-mortem formation
• Mural thrombi: Thrombi attached to the heart wall or aorta but not occlusive (e.g., overlying ventricular scars, in aortic aneurysms)
• Vegetations: Thrombi on cardiac valves - infected (infective endocarditis), sterile (non-bacterial thrombotic endocarditis in cancer/debilitating illness), or immune-mediated (Libman-Sacks in SLE)

Fates of Thrombi

1. Propagation - grows larger by accumulating more platelets and fibrin
2. Embolization - dislodges and travels to distant sites (most dangerous outcome)
3. Dissolution (fibrinolysis) - t-PA activates plasmin which degrades fibrin. This is most effective when the thrombus is fresh. Therapeutic thrombolytics (e.g., t-PA) are generally not effective if given more than a few hours after thrombus formation.
4. Organization and recanalization - older thrombi become organized by ingrowth of endothelial cells, smooth muscle cells, and fibroblasts. Capillary channels form, partially restoring lumen patency. The thrombus may ultimately be incorporated into the vessel wall as vascularized connective tissue.

Clinical Significance

Summary Box (Robbins & Kumar)

Typically caused by one or more components of Virchow's triad: endothelial injury (e.g., by toxins, hypertension, inflammation, or metabolic products); static or turbulent blood flow (e.g., from aneurysms, atherosclerotic plaque); and hypercoagulability, either primary (genetic) or secondary (acquired). - Robbins & Kumar Basic Pathology

Ischemia

Causes of Ischemia

Mechanisms of Ischemic Cell Injury

Step 1 - ATP Depletion

• Oxygen deprivation → failure of oxidative phosphorylation in mitochondria → ATP drops
• Cell switches to anaerobic glycolysis → lactic acid accumulates → intracellular pH falls → enzymes are inhibited

Step 2 - Failure of the Na⁺/K⁺ ATPase pump (Reversible Injury)

• ATP depletion disables the Na⁺/K⁺ pump
• Na⁺ and water flood into the cell → cellular swelling and membrane blebs
• K⁺ leaks out
• ER swells → ribosomes detach → reduced protein synthesis

Step 3 - Calcium Influx (Transition to Irreversible Injury)

• Intracellular Ca²⁺ rises due to failure of Ca²⁺-ATPase pumps and increased membrane permeability
• Ca²⁺ activates phospholipases (membrane damage), proteases (cytoskeletal breakdown), endonucleases (DNA damage), and ATPases (further ATP depletion)
• Ca²⁺ overload opens the mitochondrial permeability transition (MPT) pore → further ATP depletion and cytochrome c release → apoptosis

Step 4 - Irreversible Injury (Necrosis)

• Severe mitochondrial swelling and vacuolation
• Lysosome rupture → enzyme release → autodigestion
• Plasma membrane disruption → cellular leakage of contents → sterile inflammation
• Death by coagulative necrosis (most tissues) or liquefactive necrosis (brain)

Summary of Reversible vs. Irreversible Ischemic Injury

Ischemia-Reperfusion Injury

Mechanisms of Reperfusion Injury

• Reoxygenation generates a sudden surge of reactive oxygen species (ROS) - from leukocytes, damaged endothelium, and parenchymal cells
• Antioxidant defenses depleted during ischemia → cells are particularly susceptible

• Ca²⁺ influx worsens during reperfusion (membrane damage + ROS injury to the sarcoplasmic reticulum)
• Opens mitochondrial permeability transition (MPT) pore → ATP depletion → cell death

• Ischemic cells release "danger signals" and cytokines → recruitment of neutrophils into reperfused tissue
• Neutrophils cause additional injury via ROS, proteases, and eicosanoids
• Upregulation of adhesion molecules on hypoxic endothelium amplifies neutrophil recruitment

• IgM antibodies deposit in ischemic tissues
• On reperfusion, complement cascade is activated → further cell injury and inflammation

Infarction - The End Result

Types of Infarcts

• Both types are wedge-shaped, with the occluded vessel at the apex and the organ surface at the base
• Early margins are indistinct and slightly hemorrhagic; later margins become better defined by a rim of hyperemia (inflammation)
• Most infarcts are replaced by scar tissue (fibrosis) over time
• Exception: Brain infarcts undergo liquefactive necrosis, not coagulative necrosis

Factors Influencing Infarct Development

Tissue Vulnerability: Time Windows

Protective Response: HIF-1

• Promotes angiogenesis (new vessel formation)
• Stimulates cell survival pathways
• Enhances anaerobic glycolysis

Clinical Correlations

Shock

Types of Shock

Stages of Shock

Stage 1 - Nonprogressive (Compensated)

• Baroreceptor reflexes → sympathetic activation
• Catecholamine release → tachycardia, peripheral vasoconstriction
• ADH release → renal water retention
• Renin-angiotensin-aldosterone (RAA) activation → fluid conservation
• Net effect: Blood is redistributed away from skin/gut toward heart and brain
• Clinical signs: Tachycardia, cool/clammy/pale skin (except septic shock, which causes warm flushed skin due to vasodilation)

Stage 2 - Progressive

• Widespread tissue hypoxia → anaerobic glycolysis → lactic acid accumulation
• Lactic acidosis blunts arteriolar vasomotor response → arterioles dilate → blood pools in microcirculation
• Peripheral pooling → decreased cardiac output + endothelial ischemia → risk of DIC
• Vital organs begin to fail

Stage 3 - Irreversible

• Lysosomal enzyme leakage → worsens cell injury
• Myocardial contractility deteriorates severely
• Gut ischemia → intestinal flora enter circulation → superimposed bacteremic shock
• Renal failure from ischemic kidney injury
• Death follows multiorgan failure

Pathogenesis of Septic Shock (Detailed)

Four Core Pathogenic Mechanisms:

• Microbial PAMPs (pathogen-associated molecular patterns) activate:
  • Toll-like receptors (TLRs) on macrophages and neutrophils
  • G-protein-coupled receptors (detect bacterial peptides)
  • C-type lectin receptors (dectins - detect fungi)
• Activated cells release: TNF, IL-1, IL-12, IL-18, ROS, prostaglandins, PAF
• Complement cascade activation → C3a (mast cell activation), C5a (chemotaxis), C3b (opsonin)
• With time, a counterregulatory immunosuppressive phase follows, worsening vulnerability to secondary infections

• Cytokines loosen endothelial tight junctions → vascular leakage + widespread protein-rich edema
• Edema impairs nutrient delivery and waste removal
• Activated endothelium upregulates nitric oxide (NO) and vasoactive mediators → vascular smooth muscle relaxation → systemic hypotension
• Upregulated adhesion molecules amplify leukocyte recruitment

• Sepsis alters coagulation balance:
  • Increased: Tissue factor production by monocytes/endothelium, PAI-1 (blocks fibrinolysis)
  • Decreased: TFPI, thrombomodulin, endothelial protein C receptor (all anticoagulants)
• Result: Systemic thrombin activation → fibrin-rich microvascular thrombi throughout the body
• Full DIC occurs in up to 50% of septic patients → consumption of clotting factors and platelets → paradoxical concurrent bleeding and thrombosis

• Cytokines (TNF, IL-1) + stress hormones → insulin resistance + hyperglycemia
• Enhanced gluconeogenesis; suppressed insulin release
• Late phase: Adrenal insufficiency (functional or from adrenal necrosis - Waterhouse-Friderichsen syndrome)
• Mitochondrial damage + cellular hypoxia → lactic acidosis

Morphologic Effects of Shock

Clinical Features

Prognosis