Pathogenesis of Thrombosis

1. Endothelial Injury

• Direct injury exposes subendothelial von Willebrand factor (vWF) and tissue factor, triggering platelet adhesion and activation of the coagulation cascade.
• Endothelial activation/dysfunction (without frank injury) is triggered by: physical trauma, infectious agents, cytokines, turbulent flow, hypercholesterolemia, homocystinemia, and cigarette smoke toxins.
• Activated endothelium shifts to a prothrombotic phenotype:
  • Downregulates thrombomodulin, endothelial protein C receptor, and tissue factor pathway inhibitor (TFPI)
  • Upregulates tissue factor expression
  • Increases secretion of plasminogen activator inhibitors (PAI), reducing fibrinolysis
• Arterial/cardiac thrombi are platelet-rich ("white thrombi") due to the high-shear environment.

2. Abnormal Blood Flow (Stasis or Turbulence)

• Causing endothelial injury/dysfunction
• Creating countercurrents and local pockets of stasis

• Platelets and leukocytes to accumulate at the vessel wall (normally separated from endothelium by laminar flow)
• Slowed washout of activated clotting factors
• Impaired inflow of clotting factor inhibitors
• Activation of endothelial gene expression, promoting a procoagulant state

3. Hypercoagulability

• Factor V Leiden mutation - renders Factor V resistant to cleavage by protein C; heterozygotes have 3-4x risk, homozygotes 25-50x risk; found in ~60% of patients with recurrent DVT
• Prothrombin G20210A mutation - 3' UTR variant causing elevated prothrombin levels; ~3x venous thrombosis risk
• Antithrombin III deficiency
• Protein C or Protein S deficiency - loss of the key anticoagulant pathway
• Elevated homocysteine (anti-phospholipid syndrome-like effects)

• Prolonged immobility or bed rest
• Myocardial infarction, congestive heart failure
• Cancer (especially mucin-secreting adenocarcinomas - Trousseau syndrome)
• Pregnancy and the postpartum state
• Oral contraceptives/hormone replacement therapy
• Antiphospholipid antibody syndrome
• Heparin-induced thrombocytopenia (HIT)
• Disseminated intravascular coagulation (DIC)

Fate of a Thrombus

• Robbins & Kumar Basic Pathology, pp. 88-91

Classification of Receptors

The 5 known transmembrane signaling mechanisms (Katzung's Basic & Clinical Pharmacology, 16e)

A. By Location

B. By Signal Transduction Mechanism (Main Classification)

Type 1 - Intracellular (Nuclear/Cytoplasmic) Receptors

• Ligand is lipid-soluble and crosses the plasma membrane directly
• Ligands: steroids (glucocorticoids, mineralocorticoids, sex hormones), vitamin D, thyroid hormone, retinoids
• Mechanism: Hormone binds receptor → receptor dissociates from hsp90 chaperone → receptor-hormone complex enters nucleus → binds DNA response elements → regulates gene transcription
• Onset of action is slow (30 min to hours) due to need for new protein synthesis
• Effects persist for hours to days even after drug is removed (slow protein turnover)
• Example: Glucocorticoid receptor, estrogen receptor, thyroid hormone receptor

Type 2 - Ligand-Gated Ion Channels (Ionotropic Receptors)

• Receptor is the ion channel
• Ligand binding directly opens or closes the channel
• Fastest signal transduction (milliseconds)
• Ions: Na⁺, K⁺, Ca²⁺, Cl⁻
• Examples:
  • Nicotinic ACh receptor (Na⁺/K⁺ channel)
  • GABA-A receptor (Cl⁻ channel)
  • NMDA receptor (Ca²⁺/Na⁺)
  • Glycine receptor (Cl⁻)
• Also called ionotropic receptors

Type 3 - G Protein-Coupled Receptors (GPCRs / Metabotropic Receptors)

• Largest family of cell-surface receptors (~1000 known)
• Have 7 transmembrane segments (heptahelical/serpentine receptors)
• Signal via heterotrimeric G proteins (α, β, γ subunits)
• Ligand binds extracellular domain → conformational change → G protein activation (GDP → GTP exchange on α subunit) → α subunit dissociates → activates/inhibits:
  • Adenylyl cyclase → cAMP (via Gs or Gi)
  • Phospholipase C → IP₃ + DAG (via Gq)
  • Ion channels
• Gs (stimulatory) vs. Gi (inhibitory) subtypes modulate enzyme activity in opposite directions
• Signal terminated when α subunit hydrolyzes GTP → GDP; reassembles with βγ
• Examples:
  • β-adrenergic receptors (Gs → ↑cAMP)
  • Muscarinic M2 receptor (Gi → ↓cAMP)
  • α1-adrenergic receptor (Gq → IP₃/DAG)
  • All serotonin (5-HT) receptors except 5-HT3

Type 4 - Enzyme-Linked Receptors (Receptor Tyrosine Kinases and Related)

• Single transmembrane segment (single-pass, unlike GPCRs)
• Extracellular hormone-binding domain + intracellular enzyme domain
• Subtypes:
  • Receptor Tyrosine Kinases (RTKs): Ligand binding causes receptor dimerization → autophosphorylation of tyrosine residues → downstream signaling cascades (Ras/MAPK, PI3K/Akt)
  • Receptor Serine/Threonine Kinases: e.g., TGF-β receptor
  • Receptor Guanylyl Cyclase: e.g., ANP (atrial natriuretic peptide) receptor → produces cGMP
  • JAK-STAT associated receptors (cytokine receptors): lack intrinsic kinase activity; associate with JAK kinases → phosphorylate STAT proteins
• Ligands: Insulin, EGF, PDGF, VEGF, GH, leptin, prolactin, IGF-1, cytokines

Type 5 - Receptor Tyrosine Kinase-Associated Receptors

• Receptor binds and stimulates a separate (non-covalently attached) protein tyrosine kinase
• Does not have intrinsic enzymatic activity itself
• Example: Growth hormone receptor - associates with JAK2 kinase

Summary Table

Note on Pharmacological Context

• Arterial/cardiac receptors are targeted by drugs acting on GPCRs (e.g., β-blockers, ACE inhibitors) and ion channels (e.g., Ca²⁺ channel blockers)
• CNS receptors are predominantly ion-channel linked (fast synaptic) and GPCR (modulatory)
• Endocrine receptors span all classes depending on the hormone's lipid solubility
• Katzung's Basic and Clinical Pharmacology, 16e, pp. 51-53
• Guyton and Hall Textbook of Medical Physiology, pp. 909-910