coag1

Menu
Introduction Blood Coagulation: Mechanisms Thrombogenesis: Sequence/Characteristics Injury White Thrombus Red Thrombus Summary: Platelets Blood Coagulation Overview Sequence Cascade Drug Influences Clotting Factors: Drug Clotting Sites Coagulation and Fibrinolysis: Regulation Systems regulating coagulation Inactivation of coagulation proteins plasma protease inhibitors Failure of plasma protease inhibitor systems DIC Fibrolysis Drug interventions: fibrinolytic system: Activators Inhibitors Anticoagulant Drugs: Pharmacology Heparin Composition Mechanism of Action Bioassay Toxicity Contraindications Reversal of Effect Warfarin/Coumarin Chemistry/Pharmcokinetics Oral Anticoagulation Mechanism of Action Toxicity Miscellaneous Adverse Effects Drug-Drug Interactions Most Serious Interaction: increase anticoagualation Decrease in anticoagulation Pharmacodynamic Effects Reversal of Warfarin anticoagulation Other related Agents Fibrolytic Drugs Overview Pharmacology Streptokinase Urokinase Anistreplase t-PA Clinical Uses	Antithrombotic Agents- Antiplatelet Drugs Overview Regulation of Platelet Function Pharmacological Targets Aspirin Mechanims of Action Clinical Use Adverse Effects Dietary Ticlopidine Clinical Use Adverse Effects Blockade of GP IIb/IIIa Clinical Use Pharmacological Management of Thrombosis Venous Thrombosis Acquired Disease Antithrombotic Management Prevention Heparin Oral Anticoagulants Venous Thrombosis-established Arterial Thrombosis Platelet-inhibiting agents Clinical Uses Drugs Used in Bleeding Disorders Vitamin K Clinical Issues: Vitamin K Plasma Fractions-- Bleeding due to factor deficiencies Overview Coagulation Defects Factor VIII Desmopressin acetate Factor IX Fibrinogen Fibrinolytic Inhibitors: Aminocaproic Acid Clinical Uses Adverse Effects

Introduction
- Abnormal states of hemostasis
  - Bleeding (impaired hemostasis)
  - Thrombus formation (stimulated hemostasis)
return to main menu

Blood Coagulation: Mechanisms

Thrombogenesis: Sequence and Characteristics
- Normal:
  - Normal vascular endothelial cells:
    - not thrombogenic (platelet/clotting factors do not adhere)
  return to main menu
- Injury. ® thrombogenesis
  1. Immediate response: vasospasm
  2. Platelet adherence to damaged epithelium (binds to collagen) referred to as platelet adhesion. (collagen-platelet membrane glycoprotein Ia receptor interaction)
  3. Platelets binding to each other: platelet aggregation
  4. Platelets form a gelatinous mass (losing individual membranes): viscous metamorphosis. ® platelet plug (temporary cessation of bleeding)
  5. Platelet plug -- reinforcement by fibrin
  6. Fibrin reinforcement:
    - damaged vessel . ® exposed collagen + platelet content released
      - Platelet degranulation releases aggregating substances:
        
        ADP
        
        TXA₂
        
        5-HT
    - local thrombin production:
      - platelet ADP release (ADP inducer of platelet aggregation)
      - prostaglandin synthesis (derived from platelet membrane arachidonic acid)
        
        Thrombogenesis/vasoconstriction: thromboxane A₂ , TXA₂)
        
        Thrombogenesis inhibitor: prostacyclin
    return to main menu
- White Thrombus:
  - where: high-pressure arteries
  - circulating platelet adherence to regions of abnormal epithelium
  - aggregated-platelet thrombus ® reduced flow
  - red thrombus forms around white thrombus nidus
return to main menu
- Red Thrombus:
  - forms either secondary to white thrombus or de novo -- low pressure veins
  - Thrombus forms a fibrin network longer tail entraps red cells)
    - Fibrin tail may detach forming emboli which may travel to pulmonary arteries
return to main menu
- Summary: platelets
  - Platelet nidus: most significant for arterial thrombus
    - Concerns: arterial thrombi . ® local vessel occlusion/ischemia
  - Fibrin tail (red thrombus):most significant for venous thrombus
    - Concerns: venous thrombi . ® embolization at distant sites
Blood Coagulation-- soluble fibrinogen ® insoluble fiber
- Overview:blood coagulation
  - Cascade process:
    - clotting factors zymogen ® limited proteolysis® active protease ® activates next clotting factor® solid fibrin clot
return to main menu
- Sequence:
  - fibrinogen (factor I; soluble fiber precursor) substrate for thrombin (enzyme, factor IIa)® fibrin clot
    - thrombin formed from activation of its zymogen, prothrombin (factor II)
    - prothrombin (factor II): bound by a calcium to platelet phospholipid (PL); activated factor X (Xa) + activated factor Va converts prothrombin (factor II) ® circulating thrombin
  - Possible initiation step:
    - tissue factor (TF) + factor VII
  - Regulation factors:
    - tissue factor pathway inhibitor (TFPI)
    - endogenous anticoagulants: protein C, protein S: down-regulation of blood clotting amplification by proteolysis factors Va, VIIIa and IXa.
  - Drug influences:
    - oral anticoagulants: inhibits clotting factor synthesis
    - e.g.: heparin inhibits activity of certain activated factors.

return to main menu

Blood Coagulation Cascade: Proposed Model

return to main menu