Hemostasis

Question 1

Mechanism of coagulation

Answer 1

1. Responce to injury includes:

• Contraction of vasular smooth muscle
• platelet activation
• blood coagulation

2. Blood Coagulation

• Two systems of coagulation:
  
  • Intrinsic pathway (intravascular)
  • Extrinsic pathway (extravascular)
    
    • Both pathways end up in common pathway that produces Thrombin which is a molecule that converts fibrinogen to fibrin
• ​Events at the site of Vascular injury:
  
  • Platelets adhere to collagen or von willbrand factor, forming an initial platelet plug
  • Damage to enothelial cells exposes tissue factor on the surface of perivascular subendothelial cells to circulating Factor VII
    
    • Factor Vll is converted to factor Vlla complex
      
      • Factor Vlla activated factors IX and X
        
        • Factor X remaines Localized and bind to factor V, activates V and make factor Xa-Va complex or Prothrombinase complex
          
          • ​Prothombinase complex causes a conversion of small amount of prothrombin to thrombin. This is only priming mechanism for second round of clotting process which happens on surface of platlets and it is not enough for conversion of fibrinogen to fibrin.
            
            • This small amount of Thrombin activates
              
              • additiona factors X, IX, Xl
              • Cleaved factor Vlll from vWF and activate it to fom Vllla
              • Activate platlets at the site of injury
              • Converts fibrinogen to fibrin
              • activated factor Xlll that stabilizes a stable cross-linked fibrin
        • Factor IXa does not remain localized, it binds to the surface if activated platelets which contributes to full size thrombin burst
• Role of Activated platlets :
  
  • degranulate and release large number of factor V, Vlll which are necessary for efficient coagulation
    
    • Factor lXa complelexs with Vllla –> tenase complex
      
      • Tenase complex recruite and activate more factor X from plasma
        
        • Factor X forms prothrombinase complex which converts large amout of prothrombin to thrombin
          
          • sufficient thrombin is formed to generate fibrin from fibrinogen and activate factor XIII to cross link fibrin monomers
            
            • Crosslinked fibrin meshwork shrinks and traps activated platelets and red blood cells to form blood clot.

Question 2

Physiologic control of coagulation

Answer 2

1. Coagulation is mainly terminated by action of inhibitor proteins and anti-coaggulant
   proteases. The 3 regulatory molecules are:

• serine proteases
• heparins
• anticoaguant poteases

2. Serine proteases (serpines) are descibed as:

• Antithrombin
  
  • inhibits:
    
    • Thrombin
    • Factors Vlla, lX, X and Xl
• heparin Cofactor II
  
  • endogenous heparin found on endothelial cell surface:
    
    • Speeds action of antithrombin 1000 fold
      
      • this serves to protect normal enothelium from spontanous thrombus formation
      • localize the coagulation process to activated enothelium
• a2 macroglobulin
  
  • trap, inactivates and rapidly clears circulatory activated coagulation factors
• Tissue factor pathway inhibitor
  
  • Kunin protein that regulates tisse factor-factor Vlla complex and becomes more potant after binding factor Xa
• Thrombomudulin
  
  • membrane protein receptor that binds thrombin and alter it
  • altered thrombin activates protein C
    
    • Activated protein C inactivates factor Va and Vllla
    • Protein S accelerate action of protein C