Coagulation System Notes

Hemostasis

• Occurs in two phases:
  • Primary hemostasis:
    • Vascular contraction.
    • Platelet adhesion and aggregation.
    • Soft, short-lived plug formation.
  • Secondary hemostasis:
    • Responsible for stabilizing the soft plug by activating the coagulation (clotting) cascade and fibrin formation.

Five Interacting Parts of Hemostasis

• Blood vessels
• Platelet activation and function
• Plasma coagulation factors and activators
• Inhibitors of coagulation factors and platelets
• Fibrinolytic system: A system of clot breakdown

Secondary Hemostasis

• Compartment: Coagulation system
• Coagulation process:
  • A series of biochemical activations of plasma proteins that ends with fibrin clot formation to stabilize the platelet plug formed in primary hemostasis.

Introduction to Coagulation System

• Coagulation factors:
  • Described with Roman numerals (e.g., V, II, X).
  • Abbreviated as FV, FII, etc.
  • Some factors have names instead of Roman numerals.
  • Inactive factors are designated as FV, FII, etc.
  • Activated factors are designated as FVa, FIIa, etc.
• Activation of factors:
  • An activated factor activates the next factor in the reaction sequence.

Clotting Factors and Their Synonyms

• Factor I: Fibrinogen
• Factor II: Prothrombin
• Factor III: Tissue factor; Tissue Thromboplastin
• Factor IV: Calcium
• Factor V: Proaccelerin; Labile factor
• Factor VII: Serum prothrombin conversion accelerator; proconvertin
• Factor VIII: Antihemophilic factor; AHF
• Factor IX: Plasma thromboplastin component
• Factor X: Stuart-Prower factor
• Factor XI: Plasma thromboplastin antecedent
• Factor XII: Hageman factor
• Factor XIII: Fibrin-stabilizing factor
• Platelets

Coagulation System

• Coagulation factors are glycoproteins normally present in plasma in an inactive form.
• All coagulation factors are produced by the liver, except for FVIII.
  • FVIII is produced by the liver, spleen, lymph nodes, pancreas, kidneys, and muscles.
• Coagulation factors are divided into:
  • Substrate: Fibrinogen
  • Co-factors: FIII, FV, and FVIII
  • Enzymes: the rest of the coagulation factors

Cascade Theory of Coagulation System

• A series of reactions that transforms circulating blood proteins into an insoluble gel through the conversion of fibrinogen to fibrin.
• This process requires:
  • Coagulation factors
  • Phospholipids (platelet plasma membrane)
  • Calcium
• The coagulation cascade is classified into:
  • Extrinsic pathway
  • Intrinsic pathway
  • Common pathway (between extrinsic & intrinsic)
• Each factor is converted to the active form by the preceding factor in the series.
• A deficiency in any factor leads to:
  • Coagulation cannot proceed at a normal rate.
  • Initiation of the next reaction is delayed.
  • The time required for clot formation is prolonged.
  • Bleeding continues for a longer time.
• Both extrinsic and intrinsic pathways lead to the generation of thrombin, which then converts fibrinogen to fibrin.

Extrinsic Pathway

• This coagulation pathway is activated from a factor present outside the blood vessel.
• When a blood vessel is ruptured:
  • Blood contacts the exposed subendothelium, which contains TF (Tissue Factor) or Tissue Thromboplastin (FIII).
  • Then, the clotting cascade begins.
• The greater the damage to the blood vessel, the more TF that is released.
• TFa combines with FVII to form a complex capable of activating FX (Calcium-dependent).

Intrinsic Pathway

• This coagulation pathway begins from a factor present inside the blood vessel.
• It involves the activation of FXII to FXIIa when it comes into contact with exposed collagen or any substance with a negative charge.
• It occurs with the presence of platelet factor 3 (phospholipid of the platelets).
• FXIIa activates FXI into FXIa.
• FXIa activates FIX into FIXa.
• FIXa combines with FVIIIa to form an enzyme complex capable of activating Factor X.

Common Pathway

• This pathway begins when a factor from either the extrinsic or intrinsic pathways activates FX.
• FXa converts prothrombin into thrombin in the presence of ($Ca^{+2}$, PL, and FVa).
• Thrombin converts fibrinogen into fibrin.
• A fibrin network covers the surface of the platelet plug.
• Blood cells and platelets become trapped in the fibrous network, and a blood clot is formed.

Extrinsic Pathway Factors

1. Tissue factor (TF)
   • A glycoprotein found on the surface of many cells that are NOT usually in contact with the blood.
   • High concentrations in the brain, lung, and placenta.
   • Tissue damage allows the interaction of TF with the circulating coagulation system.
   • Membrane-bound TF joins with FVII and, in the presence of $Ca^{+2}$, activates it to FVIIa.
2. FVII
   • In the presence of TF and $Ca^{+2}$, it activates FX to FXa.
   • FVII is NOT used up during clotting; it is present in both plasma and serum.
3. FX
   • The key protein in all activation pathways.
   • Is converted to FXa by the FVIIa-TF complex.
4. FV
   • Heat-labile and storage-labile (although it stores well in frozen plasma).
   • FV is activated to FVa by thrombin and FXa.
   • It is USED UP during clotting, so it is present in plasma but NOT in serum.
5. Prothrombin (FII)
   • Prothrombin (FII) is converted to thrombin (FIIa) by the "prothrombinase complex," which includes FXa, FVa, $Ca^{+2}$, and phospholipid.
   • Phospholipid is Platelet Factor 3 (PF3).
6. Fibrinogen (FI)
   • Fibrinogen is converted to fibrin by the action of thrombin.
   • Fibrin is then changed from a monomer to a polymer structure and then to a network.
   • Fibrinogen is:
     • Not adsorbed by barium sulphate or aluminum hydroxide; found in adsorbed plasma.
     • Used up during clotting; NOT found in serum.
     • Stable; found in aged plasma.
7. FXIII
   • Is converted to FXIIIa by thrombin.
   • FXIIIa crosslinks glutamine and lysine groups on adjacent fibrin polymer molecules to form an insoluble fibrin clot.
   • FXIII is not essential in clot formation, but clots formed when FXIII is absent are very fragile (soft).

Formation of Fibrin Polymer

• Fibrinogen is converted to fibrin monomer by thrombin, releasing fibrinopeptides.
• Fibrin monomers spontaneously associate via hydrogen bonding to form a fibrin polymer.
• FXIIIa, a transamidase, then cross-links the fibrin polymer to form a stabilized fibrin polymer.

Factors in Extrinsic & Common Pathways

Vitamin K-Dependent Factors (Stable Factors)

A) Factors II, VII, IX & X

• Require vitamin K to become active enzymes and participate in coagulation.
  B) They are stable (remain active) for a long time.
• Present in aged plasma.
  C) They are NOT used up when a clot forms.
• Present in both serum & plasma.
  D) They are adsorbed & removed when plasma is treated with barium sulphate or aluminum hydroxide gels.
• Adsorbed plasma: does NOT contain factors II, VII, IX, or X.

Intrinsic Pathway Factors

1. FXII
   • A single-chain glycoprotein present in both plasma & serum.
   • When placed in contact with collagen, FXII changes shape.
   • This change exposes the active site of the molecule.
   • This activated form of FXII, called FXIIa, converts FXI to FXIa.
2. FXI
   • A glycoprotein made up of two identical chains, present in both plasma & serum.
   • Activates FIX to FIXa.
   • Is inhibited by antithrombin III.
   • The contact factors (FXI & FXII) are:
     • Stable → present in aged plasma
     • Not adsorbed by barium sulphate or aluminum hydroxide → present in adsorbed plasma.
3. FIX (Christmas factor)
   • A single-chain glycoprotein.
   • FIXa forms a complex with FVIIIa, phospholipid, and $Ca^{+2}$ called the “Tenase complex.”
   • This complex activates the “common pathway” by activating FX.
4. FVIII (Cofactor of factor FIX)
   • Consists of two distinct proteins, which combine to form the active coagulant factor.
     • (i) FVIII C (Antihemophilic factor or FVIII coagulant)
       • Produced by the liver, spleen, lymph nodes, pancreas, kidneys, & muscle.
       • An acute phase reactant that is increased during infection & inflammation.
       • People with Hemophilia A are deficient in this protein.
     • (ii) FVIII vWF (von Willebrand factor)
       • Produced by endothelial cells & megakaryocytes.
       • Required for normal platelet function.
       • Deficient or abnormal in “von Willebrand’s disease.”

Labile Factors (FV & FVIII)

a. Used up when blood clots. They are NOT found in serum.
b. Labile (become inactive quickly). They are NOT found in aged plasma.
c. Not adsorbed by barium sulphate or aluminium hydroxide. They are found in adsorbed plasma.

Factors in the Intrinsic & Common Pathways

Schematic of an Injury to Blood Vessel

• Vasoconstriction of the blood vessel
• Collagen exposure
• Platelet activity leading to Platelet Adhesion and Aggregation
• Formation of a Hemostatic Platelet Plug
• Activation of the Intrinsic and Extrinsic Pathways
• Activation of the Common Pathway
• Thrombin converts to Fibrin with help of Tissue Factor
• Formation of a Hemostatic Fibrin Clot