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• Coagulation


  Process where blood forms clots

  
• Secondary hemostasis


  The coagulation of plasma, also called the fibrin forming coagulation system

  
• Secondary hemostasis

  • End product is a stable fibrin clot which strengthens the platelet plug
  • Involves coagulation factors in a series of cascading reactions
  • Goal is generation of sufficient thrombin to convert fibrinogen to fibrin

  
• Coagulation factors


  Numbered according to the date of discovery, not placed in reaction sequence, each has one or more common names

  
• Coagulation factor nomenclature

  • Fibrinogen (I)
  • Prothrombin (II)
  • Tissue factor (III)
  • Calcium (IV)
  • Proaccelerin (V)
  • Proconvertin (VII)
  • Antihemophilic factor (VIII)
  • Plasma thromboplastin component (IX)
  • Stuart-Prower factor (X)
  • Plasma thromboplastin antecedent (XI)
  • Hageman factor (XII)
  • Fibrin stabilizing factor (XIII)
  • Prekallikrein (PK)
  • High-molecular-weight kininogen (HMWK)

  
• Coagulation factors

  • All are produced in the liver
  • Most are referred to by their number except fibrinogen, prothrombin, tissue factor, calcium
• Classification of coagulation factors by function

  • Zymogens
  • Cofactors
  • Substrate

  
• Zymogens


  Circulate in blood in an inactive form, proenzymes with potential proteolytic activity, activated only when needed

  
• Cofactors


  Indirectly help in the activation of a zymogen, accelerate enzymatic reactions
• Substrate


  The material or substance on which an enzyme acts, fibrinogen is the main substrate used to make fibrin
• Kinin system factors

  • Prekallikrein
  • Kallikrein
  • Kininogen (LMWK and HMWK)
  • Kinins (bradykinins, etc)

  
• 3 groups of coagulation factors by properties

  • Contact group
  • Prothrombin group
  • Fibrinogen group

  
• Contact group

  • Includes factors XII, XI, HMWK, PK
  • Activated by contact with negatively charged surfaces
  • Deficiency states often asymptomatic except for FXI deficiency
• Prothrombin group

  • Adsorbable (BaSO4 or AlOH2)
  • Affected by Coumadin
• Fibrinogen group


  • All are acted upon by thrombin
  • Found in platelet alpha granules

  
• Role of calcium and vitamin K

  • Ca++ needed for coagulation factors to bind to phospholipid surface
  • Vitamin K necessary for gamma-carboxylation of factors 2, 7, 9 and 10 to allow Ca++ binding and phospholipid binding
• Tissue factor (factor VII)


  • Lipoprotein initiator of extrinsic pathway
  • Does not circulate in blood unless tissue damage occurs
  • All cells except blood cells contain tissue factor

  
• Coagulation cascade


  1. Involves serial activation of inactive plasma proteins to activate enzymes and factors

  2. Requires plasma proteins, phospholipids, calcium

  3. Transforms fibrinogen to fibrin

  
• Cascade theory of coagulation


  • Each factor is converted to active form by preceding factor in cascade
  • Ca++ participates as a cofactor in some reactions
  • Occurs on cell surface membranes like subendothelium and platelets

  
• Coagulation pathways

  • Intrinsic
  • Extrinsic
  • Common

  
• Intrinsic pathway

  1. Initiated by exposure to negatively charged foreign substances

  2. Involves factors XII, XI, IX, VIII, prekallikrein, HMWK

  3. Factor XIIa activates XI, which activates IX, which with VIIIa activates X
• Extrinsic pathway

  1. Initiated by tissue factor entering the vascular system

  2. Dominant in vivo pathway
• Intrinsic Pathway


  1. Factor XII is activated to XIIa

  2. XIIa then interacts with the contact factors, prekallikrein and kininogen, to activate more Factor XII to XIIa

  3. XIIa activates factor XI to XIa

  4. XIa then activates Factor IX to IXa in the presence of Ca++

  5. IXa participates along with co-factor VIII:C, Ca++, and PF3, to activate Factor X
• Intrinsic Pathway

  • All factors involved in clot formation are in the vascular compartment
  • Involved factors: Prekallikrein, HMWK, Factors XII, XI, IX, VIII
  • Is initiated following exposure to negatively charged foreign substances such as collagen, subendothelium, or phospholipids

  
• Extrinsic Pathway

  1. In the presence of tissue factor and calcium (factor 4), factor 7 is activated to factor 7a

  2. Factor 7a activates factor 10 to 10a

  3. Factor 7a can also activate factor 9 in the intrinsic pathway to 9a
• Extrinsic Pathway

  • The dominant in vivo pathway
  • The extrinsic pathway is initiated when there is an injury to a blood vessel wall
  • Initiated when a tissue factor not found in blood enters the vascular system

  
• Common Pathway


  1. 10a in the presence of Factor 5, Ca++ and phospholipid converts prothrombin (Factor 2) to its active form thrombin (2a)

  2. Thrombin then feeds back to activate factors 8 and 5

  3. Thrombin converts fibrinogen to soluble fibrin

  4. Thrombin converts factor 13 to 13a

  5. 13a cross-links the fibrin monomers to form a stable fibrin polymer

  
• Common Pathway


  • Intrinsic and extrinsic pathways converge on the common pathway
  • Both pathways activate Factor 10 to 10a
• Initiation and Propagation of Thrombin

  1. VIIa binds to tissue factor (TF ) and activates both factors X and IX

  2. Cell-bound factor Xa combines with Va and generates a small amount of thrombin (Thr), which activates platelets, V, VIII, and XI and begins fibrin formation

  3. Factor IXa, activated by both TF:VIIa and XIa, combines with factor VIIIa on the platelet surface to activate X, which forms prothrombinase (Xa:Va) and produces a burst of thrombin

  
• Conversion of Fibrinogen to Fibrin

  1. Fibrinogen alpha and beta fibrinopeptides are cleaved by thrombin, forming soluble fibrin monomers

  2. Fibrin monomers spontaneously polymerize, forming soluble fibrin polymers. This is the endpoint for clot-based tests

  3. Clot stabilization occurs, requiring thrombin activation of F13 and calcium

  
• "Contact phase" factors (F12, HK, and PK) are believed not to contribute to normal physiologic hemostasis

  
• Tissue factor (TF)/F7a can directly activate 10 to 10a but this does not contribute significantly to clot formation under normal in vivo physiologic conditions
• Normal clotting in vivo is initiated when sufficient TF/F7a becomes available to activate F9 to F9a
• Coagulation Complexes


  • Extrinsic tenase: VIIa, tissue factor, phospholipid, Ca2+ - Activates IX and X
  • Intrinsic tenase: IXa, VIIa, phospholipid, and Ca2+ - Activates X
  • Prothrombinase: Xa, Va, phospholipid, and Ca2+ - Activates Prothrombin
• The prothrombinase complex accelerates thrombin generation more than 300,000-fold compared to Xa alone

  
• Thrombin Feedback


  • Positive feedback: Low thrombin levels activate factors 5, 8 and 13, induce platelet aggregation
  • Negative feedback: When thrombin levels are high, thrombin binds to thrombomodulin on endothelial cell surface and activates protein C (inhibits factors 5 and 8), Plasminogen is converted to plasmin (fibrinolysis)

  
• Fibrinolysis


  • Digestion or dissolution of fibrin clots
  • Final stage of coagulation
  • Body's defense against occlusion of blood vessels
  • The main enzyme responsible for fibrinolysis is PLASMIN that is regulated by various activators and inhibitors

  
• The fibrinolytic system must be regulated so that unwanted clots are dissolved but not broken down prematurely

  
• Plasminogen


  • Glycoprotein produced in the liver
  • Concentration of 20-40 mg/dL
  • Precursor of plasmin
  • A zymogen (inert) found in plasma
  • Activated form is plasmin
  • Plasminogen converted to plasmin by "plasminogen activators"

  
• Plasminogen Activators


  • Intrinsic activators: Factor XIIa, Kallikrein, HMWK
  • Extrinsic activators: Tissue-type plasminogen activator (t-PA) - produced by endothelial cells (veins), Urokinase-like plasminogen activator (u-KA) - produced by the kidney; single-chain urokinase plasminogen activator (ScuPA) and two-chain urokinase plasminogen activator (TcuPA)
  • Therapeutic/Exogenous activators: Streptokinase, Urokinase, Tissue-like plasminogen activator (t-PA)