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Physiology of coagulation

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					Applied Sciences Lecture Course


Physiology of coagulation

 Mahesh Nirmalan MD, FRCA, PhD
 Consultant, Critical Care Medicine
   Manchester Royal Infirmary
               Hemostasis

• Blood must be fluid
• Must coagulate (clot) at appropriate time
  – Rapid
  – Localized
  – Reversible
  Thrombosis…inappropriate coagulation
 Fibrinogen → Fibrin          Natural heparin like molecules that
                                     inactivate thrombin


       Thrombin
                                      Anti-thrombotic
Thrombosis
                                       mechanisms
               Thrombomodulin                   Fibrinolysis
           When bound to thrombin           Breakdown of fibrin
             1. Activates Protein C        Plasmin (Plasminogen)
         2. Inactivates clotting factors            tPA
     Clotting or thrombosis
Rudolph Virchow
Components of haemostasis

         COAGULATION
           PROTEINS




  Endothelium    Platelets
Endothelium
     PROCOAGULANT                              ANTICOAGULANT

     Plasminogen activator inhibitors                     Plasminogen activators



   Fibrinolytic inhibitors
                                                  Protein C→ Activated Protein C



 Thrombin/Thrombomodulin                               Thrombin/Thrombomodulin

                                        Tissue Factor Prostacyclin
   Von               Tissue               inhibitors
Willibrand           Factor
 Factor
   Pro-coagulant role of the damaged
             endothelium
• Synthesises tissue factor when damaged
   – Acquires the tissue factor from macrophages
   – Tissue factor, when bound to VIIa is the major activator of
     the extrinsic pathway
• Major site for the synthesis and storage of vWF
   – Increased Platelet adhesion
   – Carrier protein for Factor VIII
• Inhibition of Fibrinolysis
   – Thrombin activated fibrinolytic inhibitor
   – Plasminogen activator inhibitor
                    Platelets
•   Anucleate sub-cellular fragments
•   Arise from megakaryocytes in the marrow
•   Normal count: 200-400 thousand/μl
•   Several surface receptors
•   Activated by contact with extra-cellular matrix
•   Aggregation to form a platelet plug
•   Stabilisation by the formation of a fibrin clot
                   Platelets-2
•   Contact with collagen
•   Swelling and pseudopod formation
•   Contractile proteins contract forcefully
•   Release of platelet granules
•   Increased adhesion
•   Adhere to collagen and vWF
•   ADP and Thromboxane production
•   Cascade of events lead to a platelet plug
         Anti-platelet agents
• Inhibition of COX mediated Thromboxane
  synthesis: Aspirin
• ADP receptor inhibition: Clopidogrel
• Platelet phosphodiesterase inhibition:
  Dipyridamole
                 Haemostasis
• Primary
  – Vasoconstriction
  – Platelet plug formation
• Secondary
  – Coagulation
  – Organisation of clot
www.homepage.montana.edu/~awmsg/Coagulation.ppt
www.homepage.montana.edu/~awmsg/Coagulation.ppt
Secondary haemostasis
          &
 Coagulation proteins
 Newer models of coagulation:
beyond the scope of this lecture


Traditional models of coagulation
Fibrinogen   Fibrin
             Thrombin
Fibrinogen              Fibrin
                    Factor 2
              Produced in the Liver
Vit K dependant Post translational modification

                  Prothrombin (II)

                      Xa
                      Va

                   Thrombin (IIa)
     Fibrinogen                      Fibrin
                                     Extrinsic Pathway

                                          TF
             Prothrombin
                           VIIa
                Xa
                Va

             Thrombin
Fibrinogen                  Fibrin
Intrinsic pathway


   XIIa

                                               Extrinsic Pathway
          XIa
                                                    TF
                      Prothrombin
                IXa                  VIIa
                  VIIIa      Xa
                             Va

                          Thrombin
       Fibrinogen                     Fibrin
Intrinsic pathway


   XIIa

                                                  Extrinsic Pathway
          XIa
                                                         TF
                      Prothrombin
                IXa                  VIIa
                  VIIIa      Xa
                             Va

                          Thrombin             Unstable clot
     Fibrinogen                       Fibrin
                                                   XIIIa       Stable clot
                                                           Fibrin
  APTT/ACT
Intrinsic pathway
                                                   Prothrombin time
   XIIa

                                                    Extrinsic Pathway
          XIa
                                                             TF
                        Prothrombin
                  IXa                  VIIa
                    VIIIa      Xa
                               Va
                                       +
             +
                                                 Soft clot
                            Thrombin
     Fibrinogen                         Fibrin
                                                     XIIIa        Hard clot
                                                             Fibrin
     Hemophilia A
Deficiency or nonfunctional VIII
X linked recessive
Females: asymptomatic careers
1:5-10,000 male births

     Hemophilia B
Deficiency or nonfunctional IX
X linked recessive
Females: asymptomatic careers
1:20-30,000 male births
        Physiologic Inhibitors of
              coagulation

• Antithrombin III
• Activated Protein C + protein S
  – Inactivates Va and VIIIa (via proteolysis)
• Thrombomodulin (EC glycoprotein)
  – Binds to thrombin
  – Decreases ability to produce fibrin
  – Increases ability to activate Protein C
                       Heparin
•   Naturally occurring mucopolysaccharide
•   Very acidic
•   A heterogeneous group of substances
•   Inactivates thrombin and Xa
•   High affinity bonding with Anti-thrombin-3
•   Neutralised by Protamine
•   Chemical neutralisation
•   PT and APTT will be prolonged
•   Monitored through APTT
•   More functional tests available: Heparinase test
               Role of vitamin K
• Some clotting factors require a post-translational
  modification before they are active in clotting
• These factors are II, VII, IX, X, proteins C and S
• This PTM involves the addition of a COO- to certain
  Glutamate residues in the clotting factors
• Gamma-carboxyglutamate residues
• Essential for Ca2+ binding
• This PTM requires vitamin K
       Inhibitors of coagulation

• Vitamin K antagonists (in vivo only)
• Ca chelators (in vitro only)
  – EDTA
  – Citrate
  – Oxalate
• Heparin (in vivo and in vitro)
         Disseminated intravascular
                coagulation
•   Uncontrolled coagulation
•   Concurrent Fibrinolysis
•   Depletion of all clotting factors→bleeding
•   Consumptive coagulopathy
•   Increase in products of fibrin breakdown
•   Severe sepsis, massive trauma/tissue
    breakdown, burns, pancreatitis, obstetric
    (placental abruption), amniotic fluid embolism
Clot removal
     Fibrinolysis




         Plasmin
Fibrin             Fibrin degradation Products (FDP)
                            •Thrombolytic agents

     Fibrinolysis           •Streptokinase
                            •Urokinase
         Plasminogen        •tPA
                            •Alteplase: Recombinant
            tPA             natural tPA
                            •MI, acute stroke, PE

           Plasmin
Fibrin                 Fibrin Split Products (FSP)
            Inhibitors of fibrinolysis

            Plasminogen activator inhibitors (PAIs)

In excessive bleeding
DIC after CPB
Bleeding after prostatectomy

1.   Tranexamic acid
2.   α2-antiplasmin (serpin)

Should be used only after functional assays of clotting: Thrombo
    Elasto Graphy (TEG)

                Poor clotting or excessive clot lysis
               Clotting studies
•   FBC: Platelet count & platelet function studies
•   PT
•   APTT
•   Fibrinogen level
•   FDP
•   D-Dimers
•   Individual factor assays
•   Anti-Xa activity : for monitoring LMWH
    Figures obtained from freely
accessible internet sites. No personal
  or Institutional credit is claimed.
??

				
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