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Physiology of Hemostasis


Definition of hemostasis

Hemostasis literally means stoppage of bleeding.

When a blood vessel is cut or damaged, the following 3 basic processes prevent blood loss :
  1. Vasoconstriction
    This is due to serotonin and other vasoconstrictors released from the platelets.
  2. Temporary platelet plug formation
    This is formed by a loose aggregation of platelets. How? The damaged vessel exposes the collagen; the platelets bind to the exposed collagen. The bound platelets release ADP; ADP in turn attracts more platelets and helps in platelet aggregation.
  3. Blood coagulation
    The clotting mechanism forms fibrin, fibrin reinforces the loose platelet plug. Thus, the loose temporary plug is converted into a definitive plug.
  4. Physiology of coagulation

    The process of clotting is called coagulation. The various coagulation factors (also called clotting factors) bring about the coagulation. Many of the coagulation factors are present in the plasma; some are released from the platelets.

  5. Coagulation factors
    The following are the coagulation factors in the blood and their synonyms :

Factors (symbol)







Tissue thromboplastin (TPL), Tissue factor




Proaccelerin, labile factor, accelerator globulin (Ac-globulin, Ac-G)


Proconvertin, Serum Prothromobin Conversion Accelerator (SPCA), stable factor


Anti-hemophilic factor (AHF), anti-hemophilic factor A, anti-hemophilic globulin (AHG)


Plasma thromboplastin component (PTC), Christmas factor, anti-hemophilic factor B


Stuart factor, Stuart Prower factor


Plasma thromboplastin antecedent (PTA), anti-hemophilic factor C


Hageman factor, glass contact factor


Fibrin-stabilizing factor, Laki-Lorand factor


High-molecular weight kininogen, Fitzgerald factor


Prekallikrein, Fletcher factor




Platelet phospholipid


Note : there is no factor VI (it is not a separate entity and therefore it is not listed); it was earlier called as accelerin.

  1. Mechanism of blood coagulation
    Enzyme cascade mechanism
    The ultimate aim of the clotting mechanism is to form insoluble fibrin from the soluble fibrinogen. The clotting mechanism consists of a cascade of reactions in which inactive enzymes are activated; these activated enzymes in turn activate other inactive enzymes.

A. Steps involved in conversion of fibrinogen to fibrin

  1. Formation of fibrin monomer from fibrinogen
    Fibrinogen is made up of three types of polypeptide chains viz. alpha, beta and gamma polypeptide chains. 
    As a first step, two pairs of polypeptides are released from each fib­rinogen molecule; the remaining portion is the fibrin monomer.
  2. Formation of loose fibrin mesh
    The fibrin monomer polymerizes with other monomer molecules to form fibrin. This fibrin is initially a loose mesh of interlacing strands.
  3. Formation of tight fibrin mesh
    The loose fibrin mesh is converted into a tight, dense mesh by the for­mation of covalent cross-linkages; this process is called stabilization. The stabilization reaction is catalyzed by activated factor XIII and requires calcium.

Details of conversion of fibrinogen to fibrin

1.  Role of thrombin

  1. Thrombin catalyzes the conversion of fibrinogen to fibrin. Thrombin is a serine protease; it is formed from its circulating precursor, prothrombin. Prothrombin is converted to thrombin by the action of activated factor X.
  2. Other actions

Activation of platelets, endothelial cells, and leukocytes via a G protein-coupled re­ceptor.


2.  Factor X activation

There are 2 pathways for activation of factor X

a. intrinsic pathway                  


b. extrinsic pathway


3.  Intrinsic pathway for factor X activation


a.  Conversion of inactive factor XII to active factor XII (i.e. from factor XII ? factor XIIa (the ‘a’ stands for activated factor XII)


This is the initial reaction in the intrinsic pathway.


This activation is catalyzed by high-mol­ecular-weight (HMW) kininogen and kallikrein. Kallikrein is a protease present in small amounts in the plasma; it is formed from pre-kallikrein. As soon as factor XIIa is produced, it causes the conversion of prekallikrein to kallikrein; kallikrein in turn activates XII. Thus, it is another example of positive feedback mechanism.

The activation of factor XII in vitro and in vivo occurs as follows :

  1. in vitro Factor XII can be activated in vitro by exposing the blood to electronegativelv charged wettable surfaces such as glass and collagen fibers.
  2. in vivo Activation of factor XII in vivo oc­curs when blood is exposed to the collagen fibers un­derlying the endothelium in the damaged blood vessels.
  3. Activation of factor XI

Active factor XIl (i.e. XII a) in turn activates factor XI

           XII a

XI    -------------XI a


  1. Activation of factor IX

Active factor XI activates factor IX.

            XI a

IX    -------------IX a

  1. Activated factor IX forms a complex with active factor VIII

Factor VIII is activated when it is separated from von Willebrand factor.

  1. Activation of factor X
  • The complex of IXa and VIIIa activate factor X.
  • Phospholipids from ag­gregated platelets (PL) and calcium are necessary for full activation of factor X.
  1. Extrinsic pathway for factor X activation


  1. The initial step is the release of tissue thromboplastin (TPL) (also called tissue factor) from damaged tissue; TPL is a protein-phos­pholipid mixture containing proteolytic enzymes. tissue thromboplastin activates factor VII.
  2. The tissue thromboplastin forms an active complex with factor VII; this complex activates factors 1X and X. The activation of factor X by this complex of VIIa and TPL requires the presence of calcium and platelet phospholipid (PL).

1.  Common pathway beyond formation of X a

The ultimate aim of both the intrinsic and extrinsic pathway is ? to activate factor X. Once activated factor Xa is formed, the remaining coagulation pathway is the same for both intrinsic and extrinsic pathways as given below:

  1. Activated factor X (i.e. X a) converts prothrombin to thrombin (the activation requires the presence of platelet phospholipid i.e. PL, calcium and factor V
  2. Thrombin
    Converts fibrinogen to fibrin monomer polymerization of fibrin monomer to form loose fibrin mesh
Activates factor XIII (to form XIII a)
  1. Factor XIII a causes stabilization of the loose fibrin mesh to form tight fibrin meshThe extrinsic pathway is inhibited by a tis­sue factor pathway inhibitor by forming a quaternary structure with TPL, factor VIla, and factor Xa.

Blood coagulation is an example of positive feedback mechanism; formation of active factor in one step stimulates its own catalyst. Because of this, very little initiation in the system can produce an immense response.

Most of the coagulation factors in their active state are serine proteases whose active site contains a hydroxyl group.

Anti clotting Mechanisms


Clotting is essential for stopping bleeding due to injury. However, clotting should not occur inside the blood vessels. For preventing clotting inside the blood vessels, there are anti-clotting mechanisms. The anti-clotting mechanisms :

1.  prevent clotting inside the blood vessels

if any clot does form, it breaks the clot


1.  The various anti-clotting mechanisms are :

  1. Balance between thromboxane A2 and prostacyclin :
  • Thromboxane A2 causes platelet aggregation
  • Prostacyclin inhibits platelet aggregation
    The balance between the two allows clots to form at the site of injury but prevents clot within the lumen of the vessel.
  1. Antithrombin III (also called heparin cofactor II)
    This is a circulating protease inhibitor; it binds to the serine proteases in the coagulation sys­tem. As mentioned above, most of the active forms of the clotting factors are serine proteases; thus, anti-thrombin III blocks the activity of these clotting factors.
    Anti-thrombin III inhibits the active forms of factors IX, X, XI, and XII.
    Heparin increases the action of anti-thrombin III. How? Heparin increases the binding of anti-thrombin III to the serine proteases. (Heparin is a naturally occurring anticoagulant;  it is a mixture of sulphated polysaccha­rides with molecular weights between 15,000-18,000).
    The endothelium of the blood vessels
    The endothelium is another important anti-clotting mechanism; it plays an active role in preventing the extension of clots into blood vessels.
  2. Thrombomodulin


What is it?


This is a thrombin-binding protein, expressed on the endothelial cells.

Site of production

All endothelial cells except those in the cerebral microcirculation produce thrombomodulin and express it on their sur­face.

Mechanism of action

In the circulating blood, thrombin is a pro-coagu­lant that activates factors V and VIII; however, when thrombin binds to thrombomodulin, it becomes an anticoagulant. How?

The thrombomodulin-thrombin complex activates protein C. The activated protein C (APC), along with its cofactor protein S:

  • inactivates the activated factors V and VIII
  • inactivates an inhibitor of t-PA (tissue plas­minogen activator); thus, it increases the formation of plasmin from plasminogen.
  1. Fibrinolytic system
    Clots formed in the tissues have ultimately to be disposed of as healing takes place; the dissolution of the clot is called fibrinolysis and is due to the action of the proteolytic enzyme called plasmin or fibrinolysin. 

Plasmin (also called fibrinolysin)

There is no free plasmin in the blood; the blood contains its inactive precursor called plasminogen (also called profibrinolysin).

Plasmin lyses fibrin and fibrinogen; this produces fibrinogen degradation products (FDP); the fibrin degradation products inhibit thrombin.

How is the active plasmin formed from its inactive precursor, plasminogen?

This occurs by the action of thrombin tissue-type plasminogen activator (t-PA). also by urokinase-type plasminogen activator (u­-PA).

  1. Evidence
    Effect of knock out of either the t-PA gene or the u-PA gene in mice :
    -Some fibrin deposition occurs
    -and clot lysis is slowed.
  2. Effect of knock out of both the t-PA and u-PA genes :
    1. there is extensive sponta­neous fibrin deposition
    2. there is delayed wound healing
    3. there are defects in growth and fertil­ity (this is because the plasminogen system not only lyses clots but also plays a role in cell movement and in ovulation).
  3. Other actions of plasmin
    In addition to its fibrinolytic activity, plasmin can form plasma kinins (bradykinin, kallidin) and thus contribute to the vascular and sensory features (pain) of the inflammatory response to injury.
  4. Structure of human plasminogen
    It consists of a heavy chain (560-amino-acid) and a light chain (241-amino-acid)
  5. The heavy chain
    1. Has glutamate at its amino terminal
    2. It is folded into five loop structures, each held together by three disulfide bonds. These loops are called kringles because of their resemblance to a Danish pastry of the same name.
  6. Kringles
    The Kringles are lysine-bind­ing sites by which the plasminogen molecule attaches to fibrin and other clot proteins (kringles are also found in pro­thrombin)
    Plasminogen is converted to active plasmin when t-PA hydrolyzes the bond between Arg 560 and Val 561.
  7. Plasminogen receptors :
    These are located on the surfaces of many different types of cells and are plentiful on en­dothelial cells. When plasminogen binds to its recep­tors, plasminogen becomes activated; thus, clot formation does not occur in the intact blood vessel walls
  8. The protein C pathway
    Three protein factors – protein C, protein S and thrombomodulin – constitute an important negative feedback pathway to keep the clotting mechanism under control.
  1. Thrombomodulin
    As mentioned above, it is a protein present on the vascular endothelium; all endothelial cells except those in the cerebral microcirculation produce thrombomodulin and express them on their surface
​1. Protein C and protein S : these are plasma proteins

How does the system work?


a. thrombin binds to thrombomodulin
b. the thrombin-thrombomodulin complex activates protein C
c. In combination with protein S, the activated protein C (APC) inactivates factor V a and VIIIa
d. Because of the inactivation of factors Va and VIIIa, the clotting process is checked.

2. Applied aspects

With the help of recombinant DNA techniques, human t-PA is now being produced for clini­cal use. It lyses clots in the coronary arteries if given to patients soon after the onset of myocardial infarction. Streptokinase, a bacterial enzyme, is also fibrinolvtic and is also used in the treatment of early myocardial in­farction

3. Annexins

These are a group of proteins which are associated with coagulation and fibrinolysis. About 10 annexins have been described in mammals.

  1. Possible role of annexins
    1. Annexin II
      This forms a platform on endothe­lial cells on which components of the fibrinolytic sys­tem interact, producing fibrinolysis.
    2. Annexin V
      This forms a shield around phospholipids involved in co­agulation and exerts an antithrombotic effect.


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