Prothrombin activation: initiates blood clotting

2021-02-08 12:00 AM

Most clotting factors are numbered Roman order. When you want to sign the active form, you will add a small "h" after the Roman number, for example, factor VIIh is the active form of factor VII.

The coagulation process in which the mechanism in the initial stage is much more complex.

These mechanisms are divided into:

(1) damage to the vascular wall and surrounding tissue.

(2) injury to the blood, or.

(3) the blood comes into contact with damaged endothelial cells or with collagen and other tissue components other than blood vessels. All lead to the formation of prothrombin activating complex, from which the process of converting prothrombin to thrombin and subsequent steps of coagulation.

Prothrombin activated complexes are formed according to two pathways, although in practice these two are related:

(1) the exogenous coagulation pathway begins with damage to the vascular wall and surrounding tissue and.

(2) the endogenous blood-clotting pathway begins with the blood.

In both pathways, plasma proteins that are coagulation factors play an important role. Most of these proteins are in the form of precursors to proteolytic enzymes. When switched to the activated form, they will cause a blood clotting response.

Board. Coagulation factors

Most clotting factors are numbered Roman order. When you want to sign the active form, you will add a small "h" after the Roman number, for example, factor VIIh is the active form of factor VII.

The path of exogenous blood clotting

The exogenous pathway of coagulation begins with blood contact with damage to the vessel wall or in extravascular tissue. This will lead to the next steps illustrated in the figure:

  1. Release of tissue factor. Injured tissue releases a complex called tissue factor or tissue thromboplastin. This element consists of phospholipids from the tissue membrane plus a lipoprotein complex - which functions as a proteolytic enzyme.
  2. Activate factor Xvoltage role of factor VII and tissue factor. Lipoprotein complexes include tissue factor and factor VII, in the presence of calcium ions will act as enzymes to activate factor X (create Xh).
  3. Effects of Xh to form prothrombin activating complex, the role of V factor. Activated factor X combines immediately with tissue phospholipids (part of tissue factor or is further released from platelets. ), together with factor V will form prothrombin activating complex. Within a few seconds, in the presence of Ca ++, prothrombin is cleaved to form thrombin, after which the coagulation process continues as described in the previous section.


Figure. The path of exogenous blood clotting

Initially, factor V in the complex activates prothrombin in its inactive precursor, but when coagulation begins and thrombin begins to form, the proteolytic function of thrombin activates factor V.

This activation will give a strong boost to prothrombin activation. Thus, in the prothrombin activated complex, activated factor X (Xh) is actually a prothrombin-splitting prothrombin protein-lysis enzyme to form thrombin; Activated factor V (Vh) strongly promotes this proteolytic activity, and platelet phospholipids also promote this process. Note that thrombin-effect positive reverse conditioning, via factor V, will accelerate the entire process from the start.

Endogenous blood-clotting pathway

This is the second mechanism to initiate the prothrombin activation complex as well as to initiate the clotting process, starting with damage from the blood or contact with collagen from the damaged blood vessel wall. The following processes are illustrated in the figure.

  1. Damage from the blood activates factor XII and.
  2. Release of platelet phospholipids. Damage to the blood or contact of blood with collagen to the vessel wall alters two important clotting factors: factor XII and platelet. When factor XII is affected, for example in contact with collagen or a surface like glass, it converts the molecule into the activated factor XII, a proteolytic enzyme.

At the same time, the damaged blood will affect the platelets releasing platelet phospholipids containing lipoprotein molecules called platelet factor 3 that play an important role in subsequent processes.

  1. Activate factor XI. Activated factor XII (XIIh) activates factor XI by enzyme action, which is the second step in the endogenous pathway. This process requires high molecular weight kininogen and is driven by prekallikrein.
  2. Activate factor IX by factor XIh. Factor XIh will act as an enzyme on factor IX to activate this factor.
  3. Activate factor Xvoltage role of XIII. Factor IXh along with factor VIIIh, platelet phospholipid, and platelet factor III activate factor X. This process would not occur without factor VIII or platelets. Since factor VIII is absent in people with classical haemophilia, this is called the anti-haemophilia factor. Platelets will be missing in a person with a bleeding disease called thrombocytopenia.
  4. Activate factor X to form prothrombin activating complex, the role of factor V. This step is similar to the last step in the exogenous clotting pathway. It is factor X that combines with factor V and phospholipids from platelets or tissue to form prothrombin activating complex. Within a few

seconds, this complex will begin to cleave prothrombin to form thrombin, which contributes to the clotting process mentioned earlier.

Figure. Endogenous blood-clotting pathway

The role of calcium ions in endogenous and exogenous clotting pathways

Except for the initial two steps of the endogenous coagulation pathway, calcium ions are required for all coagulation. So, if calcium is deficient, blood clotting will not occur in either path.

In vivo, calcium ion concentrations rarely drop so low that it affects blood clotting. However, when blood is removed from the body, anticoagulation can be achieved by lowering the calcium concentration below the threshold or by reacting with substances such as citrate ions or precipitating it with substances such as oxalate ions. .

Relationship between exogenous and endogenous blood clotting pathways

Overview of the initiation of blood clotting

The schematic diagram of the endogenous and exogenous coagulation system clearly shows that after a blood vessel is damaged, both pathways occur simultaneously. Tissue factor initiates the exogenous pathway, while the combination of factor XII and platelets with the collagen of the vascular wall kicks off the endogenous pathway.

A particularly important difference between the exogenous and endogenous coagulation pathways is the "explosive" exogenous pathway that, once activated, is limited only by weak amounts. the tissue is released from damaged tissue and by the amount of factors X, VII and V in the blood. If tissue is severely damaged, clotting can occur in as little as 15 seconds. The endogenous pathway occurs more slowly, usually taking 1 to 6 minutes to form a blood clot.

Intravascular anticoagulants prevent blood clotting in the normal vascular system

Endothelial surface factors. Possibly the most important factors for preventing blood clotting in the normal vascular system are (1) the smoothness of the endothelial cell surface that prevents the initiation of the endogenous clotting pathway by exposure (2) a the glycocalyx layer on the endothelium (which is a mucopolysaccharide that is absorbed into the inner surface of endothelial cells), has the effect of repelling clotting factors and platelets, thereby preventing the initiation of coagulation and (3) a protein that binds to the endothelium, thrombomodulin, the mechanism by which is thrombin binding.

Not only does the binding of thrombin with thrombomodulin slow clotting by removing thrombin, but the thrombomodulin thrombin complex also activates plasma protein C, which acts as an anticoagulant by inactivating both Vh and VIII. .

When the endothelium is damaged, the smoothness and the glycocalyx thrombomodulin layer are lost, thereby activating factor XII and platelets, initiating the endogenous clotting path. If factor XII and platelet come into contact with subendothelial collagen, the activation is even stronger.

Effects of antithrombin on fibrin and antithrombin III. With the most important anticoagulants in the blood, the mechanism is to remove thrombin from the blood. The most effective are (1) fibrin fibers formed during blood clotting and (2) an αglobulin type antithrombin III or antithrombin heparin cofactor.

When a clot is formed, approximately 8590% of the thrombin made up of prothrombin is absorbed into the fibrin network. This adsorption prevents thrombin from spreading into the surrounding bloodstream, thus preventing the clot from spreading.

The thrombin fraction that is not absorbed into the fibrin network will soon bind with antithrombin III, losing the thrombin effect on fibrinogen and inactivating thrombin 12 to 20 minutes later.

Heparin. Heparin is a powerful anticoagulant, but due to its concentration in the normal bloodstream being low, its anticoagulant effect is only apparent under special physiological conditions. However, heparin is widely used in clinical practice in high concentrations to prevent intravascular clotting.

The heparin molecule is a strongly negatively integrated polysaccharide. Heparin itself has little or no anticoagulant effect, but when it is combined with antithrombin III, the effect of antithrombin of thrombin removal increases by hundreds to thousands of times, thus acting as an anticoagulant. bronze. Therefore, if a large amount of heparin is contracted, the action of antithrombin III is the immediate removal of free thrombin from the circulation.

The heparin and antithrombin III complex also remove a number of activated clotting factors other than thrombin, increasing anticoagulant effects, including factors XIIh, XIh, Xh, and IXh.

Heparin is produced by many different cells of the body, but the greatest amount is from mast cells in the connective tissue around capillaries throughout the body. These cells continuously secrete a small amount of diffuse heparin into the circulatory system. The basophils in the bloodstream, which also function as mast cells, secrete a small amount of heparin in the plasma.

The mast cells are more concentrated in the tissue surrounding the capillaries in the lungs and less often in the liver capillaries. Understandably large amounts of heparin are needed in these locations because the capillaries in the lungs and liver have many clots that form in the slow-flowing venous blood; Synthetic heparin should prevent the formation of blood clots.


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