Mechanism of Blood Coagulation

Basic Theory. More than 50 important substances that cause or affect blood coagulation have been found in the blood and in the tissues—some that promote coagulation, called procoagulants, and others that inhibit coagulation, called anticoagulants. Whether blood will coagulate depends on the balance between these two groups of substances. In the blood stream, the anticoagulants normally predominate, so that the blood does not coagulate while it is circulating in the blood vessels. But when a vessel is ruptured, procoagulants from the area of tissue damage become "activated" and override the anticoagulants, and then a clot does develop.

General Mechanism. All research workers in the field of blood coagulation agree that clotting takes place in

Conversion of Prothrombin to Thrombin

First, prothrombin activator is formed as a result of rupture of a blood vessel or as a result of damage to special substances in the blood. Second, the pro-thrombin activator, in the presence of sufficient amounts of ionic Ca++, causes conversion of prothrombin to thrombin (Figure 36-2). Third, the thrombin causes polymerization of fibrinogen molecules into fibrin fibers within another 10 to 15 seconds. Thus, the rate-limiting factor in causing blood coagulation is usually the formation of prothrombin activator and not the subsequent reactions beyond that point, because these terminal steps normally occur rapidly to form the clot itself.

Platelets also play an important role in the conversion of prothrombin to thrombin because much of the prothrombin first attaches to prothrombin receptors on the platelets already bound to the damaged tissue.

Prothrombin and Thrombin. Prothrombin is a plasma protein, an alpha2-globulin, having a molecular weight of 68,700. It is present in normal plasma in a concentration of about 15 mg/dl. It is an unstable protein that can split easily into smaller compounds, one of which is thrombin, which has a molecular weight of 33,700, almost exactly one half that of prothrombin.

Prothrombin is formed continually by the liver, and it is continually being used throughout the body for blood clotting. If the liver fails to produce prothrom-bin, in a day or so prothrombin concentration in the plasma falls too low to provide normal blood coagulation.

Vitamin K is required by the liver for normal formation of prothrombin as well as for formation of a few other clotting factors. Therefore, either lack of vitamin K or the presence of liver disease that prevents normal prothrombin formation can decrease the prothrombin level so low that a bleeding tendency results.

Conversion of Fibrinogen to Fibrin— Formation of the Clot

Fibrinogen. Fibrinogen is a high-molecular-weight protein (MW = 340,000) that occurs in the plasma in quantities of 100 to 700 mg/dl. Fibrinogen is formed in the liver, and liver disease can decrease the concentration of circulating fibrinogen, as it does the concentration of prothrombin, pointed out above.

Because of its large molecular size, little fibrinogen normally leaks from the blood vessels into the interstitial fluids, and because fibrinogen is one of the essential factors in the coagulation process, interstitial fluids ordinarily do not coagulate. Yet, when the permeability of the capillaries becomes pathologically increased, fibrinogen does then leak into the tissue fluids in sufficient quantities to allow clotting of these fluids in much the same way that plasma and whole blood can clot.

Action of Thrombin on Fibrinogen to Form Fibrin. Thrombin is a protein enzyme with weak proteolytic capabilities. It acts on fibrinogen to remove four low-molecular-weight peptides from each molecule of fibrinogen, forming one molecule of fibrin monomer that has the automatic capability to polymerize with other fibrin monomer molecules to form fibrin fibers. Therefore, many fibrin monomer molecules polymerize within seconds into long fibrin fibers that constitute the retic-ulum of the blood clot.

In the early stages of polymerization, the fibrin monomer molecules are held together by weak non-covalent hydrogen bonding, and the newly forming fibers are not cross-linked with one another; therefore, the resultant clot is weak and can be broken apart with ease. But another process occurs during the next few minutes that greatly strengthens the fibrin reticulum.

This involves a substance called fibrin-stabilizing factor that is present in small amounts in normal plasma globulins but is also released from platelets entrapped in the clot. Before fibrin-stabilizing factor can have an effect on the fibrin fibers, it must itself be activated. The same thrombin that causes fibrin formation also activates the fibrin-stabilizing factor. Then this activated substance operates as an enzyme to cause covalent bonds between more and more of the fibrin monomer molecules, as well as multiple cross-linkages between adjacent fibrin fibers, thus adding tremendously to the three-dimensional strength of the fibrin meshwork.

Blood Clot. The clot is composed of a meshwork of fibrin fibers running in all directions and entrapping blood cells, platelets, and plasma. The fibrin fibers also adhere to damaged surfaces of blood vessels; therefore, the blood clot becomes adherent to any vascular opening and thereby prevents further blood loss.

Clot Retraction—Serum. Within a few minutes after a clot is formed, it begins to contract and usually expresses most of the fluid from the clot within 20 to 60 minutes. The fluid expressed is called serum because all its fibrinogen and most of the other clotting factors have been removed; in this way, serum differs from plasma. Serum cannot clot because it lacks these factors.

Platelets are necessary for clot retraction to occur. Therefore, failure of clot retraction is an indication that the number of platelets in the circulating blood might be low. Electron micrographs of platelets in blood clots show that they become attached to the fibrin fibers in such a way that they actually bond different fibers together. Furthermore, platelets entrapped in the clot continue to release procoagulant substances, one of the most important of which is fibrin-stabilizing factor, which causes more and more cross-linking bonds between adjacent fibrin fibers. In addition, the platelets themselves contribute directly to clot contraction by activating platelet throm-bosthenin, actin, and myosin molecules, which are all contractile proteins in the platelets and cause strong contraction of the platelet spicules attached to the fibrin. This also helps compress the fibrin meshwork into a smaller mass. The contraction is activated and accelerated by thrombin as well as by calcium ions released from calcium stores in the mitochondria, endoplasmic reticulum, and Golgi apparatus of the platelets.

As the clot retracts, the edges of the broken blood vessel are pulled together, thus contributing still further to the ultimate state of hemostasis.

Vicious Circle of Clot Formation

Once a blood clot has started to develop, it normally extends within minutes into the surrounding blood. That is, the clot itself initiates a vicious circle (positive feedback) to promote more clotting. One of the most important causes of this is the fact that the proteolytic action of thrombin allows it to act on many of the other blood-clotting factors in addition to fibrinogen. For instance, thrombin has a direct proteolytic effect on prothrombin itself, tending to convert this into still more thrombin, and it acts on some of the blood-clotting factors responsible for formation of prothrombin activator. (These effects, discussed in subsequent paragraphs, include acceleration of the actions of Factors VIII, IX, X, XI, and XII and aggregation of platelets.) Once a critical amount of thrombin is formed, a vicious circle develops that causes still more blood clotting and more and more thrombin to be formed; thus, the blood clot continues to grow until blood leakage ceases.

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Essentials of Human Physiology

Essentials of Human Physiology

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Responses

  • Vihtori Ojala
    Which of the following is rate limiting factor cause blood coagulation?
    4 years ago
  • GINA
    What is the three dimensional strenght of the fibrin meshwork?
    4 years ago
  • sonja walter
    Why blood does not coagulate in the presence of procoagulants?
    4 years ago
  • Ralph
    What happens if fibrinogen leaks into interstitial fluid?
    3 years ago
  • Asphodel
    When clotting factor is retrapped and serum leakage occurs?
    3 years ago
  • Eerik
    Why does fibrinogen leak into interstitial fluid?
    2 years ago
  • MATHIAS
    Why cogulation in blood get low?
    1 year ago
  • Helen
    What causes coagulation physiology?
    3 days ago

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