Blood Coagulation Clot Formation

Blood coagulation, or clotting, is the transformation of blood into a solid gel termed a clot or thrombus and consisting mainly of a protein polymer known as fibrin. Clotting occurs locally around the original platelet plug and is the dominant hemostatic defense. Its function is to support and reinforce the platelet plug and to solidify blood that remains in the wound channel.

The events leading to clotting are summarized, in very simplified form, in Figure 14-71. These events, like platelet aggregation, are initiated when injury to a vessel disrupts the endothelium and permits the blood to contact the underlying tissue. This contact initiates a locally occurring sequence, or "cascade," of chemical activations. At each step of the cascade, an inactive plasma protein, or "factor," is converted (activated) to a proteolytic enzyme, which then catalyzes the generation of the next enzyme in the sequence. Each of these activations results from the splitting of a small peptide fragment from the inactive plasma protein precursor, thus exposing the active site of the enzyme. It should be noted, however, that several of the plasma protein factors, following their activation, function not as enzymes but rather as cofactors for the enzymes.

To reduce the risk that you might "lose sight of the forest for the trees," Figure 14-71 gives no specifics about the cascade until the point at which the plasma protein prothrombin is converted to the enzyme thrombin. Thrombin then catalyzes a reaction in which several polypeptides are split from molecules of the large rod-shaped plasma protein fibrinogen. The still-large fibrinogen remnants then bind to each other to form fibrin. The fibrin, initially a loose mesh of interlacing strands, is rapidly stabilized and strengthened by enzymatically mediated formation of covalent cross-linkages. This chemical linking is catalyzed by an enzyme known as factor Xllla, which is formed from plasma protein factor XIII in a reaction also catalyzed by thrombin.

Thus, thrombin catalyzes not only the formation of loose fibrin but also the activation of factor XIII, which stabilizes the fibrin network. But thrombin does even more than this—it exerts a profound positivefeedback effect on its own formation. It does this by activating several proteins in the cascade and also by activating platelets. Therefore, once thrombin formation has begun, reactions leading to much more thrombin generation are brought into play by this initial thrombin. We will make use of this crucial fact later when we describe the specifics of the cascade leading to thrombin.

In the process of clotting, many erythrocytes and other cells are trapped in the fibrin meshwork (Figure 14-72), but the essential component of the clot is fibrin, and clotting can occur in the absence of all

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

Circulation CHAPTER FOURTEEN

Circulation CHAPTER FOURTEEN

Vessel damage

Exposure of blood to subendothelial tissue

Cascade of plasma enzyme activations (requires activated" platelets, plasma cofactors, and Ca2+)

Loose fibrin

Stabilized fibrin

Exposure of blood to subendothelial tissue

Cascade of plasma enzyme activations (requires activated" platelets, plasma cofactors, and Ca2+)

Simplified Thrombin Formation

Fibrinogen

Loose fibrin

FIGURE 14-71

Simplified diagram of the clotting pathway. The pathway leading to thrombin is denoted by two enzyme activations, but the story is actually much more complex (as will be shown in Figure 14-73). Note that thrombin has three different effects— generation of fibrin, activation of factor XIII, and positive feedback on the cascade leading to itself.

FIGURE 14-71

Simplified diagram of the clotting pathway. The pathway leading to thrombin is denoted by two enzyme activations, but the story is actually much more complex (as will be shown in Figure 14-73). Note that thrombin has three different effects— generation of fibrin, activation of factor XIII, and positive feedback on the cascade leading to itself.

Clot Fibrin Activated Platelets

cellular elements except platelets. Activated platelets are essential because several of the cascade reactions take place on the surface of these platelets. As noted above, platelet activation occurs early in the hemosta-tic response as a result of platelet adhesion to collagen, but in addition, thrombin is an important stimulator of platelet activation. The activation causes the platelets to display specific plasma-membrane receptors that bind several of the clotting factors, and this permits the reactions to take place on the surface of the

Vander et al.: Human I III. Coordinated Body I 14. Circulation I I © The McGraw-Hill

Physiology: The Functions Companies, 2001 Mechanism of Body Function, Eighth Edition

PART THREE Coordinated Body Functions platelets. The activated platelets also display particular phospholipids, called platelet factor (PF), which function as a cofactor in the steps mediated by the bound clotting factors.

One more generalization about the clotting cascade should be noted: Plasma calcium is required at various steps. However, calcium concentration in the plasma can never get low enough to cause clotting defects because death would occur from muscle paralysis or cardiac arrhythmias before such low concentrations were reached.

Now we present the specifics of the early portions of the clotting cascade, those leading from vessel damage to the prothrombin-thrombin reaction. These early portions consist of two seemingly parallel pathways that merge at the step before the prothrombin-thrombin reaction. Under physiological conditions, however, the two pathways are not parallel but are actually brought into play sequentially, the link between them being thrombin. It will be clearer, however, if we first discuss the two pathways as though they were separate and then deal with their actual interaction. The pathways are called (1) the intrinsic pathway, so named because everything necessary for it is in the blood; and (2) the extrinsic pathway, so named because a cellular element outside the blood is needed. Figure 14-73 will be an essential reference for this entire discussion. Also, Table 14-14 is a reference list of the names of and synonyms for the substances in these pathways.

The first plasma protein in the intrinsic pathway (upper left of Figure 14-73) is called factor XII. It can become activated to factor XIIa when it contacts certain types of surfaces, including the collagen fibers

Intrinsic pathway Extrinsic pathway

Contact activation

Vessel damage

Contact activation

Vessel damage

Subendothelial cells exposed to blood

Tissue factor

VIII

IXa-

Dealing With Erectile Dysfunction

Dealing With Erectile Dysfunction

Whether you call it erectile dysfunction, ED, impotence, or any number of slang terms, erection problems are something many men have to face during the course of their lifetimes.

Get My Free Ebook


Responses

  • Fulvus Twofoot
    Is clot formation in atrial fibrillation caused by intrinsic or extrinsic pathways?
    6 years ago
  • kenneth
    Is prothrombin a plasma protein?
    1 year ago

Post a comment