Prevention of Blood Clotting in
the Normal Vascular System— Intravascular Anticoagulants
Endothelial
Surface Factors. Probably the most importantfactors for preventing clotting in the
normal vascular system are (1) the smoothness
of the endothelial cell surface, which prevents contact activation of the
intrin-sic clotting system; (2) a layer of glycocalyx
on the endothelium (glycocalyx is a mucopolysaccharide adsorbed to the surfaces
of the endothelial cells), which repels clotting factors and platelets, thereby
pre-venting activation of clotting; and (3) a protein bound with the
endothelial membrane, thrombomodulin,
which binds thrombin. Not only does the binding of thrombin with thrombomodulin
slow the clotting process by removing thrombin, but the thrombomod-ulin-thrombin
complex also activates a plasma protein, protein
C, that acts as an anticoagulant by
inactivating activated Factors V and VIII.
When the endothelial wall is damaged, its smooth-ness and its
glycocalyx-thrombomodulin layer are lost, which activates both Factor XII and
the platelets, thus setting off the intrinsic pathway of clotting. If Factor
XII and platelets come in contact with the subendothelial collagen, the
activation is even more powerful.
Antithrombin
Action of Fibrin and Antithrombin III. Amongthe most important anticoagulants in the blood itself are those that remove thrombin
from the blood. The most powerful of these are (1) the fibrin fibers that themselves are formed during the process of
clotting and (2) an alpha-globulin called antithrombin
III or antithrombin-heparin cofactor.
While a clot is forming, about 85 to 90 per cent of the thrombin
formed from the prothrombin becomes adsorbed to the fibrin fibers as they
develop. This helps prevent the spread of thrombin into the remaining blood
and, therefore, prevents excessive spread of the clot.
The thrombin that does not adsorb to the fibrin fibers soon
combines with antithrombin III, which further blocks the effect of the thrombin
on the fi-brinogen and then also inactivates the thrombin itself during the
next 12 to 20 minutes.
Heparin.
Heparin
is another powerful anticoagulant,but its concentration in the blood is
normally low, so that only under special physiologic conditions does it have
significant anticoagulant effects. However, heparin is used widely as a
pharmacological agent in medical practice in much higher concentrations to
prevent intravascular clotting.
The heparin molecule is a highly negatively charged conjugated
polysaccharide. By itself, it has little or no anticoagulant properties, but
when it combines with antithrombin III, the effectiveness of antithrombin III
for removing thrombin increases by a hundredfold to a thousandfold, and thus it
acts as an anticoagulant. Therefore, in the presence of excess heparin, removal
of free thrombin from the circulating blood by antithrombin III is almost
instantaneous.
The complex of heparin and antithrombin III removes several other
activated coagulation factors in addition to thrombin, further enhancing the
effective-ness of anticoagulation. The others include activated Factors XII,
XI, X, and IX.
Heparin is produced by many different cells of the body, but
especially large quantities are formed by the basophilic mast cells located in the pericapillary con-nective tissue
throughout the body. These cells contin-ually secrete small quantities of
heparin that diffuse into the circulatory system. The basophil cells of the blood, which are functionally almost
identical to the mast cells, release small quantities of heparin into the
plasma.
Mast cells are abundant in tissue surrounding the capillaries of
the lungs and to a lesser extent capillar-ies of the liver. It is easy to
understand why large quan-tities of heparin might be needed in these areas
because the capillaries of the lungs and liver receive many embolic clots
formed in slowly flowing venous blood; sufficient formation of heparin prevents
further growth of the clots.
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