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biopharmaceuticals biochemistry and biotecnology - Walsh G.

Walsh G. biopharmaceuticals biochemistry and biotecnology - John Wiley & Sons, 2003. - 572 p.
ISBN 0-470-84327-6
Download (direct link): biochemistryandbiotechnology2003.pdf
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Localized constriction of the blood vessel, which minimizes further blood flow through the area.
Induction of the blood coagulation cascade. This culminates in the conversion of a soluble serum protein, fibrinogen, into insoluble fibrin. Fibrin monomers then aggregate at the site of damage, thus forming a clot (thrombus), which seals it off. These mechanisms are effective in dealing with small vessel injuries, e.g. in capillaries and arterioles, although they are ineffective when the damage relates to large veins/arteries.
The coagulation pathway
The process of blood coagulation is dependent on a large number of blood clotting factors, which act in a sequential manner. At least 12 distinct factors participate in the coagulation cascade, along with several macromolecular co-factors. The clotting factors are all designated by Roman numerals (Table 9.5) and, with the exception of factor IV, all are proteins. Most factors are proteolytic zymogens, which become sequentially activated. An activated factor is indicated by inclusion of a subscript a (e.g. factor XIIa = activated factor XII).
Table 9.5. The coagulation factors which promote the blood clotting process. Note that the factor originally designated as VI was later shown to be factor Va
Factor Pathway in which
number Common name it functions Function
I Fibrinogen Both Forms structural basis of clot after its
conversion to fibrin
II Prothrombin Both Precursor of thrombin, which
activates factors I, V, VII, VIII and
III Tissue factor Extrinsic Accessory tissue protein which initi
(thromboplastin) ates extrinsic pathway
IV Calcium ions Both Required for activation of factor XIII
and stabilizes some factors
V Proaccelerin Both Accessory protein, enhances rate of
activation of X
VII Proconvertin Extrinsic Precursor of convertin (VIIa) which
activates X (extrinsic system)
VIII Anti-haemophilic factor Intrinsic Accessory protein, enhances
activation of X (intrinsic system)
IX Christmas factor Intrinsic Activated IX directly activates X
(intrinsic system)
X Stuart factor Both Activated form (Xa) converts
prothrombin to thrombin
XI Plasma thromboplastin Intrinsic Activated form (XIa) serves to acti
antecedent vate IX
XII Hageman factor Intrinsic Activated by surface contact or the
kallikrenin system. XIIa helps
initiate intrinsic system
XIII Fibrin-stabilizing factor Both Activated form cross-links fibrin,
forming a hard clot
Although the final steps of the blood clotting cascade are identical, the initial steps can occur via two distinct pathways: the extrinsic and intrinsic pathways. Both pathways are initiated when specific clotting proteins make contact with specific surface molecules exposed only upon damage to a blood vessel. Clotting occurs much more rapidly when initiated via the extrinsic pathway.
Two coagulation factors function uniquely in the extrinsic pathway: factor III (tissue factor) and factor VII. Tissue factor is an integral membrane protein present in a wide variety of tissue types (particularly lung and brain). This protein is exposed to blood constituents only upon rupture of a blood vessel, and it initiates the extrinsic coagulation cascade at the site of damage as described below.
Factor VII contains a number of g-carboxyglutamate residues (as do factors II, IX and X), which play an essential role in facilitating their binding of Ca2+ ions. The initial events initiating the extrinsic pathway entail the interaction of factor VII with Ca2+ and tissue factor. In this associated form, factor VII becomes proteolytically active. It displays both binding affinity for, and catalytic activity against, factor X. It thus activates factor X by proteolytic processing, and factor Xa, which initiates the terminal stages of clot formation, remains attached to the tissue factor-Ca2 + complex at the site of damage. This ensures that clot formation only occurs at the point where it is needed (Figure 9.2).
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