Page 299 - Color Atlas of Biochemistry

290 Tissues and organs

Blood clotting leads in five steps via factors XIIa, XIa, IXa,
and Xa to the activation of prothrombin. The
Following injury to blood vessels, hemostasis significance of this pathway in vivo has been
ensures that blood loss is minimized. Initially, controversial since it was found that a genetic
thrombocyte activation leads to contraction deficiency in factor XII does not lead to coag-
of the injured vessel and the formation of ulation disturbances.
a loose clot consisting of thrombocytes Both pathways depend on the presence of
(hemostasis). Slightly later, the action of the activated thrombocytes,onthe surfaceof
enzyme thrombin leads to the formation and which several reactions take place. For exam-
deposition in the thrombus of polymeric fi- ple, the prothrombinase complex (left) forms
brin (coagulation, blood clotting). The coagu- when factors Xa and II, with the help of Va,
lation process is discussed here in detail. bind via Ca 2+ ions to anionic phospholipids in
the thrombocyte membrane. For this to hap-
pen, factors II and X have to contain the non-
A. Blood clotting
proteinogenic amino acid J-carboxygluta-
The most important reaction in blood clotting mate (Gla; see p. 62), which is formed in the
is the conversion, catalyzed by thrombin, of liver by post-translational carboxylation of
the soluble plasma protein fibrinogen (factor the factors. The Gla residues are found in
I) into polymeric fibrin, which is deposited as groups in special domains that create contacts
a fibrous network in the primary thrombus. to the Ca 2+ ions. Factors VII and IX are also
Thrombin (factor IIa) is a serine proteinase linked to membrane phospholipids via Gla
(see p. 176) that cleaves small peptides from residues.
fibrinogen. This exposes binding sites that Substances that bind Ca 2+ ions (e. g., citrate)
spontaneously allow the fibrin molecules to prevent Gla-containing factors from attaching
aggregate into polymers. Subsequent covalent to themembraneand thereforeinhibit
cross-linking of fibrin by a transglutaminase coagulation. Antagonists of vitamin K, which
(factor XIII) further stabilizes the thrombus. is needed for synthesis of the Gla residues
Normally, thrombin is present in the blood (see p. 364) also have anticoagulatory effects.
as an inactive proenzyme (see p. 270). Pro- These include dicumarol, for example.
thrombin is activated in two different ways, Active thrombin not only converts fibrino-
both of which represent cascades of enzy- gen into fibrin, but also indirectly promotes
matic reactions in which inactive proenzymes its own synthesis by catalyzing the activation
(zymogens, symbol: circle) are proteolytically of factors V and VIII. In addition, it catalyzes
converted into active proteinases (symbol: the activation of factor XIII and thereby trig-
sector of a circle). The proteinases activate gers the cross-linking of the fibrin.
the next proenzyme in turn, and so on. Sev- Regulation of blood clotting (not shown).
eral steps in the cascade require additional To prevent the coagulation reaction from be-
protein factors (factors III, Va and VIIIa) as coming excessive, the blood contains a num-
well as anionic phospholipids (PL; see below) ber of anticoagulant substances, including
and Ca 2+ ions. Both pathways are activated by highly effective proteinase inhibitors. For
injuries to the vessel wall. example, antithrombin III binds to various ser-
In the extravascular pathway (right), tissue ine proteinases in the cascade and thereby
thromboplastin (factor III), a membrane pro- inactivates them. Heparin, an anticoagulant
tein in the deeper layers of the vascular wall, glycosaminoglycan (see p. 346), potentiates
activates coagulation factor VII. The activated the effect of antithrombin III. Thrombomodu-
form of this (VIIa) autocatalytically promotes lin, which is located on the vascular endothe-
its own synthesis and also generates the ac- lia, also inactivates thrombin. A glycoprotein
tive factors IXa and Xa from their precursors. known as Protein C ensures proteolytic deg-
2+
With the aid of factor VIIIa, PL, and Ca ,factor radation of factors V and VIII. As it is activated
IXa produces additional Xa, which finally— by thrombin, coagulation is shut down in this
2+
with the support of Va, PL, and Ca —releases way.
active thrombin.
The intravascular pathway (left) is prob-
ably also triggered by vascular injuries. It

Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
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