Biomedical Engineering Reference
In-Depth Information
fi brin network is then cross-linked by factor XIIIa (FXIIIa) to the obtain an even more stable clot.
During the formation of the clot, platelets, white blood cells and especially red blood cells get
caught. This is the reason for the reddish appearance of blood clots. After the vessel damage or
tissue damage has been repaired, the clot will be degraded by a process called fi brinolysis. The
zymogen plasminogen is cleaved to form plasmin, which degrades the fi brin network.
31,33
Thrombin is formed through cleavage of prothrombin by FXa with FVa (the prothrombinase
complex). Both extrinsic and intrinsic pathways result in the activation of FXa and assembly of the
prothrombinase complex. Because both pathways converge in this last stage of coagulation, it has
been termed as the common pathway (Figure 17.4).
The activation of thrombin is dependent on Ca
2
+
and a negatively charged phospholipid sur-
face.
30,34,35
The dependency of thrombin formation on calcium ions is exploited for anticoagulation
of blood. Blood is often collected on citrate or ethylenediaminetetraacetic acid (EDTA), both che-
lators of calcium ions and thereby blocking coagulation of blood. In this way blood can be stored
before it is used in the laboratory. Furthermore, the activity of prothrombinase relies on phospho-
lipid (PL) surfaces that are enriched in the negatively charged phosphatidyl serine. For instance,
these PLs can be the plasma membrane of (activated) platelets adhered to synthetic surfaces.
Thrombin can initiate the formation of additional thrombin by activating FVIII or FXI in a
feedback upregulation of the intrinsic pathway.
17,30
In this way, traces of thrombin can be amplifi ed
to a burst of thrombin. The threshold thrombin concentration for the formation of a stable blood clot
can be reached, and a full clotting response will follow.
Of course the inactivation of thrombin is as important as its activation. Active thrombin can be
inactivated by binding it to AT, thereby forming an irreversible complex that is targeted for degrada-
tion (Figure 17.5). AT can also inactivate FXa by a very similar mechanism. The anticoagulant drug
heparin, which mimics glycosaminoglycans present on the endothelial cells of the inner vessel wall,
Intrinsic
pathway
Extrinsic
pathway
Thrombomodulin
APC
PC
FV
FX
FXa
+
FVa
AT
Thrombin
Prothrombin
PL, Ca
2+
Fibrinogen
Fibrin
FXIII
FXIIIa
Cross-linked
Fibrin
Fibrinolysis
FIGURE 17.4
Common pathway of blood coagulation. AT, antithrombin; PC, protein C; APC, activated
protein C; F, factor; PL, phospholipids.
