Biomedical Engineering Reference
In-Depth Information
makes use of this thrombin inactivation system. Heparin is a commonly used drug in the control of
thrombosis and coagulation disorders.
35
-
37
Heparin enhances the affi nity of AT for th rombin or F Xa, accelerating clea rance of these enzymes
from the blood. The heparin will release the thrombin-AT (or FXa-AT) complex, ready to interact
with a following AT molecule. Because heparin works in a catalytic fashion, it is a favorite antico-
agulant molecule for biomedical engineers. Other anticoagulant drugs like hirudin, which is derived
from the medicinal leech
Hirudo medicinalis
targets the active site of thrombin.
38
These sorts of
drugs can only inactivate one thrombin molecule while heparin can inactivate multiple thrombin
molecules. Thrombin also induces its own inactivation, for instance by the activated protein C (APC)
pathway.
39,40
The APC cleaves FVa, inhibiting prothrombinase, or FVIIIa, which is an essential com-
ponent of the tenase complex, reducing FXa formation. A decrease in the ability of APC to inactivate
thrombin is called APC resistance, and may result in deep vein thrombosis. This clotting disorder is
often caused by mutations in the gene encoding FV, resulting in slower cleavage of FVa and thus a
prolonged thrombin activity.
41
Also the use of oral contraceptives was shown to infl uence the inac-
tivation of thrombin via this mechanism. The hormones present in oral contraceptives decrease the
sensitivity of FVa for APC, prolonging the activity of thrombin and thus increasing the chance of deep
vein thrombosis.
42
This shows that both coagulation and anticoagulation have to be kept in balance in
order to prevent complications from the blood. As a consequence, many strategies for improved blood
compatibility rely on synthetic surfaces that can induce inhibition of thrombin formation or activity.
17.5.2.2 IntrinsicPathway
This pathway of blood coagulation is often referred to as the “contact activation” pathway. This is
termed as contact activation because upon the contact of blood with a synthetic surface, a series of
events is triggered that results in thrombus formation.
1,17,43
Negatively charged surfaces are espe-
cially good substrates for contact activation. For this reason the physiological importance of contact
activation remains a matter of speculation since negatively charges surfaces
in vivo
are rare, espe-
cially in contact with blood.
In contact activation, fi rst, adsorption of high-molecular-weight kininogen (HMWK), prekalli-
krein, and FXII to a surface occurs. The adsorbed HMWK will cleave prekallikrein and the formed
kallikrein can in turn convert FXII to FXIIa. Together with HMWK, FXIIa activates FXI and the
resulting FXIa will in turn convert FIX to FIXa. In fact the intrinsic pathway is a chain of zymo-
gens that cleave and subsequently activate each other in a precise order. At the end of this pathway
the formed FIXa together with FVIIIa will form the tenase complex that catalyzes the formation
of FXa. This enzyme is a convergence point in coagulation and from here on the intrinsic pathway
is activated, ultimately resulting in formation of a blood clot (Figure 17.6). The importance of the
cofactor FVIIIa is known from the hemophilia-A patients who have a strongly increased bleeding
tendency, especially in the joints. The most famous carriers of this bleeding disorder were some
of the males in the Romanov, Russian tsar family. Hemophilia-B is caused by a defi ciency in FIX,
resulting in a much reduced thrombin response due to lack of positive feedback upregulation of the
coagulation response.
44,45
17.5.2.3 ExtrinsicPathway
The extrinsic pathway is driven by the generation of tissue factor (TF), also called thromboplastin.
1,17,46
This membrane protein is presented on the surface of cells after tissue damage, for instance, in the
vessel wall. TF is not expressed by cells exposed to blood fl ow, but is present in cells of the subendothe-
lium, the smooth muscle cells. Of course when a medical device is implanted into the patient, extensive
tissue damage will occur and this pathway of coagulation will be triggered. For the wound healing
response this is desirable, but for blood-contacting devices this response can be a complication.
TF will form a complex with FVII (TF.FVII), which can be activated to a TF.FVIIa complex by
FIXa or by TF-FVIIa itself. Small amounts of activated FVIIa are constantly present in the circulation
