Biomedical Engineering Reference
In-Depth Information
other platelets. Increased platelet activity stimulates previously inactive
coagulation factors, which are always present and circulating in normal
blood. Platelet aggregation requires the proteolytic enzyme thrombin,
which is generated locally. Thrombin also converts fibrinogen to fibrin,
which stabilizes the platelet aggregation. Membrane phospholipids are me-
tabolized to generate thromboxane A2 (TxA2). TxA2, ADP, and thrombin
recruit additional circulating platelets into an enlarging platelet aggregate
and forming blood clot. Activation of these clotting factors results in the
initiation of a series of reactions or pathways. The coagulation cascade
continues, which ultimately leads to the formation of an insoluble, stabi-
lized fibrin clot. The formation of a thrombus takes approximately 12-16
seconds in a normal individual.
In vitro blood-coagulation tests are developed and used to evaluate the blood
compatibility of materials. Typically, tests compare the weight of the thrombus
formed, the amount of unclotted blood, and the reduction in platelet count of
the blood exposed clot formation rate on a surface to that of a control material.
These data are used to calculate a relative index whereby materials can be rated
quantitatively as to the rate of clot formation on their surface. However, the rela-
tionships between material surface properties, the initially deposited protein layer,
cell-surface interactions, later events (which could be of clinical consequence for
the evaluation of biocompatibility), and the design of blood-contacting cardiovas-
cular devices, are not well understood. Hence, the experiment results have to be
carefully performed.
6.4.3.2 Fibrinolytic Sequence
In the natural process of wound healing, the clot or thrombus dissolves from the
repaired site through the degradation of the fibrin mesh with the action of many
proteins. This is termed as fibrinolytic sequence [Figure 6.8(b)] and helps restore
blood flow following thrombus formation and facilitates the healing process. The
fibrinolytic sequence is also involved in tissue repair and macrophage function.
Plasminogen, an inactive protein produced in the liver and circulating in the blood,
plays a central role in the fibrinolysis. Plasminogen adheres to a fibrin clot, being
incorporated into the mesh during polymerization. Plasminogen is converted into
an active form called plasmin by the actions of plasminogen activators, which may
be present in blood or released from tissues. Plasmin then digests the fibrin clot,
releasing soluble fibrin-fibrinogen digestion products (FDP) into circulating blood.
FDPs (e.g., fibrin D-D dimer fragment) may be assayed for in vivo fibrinolysis.
Plasmin also binds and degrades many matrix proteins including fibronectin,
von Willebrand factor, thrombospondin, and laminin. The proteolytic network of
susceptible matrix proteins is further extended to include the collagens and elastin
by the ability of plasmin to activate certain matrix metalloproteinases (MMPs),
which, in turn, can activate other proteins. Also, certain growth factors, cytokines,
and chemokines can be released, activated, and/or degraded by plasmin. The activ-
ity of plasmin is regulated by limiting the conversion of plasminogen to plasmin by
