In this lecture on Fibrinolysis,
we will cover the role of Fibrinolysis as an integral part of haemostasis,
the biochemistry of the interactions which make up the process,
where it happens with insights gained from
experiments using plasma or whole blood and what
we can practically measure and what it tells
us in relation to bleeding and thrombosis in the clinic.
Putting it all together,
you should be able to conceive of Fibrinolysis as
an active process occurring at the same time as and subsequent to haemostasis.
In normal blood, a balance exists between
a process of clot formation and its dissolution of Fibrinolysis.
An imbalance in either direction can cause,
on the one hand,
thrombosis if there's inadequate clotlysis or bleeding if clotlysis is overactive.
This diagram summarizes the actors in the dynamic process of clot formation and clot
dissolution by Fibrinolysis together with
the specific activators and
the specific inhibitors which regulate the process and keep it in balance.
Shown centrally, in red,
is Thrombin the terminal enzyme of the coagulation cascade.
Thrombin is multi-functional.
Its roles shown here,
which are a subset of its nine roles,
are firstly to convert
soluble Fibrinogen to fibrin monomers which spontaneously polymerize.
Thrombin also activates plasma factor XIII to factor XIIIa, a transglutaminase.
Factor XIIIa cross links the fibrin meshwork giving its stability.
As soon as fibrin has formed,
it begins to absorb plasminogen and tissue plasminogen activator,
thereby accelerating the generation of the active enzyme plasmin,
which in turn starts to degrade
cross-linked fibrin yielding fibrin degradation products, FDPs.
This part of the process is tightly regulated by serine proteinase inhibitors or serpins,
shown as purple lozenges,
one being specific for each active enzyme.
PAI-1 is the inhibitor of TPA,
alpha 2 anti-plasmin of plasmin,
and anti-Thrombin of Thrombin.
Another action of Thrombin in the presence of thrombomodulin or TM,
an endothelial surface receptor,
is to convert TAFI or Thrombin activatable Fibrinolysis inhibitor,
to an active form, a carboxypeptidase,
which removes specific lysine residues from fibrin,
rendering it unable to bind plasminogen and TPA and thus
switching off the process of active plasmin generation.