clots form continually in vessels throughout the body. Without
ﬁbrinolysis, blood vessels would gradually become completely
Te critical natural “clot buster” is a ﬁbrin-digesting enzyme
, which is produced when the plasma protein
is activated. Large amounts of plasminogen are
incorporated into a forming clot, where it remains inactive un-
til appropriate signals reach it. Te presence of a clot in and
around the blood vessel causes the endothelial cells to secrete
tissue plasminogen activator (tPA).
Activated factor XII and
thrombin released during clotting also activate plasminogen.
As a result, most plasmin activity is conﬁned to the clot, and
circulating enzymes quickly destroy any plasmin that strays into
the plasma. Fibrinolysis begins within two days and continues
slowly over several days until the clot ﬁnally dissolves.
Factors Limiting Clot Growth or Formation
Factors Limiting Normal Clot Growth
Once the clotting cascade has begun, it continues until a clot
forms. Normally, two homeostatic mechanisms prevent clots
from becoming unnecessarily large: (1) swi± removal of clot-
ting factors, and (2) inhibition of activated clotting factors. For
clotting to occur in the ﬁrst place, the concentration of activated
clotting factors must reach certain critical levels. Clots do not
usually form in rapidly moving blood because the activated clot-
ting factors are diluted and washed away. For the same reasons,
a clot stops growing when it contacts blood ﬂowing normally.
Other mechanisms block the ﬁnal step in which ﬁbrinogen
is polymerized into ﬁbrin. Tey work by restricting thrombin
to the clot or by inactivating it if it escapes into the general cir-
culation. As a clot forms, almost all of the thrombin produced
is bound onto the ﬁbrin threads. Tis is an important safeguard
because thrombin also exerts positive feedback eﬀects on the co-
agulation process prior to the common pathway. Not only does
it speed up the production of prothrombin activator by acting
indirectly through factor V, but it also accelerates the earliest
steps of the intrinsic pathway by activating platelets. By binding
thrombin, ﬁbrin eﬀectively acts as an anticoagulant, preventing
the clot from enlarging and thrombin from acting elsewhere.
, a protein present in plasma, quickly inac-
tivates any thrombin not bound to ﬁbrin. Antithrombin III and
, another protein produced in the liver, also inhibit the
activity of other intrinsic pathway clotting factors.
, the natural anticoagulant contained in basophil
and mast cell granules, is also found on the surface of endothe-
lial cells. It inhibits thrombin by enhancing the activity of anti-
thrombin III. Like most other clotting inhibitors, heparin also
inhibits the intrinsic pathway.
Factors Preventing Undesirable Clotting
As long as the endothelium is smooth and intact, platelets are
prevented from clinging and piling up. Also, antithrombic
substances—nitric oxide and prostacyclin—secreted by the
endothelial cells normally prevent platelet adhesion. Addition-
ally, vitamin E quinone, a molecule formed in the body when
vitamin E reacts with oxygen, is a potent anticoagulant.
dramatically and a clot begins to form. Clot formation is nor-
mally complete within 3 to 6 minutes a±er blood vessel damage.
Clot Retraction and Fibrinolysis
Although the process of hemostasis is complete when the ﬁbrin
mesh is formed, there are still things that need to be done to
stabilize the clot and then remove it when the injury is healed
and the clot is no longer needed.
Within 30 to 60 minutes, a platelet-induced process called
further stabilizes the clot. Platelets contain contractile
proteins (actin and myosin), and they contract in much the same
manner as smooth muscle cells. As the platelets contract, they
pull on the surrounding ﬁbrin strands, squeezing
minus the clotting proteins) from the mass, compacting the clot
and drawing the ruptured edges of the blood vessel more closely
Even as clot retraction is occurring, the vessel is healing.
Platelet-derived growth factor (PDGF)
released by platelets
stimulates smooth muscle cells and ﬁbroblasts to divide and
rebuild the vessel wall. As ﬁbroblasts form a connective tissue
patch in the injured area, endothelial cells, stimulated by vascu-
lar endothelial growth factor (VEGF), multiply and restore the
A clot is not a permanent solution to blood vessel injury, and a
removes unneeded clots when heal-
ing has occurred. Tis cleanup detail is crucial because small
Scanning electron micrograph of erythrocytes
trapped in a ﬁbrin mesh.