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C H A P T E R 127

REGULATORY MECHANISMS IN HEMOSTASIS

James A. Huntington and Trevor P. Baglin

MAIN POINTS (through activation of factor XIII) and suppression of the fibrinolytic
system (through activation of thrombin-activatable fibrinolysis
• Hemostasis and thrombosis result from the localized production inhibitor [TAFI]).
of thrombin. Both hemostasis and thrombosis are dependent on the action of
• Thrombin is the final protease generated in the coagulation thrombin. In order to maintain blood in a fluid state in the circula-
cascade of zymogen activation events. tion but permit rapid coagulation when a blood vessel is ruptured it
• The regulation of hemostasis relies on maintaining the lumen of is necessary to regulate thrombin formation so that it occurs rapidly
blood vessels (intravascular space) as an anticoagulant environ- and is limited to sites of vascular injury. The regulation of thrombin
ment and the extravascular space as a procoagulant environment. generation is both spatial (compartmentalization) and temporal
• The principal drivers of coagulation in the extravascular space are (kinetic). The traditional paradigm of blood coagulation is that
tissue factor (TF) and collagen. hemostasis and thrombosis are inseparable, primarily due to their
• The procoagulant activity of von Willebrand factor (vWF) is shared dependence on thrombin. There is now emerging evidence of
controlled through limited proteolysis by ADAMTS13. dissociation between hemostasis and thrombosis, potentially due to
• Tissue factor pathway inhibitor (TFPI) limits the initiation of the subtle differences in the triggering or propagation of thrombin gen-
6,7
coagulation cascade. eration. However, the most important consideration is that
• The protein C pathway regulates propagation of the thrombin hemostasis and thrombosis are distinct from a spatial perspective
explosion. (extravascular versus lumenal). Consequently, regulation of hemosta-
• Antithrombin (AT) is a serpin (serine protease inhibitor) that sis relies principally on maintaining the lumen of blood vessels
neutralizes coagulation proteases in the absence and presence of (intravascular space) as an anticoagulant environment and the extra-
heparin-like molecules. vascular space as a procoagulant environment.
• Hemostasis reflects the dynamic balance between coagulation and
fibrinolysis; excessive fibrinolytic activity relative to thrombin
generation may compromise hemostasis. THE ANTICOAGULANT INTRAVASCULAR SPACE

Blood Flow
KEY EVENTS IN BLOOD COAGULATION The importance of blood flow as a regulatory mechanism is apparent
from observations of arterial and venous thrombosis. The arterial
It is essential that blood remains fluid within the circulation, but that system is a high-pressure, high-flow system and thrombosis typically
it clots rapidly when there is loss of vascular integrity. Hemostasis occurs only in the presence of endothelial injury, for example athero-
refers to the formation of a blood clot to limit blood loss into the sclerosis with plaque rupture or vasculitis. In contrast the venous
extravascular space or hemorrhage outside the tissues. The term system is a low-pressure, low-flow system, and venous thrombosis
thrombosis refers to pathologic clot formation within the lumen of usually occurs in the absence of endothelial damage. Sluggish flow
a blood vessel that impedes blood flow. resulting from immobility or pooling of venous blood in valve pockets
Blood coagulation is the result of a biologic amplification system is an important contributory factor to venous thrombosis. Similarly,
in which plasma zymogens of serine proteases are converted into thrombus formation is common in atrial fibrillation where lack of
1,2
active enzymes (Fig. 127.1). Enzyme activation occurs in a sequen- coordinated contraction of the atria results in irregular blood flow
tial manner and is dependent on the assembly of enzyme–cofactor (stasis) in the left atrial appendage.
complexes on phospholipid membranes, principally on the surface of
3
activated platelets (Fig. 127.2). The final event in the amplification
process is the formation of the effector enzyme, thrombin. At each Blood Components
step in this process, specific protease inhibitors control the amount
of enzyme generated while simultaneous regulatory mechanisms Although the potential to convert from a liquid to a solid gel is an
control the availability of phospholipid and the cofactor-dependent inherent property of blood, the components responsible for the phase
assembly of enzymatic complexes on the membrane of activated change circulate in inactive states. The platelets are plate-like and
platelets. inactive, with a membrane unable to bind clotting proteins and with
Hemostasis is triggered by the exposure of extravascular tissue to receptors in inactive conformations. The proteases are all in inactive
certain protein and cellular components of blood. Nonendothelial zymogen states, requiring cleavage of an activation peptide and the
cells express TF on their surface and collagen is present in the extra- subsequent zymogen-to-protease conformational change typical of
8,9
cellular space. TF binds factor VIIa to initiate the coagulation cascade, the chymotrypsin family of serine proteases. A possible exception
and collagen binds platelets and initiates their activation. These to this is the small fraction of factor VII that circulates as factor VIIa;
events contribute synergistically to produce a large amount of throm- however, factor VIIa is still zymogen-like until it binds to TF to
5
10
bin from a small trigger. Thrombin ultimately converts soluble complete its activating conformational change. Clotting proteases
fibrinogen into an insoluble fibrin clot to form an impermeable that escape from the site of a clot into the blood are inhibited by a
platelet–fibrin barrier. This barrier is rapidly stabilized by platelet- reservoir of inhibitory activity provided by a high (2.3 µM) concen-
dependent clot retraction and thrombin-mediated fibrin crosslinking tration of the serpin, AT. 11
1906