Mathematical Models for Blood Coagulation - Fluid-Structure Interaction and Biomedical Applications - page 491

Serine Protease Inhibitors make a large group of proteins neutralizing specific
serine proteases. Of course their list is as long as the one of serine proteases. The
acronym serpin is frequently used to denote any of these proteins. For our purposes
we are interested in the following ones.

1. Serpins Neutralizing Pro- or Anti-coagulation Factors

Antithrombin . Most commonly referred to as Antithrombin III (ATIII), 41 it
inhibits most of the activated coagulation factors (FIXa, FXa, FXIa, and FIIa)
and the FVIIa-TF complex. Its action is enormously enhanced by Heparin . 42

•

• Tissue Factor Pathway Inhibitor (TFPI) can inhibit thrombin (FIIa) and also

FXa by forming a complex with it. In turn the latter complex can inhibit the
FVIIa-TF complex (the initiator of coagulation). It is released by endothelial
cells and also by platelets.

• Alpha 1-antitrypsin . This serpin interacts with many proteases and therefore

is particularly important. 43 It is known to inhibit APC.

• Protein C inhibitor limits the expression of Protein C.

• Protein Z-related protease inhibitor . It neutralizes FXa in the presence of PZ.

It also inhibits FXIa.

• Kallistatin , an inhibitor of Kallikrein.

• Heparin cofactor II rapidly inhibits thrombin in the presence of heparin.

Another protease inhibitor, not frequently quoted in the literature in the context
of blood coagulation, is

• Nexin II , an inhibitor of FXIa, secreted by activated platelets (see [ 244 ]).

2. Serpins Neutralizing Pro- or Anti-fibrinolytic Factors

• Plasminogen activator inhibitor-1 (PAI1) and Plasminogen activator

inhibitor-2 (PAI2) 44 inactivate both tPA and urokinase.

• Neuroserpin inhibits tPA and urokinase.

• Alpha 2-antiplasmin is an inhibitor of plasmin.

• Alpha 2-Macroglobulin is another multifunction serpin. It inhibits plasmin and

Kallikrein.

41 AT I-IV are also found in the literature, with specific targets.
42 Discovered in 1918 [ 109 ], though isolated in 1916 in canine liver tissue [ 167 ]. There has been
some controversy about heparin discovery (see [ 248 ]and[ 162 ]]). It is a large polymer, also
naturally produced by endothelial cells (as heparan sulfate ). A side effect can be a strong reduction
of platelets count ( Heparin Induced Thrombocytopenia , HIT), see [ 128 ]. HIT can be sometimes
observed in patients undergoing hemodialysis, during which heparin is supplied to prevent clotting
(after passing through the dialyzer and before being returned to the patient, protamine sulfate is
added, which neutralizes heparin's action). Platelet Factor 4 contrasts the action of heparin on
platelets.
43 Its deficiency leads to degradation of tissues, particularly in the lungs, causing emphysema.
Smoke is believed to inactivate this serpin, thus causing additional damage to lungs.
44 PAI2 is detectable only in pregnant women, a fact that may justify the increased risk of
thrombosis during pregnancy.