Page 117 - Color_Atlas_of_Physiology_5th_Ed._-_A._Despopoulos_2003

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negative charges of subendothelial collagen formation and polymerization of fibrin to pre-
and sulfatide groups. This stimulates the con- vent further clot formation. Alpha 2-antiplas-
version of prekallikrein (PKK) to kallikrein min is an endogenous inhibitor of fibrinolysis.
(KK), which enhances XII activation (positive Tranexamic acid is administered therapeuti-
feedback). Next, XIIa activates XI to XIa, which cally for the same purpose.
converts IX to IXa and, subsequently, VIII to Thromboprotection. Antithrombin III, a ser-
VIIIa. Complexes formed by conjugation of IXa pin, is the most important thromboprotective
and VIIIa with Ca on phospholipid (PL) layers plasma protein (! D).
2+
activate X. Exogenous activation now merges It inactivates the protease activity of thrombin and
with endogenous activation (! B1). In rela- factors IXa, Xa, XIa and XIIa by forming complexes
tively large injuries, tissue thrombokinase (fac- with them. This is enhanced by heparin and heparin-
tor III), present on of nonvascular cells, is ex- like endothelial glucosaminoglycans. Heparin is pro-
posed to the blood, resulting in activation of duced naturally by mast cells and granulocytes, and
VII. VII forms complexes with Ca 2+ and phos- synthetic heparin is injected for therapeutic pur-
pholipids, thereby activating X (and IX). poses.
The binding of thrombin with endothelial
Fibrin formation (! B3). After activation of thrombomodulin provides further thromboprotec-
X to Xa by endogenous and/or exogenous acti- tion. Only in this form does thrombin have anti-
vation (the latter is faster), Xa activates V and coagulant effects (! D, negative feedback).
conjugates with Va and Ca 2+ on the surface of Thrombomodulin activates protein C to Ca which,
Blood membranes. This complex, called prothrombi- after binding to protein S, deactivates coagulation
factors Va and VIIIa. The synthesis of proteins C and S
nase, activates prothrombin (II) to thrombin
is vitamin K-dependent. Other plasma proteins that
4 (IIa). In the process, Ca 2+ binds with phos- inhibit thrombin are α 2-macroglobulin and α 1-an-
pholipids, and the N-terminal end of pro-
thrombin splits off. The thrombin liberated in titrypsin (! D). Endothelial cells secrete tissue
thromboplastin inhibitor, a substance that inhibits
the process now activates (a) fibrinogen (I) to exogenous activation of coagulation, and prostacy-
fibrin (Ia), (b) fibrin-stabilizing factor (XIII), clin (= prostaglandin I 2), which inhibits platelet adhe-
and (c) V, VIII and XI (positive feedback). The sion to the normal endothelium.
single (monomeric) fibrin threads form a Anticoagulants are administered for thrombo-
soluble meshwork (fibrin S; “s” for soluble) protection in patients at risk of blood clotting. In-
which XIIIa ultimately stabilizes to insoluble fi- jected heparin has immediate action. Oral coumarin
brin (fibrin i). XIIIa is a transamidase that links derivatives (phenprocoumon, warfarin, acenocou-
marol) are vitamin K antagonists that work by in-
the side chains of the fibrin threads via hibiting liver epoxide reductase, which is necessary
covalent bonds. for vitamin D recycling. Therefore, these drugs do
not take effect until the serum concentration of
Fibrinolysis and Thromboprotection vitamin K-dependent coagulation factors has
decreased. Cyclooxygenase inhibitors, such as
To prevent excessive clotting and occlusion of aspirin (acetylsalicylic acid), inhibit platelet aggrega-
major blood vessels (thrombosis) and em- tion by blocking thromboxane A 2 (TXA2) synthesis
bolisms due to clot migration, fibrin S is re-dis- (! p. 269).
Hemorrhagic diatheses can have the following
solved (fibrinolysis) and inhibitory factors are causes: a) Congenital deficiency of certain coagula-
activated as soon as vessel repair is initiated. tion factors. Lack of VIII or IX, for example, leads to
Fibrinolysis is mediated by plasmin (! C). hemophilia A or B, respectively. b) Acquired defi-
Various factors in blood (plasma kallikrein, ciency of coagulation factors. The main causes are
factor XIIa), tissues (tissue plasminogen acti- liver damage as well as vitamin K deficiency due to
vator, tPA, endothelial etc.), and urine (uroki- the destruction of vitamin K-producing intestinal
nase) activate plasminogen to plasmin. Strep- flora or intestinal malabsorption. c) Increased con-
tokinase, staphylokinase and tPA are used sumption of coagulation factors, by disseminated in-
travascular coagulation. d) Platelet deficiency (throm-
therapeutically to activate plasminogen. This bocytopenia) or platelet defect (thrombocy-
is useful for dissolving a fresh thrombus lo- topathy). e) Certain vascular diseases, and f) exces-
cated, e.g., in a coronary artery. Fibrin is split sive fibrinolysis.
104 into fibrinopeptides which inhibit thrombin
Despopoulos, Color Atlas of Physiology © 2003 Thieme
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