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1898 Part XII Hemostasis and Thrombosis

FPA
Thrombin
D E D D E D
fXIII fXIII a D E D Solution

Thrombin
FPA

D E D D E D D E D
D E D D E D D E D D E D Initial clot

Thrombin
FPA
CPB
FPB des-Arg FPB

D E D D E D D E D D E D
D E D D D E E D D D D E E D D D D E E D D Final clot
D E D D E D D E D
Fig. 126.11 SCHEMATIC REPRESENTATION OF WHOLE-BLOOD FIBRIN FORMATION. At the
start of clot formation, thrombin simultaneously acts on fibrinogen (D-E-D) and FXIII. A portion (≈40%)
of FPA is released from fibrinogen, and an initial clot is formed from the complementary overlap of the exposed
sites between the E and D domains of adjacent fibrin molecules. fXIIIa simultaneously cross-links adjacent D
domains (D=D). Thus the initial soluble fibrin clot is composed of fibrinogen, fibrin, and γ-γ dimers with
FPB still attached. The initial clot is continuously acted on by thrombin, releasing the remaining FPA and
some of the FPB to yield a final clot with the majority of FPB still attached. The released FPB is selectively
acted on by a CPB (potentially thrombin-activatable fibrinolysis inhibitor a), which cleaves the C-terminal
arginine to produce des-Arg FPB. The significance of this cleavage is still unclear. CBP, Carboxypeptidase
B–like enzyme; FPA, fibrinopeptide A; FPB, fibrinopeptide B; FXIII, factor XIII; FXIIIa, activated factor XIIIa.
(From Brummel KE, Butenas S, Mann KG: An integrated study of fibrinogen during blood coagulation. J Biol Chem
274:22862, 1999, with permission.)

These circulating fragments are cleared by other proteases or by the generation appears critical for the stabilization of the blood clot.
kidney and liver. Plasmas with specific deficiencies in the coagulation pathway exhibit
reduced rates of thrombin production, decreased levels of TAFIa, and
premature clot lysis. 257,282,283
Inhibitors of the Fibrinolytic System Fibrinolytic drugs are often given after a myocardial infarct or
ischemic stroke to dissolve the fibrin clot blocking the coronary or
Plasminogen activation in blood is primarily inhibited by PAI-1, cerebral artery. Fibrinolytic drugs are also used in massive pulmonary
which targets u-PA and t-PA. PAI-1 also has a role in tissue remodel- embolism. Antifibrinolytics, such as aminocaproic acid (ε-aminocaproic
ing by interfering with vitronectin-dependent processes of cell adhe- acid) and tranexamic acid, are used as inhibitors of fibrinolysis.
275
sion and migration. Congenital deficiency of PAI-1 is rare, with
homozygous individuals displaying abnormal bleeding in response to
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trauma. Platelets contribute to the fibrinolytic process by binding CONNECTIVITY AND DYNAMICS IN HEMOSTASIS
t-PA and plasminogen, and supporting plasmin generation. Increased
levels of plasma PAI-1 delay fibrin removal by shortening the func- In the healthy state, the hemostatic system is relatively quiescent, with
tional lifetime of plasminogen activators, thereby shifting hemostasis the vascular endothelial cells, the blood, and the extravascular tissue
to a more thrombotic state. 277 functioning to maintain fluidity. Blood platelets remain in a quiescent
TAFI is a plasma zymogen with homology to procarboxypepti- state because of the endothelial cell lining of the blood vessel being
dases A and B (see Fig. 126.12). 55,278–280 Activation of TAFI yields the an active anticoagulant that secretes small molecules and enzymes.
exopeptidase (TAFIa) with carboxypeptidase B–like substrate speci- The endothelium also provides constituent anticoagulant proteins,
ficity. TAFIa catalyzes the removal of basic amino acids (arginine, which inhibit the blood coagulation system. These vascular antico-
lysine) from the COOH-termini of polypeptides. The activation of agulant systems are both passive and dynamic in nature, and function
many of the cofactors and zymogens of the coagulation and fibrino- in cooperation with plasma components. The blood supplies pro- and
lytic cascades results in the generation of functional proteins with anticoagulant proteins in the plasma and platelets, which contribute
COOH-terminus arginine or lysine residues. COOH-terminus lysine to the coagulation reaction. If the endothelium becomes damaged,
residues that appear in fibrin fragments degraded with plasmin have the pro- and anticoagulant levels become imbalanced, and cells that
been identified as the major substrates for TAFIa. The physiologic should remain in the blood can leak through blood vessels into
activator of TAFIa is the thrombin–thrombomodulin complex, thus adjacent body tissue, which triggers a response. The dimensions of
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defining TAFIa as a coagulation-dependent activity. Because TAFIa the response are relevant to the injury. The extravascular compart-
53
functions as an attenuator of fibrinolysis, an adequate rate of TAFIa ment and blood interact to rapidly produce a vigorous local