Syllabus PAOKC-cursus Klinische Chemie en ... - NVKC

1570 B. N. Bouma and J. C. M. Meijers
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prevents TAFIa formation [35]. On the other hand, TAFIa has
been shown to attenuate fibrinolysis by inhibiting plasmin
directly [8,26].
The physiological importance of plasmin as a regulator of
TAFIa is not clear to date. Normally, thrombin generation will
precede plasmin formation, and the role of plasmin-mediated
TAFI activation, or prevention thereof, during clot lysis may be
relatively limited. However, TAFI fragments resembling those
generated by plasmin, such as the 44.3-kDa fragment, have been
observed during t-PA-mediated lysis of thrombin-induced clots,
and the 44.3-kDa fragment was observed in plasmas of patients
treated with t-PA after myocardial infarction, but not in plasmas
of untreated patients [35]. Decreased levels of functional TAFI
might enhance the effect of increased fibrinolysis induced by t-
PA administration. Decreased levels of functional TAFI were
detected in plasmas of patients with acute promyelocytic leukemia
[36], whereas antigen levels were normal. The reduction in
TAFI was most likely caused by the action of plasmin on TAFI,
because in vitro experiments revealed that plasmin slightly
reduced TAFI antigen levels but severely reduced TAFIa activity.
The acquired functional deficiency in acute promyelocytic
leukemia may contribute to the severity of the hemorrhagic
diathesis because of the impaired capacity of the coagulation
system to protect the fibrin clot from fibrinolysis [36].
A role for the intrinsic coagulation system in the activation
of thrombin-activatable fibrinolysis inhibitor
The activation of TAFI by thrombin implies that the coagulation
system plays a role in the regulation of fibrinolysis and that any
disturbance in the generation of thrombin will result in an
increased rate of clot lysis (Fig. 5). This was first investigated
for FXI. Patients with a deficiency of FXI are prone to bleeding
from tissues with high local fibrinolytic activity (urinary tract,
nose, oral cavity, tonsils) [37,38]. The mechanism behind this
clinical observation was unclear. It was hypothesized that FXI
activation by thrombin [39,40] might play a role in this process
and therefore we studied the effect of FXI on clot lysis, using an
assay that determines both the activity of the fibrinolytic system
and the efficiency of the coagulation system to form thrombin,
which is necessary to downregulate fibrinolysis [10]. The clot
lysis time was prolonged in the presence of FXI, and the effect
of FXI was dependent on the presence of TAFI [41]. High
concentrations of thrombin are needed for both the inhibition of
clot lysis and for the activation of TAFI [27], in contrast to the
small amounts of thrombin that are sufficient for fibrin formation
and platelet activation. High concentrations of thrombin
were generated in a FXI-dependent way in parallel to the
antifibrinolytic effect [10]. Trace amounts of activated FXI
(1.25 pmol L 1 , representing 0.01% activation) were capable
of completely inhibiting fibrinolysis, indicating that continued
activation of FXI by thrombin and the amplification power of
the intrinsic system generates the amount of thrombin needed
for the activation of TAFI, thereby determining the fate of the
clot during fibrinolytic attack [10,41].
Role of thrombin-activatable fibrinolysis inhibitor in
bleeding disorders
The coagulation model (Fig. 5) provides an explanation for the
bleeding abnormalities of FXI-deficient patients. These patients
are prone to bleeding from tissues with a high local fibrinolytic
activity [37,38], and it is at these sites that the downregulation of
fibrinolysis is not provided for by the FXI-dependent generation
of thrombin and TAFI activation. A defective activation of TAFI
might also contribute to the severity of the bleeding disorder in
FVIII and FIX deficiency (hemophilia A and B) [42,43]. These
patients have a reduced thrombin formation via the extrinsic
pathway at low tissue factor concentrations and a reduced
secondary burst of thrombin generation via the intrinsic path-
Fig. 5. Model of blood coagulation. To improve the clarity of the figure, most zymogens and procoagulant surfaces are not depicted. TF-VIIa, tissue
factor-FVIIa complex; TFPI, tissue factor pathway inhibitor; Xa þ V, FXa and FV(a) (depicting the prothrombinase complex); IXa þ VIII, FIXa and FVIII(a)
(depicting the tenase complex); IIa, thrombin; APC, activated protein C; PS, protein S; TM, thrombomodulin; TAFI, thrombin-activatable fibrinolysis
inhibitor; Xia, FXIa; t-PA, tissue-type plasminogen activator. An uninterrupted line indicates activation, while an interrupted line indicates inactivation.
The uninterrupted line between Xa and TFPI indicates that FXa has to form a complex with TFPI, and that this complex then inhibits TF-FVIIa. Modified
with permission from Bouma et al. [70].
# 2003 International Society on Thrombosis and Haemostasis
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