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Feedback activation of factor XI by thrombin in plasma results in
additional formation of thrombin that protects fibrin clots from
fibrinolysis
PA von dem Borne, JC Meijers and BN Bouma
Department of Haematology, University Hospital Utrecht, The Netherlands.
Recently, an alternative pathway for factor XI activation has been
described in which factor XI is activated by thrombin. Patients with a
factor XI deficiency bleed mostly from tissues with high local fibrinolytic
activity. Therefore, the role of thrombin-mediated factor XI activation in
both fibrin formation and fibrinolysis was studied in a plasma system.
Clotting was induced by the addition of tissue factor or thrombin to
recalcified plasma in the presence or absence of tissue- type plasminogen
activator, after which clot formation and lysis were measured using
turbidimetry. Thrombin-mediated activation of factor XI was found to take
place in plasma under physiologic conditions in the absence of a dextran
sulfate-like cofactor. At high tissue factor concentrations, no effect of
factor XI was seen on the rate of fibrin formation. Decreasing amounts of
tissue factor resulted in a gradually increasing contribution of factor XI
to the rate of fibrin formation. In addition, thrombin-mediated factor XI
activation resulted in an inhibition of tissue-type plasminogen
activator-induced lysis of the clot. This inhibition occurred even at
tissue factor concentrations at which no effect of factor XI was observed
on fibrin formation. Trace amounts of activated factor XI (1.25 pmol/L,
representing 0.01% activation) were capable of completely inhibiting
fibrinolysis in our system. The inhibitory effect was found to be mediated
by thrombin that is additionally generated in a factor XI-dependent manner
via the intrinsic pathway and is capable of protecting the clot against
lysis. We also observed that formation of additional thrombin continued
after the clot had been formed. We conclude that thrombin-mediated factor
XI activation can take place in plasma. The presence of factor XI during
coagulation results in the formation of additional thrombin within the clot
capable of protecting this clot from fibrinolytic attack. The large amounts
of thrombin that are formed by the intrinsic pathway via factor XI may play
an important role in the procoagulant and thrombogenic state of clots and
may therefore have important clinical and therapeutic implications.
Volume 86,
Issue 8,
pp. 3035-3042,
10/15/1995
Copyright © 1995 by The American Society of Hematology
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