Summary
A deficiency of one of the proteins of the contact system of blood coagulation does
not result in a bleeding disorder. For this reason activation of blood coagulation
via this system is believed to be an in vitro artefact. However, patients deficient
in factor XI do suffer from variable bleeding abnormalities. Recently, an alternative
pathway for factor XI activation has been described. Factor XI was found to be activated
by thrombin in the presence of dextran sulfate as a surface. However, high molecular
weight kininogen (HK), to which factor XI is bound in plasma, and fibrinogen were
shown to block this activation suggesting it to be an in vitro phenomenon. We investigated
the thrombin-mediated factor XI activation using an amplified detection system consisting
of factors IX, VIII and X, which was shown to be very sensitive for factor XIa activity.
This assay is approximately 4 to 5 orders of magnitude more sensitive than the normal
factor XIa activity assay using a chromogenic substrate. With this assay we found
that factor XI activation by thrombin could take place in the absence of dextran sulfate.
The initial activation rate was approximately 0.3 pM/min (using 25 nM factor XI and
10 nM thrombin). The presence of dextran sulfate enhanced this rate about 8500-fold.
A very rapid and complete factor X activation was observed in the presence of dextran
sulfate. Although only minute amounts of factor XIa were formed in the absence of
dextran sulfate, significant activation of factor X was detected in the amplification
assay within a few minutes. HK inhibited the activation of factor XI by thrombin strongly
in the presence, yet only slightly in the absence of dextran sulfate (26 and 1.2 times,
respectively). Despite the strong inhibition of HK on the activation of factor XI
by thrombin in the presence of dextran sulfate, HK had only a minor effect on the
factor Xa generation.
We conclude that activation of factor XI by thrombin can take place regardless of
the presence of a surface or HK. This activation might therefore be physiologically
relevant. The inhibitory effect of HK on the thrombin-mediated factor XI activation
is largely dextran sulfate dependent. Due to the amplification in the intrinsic system,
trace amounts of factor XIa might generate physiological sufficient amounts of factor
Xa for an adequate haemostatic response.
