This is a screening test for prekallikrein deficiency
(PK or Fletcher Factor). It is not a definitive assay using deficient
plasma, but it can be mixed with a known PK-deficient plasma for
confirmation. PK is a protease enzyme and a component of "contact
activation" of the intrinsic cascade as measured by the PTT.
It also participates in activation of fibrinolysis and the complement
system. PK is initially activated by F XIIa when in contact with
surfaces, such as silicates and sub-endothelial tissue. A positive
feedback loop occurs when Kallikrein (activated PK) in turn catalyses
activation of F XII to XIIa. Activation of XII occurs more slowly
in the absence of PK and it's co-factor High Molecular Weight Kininogen
(HMWK, Fitzgerald Factor), which explains the abnormal PTT. However,
after prolonged incubation with activator at 5, 10, and 15 min.,
PK deficiency will correct to normal. That is the basis of this
test. A mild XII deficiency, and possibly decreased HMWK may also
correct with this test. In clinical practice, a Fletcher Screen
and an assay for XII are performed together to exclude XII deficiency
as a cause of an abnormal PTT and the correction with incubation.
Neither XII nor PK deficiencies are associated with bleeding, even
though the PTT is elevated. They are, in fact, associated with
venous thrombosis. This association is probably explained by the
fact that one of their major roles is to activate finbrinolysis,
i.e. the dissolution of clots.
PK circulates as 25% free protein, and 75% bound to it's co-factor, HMWK. Mean
plasma concentration is very low at 42 ug/ml (0.5 uM). PK is normally inhibited
by C1-inhibitor (complement system), alpha2 -macroglobulin, and Protein-C Inhibitor.
Antithrombin III has little inhibitory effect on this protease, but inhibiton
is greatly enhanced with heparin. Because of this, using heparin for anti-coagulation
will not only block further clotting, it will also inhibit fibrinloysis.
In a patient with isolated elevation of PTT, an inhibitor screen is run first.
If it is negative, then history is obtained to determine if bleeding symptoms
are present or not. If no inhibitor is detected and there are no bleeding symptoms,
then the first factors to be tested are the Fletcher Screen and F XII assay.
If these are normal proceed to VIII, IX, and XI assays. If inhibitor screen
is negative and there is a history of bleeding, then go to VIII, IX, and XI
assays first.
References:
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Dr. Will Armstrong, June 2003.
(posted 26 April 2004) |
