section 36.11
Coagulation Factor Measurements
cattle. The com pound responsible for the hem orrhagic
o f m icrobial
m etabolism
(sp oil-
ing) o f sw eet clover, w as identified as 3,3'-m ethylbis-
4-(hydroxycoum arin).
com pound
w as
nam ed
dicoum arol. A synthetic, clinically useful com pound w ith
the ability to function like dicoum arol is warfarin [
(4'-hydroxy-3'-coum arinyl)-1 -phenyl-3-butanone].
com pound is sold in the U nited states under the nam e
Coum adin.
T he oral anticoagulant drugs act indirectly on the
process o f Glu carboxylation o f the vitam in K -dependent
proteins. The vitam in K antagonists prevent the reduction
o f the reaction interm ediate, vitam in K epoxide. B lock age
o f the epoxide reductase reaction results in the accu-
m ulation o f vitam in K epoxide and other nonfunctional
form s o f vitam in K. W ithout regeneration o f the vitam in
K -related reaction interm ediates through the cy cle show n
in Figure 36-22, a depletion o f functional vitam in K
V itam in K antagonists are processed in the liver by
the cytochrom e P 450 system s that m etabolize m any other
drugs. Drug interactions com m only alter the effectiveness
o f oral anticoagulant drugs. This requires that oral an-
ticoagulant therapy be m onitored frequently during the
early stages o f therapy and at regular intervals after stable
Hepatic Vitamin K Metabolism
Sites of warfarin action
Adapted from
Suttie , 1994
* Thioredoxin
Thioredoxin Reductase
FIGURE 36-22
(Also see color figure.) Hepatic vitamin K metabolism. Oral anticoagulant
drugs act indirectly on the process of glu carboxylation of the vitamin K
dependent proteins. The vitamin K antagonists block the reduction of the
reaction intermediate, vitamin K-epoxide, that results in the accumulation
of vitamin K-epoxide and other nonfunctional forms of vitamin K.
Without cycling of the vitamin K-related reaction intermediates in the
cycle shown, a depletion of functional vitamin K occurs. Vitamin K
antagonists do not block polypeptide synthesis and formation of
noncarboxylated proteins occurs. These noncarboxylated proteins are still
secreted from the liver and account for nearly normal levels of each of the
vitamin K-dependent proteins that can be detected by immunoassay
(sometimes called PIVKA, proteins induced in vitamin K absence).
anticoagulation (a predeterm ined level o f effectiveness) is
achieved to prevent both ex cessive hem orrhage and inad-
equately reduced risk o f throm bosis.
Coagulation Factor Measurements
Contem porary m ethods o f coagulation factor testing have
their conceptual origins in the “classical theory o f coag-
ulation,” circa 1905, and the long-standing recognition
o f inherited bleeding disorders in the royal fam ilies o f
Europe. A . J. Q uick d eveloped the first practical m ethod
for evaluating the functionality o f the “classical” (extrin-
sic) pathway with the publication o f the “prothrombin
tim e” assay. This test w as so nam ed because the classi-
cal pathway recognized on ly fibrinogen and prothrombin,
the postulated precursor o f thrombin and throm boplastin.
This test established a m easurable relationship betw een
the tim e required for clot form ation and the presence or
absence o f the requisite com ponents (activities) and w as
a m ilestone in the advancem ent o f the study o f blood
The concept o f qualitatively distinguishable com p o-
nents (factors) is related to the observation that one could
“correct” the tim e for clotting o f plasm a from an indi-
vidual w ith a bleeding disorder by m ixing the patient’s
plasm a w ith plasm a from an individual w ithout b leed -
ing problem s. M oreover, if plasm as from tw o individ-
uals w ith b leeding disorders w ere m ixed, the disorders
could be classified as the sam e if there w ere no correc-
tive effect, or different if there w ere a corrective effect.
Variations o f this approach, coupled w ith clinical presen-
tation o f the b leeding disorder, have provided the basis
for the discovery o f m ost o f the procoagulant subsystem
com ponents.
Q uantification w as d eveloped by m easuring the rela-
tionship betw een the shortening o f the clotting tim e o f the
plasm a from the patient w ith the bleeding disorder (de-
ficient plasm a) and the am ount o f normal plasm a added
to the deficient plasm a. T his approach rem ains the basis
for specific factor assays; however, the deficient plasm as
are depleted o f individual factors by im m unoprécipitation
and separation o f the antibody-factor com p lex from the
plasm a.
The term
coagulation factor deficiency
is frequently am -
biguous. Previously, it im plied a deficit in the functional
activity o f a com ponent because the clotting tim e tests
m easured only the ability o f the com ponent to support
norm al coagulation. The reference for norm al function-
ality is the response o f dilutions o f plasm a from pooled
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