s e c t io n 36.10
Vitamin K, Oral Anticoagulants, and their Mechanisms of Action
8 6 1
F I G U R E 3 6 - 1 8
(Also see color figure.) Plasminogen activation. Plasminogen is converted
to plasmin as the result of cleaving a single peptide bond, Arg561 -Val562.
The molecular mechanism of transforming the zymogen into its active
form is the same as the activation of trypsinogen to trypsin. Two different
proteinases are responsible for the physiological activation of plasminogen:
tissue-type plasminogen activator (t-PA) and urinary plasminogen activator
(u-PA). t-PA is the principal activator of plasminogen and is synthesized
primarily in endothelial cells, which are the principal source of t-PA in the
circulating blood. t-PA is present in high concentrations in uterine tissue
and in various malignant cells. u-PA is found in the kidney and may be
particularly important in preventing the accumulation of fibrin in the
glomeruli. In the circulation, more than one-half of the t-PA is in a
complex with PAI-1. The activation of plasminogen is accompanied by the
proteolytic action of plasmin on plasminogen at Arg68-Met69 and at
Lys77-Lys78. This reaction results in the formation of a derivative of
plasminogen in which the first 77 amino acids at the N-terminal end of the
molecule are removed. This derivative of plasminogen,
lys p la sm in o g en ,
is
activated more rapidly than the native,
g lu p la sm in o g en .
In the color
version of this figure, motifs and domains are color coded as follows:
kringle domains (orange), EGF-like domain (magenta), activation peptide
(yellow), and proteinase domain (green). Light chains are indicated in dark
gray, heavy chains in light gray. Regions connecting the motifs are black.
example of proteinase protection when the proteinase
action is localized in a reaction complex.
F I G U R E 3 6 - 1 9
(Also see color figure.) Products of fibrinolysis. The products of plasmin
action are used to identify ongoing fibrinolysis and to distinguish
fibrinolysis from fibrinogenolysis. The presence of larger fibrin fragments,
which result from factor Xllla-catalyzed cross-linking, is the basis for the
distinction between fibrinogenolysis and fibrinolysis. Detection of D dimer
(DD) is particularly useful. Some of the fibrin degradation products
interfere with polymerization of fibrin. Digestion of fibrinogen by plasmin
proceeds with initial cleavages that remove polypeptides of approximately
40,000 Da from the carboxy terminal regions of the A chains. The large
fragment that is formed is designated fragment X, and it is heterogeneous.
Fragment X has a molecular weight of ~300,000 (one A-chain peptide
removed) or ~260,000 (two A-chain peptides removed). Further
proteolysis by plasmin removes polypeptides of ~ 100,000 Da total mass
from the disulfide bond-linked carboxy terminal regions of A, B, and
y
chains. The larger product of this fibrinogenolysis is designated fragment Y,
which has a molecular weight of ~ 150,000 Da. The product that contains
the cross-linked polypeptides from A, B, and
y
chains is designated
fragment D. A second round of proteolysis removes the remaining
fragment D from fragment Y to form fragment E (M.W. ~33,000 Da) and
a second fragment D. Fragment E is highly cross-linked and is also known
as the N-terminal disulfide knot (DSK). In fibrinogen, an additional
cleavage occurs early in the fibrinogenolytic process, i.e., cleavage of
Arg42 in the B/i chain to produce B/3 1^42. This can be distinguished from
the product that is produced by the cleavage of fibrin,
fl
15—42.
Degradation of Fibrin (Fibrinolysis)
The principal substrate of plasmin is fibrin and except
under pathological situations, e.g. disseminated intravas-
cular coagulation (DIC), the concentrations of the prod-
ucts of plasmin action are usually less than 10 /xg/mL
(less than 0.5% of the circulating fibrinogen). Because of
the opportunities for artifactual generation of FDPs (fibrin
degradation products) during the collection of the blood
sample and the common use of serum, the true concen-
trations of FDPs in normal plasma are probably less than
50 ng/mL. The opportunity for artifactual elevation of the
FDPs is easily understood when the fibrin enhancement
of plasminogen activation is recalled. The products of fib-
rin digestion, i.e., fibrin degradation products or FDPs, are
distinguishable from fibrinogen degradation products. The
cross-linking of fibrin by factor XHIa produces D dimers
and
a
polymers. The reactions of fibrin degradation and
the products are shown in Figure 36-19.
Under pathological conditions, e.g., (DIC), fibrinogen
can be digested by the fibrinolytic enzyme plasmin. This
leads to bleeding, even though clotting is also occurring.
36.10 Vitamin K, Oral Anticoagulants,
and Their Mechanisms of Action
Vitamin K
acts in the liver as an enzyme cofactor in the
reactions that add an additional carboxyl group to par-
ticular Glu residues in the vitamin K-related coagulation
