D dim er plus
a
chain cross-links
c o v a le n t E
v chain cross-links
C H A P T E R 3 6 , F IG U R E 19
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 XHIa-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 fibrin. Digestion of fibrinogen by
plasmin proceeds with initial cleavages that remove polypeptides of approxi-
mately 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 heteroge-
neous. 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 disul-
fide bond-linked carboxy terminal regions of A, B, and
y
chains. The larger
product of this fibrogenolysis is designated fragment Y, which has a molecu-
lar 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 fribrinogen, an additional cleavage occurs early in the fib-
rinogenolytic process, i.e., cleavage of Arg42 in the Bp chain to produce Bp
1-42. This can be distinguished from the product that is produced by the
cleavage of fibrin, p 15^12.
C H A P T E R 3 6 , F IG U R E 21
Structure of a Gla domain of prothrom-
bin. The Gla domains of the vitamin K-dependent proteins contain between
9 and 12 carboxyglutamic acid residues. Prothrombin contains 10 Gla
residues: pairs of adjacent Gla residues at positions 6 and 7; 19 and 20; and
25 and 26 and four other Gla residues at positions 14, 16, 29, and 32.
Factor VII also contains 10 Gla residues in the same positions as in pro-
thrombin. Factor IX contains 12 Gla residues. Because factor IX has an
additional amino acid between its amino terminal Tyr and the first Gla
residue, the numbering of the residues is different from prothrombin and
factor VII. However, the pattern is similar with pairs of adjacent Gla
residues at positions 7 and 8; 20 and 21; and 26 and 27. The six other Gla
residues are at positions 15, 17, 30, 33, 36, and 40. The last two Gla
residues account for 12 Gla residues in factor IX. Factor X contains 11 Gla
residues: pairs of adjacent Gla residues at positions 6 and 7; 19 and 20; and
25 and 26, with five other Gla residues at positions 14, 16, 29, 32, and 39.
Protein C contains 9 Gla residues; pairs of adjacent Gla residues at posi-
tions 6 and 7; 19 and 20; and 25 and 26, and the other Gla residues at posi-
tions 14, 16, and 29. The cartoon structures show helices in magenta, P
sheets in yellow, p bends in blue, and Ca2+ ions in gray. The space-filling
dot surfaces for the residues of the Gla domains are standard CPK colors.
Hepatic Vitamin K Metabolism
o
X
Sites of warfann action
^
Thioredoxin
/
Adapted from
Suttie
1994
Ttnoredoxin Reductase 7
C H A P T E R 3 6 , F IG U R E 2 2
Hepatic vitamin K metabolism. Oral anti-
coagulant drugs act indirectly on the process of glu carboxylation of the vita-
min K dependent proteins. The vitamin K antagonists block the reduction of
the reaction intermediate, vitamin K-epoxide, that results in the accumula-
tion 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 non-carboxylated 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).
