F I G U R E 3 6 - 8
(Also see color figure.) Fibrinogen and polymerizing fibrin monomers. The fibrinogen molecule is a 340,000-Da protein
consisting of three pairs of polypeptide chains: two A
chains, two B/i chains, and two
chains. The A and B
designations refer to the two A peptides and two B peptides cleaved from fibrinogen by thrombin to produce the
self-polymerizing fibrin monomer (Fnm), the building block of the fibrin blood clot. The polypeptide chains are linked
together by disulfide bridges between Cy-SH residues of the chains. Only after chemical reduction of the disulfide
bonds are the separate chains of the fibrinogen molecule discernible. Fibrinogen is frequently abbreviated as (Aa, B/S,
y )
The 16-residue A (FPA) and 14-residue B (FPB) peptides are at the N-terminal ends of the A and the B chains,
respectively. The central domain, also identified as the E domain, contains portions of all of the six chains of fibrinogen.
The two terminal domains, the D domains, also contain polypeptide sequences from all six chains.
polypeptide chain that enable it to bind to the platelet re-
ceptors Gplb and GpIIb/IIIa and to collagen in the extra-
cellular matrix.
Membrane Phospholipid Surfaces
In addition to these categories of proteins, the membranes
of damaged cells and activated platelets are components
of the hemostatic system and provide surfaces onto which
the proteinases, proteinase precursors, and cofactor pro-
teins bind. The formation of complexes of proteinase,
proteinase precursor, and cofactor protein is spontaneous
and is very likely triggered by the exposure of the mem-
brane surfaces. The membrane surfaces that are capa-
ble of binding these clotting proteins contain phospho-
lipids normally found only on the interior of the lipid
bilayer cell membrane. The inner membrane phospho-
lipids are phosphatidylserine and other negatively charged
phospholipids. Platelets contain an enzyme that converts
phosphatidylethanolamine to phosphatidylserine upon ac-
tivation of the platelets by thrombin and a protein that
promotes flip-flop of phospholipids to the outer surface.
This coordinated binding of the coagulation proteins to
the inner membrane phospholipids that are exposed as the
result of cell membrane rupture serves to localize the co-
agulation reactions at the hemostatic plug.
36.4 Clotting
Proteolytic cleavage of fibrinogen to fibrin results in trans-
formation of blood from a freely flowing fluid into the
gel-like clot. In this final step of the procoagulant subsys-
tem, thrombin cleaves four peptide bonds in fibrinogen.
Two A fibrinopeptides are removed from the amino
terminal ends of the
chains and two B fibrinopep-
tides are removed from the aminoterminal ends of the
B/3 chains. The other product of fibrinogen proteolysis is
fibrin monomer
(FnIIm). The removal of the
A and B peptides changes the net charge on the cen-
tral domain of the fibrin monomer to net positive from
net negative as it is in fibrinogen. This change fosters
an attractive electrostatic interaction between the posi-
tive central domain and the net negative terminal do-
mains of the FnIIm. Soluble fibrinogen is converted to
fibrin monomers that, after polymerizing, form insoluble
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