SECTION 36.4

Clotting

851

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

a

chains, two B/i chains, and two

y

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 )

2

-

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

Act

chains and two B fibrinopep-

tides are removed from the aminoterminal ends of the

B/3 chains. The other product of fibrinogen proteolysis is

designated

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