Page 2129 - Hematology_ Basic Principles and Practice ( PDFDrive )

1890 Part XII Hemostasis and Thrombosis

A
Cell-bound cofactors
Thrombomodulin Chondroitin sulfate
adducts
Lectin
6 homology 149 227 462 s
domain EGF domains
1 2 3 4 5 6 COOH

Extracellular Transmembrane Cytoplasmic
1 499 521 557

Tissue Factor
49 57
s s

COOH

s s
186 209
Extracellular Transmembrane Cytoplasmic
1 220 242 263
B
Soluble plasma procofactors
Factor VIII

NH 2 A 1 A 2 A 3 C 1 C 2 COOH
B

Factor V

NH 2 A 1 A 2 A 3 C 1 C 2 COOH
B
Fig. 126.5 CELL-BOUND AND SOLUBLE COFACTOR STRUCTURES. (A) Cell-bound cofactors:
tissue factor and thrombomodulin. Tissue factor is composed of an extracellular domain (residues 1–219), a
transmembrane domain (residues 220–242), and a cytoplasmic domain (residues 243–263). Two disulfide
bonds (-S-S-) and the sites of the three carbohydrate moieties (CHO) are identified by amino acid residue.
One cysteine (C ) contains a thiol ester linkage to a fatty acid. Tissue factor, which is the cofactor for factor
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VIIa in the extrinsic tenase complex, is exposed on the subendothelial surface after injury. Thrombomodulin
is an endothelial cell-surface glycoprotein composed of five distinct domains. These include a lectin-like
domain (residues 6–149), a domain containing six EGF–like regions (residues 227–462), a small extracellular
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domain rich in threonine and serine residues (S and S have been identified as sites of chondroitin sulfate
adducts), a membrane-spanning region (residues 499–521), and a cytoplasmic tail (residues 522–557). There
are nine known glycosylation sites (CHO) on the thrombomodulin molecule. Thrombomodulin functions as
the cofactor in the protein Case complex and assists in the generation of activated protein C. (B) Soluble
plasma procofactors: factor VIII and factor V. The linear domain structures (A1–A2–A3–C1–C2) are illustrated
with horizontal arrows bracketed by the beginning and ending amino acid number. Thrombin (IIa) and
activated protein C cleavage sites are shown with vertical arrows. The B regions (factor V, residues 709–1545;
factor VIII, residues 740–1689) are represented by the crosshatched regions. EGF, Epidermal growth factor.

also has an antifibrinolytic role via activation of the fibrinolysis Soluble Plasma Procofactors
inhibitor, thrombin-activatable fibrinolysis inhibitor (TAFI; see
reviews listed in the References 53–56 ). Factor V
Thrombomodulin activity on the surface of endothelial cells is Factor V is a large single-chain glycoprotein (GP) that circulates in
decreased by inflammatory cytokines, 57,58 and this decrease may human plasma (see Table 126.1 and Fig. 126.5B) and is also con-
contribute to the hypercoagulation characteristic of inflammatory tained in the α-granules of human platelets, with approximately
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states. 18%–25% of the total factor V found in platelets. The procofactor