Biology of Disease

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Cleaved by

thrombin

Fibrinogen

Figure 13.10 The structure of fibrinogen.

Fibrinogen has a Mrabout 340 000 and consists

of two units, each containing three polypeptides

(A,B,G   joined together at their N-terminal ends

by a number of disulfide bonds. Short lengths of

the amino terminal regions of the two A and two

B polypeptides project outwards and cleavage

of these by thrombin, as indicated, allows the

resulting fibrin molecules to aggregate to form a

‘soft clot’. This is subsequently strengthened by

the cross-linking action of Factor XIIIa which is a

transglutaminase.

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Factor

number

Name Active form/

function

Associated diseases

I fibrinogen fibrin subunit afibrinogenemia (uncommon)

II prothrombin serine protease defective function (extremely rare)

III* tissue factor receptor –

IV Ca2+ –

V labile factor cofactor –

VI initially wrongly identified, now known to be Va

VII proconvertin serine protease deficiency known (but rare)

VIII antihemophilia cofactor hemophilia A (classical hemophilia,

factor see main text)

IX Christmas factor serine protease Christmas disease (hemophilia B)

X Stuart-Prower

factor

serine protease deficiency known (but extremely

rare)

XI plasma thromboplastin

antecedent

serine protease rare, primarily in Ashkenazi Jews

XII Hageman factor serine protease –

XIII fibrin stabilizing factor

prekallikrein

von Willebrand factor

(vWF)

highMrkininogen

transglutaminase

precursor of kallikrein,

a serine endopeptidase

rare, poor wound healing, scarring

vWB disease (up to 125 in 10^6 )

*factor III is used as a synonym for thromboplastin, a mixture of tissue factor and phospholipid.

Table 13.3Clotting factors

13.4 Hemostasis and Blood Clotting

The circulatory system is self-sealing. Hemostasis rapidly stops all but the

most catastrophic bleeding in normal individuals. If the lining of a blood vessel

is damaged, eventually a platelet plug is formed that prevents further blood

loss. Blood clotting is then initiated leading to the deposition of fibrin and the

formation of a clot to seal the wound. Wound healing can then begin.

Blood clotting occurs in one of two pathways, the so-called intrinsic and

extrinsic pathways. These pathways each have a number of unique reactions

but, in the end, both pathways activate the final clotting stage, which is the

formation of fibrin. The clotting pathways involve a group of plasma proteins

that act in sequence, each activating the next in line. The end result is the

conversion of soluble fibrinogen to the insoluble fibrin, which polymerizes to

form a clot at the site of the damage and critically not elsewhere (Figure 13.10).

About 20 plasma proteins or plasma clotting factors are produced by the liver

and circulate in the blood as inactive proteins. They were called factors long

before anything was known of their chemical nature. They are identified by

Roman numerals although some of them also have common names (Table

13.3). However, their numbering is unfortunately not in a logical order with