Terminal steps of coagulation pathway

Both intrinsic and extrinsic pathways generate activated factor X. This protease, in turn, catalyses the proteolytic conversion of prothrombin (factor II) into thrombin (IIa). Thrombin, in turn, catalyses the proteolytic conversion of fibrinogen (I) into fibrin (Ia). Individual fibrin molecules aggregate to form a soft clot. Factor XIIIa catalyses the formation of covalent crosslinks between individual fibrin molecules, forming a hard clot (Figures 12.3 and 12.4).

Prothrombin (factor II) is a 582 amino acid, 72.5 kDa glycoprotein, which represents the circulating zymogen of thrombin (IIa). It contains up to six y-carboxyglutamate residues towards its N-terminal end, via which it binds several Ca2+ ions. Binding of Ca2+ facilitates prothrombin binding to factor Xa at the site of vascular injury. The factor Xa complex then proteolytically

Aggregation

Hard clot

Soft clot

Figure 12.3 Overview of the blood coagulation cascade, with emphasis upon the molecular detail of its terminal stages. Refer to text for specific detail

Covalent crosslinking

Aggregation

Hard clot

Soft clot

Figure 12.3 Overview of the blood coagulation cascade, with emphasis upon the molecular detail of its terminal stages. Refer to text for specific detail

Figure 12.4 Terminal steps of a blood clot (haemostatic plug): cross-linked fibrin molecules bind together platelets and red blood cells congregated at the site of damage, thus preventing loss of any more blood

, Thrombin

Figure 12.5 Proteolytic cleavage of prothrombin by factor Xa, yielding active thrombin. Although prothrombin is a single-chain glycoprotein, thrombin consists of two polypeptides linked by what was originally the prothrombin intrachain disulfide bond. The smaller thrombin polypeptide fragment consists of 49 amino acid residues, and the large polypeptide chain contains 259 amino acids. The N-terminal fragment released from prothrombin contains 274 amino acid residues. Activation of prothrombin by Xa does not occur in free solution, but at the site of vascular damage cleaves prothrombin at two sites (arg274-thr275 and arg323-ile324), yielding active thrombin and an inactive polypeptide fragment, as depicted in Figure 12.5.

Fibrinogen (factor I) is a large (340 kDa) glycoprotein consisting of two identical tri-polypeptide units, a, P and y Its overall structural composition may thus be represented as (a P y)2.

The N-terminal regions of the a and P fibrinogen chains are rich in charged amino acids, which, via charge repulsion, play an important role in preventing aggregation of individual fibrinogen molecules. Thrombin, which catalyses the proteolytic activation of fibrinogen, hydrolyses these N-terminal pep-tides. This renders individual fibrin molecules more conducive to aggregation, therefore promoting soft clot formation. The soft clot is stabilized by the subsequent introduction of covalent cross-linkages between individual participating fibrin molecules. This reaction is catalysed by factor Xllla.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

Get My Free Ebook


Post a comment