1. Blood Clotting

The circulatory system must be self-sealing; otherwise continued loss of blood from even the smallest injury would be life threatening.

Normally, in a process called hemostasis, "blood unmoving", is accomplished through a cascade of events.

1) platelets adhere to damaged blood vessels to form a plug.
This is mediated by von Willebrandt factor, a glycoprotein of 225 kD in mass:

von Willebrandt factor

 

The protein binds to a specific receptor on the platelet membrane AND to the collagen and other components of the subendotheials membrane. Then coagulation occurs. A blood clot (thrombus) forms by a cascade of proteolytic reactions involving at least 20 different substances. Most are liver-synthesized plasma glycoproteins.

 

Initial Purpose	Substance	Abbreviation	Is Transformed To	Final Purpose
The soluble form of fibrin.	Fibrinogen	Factor 1	Fibrin	Blood Clot
The precursor of thrombin	Prothrombin	Factor 2	Thrombin	Catalyses conversion of Fibrinogen to Fibrin
	Thromboplastin	Factor 3
	Ca2+	Factor 4
	Proaccelerin	Factor 5
	Proconvertin	Factor 6
	Antihemophilic Factor	Factor 7
	Christmas Factor	Factor 8
	Stuart Factor	Factor 9
	Plasma thromboplastin antecedent (PTA)	Factor 10
	Hageman Factor	Factor 11
	Prekallikrien	Factor 12
	High MW kininogen (HMK)	Factor 13

 

2) Coagulation takes place via the following pathway.

A. Fibronogen and Its Conversion to Fibrin

Blood clots consist of arrays of cross-linked fibrin that form an insoluble fibrous network. Fibrin is made from the soluble plasma protein fibrinogen (factor I) through a proteolytic reaction catalysed by the serine protease thrombin. Fibrinogen comprises 2 to 3% of plasma protein.

Thrombin cleaves the Arg-X peptide bond where X is a Glycine in most species, enabling fibrinogen to polymerize into fibers.

Fibrin-Stabilizing Factor (FSF) or Factor XIIIa then stabilizes fibrin clots by cross linking.

FSF joins the C-terminal segments of adjacent gamma chains by forming isopeptide bonds between the side chains of a glutamine on one gamma chain and a lysine on another.

The alpha chains are similarly cross-linked but at a slower rate. FSF deficient individuals tend to bleed.

Ca2+ is essential to several stages of the blood clotting cascade.

B. Thrombin Activation and the Function of Vitamin K

Human thombin is synthesized as a 579 residue prothombin II which is activated by two proteolytic cleavages catalysed by activated Stuart factor Xa the product of the preceding step of the clotting cascade.

Vitamin K Is an Essential Cofactor in the Synthesis of gamma-Carboxyglutamate.

Prothrombin, as well as the homologous factors 7, 9, and 10, is synthesized in the liver in a process that requires an adequate dietary intake of vitamin K. Lack of vitamin K or the presence of a competitive inhibitor such as dicoumarol, or warfarin, causes the production of an abnormal prothrombin that is activated by factor Xa at only 1 to 2% of the normal rate. NMR studies have established that normal prothrombin contains gamma-carboxyglutamate (Gla) residues, 10 of which occur between resdies 6 and 32 in human prothrombin. Abnormal prothrombin contains Glu in palce of these Gla residues. Vitamin K must therefore be a cofactor in the posttranslational conversion of Glu to Gla.