Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving blood clotting factor
Patent
1992-01-14
1995-08-08
Wityshyn, Michael G.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving blood clotting factor
435 4, 435226, 436 69, 436 86, 514 21, 530393, C12Q 156, G01N 3386, G01N 3300, A61K 3700
Patent
active
054398029
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the assay of components in the blood coagulation and fibrinolysis systems, and particularly to the assaying or determination of the functional activity of certain proteins included in these systems, namely the plasma proteins designated Protein C and Protein S.
One purpose of the blood coagulation or clotting process is to effectively stop bleeding. This process involves a complicated so-called enzymatic cascade of enzyme-activating reactions initiated by contact activation, e.g. through an injured blood vessel, of a proenzyme, Factor XII (the word Factor is abbreviated hereinafter to F, as is normal practice) to an active enzyme FXII.sub.a (the suffix "a" stands for active and this labelling method is used generally in the following text). FXII.sub.a catalyzes a subsequent activation reaction of proenzyme to enzyme and the blood coagulum or blood clot is finally formed through a series (cascade) of enzyme activations, by the conversion of soluble fibrinogen to insoluble fibrin. The many activation stages, i.e. the cascade of reactions, contribute to the rapid formation of the blood clot, so as to stop bleeding rapidly.
The reverse process, i.e. the lysis of formed blood clots, so-called fibrinolysis also comprises a similar enzyme reaction cascade, wherein plasmin is formed, in the ultimate stage of the cascade. The plasmin formed functions to degrade the clot, i.e. the fibrin, quickly into smaller, soluble fragments, by proteolysis.
These systems incorporate a large number of factors, as will be described in more detail herebelow.
Enhanced or reduced quantities of one or more of these factors in the blood, due to acquired or inherited disorders in the coagulation and/or fibrinolysis systems will often lead to pathological conditions, which may be fatal, and in the case of the individual may, for instance, mean a predisposition to the formation of arterial and/or venous thrombosis (or blood clots). Reduced quantities of functionally active antithrombin and plasminogen and enhanced quantities of FVII, fibrinogen and plasminogen activator inhibitors PAI-1 are examples of disorders which can lead to thrombosis (or blood clots).
Recently, two novel proteins, designated Protein C (PC) and Protein S (PS) have been identified in plasma. Similar to the well-known antithrombin, these proteins, which are vitamin K dependent, have an anticoagulating activity, said proteins coacting such that Protein S (molecular weight 80 kD) will stimulate the activity of activated Protein C and therewith both counteract clot formation and promote degradation of clots that have already formed. Reduced quantities of these proteins, or of one of said proteins, will also lead to disorders in the coagulation and fibrinolysis systems. The significance of Protein S has been confirmed by studies carried out on the protein. On the basis of these studes, it is believed that in the case of patients afflicted with deep venous thrombosis and younger than 50 years of age, the clinically manifested thrombosis in 5-8% of cases is due to an inherited deficiency of Protein S, whereas an inherited deficiency of antithrombin is believed to be responsible for only about 3% of all cases.
Considerable benefit would therefore be gained if it were possible to assay, or. determine the content of, both or one of the proteins as a matter of routine, since this will enable the predisposition of an individual to the formation of such thrombosis to be established more easily and to enable prophylaxis and/or therapeutic treatment to be administered in good time.
These plasma proteins, PC and PS, influence the formation of FX.sub.a and thrombin, by coacting to cleave the cofactors FV.sub.a and FVIII.sub.a, necessary for effecting formation of thrombin. In order to facilitate an understanding of the function of Protein S and Protein C (in an activated form), a brief description is given below of the essential parts of the coagulation system, of which the stages from and including activation of FXII are shown in Schedule 1: ##STR1##
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Stedmos Medical Dictionary, 24 Edition, (1982), p. 1448.
Bartl et al (Abstract); Chem. Abstract; 89(1):2596K (1978).
Chromogenix AB
Leary Louise N.
Wityshyn Michael G.
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