Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving blood clotting factor
Patent
1999-12-13
2000-09-26
Leary, Louise N.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving blood clotting factor
435 4, C12Q 100, C12Q 156
Patent
active
061241105
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to a method to determine activated blood clotting factors in plasma and plasma derivatives.
When plasma is stored at low temperatures or in the course of purification processes, activated blood clotting factors can occur in the plasma or in plasma derivatives. Generally, blood clotting factors are enzymatically inactive proenzymes that are converted into their biologically active form through limited proteolytic splitting. Thus, at the end of the clotting cascade thrombin (activated factor II-factor IIa), which splits fibrinogen, results from prothrombin (factor II), for example. In addition, thrombin activates factor XIII, which bonds fibrin to a stable coagulate. In most cases, this physiological activation is desired.
Not desired, however, is an artificial activation of blood clotting factors in stored plasma or in the production of a purified prothrombin complex of plasma, containing factors II, VII, IX, X as therapeutically effective components. When treating patients with severe coagulation deficiencies with prothrombin complex concentrates, e.g., through blood loss at serious operations, thrombo-haemorrhagic complications, whose cause is unknown, may occur as undesired side effects. It is certain, however, that the risk of such complications is increased through tissue thromboplastin, which circulates in a pathologically high concentration in the circulatory system of a patient after a severe operation. It is also suspected that activated factors IX or X in prothrombin complex concentrates contribute to an increased thromboses risk.
For this reason, laboratory tests are performed on the mentioned plasmas and plasma derivatives to verify the absence of activated factors. For plasma, a method is known for selective measurement of factor VIIa in the presence of factor VII (U.S. Pat. No. 5,472,850). In the patent publication, an assay for factor VIIa is described which uses a truncated (shortened) tissue factor tTF. The tissue factor is an integral membrane protein that binds both factor VII and factor VIIa with great affinity and in doing so initiates the clotting cascade. In addition, the complex consisting of factor VIIa and tissue factor catalyzes the activation of factor VII to factor VIIa. The patent describes a mutant form of the tissue factor, whose amino acid sequence is truncated by the portion of the protein that is responsible for the bonding to the membrane. The now soluble tissue factor tTF can bind factor VIIa and is fully active in a coagulation test. However, it lost its capability for auto-catalysis of factor VII to factor VIIa. Thus, with the use of such a soluble mutant tissue factor in a coagulation test, it is possible to determine selective factor VIIa in the presence of factor VII in plasma. However, the test is relatively complicated to carry out and offers only a result stating the presence of factor VIIa.
With prothrombin complex PPSB, a coagulation test is known and described under the designation NAPPT (non-activated partial prothrombin time) is stipulated as standard test (cf. H. S. KINGDON et al.; "Potentially Thrombogenic Materials in Factor IX Concentrates"; Thromb. Diath. Haemorrh. 1975; pp. 617-631).
In this test, the clotting time of plasma is measured in the presence of the sample to be analyzed in the absence of substances such as kaolin that initiate coagulation in vitro. In the absence of activating factors, the clotting time is about 150 sec; in the presence of activating factors, the clotting time is shortened. However, this test is not very sensitive and does not indicate activating factors in all instances. A critique of this test can be found in the article by C. V. PROWSE and A. E. WILLIAMS; "A Comparison of the in vitro and in vivo Thrombogenic Activity ... "; Thromb. Haemost. 1980, pp. 81-86.
SUMMARY OF THE INVENTION
This poses the task, and the present invention has the objective, of presenting a more precise and more sensitive test to determine the presence of activating factors where said tes
REFERENCES:
patent: 5059525 (1991-10-01), Bartl et al.
patent: 5472850 (1995-12-01), Morrissey
patent: 5677162 (1997-10-01), Zou et al.
patent: 5972681 (1999-10-01), Morita
Gesien Beate
Wober Guenter
DRK-Blutspendedienst Nordrheinwestfalen gGmbH
Leary Louise N.
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