Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1998-02-20
1999-11-30
Marschel, Ardin H.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 912, 435 911, 536 221, C12Q 168, C12P 1934, C07H 2102
Patent
active
059940808
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
Blood clot formation is the key event in acute manifestations of vascular diseases like myocardial infarction, thrombi in peripheral blood veins and cerebral infarction. Apart from increased coagulation, failure in blood clot lysis can induce undesired coronary thrombosis. In many cases a longer or shorter period of time has been discerned during which the clot is formed and subsequently is dissolved prior to the permanent closure by the clot. During this phase of closure and reopening of blood vessels the clot dissolving or anticoagulant system, the fibrinolysis plays an important role. The exact nature is yet unclear, however in a definite infarction the clotting impulse has clearly been stronger than the reaction of the fibrinolytic system to react i.e. to dissolve the clot.
The proteolytic enzyme plasmin is essential for degradation of fibrin clots. Tissue-type plasminogen activator (t-PA) is a serine protease that converts plasminogen into plasmin. T-PA is widely accepted now as a therapeutic agent in the vast majority of cases of acute myocardial infarction.sup.1. When given in high doses it degrades occlusive thrombi promptly. T-PA is regarded as one of the most important activators of fibrinolysis and is known to have antithrombotic activity (There are numerous t-PA patent publications and other publications such as ref. 25 and 26 that illustrate this.)
Recent longitudinal studies have indicated that on the one hand decreased endogenous t-PA activity levels in plasma may be associated with increased risk of myocardial infarction in patients with angina pectoris.sup.2, and with recurrent myocardial infarction.sup.3. On the other hand increased concentrations of endogenous t-PA antigen in plasma have also been associated with increased risk of recurrent myocardial infarction.sup.4, cardiovascular events in patients with angina pectoris and coronary artery stenosis.sup.5,6, and with risk of myocardial infarction in healthy males.sup.7. It has been suggested in support of the latter that the significant positive association between concentrations of t-PA antigen and the inhibitor, of free t-PA, the socalled plasminogen activator inhibitor (PAI-1) antigen.sup.8, reflects that increased concentrations of t-PA antigen can also reflect circulating t-PA/PAI-1 complex to a large degree. Thus a high concentration of t-PA antigen could indicate a reduced rather than an enhanced fibrinolytic activity. The increase in production of t-PA inhibitor, PAI-1 could largely neutralize t-PA activity. Thus although an increase in the t-PA concentration would largely be attributed to the inactive complex of t-PA-PAI-1 in this manner increased PAI-1 could manifest itself and thus become the actual cause of the risk. Indeed increased plasma concentrations and PAI-1 activity have been indicated as predictive of risk. Recently heredity for increased PAI-1 has also been indicated as predictive of risk. Eriksson P..sup.24 et al. e.g. describe genotyping for the 4G/5G polymorphism in the PAI-1 promoter region with an allele specific oligonucleotide melting technique known per se. The 4G allele was associated with a higher plasma PAI-1 activity. Thus this group provided evidence for an independent etiological role of PAI-1 in myocardial infarction.
In Iacoviello L. et al .sup.23 an association between family history of thrombosis and acute myocardial infarction (AMI) has been suggested. Moreover, changes in fibrinolysis are suggested as being correlated with the risk of ischemic vascular disease. T-PA levels in a group of patients with AMI, selected from the GISSI-2 study population were studied. Patients with a family history of thrombosis (at least two first degree relatives affected by MI and/or stroke before 65 years) were studied in parallel with MI patients with no family history of thrombosis 6 months after the AMI episode. The results of the study were that the levels of t-PA antigen in the group with family history of thrombosis (10.1.+-.6 ng/ml, mean.+-.SE.n=53) did not differ significantly from the
REFERENCES:
Iacoviello et al., Fibrinolysis, 8:1:49, 1994.
Ludwig et al., Human Genetics, 88:388-392, 1992.
Degen et al., Journal of Biological Chemistry, 261:15:6972-6985, 1986.
Iacoviello et al., Fibrinolysis, 10:Sup 2:13-16, 1996.
Bom et al., Fibrinolysis, 10:Sup 3:3, 1996.
Bom et al., Circulation, 92:8 (Sup 1):30-31, 1995.
van den Eijnden-Schrauwen et al., Thrombosis and Haemostasis, 74:4:1202, 1995.
Tishkoff et al., Human Genetics, 97:759-764, 1996.
Grobbee Diederick Egberstus
Kluft Cornelis
Akzo Nobel N.V.
Gormley Mary E.
Marschel Ardin H.
Tung Joyce
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