Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-01-22
2000-07-04
Zitomer, Stephanie W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 21, 514802, 514822, 530381, A01N 3718, A61K 3514
Patent
active
060839058
DESCRIPTION:
BRIEF SUMMARY
This application claims the benefit of prior filed copending International Application PCT/NL95/00149 having an International filing date of Apr. 21, 1995 which claimed priority for copending European Patent application 94201116.4, filed Apr. 22, 1994.
FIELD OF THE INVENTION
The present invention relates to the field of the detection and/or treatment of (genetic) disorders which lead to defects in the blood coagulation cascade, which may lead to either bleeding disorders or thrombotic disorders. The invention relates specifically to the detection of genetic disorders which lead to said haemostatic disorders and to treatment of said disorders as well as treatment or correction of bleeding tendencies.
BACKGROUND OF THE INVENTION
Maintenance of normal hemostasis requires a delicate balance of the pro- and anti-coagulant mechanisms that are involved in blood coagulation. A dysfunction of one of the proteins may result in bleeding tendencies or thrombotic events. A molecular defect in one of the pro-coagulant proteins is commonly associated with bleeding tendencies, that can be overcome by replacement therapy. This is best illustrated by the bleeding disorder haemophilia A, which is associated with a functional absence of Factor VIII, an essential cofactor in the conversion of Factor X to factor Xa, by activated Factor IX (Kane and Davie. 1988. Blood, vol. 71, 539-555). Diagnosis of bleeding tendencies is performed by simple laboratory tests which are well known in the art. In addition, more specific assays have been developed employing chromogenic substrates in conjunction with purified coagulation Factors that are used to monitor the precise levels of several pro-coagulant proteins. Currently, adequate diagnostic techniques are available to monitor the majority of deficiencies observed in patients with bleeding tendencies.
The anticoagulant pathway, ultimately resulting in the inactivation of the pro-coagulant cofactors V and VIII, by APC, has been described in considerable detail (Esmon, C. T. 1993, Thromb. Haemost. vol. 70, 29-35). Protein S has been implicated as a cofactor in the inactivation of both Factor V and VIII, although the effect of protein S on the catalytic efficiency of cleavage of both Factor V and VIII is relatively small (Koedam et al., 1988, J. Clin. Invest. vol. 82, 1236-1243; Kalafatis and Mann. 1993. J. Biol. Chem., vol. 268, 27246-27257). Functional absence of one of the proteins involved in the anticoagulant pathway is commonly associated with thrombosis. Molecular defects in several proteins involved in the anti-coagulant pathway have found to be associated with thrombotic events. Homozygous protein C deficiency clearly is associated with severe thrombotic events which can be corrected by replacement-therapy (Dreyfus et al., 1991, N. Eng. J. Med. vol. 325, 1565-1568). Heterozygous protein C deficiency has also been established as an increased risk for thrombosis (Bertina et al., 1982, Thromb. Haemost. vol. 48, 1-5), although additional factors seem to be involved in at least some cases (Miletich et al. 1987, N. Eng. J. Med. vol. 317, 991-996). Similar to protein C, protein S deficiency is associated with an increased risk of thrombosis (Comp et al., 1980, J. Clin. Invest. vol. 74, 2082-2088). Relatively rare genetic defects in anti-thrombin III, fibrinogen and plasminogen have also been implicated in thrombosis. Taken together, several deficiencies of proteins involved in the anti-coagulant pathway have been associated with an increased risk of thrombosis. However, the deficiencies outlined above offer an explanation in no more than 10 to 30% of patients suffering from thrombo-embolic disease, while the remainder of the cases remains unexplained (Heijboer et al., 1990, N. Eng. J. Med. 22, 1512-1516). Thus, diagnosis of patients suffering from thrombo-embolic disease is inadequate in 70 to 90% of the cases. Recent advances have decreased the percentage of unexplained thrombosis to 40 to 60%. Dahlback and co-workers have observed resistance to APC in a patient suffering from mult
REFERENCES:
Dahlback, Haemostasis 24 (2): 193-151 (abstract), 1994.
Bertina et al., Nature 369:64-67, May 5, 1994.
Zoller et al., The Lancet 343:15361538.
B. Dahlback et al., "Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of facor V", Proceedings of the National Academy of Science of USA, vol. 91, Feb. 1994, pp. 1396-1400.
P.J. Fay et al., "Activated Protein C-catalyed Inactivation of Human Factor VIII and Factor VIII", Journal of Biological Chemistry, vol. 266, No. 30, Oct. 1991, pp. 20139-20145.
M. Kalafatis et al., "Role of the Membrane in the Inactivation of Factor Va by Activated Protein C*", Journal of Biological Chemistry, vol. 268, No. 36, Dec. 25, 1993, pp. 27246-27257.
B. Dahlback et al., "Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated Protein C: Prediction of a cofactor to activated protein C", Proceedings of the National Academy of Science of USA, vol. 90, Feb. 1993, pp. 1004-1008.
J. Voorberg et al., "Association of idiopathic venous thromboembolism with single point-mutation at Arg.sup.506 of factor V" The Lancet, vol. 343, Jun. 18, 1994, pp. 1535-1536.
Mertens Koenraad
van Mourik Jan Aart
Voorberg Johannes Jacobus
Stichting Sanquin Bloedvoorziening
Zitomer Stephanie W.
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