Method of treating heparin-induced thrombocytopenia

Details Method of treating heparin-induced thrombocytopenia Method of treating heparin-induced thrombocytopenia

2001-05-11

2004-06-01

Weber, Jon P. (Department: 1651)

Drug, bio-affecting and body treating compositions

Enzyme or coenzyme containing

Hydrolases

C435S212000

Reexamination Certificate

active

06743426

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to medical science particularly the treatment of heparin-induced thrombocytopenia with protein C.
BACKGROUND OF THE INVENTION
Protein C is a vitamin K dependent serine protease and naturally occurring anticoagulant that plays a role in the regulation of hemostasis by inactivating Factors Va and VIIIa in the coagulation cascade. Human protein C circulates as a 2-chain zymogen, but functions at the endothelial and platelet surface following conversion to activated protein C (aPC) by limited proteolysis with thrombin in complex with the cell surface membrane protein, thrombomodulin.
In conjunction with other proteins, aPC functions as perhaps the most important down-regulator of blood coagulation resulting in protection against thrombosis. In addition to its anti-coagulation functions, aPC has anti-inflammatory effects through its inhibition of cytokine generation (e.g. TNF and IL-1) and also exerts profibrinolytic properties that facilitate clot lysis. Thus, the protein C enzyme system represents a major physiological mechanism of anti-coagulation, anti-inflammation, and fibrinolysis.
Heparin is a frequently used anti-coagulant that prolongs the clotting time of blood by preventing the formation of fibrin by its ability to catalyze anti-thrombin-III (AT-III). The heparin-AT-III complex inactivates thrombin and other proteases of the coagulation cascade.
Heparin is administered parenterally in vascular surgery and in the treatment of postoperative thrombosis and embolism. Approximately 1 to 30% (average 5%) of patients receiving heparin have an immunologic reaction resulting in heparin-induced thrombocytopenia (HIT) [Phillips, et al., Annals of Pharmacotherapy, 28: 43-45, 1994]. These adverse effects may develop into a syndrome known as heparin induced thrombocytopenia and thrombosis syndrome (HITTS). Patients with HITTS are at substantial risk for a debilitating or life-threatening venous or arterial thrombosis, such as lower limb swelling or ischemia, stroke, or myocardial infarction, with a reported combined mortality and major morbidity of 25% to 37% [Boshkov, et al.,
British Journal of Haematology
, 84:322-328, 1993].
HIT is one of the most important drug-induced immune thrombocytopenic disorders that a physician must manage. Its importance is evident for several reasons, including, the high prevalence of heparin usage; the high frequency of thrombocytopenia; the lack of a better alternative anti-thrombotic agent; and the concomitant occurrence of thrombotic complications. It has been clearly demonstrated that HIT is caused by the activation and aggregation of platelets induced by heparin-specific antibodies. Activated platelets have potent procoagulation activity, and by this mechanism, fibrin thrombus (which appear macroscopically pale white, consequently the “white clot syndrome”) may form [Arthur, et al., Pathology, 17:82-86, 1985]. The treatment of HIT includes the discontinuation of heparin and the administration of alternative anti-thrombotic therapy. Unfortunately, the patients are undergoing heparin therapy because they have thrombo-emboli or are at high risk of thromboembolism and discontinuing heparin leaves them without anti-coagulation. Agents such as low molecular weight heparins, the heparinoid Org 10172, hirudin, or warfarin, have been administered after cessation of heparin therapy [Ratnoff, et al., Disorders of Hemostasis, Chapter 8, W. B. Sanders Company, Philadelphia; Laposata et al., Arch Pathol Lab Med, 22:799-807, 1998]. However, such therapy is not effective in many patients because Org 10172 and low-molecular weight heparins can cross react with the heparin-specific antibodies of some patients with heparin induced thrombocytopenia. Furthermore, warfarin takes several days to take effect and has also been linked to venous limb gangrene when administered to patients with HIT [Warkentin et al., Ann Intern Med., 127: 804-812, 1997]. Therefore, a need exists to develop an effective therapy for the treatment of HIT.
The present invention is the first to describe the treatment of HIT with protein C. Protein C, with its anticoagulant and profibrinolytic activities, is useful for the treatment of arterial and venous thrombosis, including the fibrin rich “white clot syndrome”, that occur in HIT patients.
SUMMARY OF THE INVENTION
The present invention provides a method of treating a patient suffering from heparin-induced thrombocytopenia (HIT) which comprises, administering to said patient a pharmaceutically effective amount of protein C.
The present invention further provides a method of treating heparin-induced thrombocytopenia in a patient in need thereof, which comprises administering to said patient a pharmaceutically effective amount of activated protein C such that an activated protein C plasma level of about 2 ng/ml to about 300 ng/ml is achieved.
DETAILED DESCRIPTION OF THE INVENTION
For purposes of the present invention, as disclosed and claimed herein, the following terms are as defined below.
Protein C refers to a vitamin K dependent serine protease with anticoagulant, anti-inflammatory, and profibrinolytic properties which includes, but is not limited to, plasma derived and recombinant produced protein C. Protein C includes and is preferably human protein C although protein C may also include other species or derivatives having protein C proteolytic, amidolytic, esterolytic, and biological (anticoagulant, pro-fibrinolytic, and anti-inflammatory) activities. Examples of protein C derivatives are described by Gerlitz, et al., U.S. Pat. No. 5,453,373, and Foster, et al., U.S. Pat. No. 5,516,650, the entire teachings of which are hereby included by reference.
Zymogen—an enzymatically inactive precursor of a proteolytic enzyme. Protein C zymogen, as used herein, refers to secreted, inactive forms, whether one chain or two chains, of protein C.
Activated protein C or aPC refers to protein C zymogen which has been converted by limited proteolysis to its activated form. aPC includes and is preferably human protein C although aPC may also include other species or derivatives having protein C proteolytic, amidolytic, esterolytic, and biological (anticoagulant or pro-fibrinolytic) activities. Examples of protein C derivatives are noted above in the description of protein C.
HPC—human protein C zymogen.
r-hPC—recombinant human protein C zymogen.
r-aPC—recombinant human activated protein C produced by activating r-hPC in vitro or by direct secretion of the activated form of protein C from procaryotic cells, eukaryotic cells, and transgenic animals or plants, including, for example, secretion from human kidney 293 cells as a zymogen then purified and activated by techniques well known to the skilled artisan and demonstrated in Yan, U.S. Pat. No. 4,981,952, and Cottingham, WO97/20043, the entire teachings of which are herein incorporated by reference.
Plasma derived activated protein C—activated protein C produced by activating plasma HPC as described in Eibl, U.S. Pat. No. 5,478,558, the entire teaching of which is herein incorporated by reference.
Continuous infusion—continuing substantially uninterrupted the introduction of a solution into a vein for a specified period of time.
Bolus injection—the injection of a drug in a defined quantity (called a bolus) over a period of time up to about 120 minutes.
Suitable for administration—a lyophilized formulation or solution that is appropriate to be given as a therapeutic agent.
Unit dosage form—refers to physically discrete units suitable as unitary dosages for human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
Pharmaceutically effective amount—represents an amount of a compound of the invention that is capable of inhibiting sepsis in humans. The particular dose of the compound administered according to this invention will, of course, be determined by the attending physician evaluat

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