Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2001-01-10
2004-11-30
Wax, Robert A. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C514S002600, C514S822000
Reexamination Certificate
active
06825323
ABSTRACT:
TECHNICAL FIELD
The invention relates to pharmaceutical compositions and methods of treatment that promote hemostasis, slow or stop internal and/or external bleeding at sites of blood vessel injury. The compositions contain factor VIIa and fibrinogen.
BACKGROUND ART
Hemorrhage is the most common cause of death among injured or treated individuals including those who die prior to reaching care, who die in emergency medical care, e.g. emergency room, or who die in the operating room (Holcomb J B, Pusateri A E, MacPhee M J, Hess J R. New technologies in hemorrhage control. Current Opinion in Critical Care. 1997 December; 3:488-493; Holcomb J B, Pusateri A E, Harris R A, Reid T J, Hess J R, MacPhee M J. Dry fibrin sealant dressings reduce blood loss and improve survival in hypothermic coagulopathic swine with grade V liver injury. J Trauma. 1999 August; 46:233-242). The most common causes of death of individuals in post-operative critical care are those involving sequellae of poorly controlled hemorrhage and shock. In the prehospital setting, most internal bleeding is not accessible for direct intervention. In the hospital setting, there are sources of bleeding which cannot be immediately controlled with the best surgical techniques, e.g. deep liver injuries with liver vein disruption, pelvic ring fractures with direct bone bleeding, pelvic venous plexus tears, etc.
Blood coagulation is a complex process that involves formation of a preliminary clot by platelets followed by a cascade of events involving several factors that eventually leads to strengthening of the clot. A critical step in this process is the production of thrombin, a proteolytic enzyme. This enzyme is involved in aggregation of platelets and in the activation of cleavage of fibrinogen into fibrin. Fibrin forms much of the stabilizing matrix for the platelet plug. Through a multistep cascade, various blood coagulation proenzymes and procofactors that circulate in the blood are sequentially or simultaneously converted to their activated forms (designated by a lower case “a”, e.g. factor VIIa). The proenzymes are generally inactive and are converted to the active form by proteolytic enzymes present in the cascade. This cascade involves two separate multistep pathways which lead to the conversion of prothrombin to thrombin.
The first pathway is rapid and is known as the extrinsic pathway. This pathway involves the activation of coagulation factor VII to factor VIIa (Jack Hirsh and Elizabeth A. Brain, Hemostasis and Thrombosis-A Conceptual Approach. (2d ed. 1983)). Coagulant factor VII circulates in the blood at a concentration of 0.5 &mgr;g/ml plasma. The vast majority of circulating factor VII is inactive with about 1% of factor VII being in an active form. Activation of circulating factor VII requires exposure of factor VII to several cofactors. Factor VIIa, the active form, has little enzymatic activity until it complexes with tissue factor. Complex formation occurs at sites where the blood vessel endothelium is damaged or where underlying tissues, rich in tissue factor, is exposed, Also platelet activation exposes Factor VIIa to tissue factor that is normally stored internally in platelets. White blood cells will express tissue factor in response to inflammatory mediators and thereby cause the complex to be formed. Thus, seemingly large amounts of factor VIIa can circulate with little effect, but can be highly active at the requisite site by formation of the complex with tissue factor.
Activated factor VIIa converts factor X to factor Xa which in turn converts prothrombin to thrombin in the presence of the cofactors factor V, calcium ions and phospholipid.
The second, slower coagulation cascade is termed the intrinsic pathway and also involves factor VIIa as well. The intrinsic pathway comprises a series of reactions that leads to the activation of thrombin via activation of the Hageman factor (factor XII). This leads to the activation of factor XI which in turn results in the activation of factor IX in the presence of phospholipid. The activated factor IX (IXa), in the presence of factor VIII and phospholipid activates factor X, which cleaves prothrombin into the active form, thrombin. Factor VII is converted to the active form either by factor Xa in the presence of calcium and phospholipids, or by factor II (thrombin). In contrast to the extrinsic pathway, which leads to rapid blood coagulation at the point of injury, the intrinsic pathway strengthens the clot.
Factor VII has been purified and characterized as a single-chain glycoprotein of approximately 47,000 Daltons. It is converted to the active form by cleavage of an arginine-leucine bond which creates two chains held together by disulfide bonds (U.S. Pat. No. 5,504,067). Factor VIIa is more active than Factor VII by 100-fold. Efforts to use isolated factor VIIa in individuals with severe bleeding episodes have produced positive results, e.g. diminished blood loss of up to 50%. Recombinant factor VIIa has also been administered to individuals with various bleeding disorders, e.g. coagulation abnormalities with beneficial results.
Recombinant factor VIIa was also administered to a 19 year old Israeli soldier shot in the abdomen (Blauhut B. Indications for prothrombin complex concentrates in massive transfusions. Thromb Res 1999; 95(4 Supp 1):S63-9.). This patient arrived at the hospital in shock with a large paraspinal exit wound. Upon abdominal exploration, the patient was found to have multiple organ injuries and a laceration of the inferior vena cava. Surgeons rapidly repaired the injuries and tied off the inferior vena cava. At this point, the patient had received 40 units of blood. The patient was cold and coagulopathic, bleeding 300 ml/minute from soft tissue injuries. The surgeons thought the case was unsalvageable. However, upon administration of recombinant factor VIIa, the bleeding was immediately decreased to 15 ml/min, allowing surgeons to identify and the several more bleeding sites. A second dose of recombinant factor VIIa resulted in complete cessation of bleeding. Other conditions where beneficial results have been achieved include gastric ulcer bleeding from arterial erosion, thrombocytopathies, and children with dengue hemorrhage fever and shock.
A study (submitted for publication) was conducted involving recombinant factor VIIa as an adjunct to conventional liver packing for the treatment of a model of American Association for the Surgery of Trauma (AAST) grade 5 liver injury in swine rendered cold and coagulopathic by exchange transfusion of 60% of their blood volume with cold hydroxyethyl starch. This study examined the efficiency of factor VIIa on extreme cases where large amounts of blood loss have occurred and the patient is in trauma. It is well understood that patient chances of survival and quality of life will improve as blood loss is diminished. There was a 46% reduction in blood loss, which is a statistically significant decrease. The treatment corrected coagulopathy and caused no identifiable untoward effects.
Hemophilia is an excessive bleeding disorder due to the lack of one or more factors involved in the blood coagulation cascade. Hemophilia A is characterized by a lack of function associated with coagulation factor VIII, either through an absence of active factor VIIIa or inhibition of factor VIII. Hemophilia B is characterized by an absence of coagulation factor IX. Both forms of hemophilia are associated with bleeding disorders potentially leading to severe injury or death. In the 1970's, hemophilia patients were sometimes treated with “active factor concentrates”. These mixtures of the activated Vitamin K dependent factors (factors II, VII, IX, and X) were frequently effective in stopping hemophilic bleeding, but were associated with thrombotic side effects. Efforts to isolate the beneficial components in these mixtures culminated in 1982 with Hedner's isolation of factor VIIa in pure form from large volumes of plasma and her subsequent successful treatment of bleeding episodes in two patients with hemophilia
Arwine Elizabeth
Mayer Suzanne M.
The United States of America as represented by the Secretary of
Wax Robert A.
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