MXPA06008483A - Use of factor viia factor for treating trauma - Google Patents

Abstract

The invention relates to the use of Factor VIIa or a Factor VIIa equivalent for the manufacture of a medicament for treatment of trauma.

Description

USE OF THE VIIA FACTOR FOR THE TREATMENT OF TRAUMATISMS Field of the Invention The invention concerns methods for the treatment of victims of acute injury, including the prevention or reduction of subsequent severity or complications. in patients with trauma. Background of the Invention Hemostasis is a complex physiological process that results in the arrest of bleeding. This is dependent on the proper function of three main components: blood vessels (especially the endothelial lining), coagulation factors and platelets. Once a hemostatic plug is formed, the activation time of the fibrinolytic system is equally important to prevent additional hemostatic activation. Any malfunctioning of this system (due to a reduced number or molecular dysfunction of hemostatic components or increased activation of fibrinolytic components) can lead to clinical bleeding, such as, for example, hemorrhagic diathesis of varying severity. In more physiological situations, hemostasis is triggered by the interaction of circulating activated clotting factor VII (FVIIa) with the tissue factor (TF) subsequent to the exposure of the TF at the site of a REF: 174328 traumatism. The endogenous FVIIa becomes ~ proteolytically. active only after forming a complex with TF. Normally, TF is expressed in the deep layers of the venous wall and is exposed followed by trauma. This ensures a highly localized activation of coagulation and prevents disseminated coagulation. TF is also observed to exist in a non-active form, called encrypted TF. The regulation of the encrypted TF against active TF is still unknown. TF in recent years has been discovered in circulating blood in a variety of situations such as trauma, sepsis, abdominal surgery. These studies used immunochemically active methods for the determination of TF (ELISA). These methods determine both active and inactive TF as well as TF in complex with any other proteins (such as FVIIa, TFPI, etc.) and these do not indicate whether the TF that is found is active or not. The respective individuals undergoing surgery for idiopathic thoracic scoliosis, an extensive surgical trauma associated with significant tissue damage. Another study failed to demonstrate any TF in the circulation followed by major orthopedic surgery (total hip replacement and knee replacement) known to be associated with a high frequency of postoperative deep vein thrombosis (DVT). Recombinant activated human factor VII (rFVIIa) is indicated for the treatment of bleeding responses in patients with hemophilia A or B with inhibitors for Factor VIII or Factor IX. When provided in high doses (pharmacological), rFVIIa can bind independently of TF to activated platelets and initiate the generation of local thrombin which is important for the formation of the initial hemostatic plug. Uncontrolled bleeding is the leading cause of death (39%) in victims of domestic trauma. Sixty-five percent (65%) of "deaths occur after hospital admission and bleeding is responsible for between 15-40% of deaths in the hospital of patients with trauma." In patients with complex liver trauma, Mortality exceeds 40% There is a correlation between transfusion with blood products and mortality Many patients with critical trauma have a deep coagulopathy that correlates with the severity of the trauma Uncontrolled bleeding threatens life and coagulopathy secondary acquired by transfusion, hypothermia and other related causes that these patients face may also cause the so-called subsequent complications including pulmonary embolism, disseminated intravascular coagulation (DIC), acute myocardial infarction, cerebral thrombosis, multiple organ failure (MOF), systemic inflammatory response syndrome (SIRS) and acute respiratory distress syndrome (ARDS), whose complications contribute significantly to the subsequent death of trauma victims. Thus, there is a need in the art for improved methods and compositions for the treatment against acute trauma, as well as for the prevention and reduction of subsequent complications resulting from the same trauma and from conventional modalities that are useful for treating victims with traumas. Brief Description of the Invention The invention provides the use of Factor Vlla or an equivalent of Factor Vlla for the preparation of a medicament for the treatment against traumatisms. Typical patients for whom the drug is used are those who suffer from coagulopathic bleeding, including, without limitation, patients who have experienced superficial trauma or penetrating trauma. The invention also provides methods for the treatment of injuries, which are carried out by administering to a patient an effective amount of Factor Vlla or an equivalent of Factor Vlla to prevent or attenuate. Typical patients are those who have experienced superficial trauma or penetrating trauma. In some modalities, the initial administration stage is carried out 5 hours after the onset of traumatic trauma. In some embodiments, the effective amount comprises at least about 150 μg / kg of the Vlla Factor or a corresponding amount of one equivalent of the Vlla Factor. In some embodiments, a first amount of at least about 200 ug / kg Factor Vlla or a corresponding amount of one equivalent of Factor Vlla is administered at the start of treatment and a second amount of about 100 μg / kg Factor Vlla or an amount The corresponding Vlla Factor equivalent is administered to the patient one or more hours after the start of treatment. In some embodiments, a third amount of approximately 100 μg / kg Factor Vlla or a corresponding equivalent of Factor Vlla is subsequently administered such as, for example, three hours after the start of treatment. In some embodiments, the method further comprises administering to the patient a second coagulation agent in an amount that increases the Vlla Factor or the equivalent of Factor Vlla. Preferably, a second coagulation agent is a coagulation factor (including without limitation, the Factor VIII, Factor IX, Factor V, Factor XI, Factor XIII and any combination thereof) or an antifibrinolytic agent (including, without limitation, PAI-1, aprotinin, e-aminocaproic acid, tranexamic acid or any combination thereof).

The invention further provides "methods for the treatment against trauma in most trauma patients, which are carried out by: (i) administering to a group of trauma patients an effective amount of Vlla Factor treatment or an equivalent of the Factor Vlla, and (ii) observe a reduction in the lesion between the group of patients who received the Factor Vlla or an equivalent of the Factor Vlla relative to the frequency of appearance of later complications that can be expected in the same group of patients who have not received the Vlla Factor or an equivalent of the Vlla Factor Brief Description of the Figures Figure 1 shows the distribution of erythrocyte requirements within a 48 hour observation period after the first dose of the test product. percentage of patients alive at 48 hours after receiving more than 12 units of erythrocytes within a period of 48 hours after the first dose, with more than 20 equivalent units of erythrocytes inclusive of the 8 units of previous dose. Figure 3 shows the survival curves for populations with penetrating and superficial traumatisms. Detailed Description of the Invention The present invention provides methods and compositions that can be advantageously used to treat patients with trauma. The methods are carried out when administering to a patient with lesion the Factor Vlla or an equivalent of Factor Vlla, in such a way that it is effective for the treatment. An effective form of treatment may comprise administering a predetermined amount of Factor Vlla or an equivalent of Factor Vlla and / or using a particular dosage regimen, formulation, administration form, combination with other treatments and the like. The effectiveness of the methods of the invention in the treatment against injuries can be evaluated using one or more useful parameters of the immediate consequences of the damage and / or subsequent complications (see below). Immediate consequences include, for example, blood loss and shock symptoms; whereas later complications include without limitation, pulmonary embolism (PE), acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), acute myocardial infarction (AMI), cerebral thrombosis (CT), systemic inflammatory response syndrome (SIRS), infections, multiple organ failure (MOF) and acute lung injury (ALI), including death caused by one or more of these symptoms. Patient Selection: Patients who could benefit from the use of the methods of the present invention included, without limitation, patients who suffered superficial trauma and / or penetrating trauma. The superficial trauma includes sudden injuries such as, for example, those caused by automobile accidents or failures, which could result in one or more injuries to the liver, multiple fractures, brain contusions, as well as. lacerations of the spleen, lungs or diaphragm. Surface trauma is usually accompanied by more extensive tissue damage compared to penetrating trauma and, consequently, bleeding from smaller veins. Penetrating trauma includes penetrating trauma such as, for example, injuries caused by firearms or sharp trauma that can result in penetration of the inferior vena cava, injury to the liver, lung injury, injury to the prostate, urinary bladder, thorax and lacerations in the liver, as well as trauma to the pelvis or chest. The injury can cause damage to and subsequently bleeding from small veins as the main ones. Excessive or massive bleeding in many cases of injury presents a combination of bleeding from the veins that need surgical treatment ("surgical bleeding") with an uncontrolled and diffuse bleeding of the small veins ("coagulopathic bleeding"). Even more, patients with trauma who receive massive transfusions often suffer from coagulopathy and continue to bleed profusely due to the intervention with-surgical procedures, packaging and embolization of the major veins. Bleeding refers to the extravasation of blood from any component of the circulatory system and includes any bleeding (including without limitation, excessive bleeding, uncontrolled, ie, hemorrhage) in connection with the injury. In a number of modalities, excessive bleeding is caused by superficial trauma; in others, it is caused by penetrating trauma. In a series of modalities, the traumatisms are in the liver, spleen, lungs, diaphragm, head including the brain. In another series of modalities, the traumas are in the inferior vena cava, liver damage, lung damage, damage to the prostate, urinary bladder, thorax and lacerations in the liver, pelvis or chest, or in the head including the brain. The coagulopathy in the lesion is multifactorial, comprising abnormalities in coagulation that resemble DIC, caused by the systemic activation of coagulation and fibrinolysis; excessive fibrinolysis that may be evident from the first day in some trauma patients; and dilutional coagulopathy, which is caused by the excessive administration of fluids. Some fluids such as hydroxyethyl starch (HES) preparations can directly compromise coagulation. The massive transfusion syndrome results in the breakdown of coagulation factors and the worsening of platelet function. Hypothermia causes a low enzyme activity of the coagulation cascade and dysfunctional platelets. Metabolic abnormalities, such as acidosis, also compromise coagulation, especially when associated with hypothermia. Non-limiting examples of patients in need of treatment according to the invention, include those exhibiting one or more of the following symptoms: Abnormal CID-like coagulation, caused by systemic activation of coagulation and fibrinolysis Excess fibrolyolysis > Dilutional coagulopathy caused by excessive fluid treatment including, without limitation, a limited number of platelets and / or abnormal platelet function compared to platelet count and platelet activity of the normal blood sample. Receive preparations of hydroxyethyl starch ( HES) Hypothermia, which includes having the body temperature below about 37 ° C such as, for example, below 36 ° C, below 35 ° C, or below 34 ° C At least one indication of metabolic abnormalities including without limitation, acidosis with a pH in the blood below 7.5, such as, for example, below about 7.4, below about 7.3, below about 7.2, or below about 7.1. The methods of the present invention can be advantageously applied to any patient who has suffered superficial and / or penetrating trauma which, without treatment, has resulted in a significant loss of blood, such as, for example, about 10% of the total blood volume. of the patient (loss close to 40% of the total volume of blood immediately threatens life). A normal volume of blood represents approximately 7% of the ideal body weight in an adult and approximately 8-9% of the ideal body weight in children. In a number of embodiments, patients undergoing treatment according to the invention are those who have received less than 10 units of whole blood (whole blood), packed red blood cells (pRBC) or fresh frozen plasma (FFP) between the time of their traumatic injury and the time of administration of Factor Vlla or an equivalent of Vlla Factor Typically, a whole blood unit contains approximately 450 ml of blood and 63 ml of conventional anticoagulant / preservative (having a hematocrit of 36-44%). A pRBC unit typically contains 200-250 ml of conventional blood, plasma and anticoagulant / conservative erythrocytes (having a hematocrit of 70-80%). In other embodiments, patients undergoing treatment according to the invention have received less than about 8 units of whole blood, pRBC or FFP, such as, for example, less than about 5 units or less than about 2 units or have not received any blood products. and / or substitute products of the volume before the administration of Factor-Vlla or an equivalent of Factor Vlla. In a "series of embodiments, patients undergoing treatment according to the invention do not suffer from a blood disorder, either congenital or acquired, such as, for example, hemophilia A, B or C- In different embodiments of the invention, patients can be excluded from treatment if they received transfusion of 10 units or more of pRBC, such as more than 15, 20, 25 or 30 units, or if they were diagnosed with a congenital blood disorder Factor Vlla or factor Vlla equivalents: In the practice of the present invention, any Factor Vlla or equivalent of Factor Vlla can be used effectively in the treatment of injuries In some embodiments, the Vlla Factor is the Factor Vlla of human as described, for example, in the Patent of US No. 4,784,950 (Factor VII wild type) The term "Factor VII" is intended to encompass factor VII polypeptides in their closed form (cytogen), as well as those that can be r processed proteolytically to produce their respective bioactive forms, which can be designated as Factor Vlla. Typically, Factor VII is opened between residues 152 and 153 to produce Factor Vlla. Vlla Factor equivalents include without limitation, Factor VII polypeptides that have been either chemically modified relative to the Vlla Factor of human and / or that contain one or more alterations in the amino acid sequences relative to the Factor Vlla of human. These equivalents may show different properties relative to the Vlla Factor of human, including stability, phospholipid binding, altered specific activity and the like. In a series of embodiments, an equivalent of Factor Vlla includes polypeptides that show at least about 10%, preferably at least about %, more preferably at least about 50% and more preferably at least about 70% of the specific biological activity of Factor Vlla of human. For purposes of the invention, the biological activity of the Factor Vlla can be quantified by determining the ability of a preparation to promote blood coagulation using a plasma deficient in Factor VII and thromboplastin as described, for example, in U.S. Pat. No. 5,997,864. In this titration, biological activity is expressed as the reduction of coagulation time in a control sample and becomes "Factor VII units" compared to a conventional sample of human serum containing one unit / ml of activity of Factor VII. Alternatively, the biological activity of Factor Vlla can be quantified by (i) determining the capacity of Factor Vlla or an equivalent of Factor Vlla for the production of Factor Xa in a system comprising TF embedded in a lipid membrane and Factor X ( Persson et al., J. Biol. Chem. 272: 19919-19924, 1997); '(ii) determining the hydrolysis of Factor X in an aqueous system (see Example 5 below); (iii) determine the physical binding of the Vlla Factor or an equivalent of the Vlla Factor to the TF using an instrument based on the plasmon surface resonance (Persson, FEBS Letts, 413: 359-363)., 1997) and (iv) determine the hydrolysis of a synthetic substrate for the Vlla Factor and / or an equivalent of the Vlla Factor. Examples of Factor VII equivalents include, but are not limited to, wild-type Factor VII, L305V-FVII, L305V / M306D / D309S-FVII, L305I-FVII, L305T-FVII, F374P-FVII, V158T / M298Q-FVII, V158D / E296V / M298Q-FVII, K337A-FVII, M298Q-FVII, V158D / M298Q-FVII, L305V / K337A-FVII, V158D / E296V / M298Q / L305V-FVII, V158D / E296V / M298Q / K337A-FVII, V158D / E296V / M298Q / L305V / K337A-FVII, 157A-FVII, E296V-FVII, E296V / M298Q-FVII, V158D / E296V-FVII, V158D / M298K-FVII and S336G-FVII, L305V / K337A-FVII, L305V / V158D-FVII, L305V / E2 6V-FVII, L305V / M298Q-FVH, L305V / V158T-FVH, L305V / K337A / V158T-FVH, L305V / K337A / M298Q-FVII, L305V / 337A / E296V-FVII, L305V / K337A / V158D-FVII , L305V / V158D / M298Q-FVII, L305V / V158D / E296V-FVII, L305V / V158T / M298Q-FVII, L305V / V158T / E296V-FVII, L305V / E296V / M298Q-FVII, L305V / V158D / E296V / M298Q-FVII , L305V / V158T / E296V / M298Q-FVII, L305V / V158T / K337A / M298Q-FVII, L305V / V158T / E296V / K337A-FVII, L305V / V158D / K337A / M298Q-FVII, L305V / V158D / E296V / K337A-FVII , L305V / V158D / E296V / M298Q / K337A-FVII, L305V / V158T / E296 V / M298Q / K337A-FVII, S314E / K316H-FVII, S314E / K316Q-FVII, S314E / L305V-FVII, S314E / K337-FVII, S314E / V158D-FVII, S314E / E296V-FVII, S314E / M298Q-FVII, S314E / V158T-FVII, K316H / L305V-FVII K316H / K337A-FVII, K316H / V158D-FVII, K316H / E296V-FVII, K316H / M298Q-FVII, 316H / V158T-FVII, K316Q / L305V-FVII, K316Q / K337A -FVII, K316Q / V158D-FVII, K316Q / E296V-FVII, K316Q / M298Q-FVII, K316Q / V158T-FVII, S314E / L305V / K337A-FVII, S314E / L305V / V158D-FVII, S314E / L305V / E296V-FVII , S314E / L305V / M298Q-FVII, S314E / L305V / V158T-FVII, S314E / L305V / K337A / V158T-FVII, S314E / L305V / K337A / M298Q-FVII, S314E / L305V / 337A / E296V-FVII, S314E / L305V / K337A / V158D-FVII, S314E / L305V / V158D / M298Q-FVII, S314E / L305V / V158D / E296V-FVII, S314E / L305V / V158T / M298Q-FVII, S314E / L305V / V158T / E296V-FVII, S314E / L305V / E296V / M298Q-FVII, S314E / L305V / V158D / E296V / M298Q-FVII, S314E / L305V / V158T / E296V / M298Q-FVII, S314E / L305V / V158T / K337A / M298Q-FVII, S314E / L305V / V158T / E296V / K337A-FVII, S314E / L305V / V158D / K337A / M298Q-FVII, S314E / L305V / V158D / E296V / K337A-FVII, S314E / L3 05V / V158D / E296V / M298Q / K337A-FVII, S314E / L305V / V158T / E296V / M298Q / K337A-FVII, K316H / L305V / K337A-FVII, K316H / L305V / V158D-FVII, K316H / L305V / E296V-FVII, K316H / L305V / M298Q-FVII, K316H / L305V / V158TFVII, K316H / L305V / K337A / V158T / -FVII, K316H / L305V / K337A / M298Q-FVII, K316H / L305V / K337A / E296V-FVII, K316H / L305V / K337A / V158D-FVII, K316H / L305V / V158D / M298Q-FVII, K316H / L305V / V158D / E296V-FVII, K316H / L305V / V158T / M298Q-FVII, K316H / L305V / V158T / E296V-FVII, K316H / L305V / E296V / M298Q-FVII, K316H / L305V / V158D / E296V / M298Q-FVII, K316H / L305V / V158T / E296V / M298Q-FVII, K316H / L305V / V158T / K337A / M298Q-FVII, K316H / L305V / V158T // E296V / K337A-FVII, K316H / L305V / V158D / K337A / M298Q-FVII, K316H / L305V / V158D / E296V / K337A-FVII, K316H / L305V / V158D / E296V / M298Q / K337A-FVII, K316H / L305V / V158T / E296V / M298Q / K337A-FVII, K316Q / L305V / K337A-FVII, K316Q / L305V / V158D-FVII, K316Q / L305V / E296V-FVII, K316Q / L305V / M298Q-FVII, K316Q / L305V / V158T-FVII, K316Q / L305V / K337A / V158T-FVII, K316Q / L305V / K337A / M298Q-FVII, K316Q / L305V / K337A / E296V-FVII, K316Q / L305V / K337A / V158D-FVII, K316Q / L305V / V158D / M298Q-FVII, K316Q / L305V / V158D / E296V-FVII, K316Q / L305V / V158T / M298Q-FVII, K316Q / L305V / V158T / E296V-FVII, K316Q / L305V / E296V / M298Q-FVII, K316Q / L305V / V158D / E296V / M298Q-FVII, K316Q / L305V / V158T / E296V / M298Q-FVII, 316Q / L305V / V158T / K337A / M298Q-FVII, K316Q / L305V / V158T / E296V / K337A -FVII, K316Q / L305V / V158D / K337A / M298Q-FVII, 316Q / L305V / V158D / E296V / K337A-FVII, K316Q / L305V / V158T / K337A / M298Q-FVII, K316Q / L305V / V158D / E296V // M298Q / K337A-FVII and 316Q / L305V / V158T / E296V // M298Q / K337A-FVII. In some embodiments, the equivalent factor VII is V158D / E296V / M298Q-FVII. Preparations and formulations: The present invention comprises the therapeutic administration of Factor Vlla or equivalents of Factor VIIA, which is achieved using formulations comprising preparations of Factor Vlla. As used herein, "Factor VII preparation" refers to a plurality of Vlla Factor polypeptides or equivalent Vlla Factor polypeptides., which include variants and chemically modified forms, which have been separated from the cell in which they were synthesized, either from a cell of origin or a recombinant cell that has been programmed to synthesize Factor Vlla or an equivalent of Factor Vlla.

The separation of polypeptides from their cell of origin can be achieved by any method known in the art including, without limitation, removal of the cell culture medium containing the desired product from a culture of adherent cells; centrifugation or filtration to remove non-adherent cells and the like Optionally, Factor VII polypeptides can be further purified Purification can be achieved using any method known in the art, including without limitation, affinity chromatography such as a column of an anti-Factor VII antibody (see for example, Wakabayashi et al., J. Biol. Chem. 261: 11097, 1986; and Thim et al., Biochem. 27: 7785, 1988); hydrophobic interaction chromatography; ion exchange chromatography, size exclusion chromatography, electrophoretic procedures (eg, directed isoelectric preparation (IEF), differential solubility (eg, precipitation of ammonium sulfate), or extraction and the like. Protein Purification, Springer-Verlag, New York, 1982, and Protein Purification, J.-C. Janson and Lars Ryden, editors, VCH Publishers, New York, 1989. After the pu In one embodiment, the preparation preferably contains less than about 10% by weight, more preferably less than about 5% and more preferably less than about 1% of proteins without Factor VII derived from the host cell. Factor VII polypeptides and those related to Factor VII can be activated by proteolytic opening, using Factor Xlla or other proteases that have trypsin-like specificity, such as, for example, Factor IXa, kallikrein, Factor Xa and thrombin. See for example, Osterud et al., Biochem. 11: 2853 (1972); Thomas, Patent of USA UU No. 4,456,591 and Hedner et al., J. Clin. Invest. 71: 1836 (1983). Alternatively, Factor VII can be activated by passing through ion exchange chromatography, such as Mono Q® (Pharmacia) or the like. The resulting activated Factor Vlla can then be formulated and administered as described below. The pharmaceutical compositions or formulations for use in the present invention comprise a preparation of the Vlla factor in combination with, preferably dissolved in a pharmaceutically acceptable carrier, preferably an aqueous carrier or diluent. A variety of aqueous carriers can be used, such as water, buffered water, 0.4% saline, 0.3% glycine and the like. The preparations of the invention can also be formulated into liposome preparations to release or bind to the sites of injury. Liposome preparations are generally described in, for example, US Pat. UU Nums. 4,837,028, 4,501,728 and 4,975,282. The compositions can be sterilized by conventional well-known sterilization techniques. The resulting aqueous solutions can be packaged for use or filtered under aseptic conditions and lyophilized, the lyophilized preparation is combined with a sterile aqueous solution before administration. The compositions may contain pharmaceutically acceptable auxiliary substances or adjuvants, including without limitation, buffering agents and pH buffers and / or tonicity regulating agents, such as, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, etc. Treatment program: In the practice of the present invention, Factor Vlla or Factor Vlla equivalent can be administered to a patient as a single dose comprising an effective amount in a single dose for the treatment of a trauma, or in a series of established doses that together comprise an effective amount for the treatment of a trauma. An effective amount of the Vlla Factor or an equivalent of the Vlla Factor (see below) refers to the amount of the Vlla Factor or an equivalent of the Vlla Factor that when administered in a single dose or in the aggregate of multiple doses., or as part of any other type of defined treatment program, produces a quantifiable improvement in at least one clinical parameter associated with the lesion (see below). When the Vlla Factor equivalents are administered, an effective amount can be determined by comparing the coagulation activity of the Vlla Factor or Vlla Factor equivalent and adjusting the amount to be administered proportionally to the predetermined effective dose of Factor Vlla. The administration of Factor Vlla or an equivalent of Factor Vlla according to the present invention is preferably initiated in a period of time of approximately 6 hours after the traumatic injury has occurred, such as, for example, within approximately 4 hours, within approximately 2 hours. or in about an hour. The administration of a single dose refers to the administration of a total dose of Factor Vlla or an equivalent of Factor Vlla as a bolus for a period of time of approximately 5 minutes. In some embodiments, the administration occurs for a period of time less than about 2.5 minutes and in some cases, for less than about one minute. In general, an effective amount of single dose comprises at least about 40 ug / kg Human Factor Vlla or a corresponding amount of one equivalent of Factor Vlla, such as at least about 50 ug / kg, 75 ug / kg or 90 ug / kg, or at least 150 ug / kg Factor Vlla. In some embodiments, after administration of a single dose of Factor Vlla or an equivalent of Factor Vlla according to the invention, the patient does not additionally receive the Factor Vlla or an equivalent of Factor Vlla during a time interval of 15 minutes. In some embodiments after administration, the time interval is at least about 30 minutes, such as at least about 45 minutes, at least about one hour, at least about 1.5 hours or at least about 2 hours. In other modalities, the patient receives the Vlla Factor or an equivalent of the Vlla Factor according to the following regimen: (i) The patient receives a first quantity of the Vlla Factor or an equivalent of the Vlla Factor comprising at least about 40 ug / kg; (ii) after a period of time of at least about 30 minutes, a second amount of Factor Vlla or an equivalent of Factor Vlla is administered, the amount comprising at least about 40 ug / kg; and • (iii) after a period of at least 30 minutes after the administration of the second dose, a third dose of Factor Vlla or an equivalent of Factor Vlla is administered, the amount comprises at least about 40 ug / kg . After a period of time of at least about 30 minutes after the administration of the third amount, the patient can then receive an additional (fourth) amount of Factor Vlla or an equivalent of Factor Vlla comprising at least about 40 ug / kg . In other embodiments, the first Vlla Factor amount or an equivalent of the Vlla Factor comprises at least about 100 ug / kg, such as at less about 150 ug / kg or at least about 200 ug / kg; in other embodiments, the second amount of Factor Vlla or an equivalent of Factor Vlla comprises at least about 75 ug / kg, such as at least about 90 ug / kg; in other embodiments, the third (and optionally the fourth) amount of the Factor Vlla or an equivalent of the Vlla Factor comprises at least about 75 ug / kg, such as at least about 90 ug / kg. In one embodiment, the first dose comprises approximately 200 ug / kg, the second dose approximately 100 ug / kg and the third dose (and optionally the fourth dose) approximately 100 ug / kg. In other modalities, the patient receives the second amount of Factor Vlla or an equivalent of Factor Vlla after a period of time of at least about 45 minutes a. starting from the first administration, such as about one hour, at least about 1.5 hours, at least about 2 hours, at least about 2.5 hours or at least about 3 hours. In other embodiments, the patient receives the third (and optionally fourth) amount of the Factor Vlla or an equivalent of the Factor Vlla after a period of time of about 45 minutes from the previous "administration, such as at least about one hour, at least about 1.5 hours, at least about 2 hours or at least about 3 hours In one embodiment, the patient receives a first dose comprising approximately 200 ug / kg, after a period of about one hour, the patient receives a second dose comprising approximately 100 ug / kg and after a period of approximately 3 hours from the first dose, the patient receives a third dose comprising approximately 100 ug / kg. Limitations of the invention: It should be understood that an effective amount of the Vlla Factor or an equivalent of the Vlla Factor, such as the general dosing schedule, may vary according to the patient's hemostatic state which may also be reflected in one or more clinical parameters, including, for example, relative levels of coagulation factors; the amount of blood loss; bleeding speed, hematocrit and the like. It should be further understood that the effective amount can be determined by those of ordinary skill in the art by routine experimentation, by constructing a matrix of values and evaluating different points in the matrix. For example, in a number of embodiments, the invention includes: (i) administering a first dose of Factor Vlla or an equivalent of Factor Vlla; (ii) assessing the coagulation status of the patient after a predetermined period of time; and (iii) based on the. evaluation, administer an additional dose - of the Vlla Factor or an equivalent of the Vlla Factor if • it is necessary. Steps (ii) and (iii) can be repeated until satisfactory hemostasis is achieved. According to the invention, Factor Vlla or an equivalent of Factor Vlla can be administered by any effective route, including -without limitation, an intravenous, intramuscular, subcutaneous, mucosal and pulmonary administration route. Preferably, the administration rate is intravenously. Combination of treatments: The present invention encompasses the combined administration of additional agents adjusted with the Factor Vlla or an equivalent of Factor Vlla. In some embodiments, the additional agent comprises a coagulant that includes, without limitation, a coagulation factor, such as, for example, Factor VIII, Factor IX, Factor V, Factor XI or Factor XIII; or an inhibitor of the fibrinolytic system, such as, for example, PAI-1, aprotinin, e-aminocaproic acid or tranexamic acid. It should be understood that the modalities comprising the administration of Vlla Factor combinations with other agents, the dosage of the Vlla Factor or an equivalent of the Vlla Factor can on its own comprise an effective amount and additional agents that can also increase the therapeutic benefit of the patient. Alternatively, the combination of Factor Vlla or an equivalent and the second agent may together comprise an effective amount for the treatment of a trauma. It should be understood that the actual amounts can be defined in the context of the particular treatment regimens, including for example, time and number of administrations, administration forms, formulations, etc. Results of the treatment: The present invention provides methods and compositions for the treatment of a trauma. The treatment includes any quantifiable improvement or reduction of any parameter that is an indicator of the degree of injury. Non-limiting examples of these parameters include: > Coagulation status, reflected for example, in abnormalities similar to CID; excessive fibrinolysis; Dilutional coagulopathy including, without limitation, a limited number of platelets and / or impaired platelet function compared to the platelet count and platelet activity of a normal blood sample. Hypothermia, which includes having a body temperature below about 37 ° C, such as below 36 ° C, below 35 ° C or below 34 ° C. > Indicators of metabolic abnormalities, including without limitation, acidosis having a blood pH below about 7.5, such as, for example, below about 7.4, below about 7.3, below about 7.2, or below about 7.1. > Loss of blood . The effectiveness of the methods of the present invention in the treatment of traumatisms can be determined by evaluating a statistical decrease in subsequent complications, including without limitation, pulmonary embolism (PE), acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation ( CID), acute myocardial infarction (AMI), cerebral thrombosis (CT), systemic inflammatory response syndrome (SIRS), infections, multiple organ failure (MOF) and acute lung injury (ALI), including death caused by one or more of these syndromes. In the practice of the present invention, subsequent complications can be evaluated using conventional methods, such as, for example, the scores described in Tables 1 to 5 here. The evaluations may be carried out at least about 20 days from the start of the treatment according to the invention, such as, for example, at least about 30 days, at least about 35 days or at least about 40 days from the start of treatment.

Damage to an organ or failure of an organ includes, without limitation, damage to the "structure and / or damage to the functioning of the organ in the kidney, lung, adrenal gland, liver, intestine, cardiovascular system and / or hemostatic system. Examples of organ damage include but are not limited to structural / morphological damage and / or damage to organ functioning, such as, for example, accumulation of proteins (eg, surfactant) or fluids due to deterioration or damage of the pulmonary interstitium or damage to the mechanisms of pulmonary exchange or damage to the capillary membrane of the alveoli.The terms "organ injury", "organ damage" and "organ failure" can be used interchangeably. Normally the damage of an "organ" results in the failure of an organ, "Failure of an organ" means a reduction of the normal function of an organ compared with the normal, normal functioning of a corresponding organ in a normal and healthy personnel. Failure of an organ may be a minor reduction of its functioning (eg, 80-90% of normal) or may be a greater reduction of its functioning (eg, 10-20% of normal), the reduction may be a complete failure of the functioning of the organ Failure of an organ includes, without limitation, the biological reduction of functioning (eg, leakage of urine), for example, due to tissue necrosis, loss of glomeruli (kidney), deposition of fibrin, haemorrhage, edema or inflammation.Damage to an organ includes without limitation, tissue necrosis, loss of glomeruli (kidney), fibrin deposition, hemorrhage, edema or inflammation. Lung damage includes, but is not limited to, structural / morphological damage and / or damage to lung function, such as accumulation of proteins (eg, surfactant) or fluids due to deterioration or damage of the pulmonary interstitium or damage to the lung. The mechanisms of "lung exchange or damage to the capillary membrane of the alveoli." The terms "lung injury", "lung damage" and "lung failure" can be used interchangeably.The methods to evaluate the function and efficiency of an organ and the parameters clinical or biochemical to be evaluated, are well known by clinical experts.These markers or biochemical parameters of the function of an organ are, for example: Breathing: ratio Pa02 / Fi02 Coagulation: Platelets Liver: Cardiovascular Bilirubin: Blood pressure and need for a renal vasopressor treatment: Creatinine and urine output Other clinical assessments include days without a ventilator, days no organ failure, days without vasopressor treatment, SOFA score and lung injury evaluation scores as well as vital signs. The evaluation methods for coagulopathy or inflammation are well known to the expert clinician. These markers of coagulation or inflammatory status are for example PTT, fibrinogen disruption, evaluation in TAT complexes, ATIII activity, IL-6, IL-8 or TNFR-1. Chronic organ damage includes but is not limited to the long-term damage that results from ARDS. This residual worsening, in particular of pulmonary mechanics, may include without restriction, medium restriction, obstruction, worsening of the ability to diffuse carbon monoxide or abnormalities in gas exchange with exercise, fibrous alveolitis with persistent hypoxemia, increased immobile alveolar space and an additional reduction of lung or alveolar function. Pulmonary hypertension is due to the occlusion of the pulmonary-capillary bed, which can be severe and cause right ventricular failure. In the present context, prevention includes without limitation, the attenuation, elimination, minimization, alleviation or reduction of one or more symptoms or conditions associated with subsequent complications associated with injury, including but not limited to the prevention of further damage to and / or or failure of currently patient organs to a certain degree of organ failure and / or damage, as well as the prevention of damage and / or failure of additional organs that are not patients to a failure and / or organ damage. Examples of these symptoms or conditions include, but are not limited to, morphological / structural damage and / or damage to organ functioning such as, but not limited to, lung, kidney, adrenal gland, liver, intestine, cardiovascular system and / or hemostatic system. Examples of these symptoms or conditions include but are not limited to morphological / structural damage and / or damage to the functioning of organs such as, for example, accumulation of proteins (eg, surfactant) or fluids due to deterioration or damage of the pulmonary interstitium or damage of pulmonary exchange mechanisms or damage of the capillary membrane of the alveoli, reduction in urine output (kidney), tissue necrosis, loss of glomeruli (kidney), fibrin deposition, hemorrhage, edema or inflammation. The attenuation of organ failure or damage includes any improvement in organ function that is determined by at least one of the known markers of function of these organs (see Tables 1 to 4) compared to the corresponding values found in patients with injury that have not been treated according to the present invention. Prevention also includes preventing the development of acute lung injury (ALI) in ARDS. ALI is defined by the following criteria (Bernard et al., Am. J. Respir. Crit. Care Med. 149: 818-24, 1994); acute access; bilateral infiltrates in chest x-ray; Lung Artery Interlocking Pressure < 18 mm Hg or absence of clinical evidence of left atrial hypertension; and Pa02: Fi02 < 300. ARDS is defined by the following criteria (Bernard et al., Am. ". Respir Crit. Care Med. 149: 818-24, 1994): acute access, bilateral chest X-ray infiltrates, wedge pressure of the pulmonary artery <18 mm Hg or absence of clinical evidence of left atrial hypertension and Pa02: Fi02 <200. (Pa02 denotes the partial pressure of arterial oxygen and Fi02 is the fraction of inspired oxygen.) Measurement of later complications: - • - The following non-limiting examples are to assess the incidence and severity of injury complications: 1. Coma Glasgow score is determined as follows: Normal = 15 Vegetatives = 0 2. The multiple organ failure score is determined as follows: Multiple organic fault score Healthy = 0 Severe = 15 3. The ARDS score is determined as follows: ARDS score A. Pulmonary finding by X-ray D. Explosive and positive pressure (cm H2O) of simple chest 0 = < 6 0 = Normal 1 = 6-9 1 = Diffuse, interstitial marks 2 = 30-39 means / opacities 3 = 14-17 3 = Diffuse, moderate consolidation of 4 = > 17 airspace 4 = Diffuse, severe consolidation of airspace B. Hypoxemia - PaO2 / FiO2 (mm Hg) E. Static docility (ml / cm H2O) 0 = Normal 0 = > fifty Normal = 0 Severe = 20 4. The SIRS score is determined as follows: Systemic Inflammatory Response Syndrome Score A SIRS score (1 to 4) is calculated for each patient. One point for each component present: - Fever or hypothermia - Tachypnea. • Tachycardia • SIRS leukocytosis is present when two or more of the following criteria are met: • Temperature greater than 38 ° C or less than 36 ° C »Heart rate greater than 90 beats per minute • Respiratory rate greater than 20 breaths per minute or PaCO2 less than 32"White cell count greater than 12,000 / mm3 or less than 4,000 / mm3 or presence of 10% bands Normal = 0 Severe = 4 5. CID is determined as follows: CID In a number of embodiments, the practice of the present invention results in one or more of the following clinical responses: "A reduction in blood loss, including a complete cessation of blood loss" An improvement in one or more parameters of shock, including for example, hypothermia and blood pH In a number of embodiments, the practice of the present invention results in one or more of the following clinical responses: "Glasgow Coma score greater than approximately 9 determined 20 days after initiation the treatment; "Glasgow Coma Score greater than approximately 11 determined 30 days after initiating treatment; "Glasgow Coma score greater than approximately 13 determined 40 days after starting treatment;" MOF score less than 4 when determined 20 days after the start of treatment; B MOF score less than 3 when determined 30 days after the start of treatment; "MOF score less than 2 when it is determined 40 days after the start of treatment;" ARDS Score or less than approximately 8 when determined 20 days after the start of treatment; "ARDS score or less than approximately 6 when determined 30 days after the start of treatment; "ARDS score or less than about 4 when determined 40 days after the start of treatment;" SIRS score less than about 3 when determined 20 days after the start of treatment, - "SIRS score less than about 2 when determined 30 days after initiation of treatment; "SIRS score less than about 1 when it is determined 40 days after the start of treatment; "Any combination of any of the above Coma Glasgow, MOF, ARDS and / or SIR scores." Other treatment indices: The efficacy of the methods of the present invention can be evaluated using other clinical parameters, including without limitation, the reduction of any one or more of the fwing relative parameters of a similar patient to whom the Factor Vlla or an equivalent of the Vlla factor according to the invention: a reduction in units of blood, plasma, blood erythrocytes, globular package or "volume replacement products that • need to be administered, a reduction in the number of hospital days after a trauma, including a reduction in the number of days a patient can remain in the intensive care unit (ICU) and a reduction in the number of days where certain interventions (this is for example, a ventilator) are "required." Non-limiting examples of responses include: (i) a reduction of blood units, plasma, erythrocytes, globular packets or replacement of volume products that need to be administered in at least approximately 2 units, 4 units or 6 units, (ii) a reduction in days in ICU for one day, 2 days, or 4 days, (iii) a reduction in the number of days with a ventilator for one day, 2 days or 4 days, (iv) a reduction in the total days of hospitalization by 2 days, 4 days or 8 days The fwing examples are intended non-limiting illustrations of the present invention.

Example lt Administration of Factor VIIA to trauma victims The fwing study was carried out in order to evaluate the efficacy and safety of factor VII of recombinant coagulation (rFVIIa, NovoSeven®) as adjunctive therapy for the control of bleeding in severe traumas. Methods A double-blind, randomized, multi-center study compared rFVIIa with placebo. The study product was administered in 3 injections i.v. (200, 100 and 100 μg / kg) at the times of 0, 1 and 3 hours after the transfusion of 8 units of erythrocytes (RBC). The patients were monitored for 48 hours after the dose with a fw-up of 30 days. Conventional local treatment of the hospital was provided throughout the study; groups with superficial and penetrating trauma were analyzed separately. Results A total of 143 patients with superficial trauma and 134 with penetrating traumatism were analyzed. In patients with superficial trauma (mean trauma severity score: 33 + 13), there was a tendency to reduce erythrocyte transfusion 48 hours after the dose (primary point) in the rFVlla versus placebo group where the adjustment was made of patients who died after 48 hours (p = 0.07). The deceased patients were excluded, the reduction in erythrocytes was significant (p = 0.02). In particular, few patients in the rFVIIa group received a massive transfusion (more than 20 units of erythrocytes). Few patients with predefined critical complications were observed with rFVIIa in the superficial trauma group (Table). For patients with penetrating trauma, the transfusion results were similar but not statistically significant, the number of thromboembolic events was similar between the treatment groups. Conclusions rFVIIa showed a good safety profile in this high-risk injured population. The requirements of erythrocytes were significantly reduced in the group of superficial trauma. Trends to reduce complications warrants further investigation. Table: Patients with critical results in a period of 30 days (group of superficial injuries) Placebo rFVIIa (N = 74) (N = 69) Multiple organic failure 7 (9%) 3 (4%) Syndrome of Difficulty 12 (16%) 3 (4%) respiratory Acute Death 22 (30%) 17 (25%) Time without ICU Average 10.5 d Average 12.6 d Time without fan Media 13.7 d Average 15.4 d The results of the superficial trauma group indicate that patients undergoing treatment with NovoSeven® have few complications and spent less time in the intensive care units than patients who received conventional treatment and the mortality overlap was lower in the group treated with NovoSeven. ®. Example 2: Efficacy of the Vlla Factor provided in conjunction with conventional therapy for trauma treatment DESIGN OF THE TEST A double-blind, placebo-controlled, parallel-group, double-blinded, randomized, multi-center study was carried out patients with severe traumatic injuries and / or penetrating. Patients were recruited by observation for admission to the trauma center. In conjunction with the test product, they received conventional treatments for trauma and bleeding and any other procedures considered necessary by the doctor responsible for coordinating the trauma kit. The test was comprised of two treatment arms. Patients selected after receiving 6 pRBC units in a 4-hour time period were also placed in one of the following arms: Conventional therapy together with three single doses (volume equal to 200 μg / kg + 100 μg / kg + 100 μg / kg) of placebo administered in a period of 3 hours. Conventional therapy together with three single doses (200 μg / Jkg '+ 100 μg / kg + 100 μg / kg) of rFVIIa administered in a period of 3 hours. The first dose of rFVIIa or placebo (test product) was administered once the patient received 8 units of PRBC after one hour for the second dose and 2 additional hours for the third and last dose of the test product. The test was given to patients who, in the opinion of the attending surgeon, required a transfusion of more than 8 units of PRBC, and after an observation period of 48 hours, it was initiated with the administration of the first dose and was carried out with a 30-day evaluation follow-up The test product was administered intravenously as a slow bolus injection, and specific procedures such as physical examination, laboratory analysis and evaluation of adverse events were carried out throughout the test. were monitored through the study in the severe points including the number of units required of PRBC, adverse events, survival and parameters cured with changes in coagulation. In order to evaluate the mortality due to hemorrhage, a sequential analysis of each set of 20 treated patients was started, beginning when the data of the first 100 patients were available. Safety was continuously assessed and monitored taking into consideration all SAEs as reported during the test. TEST PRODUCTS: Recombinant human activated factor FVII (rFVII) and placebo were provided as a dry powder frozen in a single use 2.4 mg bottle to be reconstituted with sterile water by Ph.Eur injection. TEST POPULATION: Approximately 280 patients (140 per treatment arm) aged 16 years or older were recruited with severe superficial and / or penetrating trauma injuries. Inclusion criteria Patients who entered the test met the following inclusion criteria: 1. Trauma due to superficial and / or penetrating trauma. 2. Receive 6 units of PRBC in a time period of 4 hours followed by admission to a trauma center. 3. Receive 8 units of PRBC plus administration of the test drug. 4. Known age of > 16 years or legally age according to local laws and < 65 Exclusion criteria: Patients who met the following criteria were excluded from the study: 1. Prehospital cardiac arrest. 2. Cardiac arrest in the emergency room or OR. 3. Bullet wound in the head. 4. Glasgow Coma Scale < 8. 5. Basal deficit of > 15 mEq / 1 or severe acidosis (pH < 7.0). 6. Transfusion of 8 units or more of PRBC before arriving at the trauma center. 7. Known congenital blood disorder. 8. Currently participate or have participated in other research drug trials in a period of 30 days. 9. Known pregnancy or positive pregnancy test during recruitment. 10. Previous participation in this test. 11. Known treatment with vitamin K antagonists, low doses of heparin before administering the test drug. 12. Injuries sustained for more than 12 hours before random selection. 13. Estimated weight > 130 kg.

EVALUATIONS: The effectiveness of the treatment is based on the evaluation of the following variables for the period of 48 hours of SOT: Time and number of deaths due to bleeding and other causes. > Time and number of transfusion units of the following administered products: PRBC (time) FFP Platelets Cryoprecipitate > Number of times the patient undergoes surgery due to bleeding. > Time interval between the first dose of the study drug and when it reaches the normal PT coagulation range, normal temperature and acid base status. > Pharmacokinetic evaluations and evaluation of the pharmacokinetic population. Survival overlap on Day 30. > Time and number of complications including MOF, ARDS and infections that occurred from SOT on Day 30. > Number of days of hospitalization including days in the Intensive Care Unit (ICU), bed confinement and / or ventilator in the SOT period through Day 30.

Before the results of treatment (Treatment period 0) Blood sampling was carried out for: FVII: C (or below) Parameters related to coagulation and hematology (below) -_- PT (below) Blood chemistry (below) After the first administration of the test product and the next 24 hours. The following were recorded and / or investigated: Mortality and time of death Vital signs at 30 minutes, 1, 2, 4, 6, 8, 12, 18 and 24 hours (below). Glasgow Coma Score at 24 hours Number of transfusion unit products required (below) Intravenous fluid included in the composition, eg, colloids, crystalloids (below) Number of times the patient was taken for surgery and reasons for surgery (below) Adverse events ARDS, infection, MOF. The blood sampling was carried out for: Parameters related to coagulation at 1, 4, 8, 12 and 24 hours (below) Hematology at 1, 4, 8, 12 and 24 hours (below) FVII: C 2 to 4 samples, one in each time interval: 0-1 hour, 1-3 hours, 3-8 hours and 8-12 hours (below) Frequent sampling: FVII: C at 30 minutes, 1, 2 , 3, 4, 6, 8 and 12 hours (below) PT at 1, 4, 8, 12 and 24 hours (below) Frequent sampling: at 30 minutes and 1, 2, 3, 4, 6, 8 , 12, 18 and 24 hours (below) Blood chemistry at 24 hours (below) From 24 to 48 hours Mortality and time of death. Vital signs every 6 hours. Number of products of transfusion units required. Volume of intravenous fluid including composition, for example, colloids, crystalloids. Physical examination of changes in the baseline. Number of times the patient was taken to surgery and reasons for surgery. ECG at 48 hours. ARDS, infections, MOF. Adverse events . Sampling of blood to be carried out at 36 and 48 hours for the following: Parameters related to coagulation Hematology PT Blood chemistry - only at 48 hours Follow-up visit - Day 30 Mortality, date and time of death Days of hospitalization including number of days in the Intensive Care Unit and confinement in bed. Days with fan. Serious adverse events. -ARDS, infection, MOF. ANALYSIS Parameters related to coagulation and hematology The blood was obtained at the following time points: immediately before the first treatment and at 1, 4, 8, 12, 24, 36, 48 hours after the first treatment for the analysis of: Related parameters with APTT coagulation, fibrinogen, D dimers, anti thrombin-III, Fl + 2, TAT Hematology Platelets, hematocrit, hemoglobin and white blood cells Blood was obtained at the following time points: before the first treatment and at 24, 48 hours after the first treatment for the analysis of: S-bilirubin, S-albumin, S-creatinine, S-potassium, S-sodium, S-alaninaminotransferase. FVII: C ~ (pharmacokinetics) Fifty patients were sampled frequently for the determination of FVII: C and blood was obtained at the following time points: immediately before the first treatment and at 30 minutes, 1, 2, 3, 4, 6, 8 and 12 hours for the analysis of FVII: C. All other patients were sampled 2-4 times to obtain blood, one sample in 2 to 4 of the following time intervals: 0-1 hour (immediately after the first dose and before administering the next dose), 1-3 hours (immediately after the second dose and before the next dose is administered), 3-8 hours (immediately after the third dose) and 8-12 hours. The samples were taken at any time within the time interval. The exact time of sampling was recorded. Prothrombin time For the 50 patients who had frequent sampling of FVII: C, the blood was obtained at the following time points: immediately before the first treatment and at 30 minutes, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 hours for the analysis of prothrombin time (PT). The other patients had blood samples at the following time points: immediately before the first treatment and at 1, 4, 8, 12, 24, 36 and 48 hours.

Vital signs Vital signs were recorded before treatment and at 30 minutes, 1, 2, 4, 6, 8, 12, 16, 18 hours and every 6 hours until 48 hours after the first dose of administration of the first dose of the study drug (on the other hand as the condition demanded by the patient). The following was recorded: Body temperature (° C [rectal, oral or ear]). Blood pressure (mm Hg) (systolic / diastolic) in addition to registering at the scene of the accident during the prehospital stage. Pulse (beats / minute) in addition to registering at the scene of the accident during the prehospital stage. pH Respiratory rate (only when they had no ventilator) in addition to registering at the scene of the accident during the prehospital stage Pa02 / Fi02 respiratory rate, PaC02 Positive and expiratory pressure (cm H20) Glasgow coma score (as in the present specification) that was taken at the scene of the accident during the prehospital stage in the trauma center: before treatment, 24 and 48 hours after the first dose of the study drug. If the patient had a ventilator, the GCS was not recorded. Example 3: In vitro evaluation of the impact of colloid hemodilution, acidosis and hypothermia on the effect of the recombinant Factor Vlla The following experiments were carried out to evaluate the effect of factor Vlla clot formation under physiological conditions that are clinically relevant in trauma. , that is, low pH (acidosis), low temperature (hypothermia) and colloid hemodilution. 1. Methods Blood collection: Complete blood was collected from six healthy volunteers using a 21-gauge syringe. Samples were placed in tubes containing citrate, one part citrate was mixed with nine parts blood. The first tube cpn the blood sample of each participant was discarded. Then, the blood samples were kept at rest for 30 min. at room temperature and were manipulated to represent a clinical situation as described below. To simulate acidosis, whole blood was acidified (2 ml) by the addition of 140 μl of 1 M buffer of N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), adjusted to pH 7. To simulate hypothermia, the The temperature of the blood samples was lowered to 32 ° C. To simulate hemodilution, all solutions were mixed with citrate (10% v / v) to ensure anticoagulation of the hemodiluted whole blood. Then, whole blood was diluted by 20%, 40% and 60% (V / V) with one of the three different solutions of colloids: human albumin serum 5% MW = 68 000; Hetastarch 6% (Hespan®, duPont Merck, Wilmington, Del, USA), MW = 450,000 or hydroxyethyl starch (HES) 130 / 0.4 (Voluven®, Fresenius Kabi, Bad Homburg, Germany), MW = 130,000. blood coagulation, total thromboetastography: coagulation was started by adding tissue factor 1:50 000 (Innovin®, Dade Behring, Deerfield, 111, USA) to whole blood and recalcitrated with 15 mM calcium chloride (Free CaCl2 ~ 2-3 mM). The final concentration of tissue factor in whole blood corresponded to 0.12 pM. The experiments were carried out in the absence or presence of 25 nM rFVIIa (25 nM «90 μg / kg). The hemostatic process was recorded with the use of the TEG coagulation analyzer (TEG 5000 series analyzer, Haemoscope Corporation). The clotting velocity (CFR) was recorded as the angle at TEG (Figure); a higher CFR value is indicative of a thicker clots formation. Statistical analysis: Pharmacodynamic parameters were summarized as means and standard deviations (SD). The two-tailed student t-test was carried out on the average data with a placed at 0.05. 2. Results Acidosis: Reducing the pH to 7.0 significantly reduced the CFR. The addition of rFVIIa resulted in a significant increase in CFR. Hypothermia: Reducing the temperature of whole blood to 32 ° C resulted in a trend towards a moderate reduction of CFR. The addition of 25 nM of rFVIIa significantly increased the CFR. Hemodi luc ion: Albumin: Hemodilution with albumin was not associated with the worsening of clot formation (Table). For the 20% and 40% dilutions, but not for the 60% dilution, the addition of rFVIIa significantly increased the CFR. Hetastarch: Hemodilution with Hetastarch was associated with worsening clot formation at 40% and 60% dilutions only (Table). For 20% dilutions, but not at 40% and 60% dilutions, the addition of rFVIIa significantly increased the CFR. At the 60% dilution, the CFR followed by the addition of rFVIIa remained significantly reduced compared to the CFR in normal whole blood.

HES: All dilutions of whole blood with HES were associated with reduced CFR in relation to normal whole blood (Table). The addition of rFVIIa improved the CFR only at the 20% dilution level. In the 40% and 60% dilutions. The CFR after the addition of rFVIIa remained significantly reduced compared to the CFR in normal whole blood. It should be noted that the increase in the concentration of rFVIIa at 200 nM (corresponding to the concentration of plasma after administration of 720 - "5 μg / kg) significantly improved the CFR at a dilution of 40% (48 + 3) but failed to improve the CFR at the 60% dilution, which remained significantly reduced compared to the CFR in normal whole blood. 3. Conclusions 0 The effects that promote the in vitro coagulation of rFVIIa were not adversely affected by acidosis, hypothermia or hemodilution below 40%, however, in more severe degrees of colloid hemodilution with 6% starch and HES 130 / 0.4 worsening the effect of rFVIIa on the formation of 5 clots, as determined by TEG in vitro. 0 Example 4: Efficacy of Factor Vlla administered in conjunction with conventional therapy in the treatment of injuries The following study was carried out in order to evaluate the efficacy and safety of factor VII of recombinant activated coagulation (rFVIIa, NovoSeven®) as adjunctive therapy for the control of bleeding in severe traumas. 1. Methods The severity of bleeding in patients with superficial traumatic and / or penetrating lesions was randomly selected for a conventional treatment in addition to rFVIIa (200 + 100 + 100 μg / kg) or placebo. The first dose was administered after the eighth unit of blood (erythrocytes) with additional doses after 1 and 3 hours. The patients were monitored closely during the time period of 48 hours after the first dose of the test drug. This included recording the transfusion and infusion requirements, adverse events and surgical procedures. Blood was taken at frequent intervals to evaluate changes in blood clotting and blood chemistry parameters. Mortality, ventilator time, date of hospitalization and various adverse events concluding the predefined critical complications (MOF and acute respiratory distress syndrome (ARDS)) reported in the test sites were recorded until day 30.

Endpoints To assess the haemostatic effect, the primary endpoint was the number of units of erythrocytes (allogeneic erythrocytes, autologous erythrocytes, and whole blood) transfused during the 48-hour period from the first dose of the test product. The results of the therapy were also evaluated through the requirement of other transfusion products, mortality, days with the ventilator and date of hospitalization. The results of -security included the frequency and duration of events "Adverse events and changes in laboratory variables related to coagulation (activated partial thromboplastin time (aPTT), platelets, fibrinogen, D-dimer, antithrombin III, prothrombin fragments 1 + 2, and thrombin-antithrombin complex). Mortality is not a sensitive variable in an injured population, a composite endpoint was studied that included death, MOF and ARDS The safety report on MOF and ARDS was based on the specified definitions previously provided in the study protocol. The sample size was calculated according to the transfusion data from a retrospective study in a population of 14 patients with superficial traumas.In patients with an initial GCS> 8, a requirement of 12.4 units of red blood cell transfusion was found at 0- 48 hours It was estimated that 70 patients in each treatment group were required to detect the reduction of 60% of the from 4.4 units of erythrocytes to 1.8 units at 0-48 hours in addition to the 8 units of previous dose, with 80% power and 5% error type 1. As the test involved two groups with trauma and two groups Different, a total sample size of 280 patients was planned for the populations with superficial and penetrating traumatisms that were analyzed separately. The relevant results were for all randomly agreed patients who received the test drug. The Type 1 error was established for 5%. All analyzes were defined a priori, unless indicated otherwise. The total number of units of red blood cells transfused in the 48-hour period of initiation of treatment with the test product (the primary endpoint) was compared between the treatment groups using a Wilcoxon-Mann-Whitney classification test. This one-tailed test was selected since the administration of rFVIIa was not expected to increase transfusion requirements. Separate analyzes were carried out when patients died within the 48-hour period and were excluded or assigned as an erroneous result. Priority was given to analyzes where patients who died within the 48-hour period were excluded due to 1) care was useless in a proportion of these patients; 2) transfusion requirements in the 48-hour period were not evaluated objectively for patients who lived for only a few hours. The Hodges-Lehman estimate was used to estimate the difference of erythrocyte transfusions. The total amount of erythrocytes was calculated as the sum of autologous erythrocytes, allogeneic erythrocytes and whole blood, where each component was normalized to conventional units of erythrocytes (equivalent to a volume of 295 ml with a hematocrit of 63%, which was the average established in all sites). Fisher's exact test was used to compare the number of patients who required a massive transfusion (defined later as more than 20 units of RPC inclusive of the 8 units of previous dose) and the number of patients who experienced MOF, ARDS and / or death during the 30-day period. The relative reduction of risk of massive reduction and its 95% confidence interval (CI) was calculated. The effects of mortality in the 48-hour period were analyzed using the xi-square test. 2. Results Of the 301 patients selected at random, 143 patients with superficial trauma and 134 patients with penetrating trauma were selected for the analysis. The treatment groups were marked in terms of baseline characteristics within each population with trauma (Table 1). The patients were predominantly young men and were characterized by their "coagulopathic, acidic and hypothermic conditions." The causes of penetrating traumas were mainly by firearm (68%) and sharps weapons (30%) while 75% of superficial injuries were due to injuries related to automobile accidents Control of bleeding At the primary endpoint, the requirements of erythrocytes during the observation period of 48 hours after the initial dose of the test product, was shown for live patients in the 48-hour period in Figure 1. In patients with superficial trauma, rFVIIa significantly reduced erythrocyte requirements in the 48-hour period to 2.6 units compared to placebo (p = 0.02) .The need for massive transfusion was reduced by 20/61 patients (33%) in the group undergoing placebo treatment at 8/56 (14%) in the group subjected to treatment with rFVIIa, where a relative risk reduction of 56% was represented (95% Cl: [9%; 79%]; p = 0.03) (Figure 2). In patients with penetrating trauma, no significant effects were observed with respect to the requirements of erythrocytes within the 48-hour period with a reduction of 1.0 units of erythrocytes (p = 0.10). The need for massive transfusion in penetrating trauma was reduced from 10/54 (19%) patients in the placebo group to 4/58 (7%) in the group undergoing treatment with rFVIIa, which represents a relative reduction Risk score of 63% (95% CI: [-12%; 88%]; p = 0.08) (Figure 2). When patients who died were assigned an erroneous result, the statistical significance was not reached in the trauma population (Table 2). No significant differences were observed between the treatment groups in the trauma population with respect to the administration of fresh frozen plasma, platelets, cryoprecipitates, crystalloids or colloids (data not shown). Clinical response and safety The results for adverse events, mortality, days without ventilator and days out of ICU were summarized in Table 3. Positive trends in favor of rFVIla were observed for these endpoints, especially those concerning critical complications (ARDS, MOF and / or deaths). Survival curves are described in Figure 3. Adverse events occurred at a similar frequency and severity among the treatment groups. However, the profile of adverse events was similar between patients undergoing treatment with rFVIIa and patients undergoing treatment with placebo and there were no apparent treatment patterns depending on the types of adverse events reported. As can be expected in this severely damaged population, the three most frequent and seriously reported adverse events were ARDS, MOF and sepsis. A total of 12 thromboembolic adverse events were reported by the researchers during the trial period; 6 patients in the treatment group with rFVIIa dose and 6 in the placebo treatment group. In patients with superficial trauma, two incidences of pulmonary embolism and subclavian vein thrombosis (after the central line) were recorded in the placebo group, while a jugular vein thrombosis (after the central line and a thrombosis in the In patients with penetrating trauma, cerebral infarction and DVT were noted in each treatment group, and mesenteric vein thrombosis was recorded in the group treated with placebo and intestinal infarction (in the group treated with rFVIIa). site of operation) as well as a phlebothrombosis event that was observed in the group treated with rFVIIa.All 12 thromboembolic events were reported as serious adverse events.Conclusions The rFVIIa assisted in the control of bleeding in severe superficial trauma resulted in a significant reduction in red cell transfusion, similar tendencies were observed in traumatism s penetrating. The safety of rFVIIa was established in this damaged population with the dose proportion investigated. Table 1: Baseline characteristics - The data intervals refer to the means ± DS. Other data refer to the number (and percentage) of patients. * Body regions as defined by the Harm Severity Scale (ISS). There are no significant differences between the groups treated with rFVIIa and the groups treated with placebo that were observed. aPTT: activated partial thromboplastin time; PT: prothrombin time. Table 2: Total erythrocyte transfusions (units) during the 48-hour period after the first dose of the test drug.

* Hodges-Lehman point estimate of the increase in the amount of placebo transfusion to the active group. Patients who died in the 48-hour period were assigned to the elevated range.

Table 3: Adverse events and clinical responses All of the patents, patent applications and reference literature referred to herein were incorporated by reference in their entirety. Many variations of the ent invention suggest themselves to those skilled in the art in clarity of the foregoing detailed description, these variations are obvious and are contemplated within the intended scope of the appended claims. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the ent description of the invention.

Claims (23)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. The use of Factor Vlla or an equivalent of Factor Vlla for the manufacture of a medicament for the treatment of a trauma.
2. 2. The use according to claim 1, wherein the patient suffers from superficial trauma.
3. 3. E? use according to claim 1, wherein the patient suffers from penetrating trauma. .
4. The use according to any of claims 1 to 3, wherein the medicament comprises at least about 150 μg / kg Factor Vlla or a corresponding amount of one equivalent of Factor Vlla.
5. 5. The use according to any of claims 1 to 4, wherein the medicament is for the administration of a first dose containing at least about 150, preferably 200 ug / kg Factor Vlla or a corresponding amount of one equivalent of the Vlla factor, followed by a second dose containing approximately 100 ug / kg Factor Vlla or a corresponding amount of one equivalent of Factor Vlla administered one hour after the start of treatment.
6. 6. The use according to claim 5, wherein a third dose containing approximately 100 ug / kg Factor Vlla or an amount corresponding to an equivalent of Factor Vlla is administered three hours after the start of treatment.
7. The use according to any of claims 1 to 6, wherein the medicament is for the treatment of patients who have received less than about 10 units of whole blood (whole blood), erythrocyte globular packets (pRBC) or fresh frozen plasma (FFP), such as less than about 8 units, 5 units or less than about 2 units, between the time of your traumatic injury and the time of administration of Factor Vlla or an equivalent of Factor Vlla, or that they have not received any blood product and / or volume replacement products before the administration of Factor Vlla or an equivalent of Factor Vlla.
8. The use according to any of claims 1 to 7, wherein the medicament further comprises a second coagulation agent in an amount that increases the prevention or attenuation of Factor Vlla or an equivalent of Factor Vlla.
9. 9. The use according to claim 8, wherein the second coagulation agent is selected from the group comprising a coagulation factor and an antifibrinolytic agent.
10. The use according to claim 9, wherein the coagulation factor is selected from the group, comprising Factor VIII, Factor IX, Factor V, Factor XI, Factor XIII and any combination of the foregoing; and the antifibrinolytic agent is selected from the group comprising PAI-1, aprotinin, e-aminocaproic acid and tranexamic acid.
11. 11. A kit for treatment against injuries, characterized in that it comprises: (I) A medicament comprising the Factor Vlla or an equivalent of Factor Vlla; and (II) Instructions for use describing: a. A first dose containing at least about 150, preferably at least about 200 ug / kg Factor Vlla or a corresponding amount of one equivalent of Factor Vlla, can be administered at the start of treatment; b. A second dose containing approximately 100 ug / kg Factor Vlla or a corresponding amount of an equivalent of factor Vlla can be administered one hour after the start of treatment.
12. 12. The kit according to claim 11, characterized in that the instructions for use further describe that it may optionally contain a third dose containing approximately 100 ug / kg Factor Vlla or a corresponding amount of one equivalent of Factor Vlla that can be administered the patient at three hours after starting the treatment.
13. 13. A method for - the treatment of trauma, characterized in that it comprises administering to a patient in need of this treatment an amount of the Factor Vlla treatment or an equivalent of Factor Vlla.
14. 14. A method according to claim 13, characterized in that the patient suffers from superficial trauma.
15. 15. A method according to claim 13, characterized in that the patient suffers from penetrating trauma.
16. 16. A method according to claim 13, characterized in that the effective amount comprises at least about 150 μg / kg of the Vlla Factor or a corresponding amount of one equivalent of the Vlla Factor.
17. 17. A method according to claim 16, characterized in that a first amount of at least about 200 ug / kg of Factor Vlla or a corresponding amount of one equivalent of Factor Vlla is administered at the start of treatment and a second amount of about 100. μg / kg of Factor Vlla or a corresponding amount of an equivalent of Factor Vlla is administered to the patient one hour after starting treatment.
18. 18. A method according to claim 17, characterized in that it comprises administering to the patient a third amount of approximately 100 μg / kg Factor Vlla or a corresponding equivalent of Factor Vlla is administered at three hours after initiating the treatment.
19. 19. A method according to claim 13, characterized in that it further comprises administering to the patient a second coagulation agent in an amount that increases the treatment with Factor Vlla or an equivalent of Factor Vlla.
20. 20. A method according to claim 19, characterized in that the coagulation agent is selected from the group comprising a coagulation factor and an antifibrinolytic agent.
21. 21. A method according to claim 20, characterized in that the coagulation factor is selected from the group comprising Factor VIII, Factor IX, Factor V, Factor XI, Factor XIII and any combination of the preceding ones; and the antifibrinolytic agent is selected from the group comprising PAI-1, aprotinin, e-aminocaproic acid and tranexamic acid.
22. 22. A method for preventing the treatment of a trauma, characterized in that it comprises intentionally administering to a patient in need of this treatment an effective amount of this treatment of Factor VIIA or an equivalent of Factor Vlla for purposes of treating a trauma.
23. 23. A method for the treatment of trauma in most trauma patients, characterized in that it comprises (i) administering to a group of trauma patients an effective amount of Factor Vlla treatment or an equivalent of Factor Vlla; and (ii) observe a reduction in one or more clinical parameters among the group of patients relative to the level of clinical parameters expected in the same group of patients who have not received the Vlla Factor or an equivalent of the Factor Vlla.