MXPA06008482A - Use of factor viia for treating late complications of 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 preventing late complications in trauma patients.

Description

USE OF THE VIIA FACTOR FOR THE TREATMENT OF SUBSEQUENT COMPLICATIONS FOR TRAUMATISM Field of the Invention The invention concerns the prevention of, or reduction in, severity of subsequent complications in trauma patients. 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 tissue factor (TF) subsequent to exposure of TF at the site of a REF: 174329 traumatism The endogenous FVIIa becomes proteolytically active only after forming a complex with TF. Normally, the 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 an 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 in immunochemically active methods for the determination of TF (ELISA). 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 who undergo surgery for thoracic scoliosis idiopathic, an extensive surgical injury 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 venous thrombosis deep postoperative (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 the deaths occur after hospital admission and bleeding is responsible for between 15-40% of deaths in the hospital of trauma patients. In patients with complex injuries of the liver, 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 the secondary coagulopathy acquired by transfusion, hypothermia and other related causes that these patients face can also cause the so-called later complications including pulmonary embolism, disseminated intravascular coagulation (DIC), acute myocardial infarction, cerebral thrombosis, multiple organ failure (MOF), systemic inflammatory response syndrome (SIRS) and difficulty syndrome acute respiratory 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 of acute trauma, as well as for the prevention and reduction of subsequent complications resulting from the same injury and conventional modalities that are useful for treating victims with trauma. 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 of traumas. Typical patients for whom the drug is used are those who suffer from coagulopathic bleeding, including without limitation, patients who have experienced superficial or penetrating trauma. In another modality, the medication is used to reduce the severity of later complications. In one embodiment, subsequent complications include one or more of: organ failure, pulmonary embolism (PE), acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), acute myocardial infarction (AMI), cerebral thrombosis ( CT), systemic inflammatory response syndrome (SIRS), multiple organ failure (MOF), response syndrome systemic inflammatory (SIRS), infection, multiple organ failure (MOF), acute lung injury (ALI), including death caused by one or more of these syndromes. The invention also provides the use of Vlla Factor or an equivalent of Factor Vlla for the manufacture of a medicament for increasing the overall survival of a patient up to day 20, preferably up to day 30 after starting treatment. In another aspect, the invention provides for the use of Factor Vlla or an equivalent of Vlla Factor for the manufacture of a medicament to reduce the number of days of hospitalization of a trauma patient, including days in the Intensive Care Unit (ICU). , confinement in bed and / or the use of ventilator in the period of initiation of treatment (SOT) until day 20, preferably until day 30 after starting treatment or to reduce the risk of death in a trauma patient. In yet another aspect, the invention provides for the use of Factor Vlla or an equivalent of Factor Vlla for the manufacture of a medicament for improving lung function in a trauma patient. In one embodiment, (i) the patient is administered an amount of 200 μg / kg Factor Vlla or an equivalent of factor Vlla at the start of treatment; (ii) about one hour later, the patient is administered an amount of about 100 μg / kg Factor Vlla or an equivalent of Factor Vlla; Y (iii) approximately two hours later, the patient is administered an amount of approximately 100 μg / kg Factor Vlla or an equivalent of Factor Vlla. The invention also provides methods for preventing or attenuating one or more subsequent complications of trauma, 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 have experienced superficial injury or penetrating injury. In some embodiments, the initial administration stage is carried out 5 hours after the onset of a traumatic injury. 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, as for example, at three hours after the start of the treatment. In some embodiments, the method further comprises administering to the patient a second coagulation agent in an amount that increases the prevention or attenuation by the Factor VITa or the equivalent of Factor Vlla. Preferably, the second coagulation agent is a coagulation factor (including without limitation, 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 also provides methods to 'reduce the number of days of a patient with injury when hospitalized after the injury, which are carried out by administering to the patient an effective amount to achieve a reduction by the Factor Vlla or an equivalent of the Factor Vlla. The invention also provides methods to reduce the number of days a patient with an injury in the Intensive Care Unit (ICU) undergoes after the injury, which is carried out by administering to the patient an effective amount to achieve a reduction by the Factor Vlla or an equivalent of the Factor Vlla. The invention also provides methods to improve the Pulmonary function in a patient with trauma, which is carried out by administering to the patient an effective amount to achieve an improvement through the Factor Vlla or an equivalent of Factor Vlla. The invention also provides methods for reducing the risk of developing acute lung injury (ALI) and / or acute respiratory distress syndrome (ARDS) in a trauma patient, which are carried out by administering to the patient an effective amount to achieve a reduction by the Vlla Factor or an equivalent of the Vlla Factor. In some embodiments, the methods of the invention reduce the risk of progression of ALI or ARDS: The invention also provides methods to reduce the risk of developing disseminated intravascular coagulation (DIC) in a trauma patient, which is carried out by administering the patient an effective amount to achieve a reduction by the Factor Vlla or an equivalent of Factor Vlla. The invention further provides methods to reduce the risk of developing the systemic inflammatory response syndrome (SIRS) in a trauma patient, which is carried out by administering to the patient an effective amount to achieve a reduction of the Vlla Factor or an equivalent by the Vlla Factor The invention also provides methods to reduce the risk of developing multiple organ failure (MOF) in a patient with trauma, which is carried out by administering it to the patient an effective amount to achieve a reduction by the Vlla Factor or an equivalent of the Factor Vlla. The invention also provides methods for reducing the risk of death in a trauma patient, which are carried out by administering to the patient an effective amount to achieve a reduction by the Factor Vlla or an equivalent of Factor Vlla. The invention also provides methods to prevent or attenuate one or more subsequent complications of injury in the majority of trauma patients, which are carried out at: (i) administer to a group of patients with an injury an effective amount to achieve prevention or attenuation by Factor Vlla or an equivalent of Factor Vlla; Y (ii) observe a reduction in the frequency of occurrence in one or more subsequent complications of injury between the group of patients who received the Vlla Factor or an equivalent of the Vlla Factor relative to the frequency of occurrence of these later complications that are expected in the same group of patients who did not receive the Vlla Factor or an equivalent of the Factor Vlla. Brief Description of the Figures Figure 1 shows the distribution of requirements for erythrocytes within a period of 48 hours of observation after the first dose of. test product. Figure 2 shows the percentage of patients alive at 48 hours after. receive 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 to the 8 units of previous dose. Figure 3 shows the survival curves for populations with superficial and penetrating traumatisms. Detailed Description of the Invention The present invention provides methods and compositions that can be advantageously used to prevent or attenuate subsequent complications that patients with injury may experience following their injury and / or as a result of medical interventions that can be performed for the patient. treatment of their injuries. The methods are carried out when administering to a patient with an injury the Factor Vlla or an equivalent of Factor Vlla, in such a way that it is effective to prevent or attenuate one or more subsequent complications of trauma. An effective way to prevent or attenuate subsequent complications 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 preventing further complications of trauma can be evaluated by using one or more useful conventional parameters of later complications (see below). Subsequent complications that can be prevented by methods of the invention or whose severity can be mitigated include without limitation, pulmonary embolism (PE), acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), acute myocardial infarction (AMI). , cerebral thrombosis (CT), acute inflammatory response syndrome (SIRS), infections, multiple organ failure (MOF) and acute lung injury (ALI), "including death caused by one or more of these syndromes. Patients who could benefit from the use of the methods of the present invention included, without limitation, patients who suffered from a superficial injury and / or penetrating injury The superficial injury includes superficial trauma 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 ales, as well as lacerations of the spleen, lungs or diaphragm. The superficial lesion is usually accompanied by more extensive tissue damage compared to the penetrating lesion and, consequently, bleeding from the smaller veins. Penetrating injury includes trauma .penetrating, such as, for example, injuries caused by firearms or puncture-related injuries that may result in penetration of the inferior vena cava, injury to the liver, lung injury, injury to the prostate, urinary bladder, chest, and lacerations in the liver , as well as traumatisms in 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 veins, which require surgical treatment ("surgical bleeding") with uncontrolled and diffuse bleeding of small veins ("coagulopathic bleeding"). Moreover, patients with trauma who receive massive transfusions often suffer from coagulopathy and continue to bleed profusely due to surgical intervention, packaging and embolization of the larger 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 traumas 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, the deterioration or damage of platelet function. Hypothermia causes a low enzymatic activity of the coagulation cascade and dysfunctional platelets. Metabolic abnormalities, like 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 the systemic activation of coagulation and fibrinolysis > Excessive fibrinolysis Dilutional coagulopathy caused by excessive fluid treatment including, but not limited to, a limited number of platelets and / or impaired or impaired 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 blood pH below 7.5, such as, for example, below about 7.4, below about 7.3, below about-7.2, or below of approximately 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. patient (loss close to 40% of the volume total 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 (WB), packed red blood cells (pRBC) or fresh frozen plasma (FFP) between the time of their injury traumatic and the time of administration of Factor Vlla or an equiv of Factor Vlla. A WB unit typically contains -about 450 ml of blood and 63 ml of conventional anticoagulant / preservative (having a hematocrit of 36-44%). One pRBC unit typically contains 200-250 ml of conventional erythrocytes, plasma and anticoagulant / preservative (having a hematocrit of 70-80%). In other embodiments, patients undergoing treatment according to the invention have received less than about 8 units of WB, 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 modalities, patients undergoing treatment according to the invention do not suffer from a disorder blood, either congenital or acquired, such as, for example, hemophilia A, B or C. In different embodiments of the invention, patients may be excluded from treatment if they received the transfusion of 10 units or more of pRBC, such as, for example, of 15, 20, 25 cr 30 units, or if they were diagnosed with a congenital blood disorder. Factor Vlla or Vlla factor equivalents: In the practice of the present invention, any Vlla Factor or Factor Vlla equivalent can be used in such a way that it is effective in preventing further complications when administered to a patient with a lesion. In some embodiments, the Vlla Factor is the Vlla Factor of human as described, for example, in U.S. Pat. Num. 4,784,950 (Factor VII wild type). The term "Factor VII" is intended to encompass factor VII polypeptides in their closed form (zymogen), as well as those which can be processed proteolytically to produce their respective bioactive forms, which may 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 Factor Vlla of human and / or that contain one or more alterations in the sequences of amino acids relative to Factor Vlla of human.

These equivalents may show different properties relative to the human Vlla Factor, including stability, "Phospholipid binding, altered specific activity and the like In a number of embodiments, an equivalent of Factor Vlla includes polypeptides that show at least about 10%, preferably at least about 30%, more preferably at least about 50%, and more preferably at least about 70% of the specific biological activity of human Factor-Vlla For purposes of the invention, the biological activity of 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. Patent No. 5,997,864.In this assessment, the biological activity is expressed as the reduction of the coagulation time in a control sample and converted into "Factor VII units". compared to a conventional sample of human serum containing one unit / ml of activity Addition 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 the X Factor (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 Factor Vlla and / or an equivalent of Factor Vlla. Examples of the factor VII equivalent include, without limitation, 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, K157A-FVII, E296V-FVII, E296V / M298Q-FVII, V158D / E29V- FVII, V158D / M298K-FVII and S336G-FVII, L305V / K337A-FVII, L305V / V158D-FVII, L305V / E296V-FVII, L305V / M298Q-FVII, L305V / V158T-FVII, L305V / K337A / V158T-FVII, L305V / K337A / M298Q-FVII, L305V / K337A / 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 / 337A / 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 / E296V / M298Q / K337A-FVII, S314E / K316H-FVII, S314E / K316Q-FVII, S314E / L305V-FVII, S314E / K337A-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, K316H / V158T-FVII, K316Q / L305V-FVII, 316Q / 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 / K337A / 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 / 337A-FVII, S314E / L305V / V158D / K337A / M298Q-FVII, S314E / L305V / V158D / E296V / K337A-FVII, S314E / L305V / V158D / E296V / M298Q-FVII, S314E / L305V / V158T / E296V / M298Q / K337A-FVII, K316H / L305V / K337A-FVII, K316H / L305V / V158D-FVII, 316H / L305V / E296V-FVII, K316H / L305V / M298Q-FVII, K316H / L305V / V158T-FVII, 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 / K337A-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, 316Q / 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, K316Q / L305V / V158T / K337A / M298Q-FVII, K316Q / L305V / V158D / E296V / K337A-FVII, K316Q / L305V / V158D / K337A / M298Q-FVII, K316Q / L305V / V158D / E296V / K337A-FVII, K316Q / L305V / V158D / E296V / M298Q / K337A-FVII and K316Q / L305V / V158T / E296V / M298Q / K337A-FVII. In some embodiments, the equivalent of factor VII is V158D / E296V / M298Q-FVII. Preparations and formulations: The present invention comprises the therapeutic administration of Factor Vlla or, equivalents of Factor Vlla, 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 the 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 the non-adherent cells and the like. Optionally, Factor VII polypeptides can • also be purified. Purification can be achieved using any method known in the art, including without limitation, affinity chromatography such as, for example, a column of an anti-Factor VII antibody (see for example, Wakabayashi et al., J *. Biol. Chem. 261: 11097, 1986; and Thim e't al., Biochem. 27: 7785, 1988); hydrophobic interaction chromatography; ion exchange chromatography; size exclusion chromatography; electrophoretic methods (eg, directed isoelectric preparation (IEF), differential solubility (eg, precipitation of ammonium sulfate), or extraction and the like See, generally, Scopes, Protein Purification, Springer-Verlag, New York, 1982; and Protein Purification, J.-C. Janson and Lars Ryden, editors, VCH Publishers, New York, 1989. After purification, the preparation preferably contains less than about 10% by weight, more preferably less than about 5% by weight. % and more preferably less than about 1% of proteins without Factor VII derived from the host cell Factor VII and Factor VII related polypeptides can be activated by proteolytic opening, using Factor Xlla or other proteases having specificity similar to trypsin, such as, for example, Factor IXa, kallikrein, Factor Xa and thrombin See, for example, Osterud et al., Biochem 11: 2853 (1972); Thomas, Patent from U.S. Patent No. 4,456,591 and Hedner et al., J. Clin. Invest. 71: 1836 (1983). Alternatively, Factor VII can be activated when passing through an ion exchange column, such as Mono Q® (Pharmacia) or similar. 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 Factor Vlla 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 trauma. Liposome preparations are generally described in, for example, U.S. Pat. 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 an equivalent of Factor Vlla can be administered to a patient as a single dose comprising an effective single dose amount to prevent or treat subsequent complications, or in "a series of dosage steps that together comprise an effective amount to prevent or treat subsequent complications.An effective amount of Factor Vlla or an equivalent of Factor Vlla (see below) refers to the amount of Factor Vlla or an equivalent 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 statistically quantifiable improvement in the outcome, as shown by at least one clinical parameter associated with subsequent complications of injury (See below.) When the Vlla Factor or an equivalent is administered, you can determine an effective amount is obtained by comparing the coagulation activity of the Factor Vlla equivalent with that of the Factor Vlla and adjusting the quantity 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 within a period of approximately 6 hours after the traumatic injury has occurred, such as, for example, within approximately 4 hours, within about 2 hours or within 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, administration occurs over a period of time less than about 2.5 minutes and in some cases, less than about one minute In general, an effective amount of a single dose comprises at least about 40 ug / kg Human Factor Vlla or a corresponding amount of one equivalent of Factor Vlla, 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 Vlla Factor or an equivalent of the Vlla Factor during a time interval of 15 minutes. ion, 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 embodiments, 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 time 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 comprising at least about 40 ug / kg. After a period of at least about 30 minutes after the administration of the third amount, the patient can then receive an additional (fourth) amount of the Vlla Factor or an equivalent of the Vlla Factor 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 others 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 Vlla Factor 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 embodiments, the patient receives the second amount of the Vlla Factor or an equivalent of the Factor Vlla after a period of time of at least about 45 minutes 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 the fourth) amount of the Factor Vlla or an equivalent of the Factor Vlla after a period of time of approximately 45 minutes from the previous administration, such as at least 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 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 time of approximately 3 hours from the first dose, the patient receives a third dose comprising approximately 100 ug / kg. The following table illustrates different non-limiting embodiments 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 Factor Vlla or an equivalent of Factor Vlla if necessary. Steps (ii) and (iii) can be repeated until hemostasis is achieved satisfactory. According to the invention, the 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 route of administration is intravenously. Combination of treatments: The present invention encompasses the: combined administration of additional agents adjusted with 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 to prevent subsequent complications associated with injury. It should be understood that the actual amounts may defined in the context of particular treatment regimens, including for example, time and number of administrations, forms of administration, formulations, etc. Results of treatment: The present invention provides methods and compositions for preventing and / or attenuating one or more subsequent complications of trauma. Subsequent 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 syndromes. In the practice of the present invention, subsequent complications can be evaluated using conventional methods, such as, for example, the scores described herein in the Tables. 1 to 5. The evaluations can be carried out at least approximately up to 20 days after starting the treatment according to the invention, such as, for example, at least about 30 days, at least about 35 days, or at least 40 days after the start of the treatment. treatment. Organ damage or organ failure includes, without limitation, damage to structure and / or damage to function of the organ in kidney, 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 in the pulmonary exchange mechanisms or damage of 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 in the normal function of an organ compared to the normal, normal functioning of a corresponding organ in a normal and healthy staff. The failure of an organ may be a minor reduction in its functioning (for example, 80-90% of normal) or it may be a greater reduction in its functioning (for example, 10-20% of normal); the reduction may be a complete failure of the functioning of the organ. Failure of an organ includes, without limitation, biological reduction of functioning (eg, leakage of urine), for example, due to tissue necrosis, loss of glomeruli (kidney), fibrin deposition, hemorrhage, edema, or inflammation. Damage to an organ includes, without limitation, tissue necrosis, loss of glomeruli (kidney), deposition of fibrin, 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 pulmonary 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 clinical or biochemical parameters to be evaluated, are well known by the expert clinicians. 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 vasopressor treatment Renal: Creatinine and urine output Other clinical assessments include days no ventilator, days without organ failure, days without vasopressor treatment, SOFA score and lung injury evaluation scores as well as vital signs. Evaluation methods for coagulopathy or inflammation They are well known by 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 deterioration or residual damage, in particular of the pulmonary mechanics, may include without restriction, medium restriction, obstruction, deterioration or damage of the ability to diffuse carbon monoxide or abnormalities in gas exchange with exercise, fibrous alveolitis with persistent hypoxemia, increased immobile alveolar space and 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 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, damage morphological / structural and / or damage to the functioning of organs 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 the pulmonary exchange mechanisms or damage of the capillary membrane of the alveoli, reduction in the exit of urine (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., Mi.J. Respir Crit. Care Med. 149: 818-24, 1994): acute access; bilateral chest radiography infiltrates; Lung Artery Interlocking Pressure < 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 trauma complications. 1. The Glasgow Coma Score is determined as follows: Normal = 15 Vegetatives = 0 2. The Multiple Organic Ealla score (MOF) is determined as follows: Multiple organic failure score Salivable = 0 Severe = 15 3. The ARDS score is determined as follows: Normal = 0 Severe = 20 4. The SIRS score is determined as follows: Systemic Inflammatory Response Syndrome Score 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 . 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 outcomes: "Glasgow Coma Score greater than approximately 9 determined 20 days after the start of treatment;" Glasgow Coma Score greater than approximately 11 determined 30 days after the start of treatment; "Glasgow Coma score greater than approximately 13 determined 40 days after the start of treatment;" MOF score less than 4 when determined 20 days after the start of treatment; "MOF score less than 3 when determined 30 days after the start of treatment;" MOF score less than 2 when determined 40 days after the start of treatment; 1 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 initiation of treatment;" ARDS score or less than approximately 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 the start of treatment; "SIRS score less than about 1 when determined 40 days after the start of treatment;" Any combination of any of the Coma Glasgow, MOF, ARDS and / or previous 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 following parameters relative to a patient similar to the one who has not been administered Factor Vlla or a Vlla Factor equivalent according to the invention: a reduction in units of blood, plasma, erythrocytes, globular pack or volume replacement products that need to be administered; a reduction in the number of days of hospitalization after suffering an injury, 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 in which certain interventions (this is for example, a ventilator) are required. Non-limiting examples of results include: (i) a reduction of units of blood, plasma, erythrocytes, globular packets or volume substitute products that need to be administered in at least about 2 units, 4 units or 6 units; (ii) a reduction in days in ICU by ün_. 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 total days of hospitalization for 2 days, 4 days or 8 days." The following examples are intended non-limiting illustrations of the present invention Example 1: Factor Vlla Administration to Trauma Victims The following study is In order to evaluate the efficacy and safety of recombinant coagulation factor VII (rFVIIa, NovoSeven®) as adjunctive therapy for the control of bleeding in severe traumas Methods: Double-blind, randomized, multi-center study compared rFVIIa with placebo. The study product was administered in 3 iv injections (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 follow-up of 30 days. The conventional local treatment of the hospital was provided throughout the study. The groups with superficial and penetrating traumatisms were analyzed separately. Results A total of 143 patients with superficial lesions and 134 with penetrating lesions were analyzed. In patients with superficial lesions (mean of the severity score - of trauma: 33 + 13), there was a tendency to reduce red blood cell transfusion 48 hours after the dose (primary point) in the rFVIIa group versus placebo where the adjustment was made for 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 (< 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 lesion population.Reduced requirements were significantly reduced in the group of abrupt lesions.The tendencies to reduce complications guarantee an additional investigation." Table: Patients with critical results in a 30-day period (group of superficial trauma) Placebo rFVIIa (N = 74) (N = 69) Multiple organ failure 7 (9%) 3 (4%) Difficulty syndrome 12 (16%) 3 (4%) respiratory Acute Death 22 (30%) 17 (25%) ) Time without ICU Media 10.5 d Average 12.6 d Time without ventilator Mean 13.7 d Mean 15.4 d The results of the group of superficial injuries indicate that patients undergoing treatment with NovoSeven® have few complications and spent less time in intensive care units than patients who received conventional treatment and mortality overlap was lower in the group treated with NovoSeven®.

Example 2; Efficacy of the Vlla Factor provided in conjunction with conventional therapy in the treatment of traumatisms TEST DESIGN: A double-blind, placebo-controlled, parallel-group, randomized, multi-center study was conducted in patients with severe traumatic injuries and / or penetrating. Patients were recruited by observation for admission to the traumatology 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. The patients selected after receiving 6 units of pRBC in a period of 4 hours 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 / kg + 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 drug was given to patients who in the opinion of the surgeon who attended them required a transfusion greater than 8 units of PRBC. After an observation period of 48 hours, it was started 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. Specific procedures such as physical examination, laboratory analysis and evaluation of adverse events were carried out throughout the trial.The patients were monitored through the study in the severe points including the number of required units of PRBC, adverse events, Survival and parameters related to 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. Continuously taking safety into account all SAEs as reported during the test. TEST TEST: Human Recombinant Activated FVII Factor (rFVII) and Placebo were provided as a dry frozen powder in a single-use bottle of 2.4 mg to be reconstituted with sterile water by injection Ph.Eur. TEST POPULATION: Approximately 280 patients (140 per treatment arm) aged 16 years or older were recruited with severe and / or penetrating severe trauma injuries. Inclusion criteria Patients who entered. The test met the following inclusion criteria: 1. Injuries due to a superficial and / or penetrating injury. 2. Receive 6 units of PRBC in a 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 arrival 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. c 12. Injuries maintained 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 48 hour period 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 Cryoprecipitate platelets > Number of times the patient undergoes surgery due to bleeding, -. > Interval of "time between the first dose of the study drug and when it reaches the normal range of PT coagulation, 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), confinement in bed and / or ventilator in the period of SOT until Day 30. Prior to treatment results (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 '' products of required transfusion units (below) Intravenous fluid included in the composition, eg, colloids, crystalloids (below) Number of times the patient was taken to surgery and reasons for surgery (below) Adverse events ARDS, .infection, MOF 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 . Blood sampling 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 coagulation APTT, fibrinogen, D dimers, anti tro bina-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 hours , 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 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, a sample in 2 to 4 of the following time intervals: 0-1 hour (immediately after the first dose and before the next dose is administered), 1-3 hours (immediately after the second dose and before to administer the next dose), 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 Frequency of FVII: C, 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 prothrombin time (PT) analysis, 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 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 drug of study (on the other hand as the condition demanded by the patient.) The following was registered: 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 did not have a ventilator) in addition to registering at the scene of the accident during the prehospital stage. Respiratory rate Pa02 / Fi02, 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 at the trauma center: before treatment, 24 and 48 hours from 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 hemodilucidn, 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: WB was obtained 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 with 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 stimulate acidosis, WB (2 ml) was added 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 temperature of the blood samples was lowered to 32 ° C. To simulate hemodilucon, all solutions were mixed with citrate (10% v / v) to ensure anticoagulation of the hemodiluted WB, then WB were diluted by 20%, % 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 analysis, total thrombostastography: Coagulation was initiated by adding tissue factor 1:50 000 (Innovin®, Dade Behring, Deerfield, 111, USA) to WB and recalcitrated with 15 mM calcium chloride (free CaCl2 ~ 2-3 mM). The final concentration of tissue factor in WB 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 TEG angle (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 t-student two-tailed analysis was carried out on the average data with a placed at 0.05. 2. Acidosis Results: Reducing the pH to 7.0 reduced the CFR significantly. The addition of rFVIIa resulted in a significant increase in CFR. Hypothermia: Reducing the temperature of WB to 32 ° C resulted in a trend towards a moderate reduction of CFR. The addition of 25 nM of rFVIIa significantly increased the CFR. Hemodialysis: Albumin: Hemodilution with albumin was not associated with deterioration or damage of clot formation (Table). For dilutions at 20% and 40%, but not for 60% dilution, the addition of rFVIIa significantly increased the CFR. Starch: Hemodilution with starch was associated with the deterioration or damage of clot formation in 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 WB. HES: All dilutions of WB with HES were associated with reduced CFR in relation to normal WB (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 WB. 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 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 in comparison with the CFR in normal WBs. 3. Conclusions 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 worsened the effect of rFVIIa on clot formation, as determined by TEG in vitro.

Example 4: Efficacy of Factor Vlla administered in conjunction with conventional therapy in treatment against trauma The following study was carried out in order to evaluate the efficacy and safety of factor VII 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 selected at random for 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. The blood was taken at frequent intervals to evaluate the changes in coagulation and in the parameters of blood biochemistry. Mortality, ventilator time, hospitalization date and various adverse events concluding the predefined critical complications (MOF and acute respiratory distress syndrome (ARDS)) reported in the test sites were recorded until the 30th. Final points To evaluate the effect haemostatic, 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 safety results included the frequency and duration of 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). Because mortality is not a sensitive variable in an injured population, we studied a composite endpoint that comprised death, MOF and ARDS. The safety report on MOF and ARDS was based on the specified definitions previously provided in the study protocol. Statistical analysis The sample size was calculated according to the transfusion data from a retrospective study in a population of 14 patients with sudden trauma. In patients with an initial GCS * _ > 8, a requirement of 12.4 units of erythrocyte transfusion was found at 0-48 hours (50: 6.2). It was estimated that 70 patients in each treatment group were required to detect the reduction of 60% of the requirement of 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 a 5% error rate of type 1. As the test involved two trauma populations and two different groups, a total sample size of 280 patients was planned for populations with superficial and penetrating trauma 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. The analyzes- separately were carried out. when the 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 number of erythrocytes was calculated as the sum of the 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 the 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 lesions 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 firearms (68%) and sharps weapons (30%) while 75% of superficial injuries were due to injuries related to car accidents. Control of bleeding At the primary end point, 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 the placebo (p = 0.02). The need for massive transfusion was reduced from 20/61 patients (33%) in the group undergoing placebo treatment to 8/56 (14%) in the group undergoing rFVIIa treatment, where a relative risk reduction was represented. 56% (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 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 rFVIIa 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 between 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, they were registered in the group with placebo two incidences of pulmonary embolism and a subclavian vein thrombosis (after the central line), while a jugular vein thrombosis (after the central line and a thrombosis in the arterial extremity in patients treated with rFVIIa) were recorded. With penetrating injury, cerebral infarction and DVT were observed in each treatment group, as well as mesenteric vein thrombosis in the placebo group and intestinal infarction (at the site of operation) as well as an phlebothrombosis 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 of erythrocyte transfusion. The safety of rFVIIa in this population was observed in penetrating traumatisms. with the proportion of dose investigated.

Table 1: Characteristics of the baseline 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 estimate point of 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 MOF: Multiple organ failure; AROS: Acute respiratory distress syndrome; ICU: Intensive Care Unit.

All of the patents, patent applications and reference literature referred to herein were incorporated by reference in their entirety. Many variations of the present 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 by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Claims (42)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1.
2. The use of Factor Vlla or an equivalent of Factor Vlla for the manufacture of a medicament to prevent or attenuate one or more subsequent complications of a trauma. - The use according to claim 1, wherein the subsequent complication is selected from the list of: organ failure, pulmonary embolism (PE), acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), acute myocardial infarction (AMI), cerebral thrombosis (CT), acute inflammatory response syndrome (SIRS), infection, multiple organ failure (MOF), acute lung injury (ALI) and death.
3. 3. The use according to any of claims 1 to 2, wherein the patient suffers from a superficial injury.
4. 4. The use according to any of claims 1 to 2, wherein the patient suffers from a penetrating injury.
5. 5. The use according to any of claims 1 to 4, wherein the medicament comprises the less about 150 μg / kg Factor Vlla or a corresponding amount of one equivalent of Factor Vlla.
6. 6. The use according to claim 5, 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 Factor Vlla, followed of 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.
7. The use according to claim 6, 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.
8. 8. The use of Factor Vlla or an equivalent of Factor Vlla for the manufacture of a medication to reduce the number of days of hospitalization of a patient with injury after the trauma.
9. The use according to claim 8, wherein the medicament is for reducing the number of days a patient with an injury in the Intensive Care Unit (ICU) undergoes after the trauma.
10. 10. The use of Factor Vlla or an equivalent of the Factor Vlla for the manufacture of a medicine to improve lung function in a trauma patient.
11. The use according to claim 10, wherein the medicament is for reducing the risk of developing acute lung injury (ALI) and / or acute respiratory distress syndrome (ARDS) in a trauma patient.
12. 12. The use according to claim 11, wherein the medicament is for reducing the risk of progression from ALI to ARDS. "
13. 13. The use of Factor Vlla or an equivalent of Factor Vlla for the manufacture of a medicament to reduce the risk of disseminated intravascular coagulation (DIC) in a patient with trauma
14. 14. The use of Vlla Factor or an equivalent of Vlla Factor for the manufacture of a drug to reduce the risk of developing the systemic inflammatory response syndrome (SIRS) in a patient with trauma
15. 15. The use of Vlla Factor or a Vlla Factor • equivalent for the manufacture of a drug to reduce the risk of developing multiple organ failure (MOF) in a trauma patient
16. 16. The use of Factor Vlla or an equivalent of Factor Vlla for the manufacture of a drug to reduce the risk of death in a trauma patient
17. 17. Use in accordance with any of the claims 1 to 16, the medicament further comprises a second coagulation agent in an amount that increases prevention or attenuation by the Vlla Factor or an equivalent of the Factor Vlla.
18. 18. The use according to claim 17, wherein the second coagulation agent is selected from the group comprising a coagulation factor and an antifibrinolytic agent.
19. 19. The use according to claim 18, wherein the coagulation factor is selected from the group comprising Factor VIII, Factor IX, Factor V, Factor XI, Factor XIII and. any combination of precedents; and the antifibrinolytic agent is selected from the group comprising PAI-1, aprotinin, e-aminocaproic acid and tranexamic acid.
20. 20. A kit for preventing or attenuating subsequent complications of traumas, characterized in that it comprises: (I) A drug that comprises Factor Vlla or an equivalent of Factor Vlla; and (II) Instructions for use indicating that: a. A first dose containing at least 150, preferably at least about 200 ug / kg Factor Vlla or a corresponding amount of an equivalent of Factor Vlla, can be administered at the start of treatment; b. A second dose containing approximately 100 ug / kg of Factor Vlla or a corresponding amount of an equivalent of Factor Vlla can be administered one hour after the start of treatment.
21. 21. The kit according to claim 20, 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 to the patient at three hours after starting treatment.
22. 22. A method for preventing or attenuating one or more subsequent complications of trauma, characterized in that it comprises administering to a patient in need of prevention or attenuation, an effective amount of Factor Vlla or an equivalent of Factor Vlla for prevention or attenuation.
23. 23. A method according to claim 22, characterized in that the subsequent complications are selected from the group comprising: organ failure, pulmonary embolism (PE), acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), acute myocardial infarction myocardium (AMI), cerebral thrombosis (CT), systemic inflammatory response syndrome (SIRS), multiple organ failure (MOF), systemic inflammatory response syndrome (SIRS), infection, multiple organ failure (MOF), acute lung injury (ALI) and death.
24. 24. A method according to claim 22, characterized in that the patient suffers from a superficial lesion.
25. 25. A method according to claim 22, characterized in that the patient suffers from a penetrating injury.
26. 26. A method according to claim 22, 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.
27. 27. A method according to claim 26, 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 Factor Vlla or a corresponding amount of one equivalent of Factor Vlla is administered to the patient one hour after initiating treatment.
28. 28. A method according to claim 27, characterized in that it further comprises administering to the patient a third amount of approximately 100 μg / kg Factor Vlla or a corresponding amount of one equivalent of Factor Vlla three hours after starting the treatment.
29. 29. A method according to claim 22, further characterized in that it comprises administering to the patient a second coagulation agent in an amount that increases the prevention or attenuation by the Factor Vlla or an equivalent of Factor Vlla.
30. 30. A method according to claim 29, characterized in that the second coagulation agent is selected from the group comprising a coagulation factor and an antifibrinolytic agent.
31. 31. A method according to claim 30, 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 fibrinolytic agent is selected from the group comprising PAI-1, aprotinin, e-aminocaproic acid and tranexamic acid.
32. 32. A method for reducing the number of days of hospitalization of a patient with injury after the injury, characterized in that it comprises administering to the patient an effective amount for a reduction by the Vlla Factor or an equivalent of the Factor Vlla.
33. 33. A method to reduce the number of days a patient with an injury spends in the Intensive Care Unit (ICU) after the injury, characterized in that it comprises administering to the patient an effective amount for a reduction by the Factor Vlla or an equivalent of the Factor Vlla.
34. 34. A method for improving lung function in a trauma patient, characterized in that it comprises administering to a patient an effective amount for an improvement by the Factor Vlla or an equivalent of Factor Vlla.
35. 35. A method for reducing the risk of developing acute lung injury (ALI) and / or acute respiratory distress syndrome (ARDS) in a trauma patient, characterized in that it comprises, administering to the patient an effective amount for a reduction by the Factor Vlla or an equivalent of the Factor Vlla.
36. 36. A method according to claim 35, characterized in that the administration reduces the risk of ALI progression towards ARDS, the method comprises administering to the patient an effective amount for a reduction by the Vlla Factor or an equivalent of the Vlla Factor.
37. 37. A method for reducing the risk of developing disseminated intravascular coagulation (DIC) in a trauma patient, characterized in that it comprises administering to the patient an effective amount for a reduction by Factor Vlla or an equivalent of Factor Vlla.
38. 38. A method to reduce the risk of developing systemic inflammatory response syndrome (SIRS) in a patient with trauma, characterized in that it comprises administering to the patient an effective amount for a reduction by the Vlla Factor or an equivalent of the Factor Vlla.
39. 39. A method for reducing the risk of developing multiple organ failure (MOF) in a trauma patient, characterized in that it comprises administering to the patient an effective amount for a reduction by the Vlla Factor or an equivalent of the Vlla Factor.
40. 40. A method for reducing the risk of developing death in a trauma patient, characterized in that it comprises administering to the patient an effective amount for a reduction by the Factor Vlla or an equivalent of Factor Vlla.
41. 41. A method for preventing or attenuating one or more subsequent complications of trauma, characterized in that it comprises intentionally administering to a patient in need of prevention or attenuation, an effective amount to prevent or attenuate by Factor Vlla or an equivalent of Factor Vlla for purposes of preventing or mitigating these later complications.
42. 42. A method to prevent or attenuate one or more subsequent complications of injury in most patients with injury, this method includes (i) administering to a group of patients with an injury an effective amount for prevent or attenuate by the Vlla Factor or an equivalent of the Vlla Factor; and (ii) observe a reduction in the frequency of occurrence of one or more subsequent complications of injury among this group of patients relative to the frequency of occurrence of later complications expected in the same group of patients who did not receive the Factor Vlla or an equivalent of the Factor-Vlla.