Seguridad y eficacia de facto VII recombinante activado para el tratamiento de pacientes con hemofilia a severa con presencia de inhibidores y alto riesgo de eventos agudos de sangrado o hemorragia que no responden al concentrado de complejo protrombínico activado / Safety and efficacy de facto Recombinant VII activated for the treatment of patients with hemophilia to severe with inhibitors and high risk of acute bleeding or bleeding events that do not respond to activated prothrombin complex concentrate

INTRODUCCIÓN: Antecedentes: El presente informe expone la evaluación del Facto VII recombinante en el manejo de pacientes con diagnóstico de Hemofilia A severa, con presencia de inhibidores y que presentan o estén en riesgo de presentar evento agudo de sangrado o hemorragia, con el objetivo de prevenir muerte por sangrado no controlado. Aspectos Generales: La hemofilia es un desorden hematológico congénito ligado al cromossoma X. Se han identificado dos tipos principalmente, la Hemofilia A que es causado por deficiencia de factor de coagulación VIII (FVIII) y la Hemofilia B que es causado por deficiencia de factor de coagulación IX (FIX). La deficiencia de estos factoes es el resultado de mutaciones en los genes de los factores de coagulación respectivos. Tecnología Sanitaria de Interés: Factor VII Recombinante Activado-RFVIIA (Novoseven - Marca Registrada): El RFVIIA es un glicoproteina dependiente de la vitamina K que consiste em 406 residuos de aminoácidos (MW 50K Dalton). Es estructuramente similar al factor VIIa derivado de plasma hmano y actúa de manera semejante al factor VII en la cascada de coagulación. Debido a que el factor VII actúa directamente sobre el factor X independientemente del facto VIII y IX, este medicamento puede ser usado en pacientes con hemofilia que han desarrollado inhibidores a los factores VII oIX. METODOLOGIA: Estratégia de Búsqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de Factor VII recombinante activado con diagnóstico de Hemofilia A severa, con presencia de inhibidores altos respondedores definido por presentar una alta respuesta (>= 5 unidades Bethesda UB), que presentan o estén en alto riesgo de presentar evento agudo de sangrado o hemorragia y que haya usado aPCC previamente. RESULTADOS: Se realizó la búsqueda bibliografica y de evidencia cientifica para el sustento del uso del Factor VII recombinante activado en pacientes con Hemofilia A severa con titulos elevados de inhibidores, que sean altos respondedores (>= 5 unidades Bethesda UB), que tengan o estén en alto riesgo de presentar evento agudo de sangrado y que hayan usado aPCC previamente. CONCLUSIONES: En la presente evaluación de tecnología sanitaria se ha encontrado escasa evidencia que muestre que facto VII recombinante activado (rFVIIa) ofrezca beneficios para los pacientes con diagnóstico de hemofilia A severa con presencia de inhibidores y con alto riesgo de hemorragia de evento agudo de sangrado o hemorragia que hayan usado el concentrado de complejo protrombínico activado (aPCC). La evidencia que respalda esto uso de rFVIIa es aún muy limitada, se establece que el efecto de rFVIIa se evaluará con los datos de los pacientes que los hayan recibido por el periodo de vigencia de este Dictamen, para determinar el impacto de su usi en los desenlaces de interés de este Dictamen. Esta información será tomada en cuenta en la reevaluación de este medicamento para efectos de un nuevo dictamen al terminar la vigencia del presente Dictamen Preliminar.

Long-term safety and efficacy of a pasteurized nanofiltrated prothrombin complex concentrate (Beriplex P/N): a pharmacovigilance study.

BACKGROUND: The rapid reversal of the effects of vitamin K antagonists is often required in cases of emergency surgery and life-threatening bleeding, or during bleeding associated with high morbidity and mortality such as intracranial haemorrhage. Increasingly, four-factor prothrombin complex concentrates (PCCs) containing high and well-balanced concentrations of vitamin K-dependent coagulation factors are recommended for emergency oral anticoagulation reversal. Both the safety and efficacy of such products are currently in focus, and their administration is now expanding into the critical care setting for the treatment of life-threatening bleeding and coagulopathy resulting either perioperatively or in cases of acute trauma. METHODS: After 15 yr of clinical use, findings of a pharmacovigilance report (February 1996-March 2012) relating to the four-factor PCC Beriplex P/N (CSL Behring, Marburg, Germany) were analysed and are presented here. Furthermore, a review of the literature with regard to the efficacy and safety of four-factor PCCs was performed. RESULTS: Since receiving marketing authorization (February 21, 1996), ~647 250 standard applications of Beriplex P/N have taken place. During this time, 21 thromboembolic events judged to be possibly related to Beriplex P/N administration have been reported, while no incidences of viral transmission or heparin-induced thrombocytopenia were documented. The low risk of thromboembolic events reported during the observation period (one in ~31 000) is in line with the incidence observed with other four-factor PCCs. CONCLUSIONS: In general, four-factor PCCs have proven to be well tolerated and highly effective in the rapid reversal of vitamin K antagonists.

Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial.

BACKGROUND: Prothrombin complex concentrate (PCC) can substantially shorten the time needed to reverse antivitamin K oral anticoagulant therapy (OAT). OBJECTIVES. To determine the effectiveness and safety of emergency OAT reversal by a balanced pasteurized nanofiltered PCC (Beriplex P/N) containing coagulation factors II, VII, IX, and X, and anticoagulant proteins C and S. PATIENTS AND METHODS: Patients receiving OAT were eligible for this prospective multinational study if their International Normalized Ratio (INR) exceeded 2 and they required either an emergency surgical or urgent invasive diagnostic intervention or INR normalization due to acute bleeding. Stratified 25, 35, or 50 IU kg(-1) PCC doses were infused based on initial INR. Study endpoints included INR normalization (

[Subarachnoid hemorrhage in a patient with corrected cyanotic congenital cardiopathy]. / Hemorragia subaracnoidea en un paciente con una cardiopatía congénita cianótica corregida.

A 19-year-old man with congenital cyanotic heart disease experienced subarachnoid bleeding from a ruptured cerebral aneurysm. Immediate rebleeding with disordered hemostasis caused by prophylactic anticoagulation treatment was the cause of death. Medical progress in repairing congenital heart disease or attenuating its effects has increased the life expectancy of such patients. Anesthesiologists who are not specialized in this area may find themselves assuming responsibility for these patients during non-cardiac surgery of greater or lesser extension.

Postinfection purpura fulminans in a patient heterozygous for prothrombin G20210A and acquired protein S resistance.

Purpura fulminans usually consists of large, often symmetrical, spreading ecchymosis, which may later develop into extensive areas of skin necrosis and peripheral gangrene. Postinfectious purpura fulminans associated with an autoantibody directed against protein S has been described. The interaction and the contribution of recently described mutations such as factor V Leiden and prothrombin G20210A to the development and progression of postinfectious purpura fulminans and venous thrombosis is not known. The authors describe a patient heterozygous for prothrombin G20210A who developed purpura fulminans and extensive venous thrombosis secondary to acquired protein S deficiency.

Thrombogenicity of prothrombin complex concentrates.

Thrombogenicity of factor IX complex or prothrombin complex concentrates (PCC) is a well-acknowledged problem. The exact incidence is unknown but has decreased with the improvement of the quality of coagulation factor concentrates and a more judicious use of these products. The clinical spectrum of thrombogenicity ranges from superficial thrombophlebitis, deep-vein thrombosis and pulmonary embolism, and arterial thrombosis to disseminated intravascular coagulation. Several risk factors have been identified: (a) predisposing clinical factors (underlying disease and clinical condition), (b) therapy factors (dosing, concomitant therapy and drug interactions), and (c) quality of the PCC used. It is generally assumed that the risk of thromboembolic adverse effects is greater in patients with acquired disorders of hemostasis than in patients with inherited coagulation factor deficiencies. In hemophilia B, clinical conditions with an increased risk include large muscle hematomas, immobilization, surgery (especially orthopedic surgery), and liver disease. In acquired disorders of hemostasis, a prethrombotic state can be assumed in all patients where an indication for PCC concentrates is considered. Liver disease and/ or antithrombin deficiency are considered as major risk factors. Therapy factors with an increased risk include large, repetitive doses of PCC. It is assumed that heparin and, in the case of antithrombin deficiency, antithrombin substitution decrease the incidence of thromboembolic adverse effects. Heparin neutralisation with protamine and aprotinin therapy may be additional risk factors. The declining incidence and the recent cluster of fatal thromboembolic adverse events in Germany with one brand of PCC is strong evidence for the crucial role of the quality of PCC in the occurrence of thromboembolic adverse effects.

The use of prothrombin complex concentrates in the treatment of hemorrhages induced by oral anticoagulation.

Bleeding events are a common adverse effect in oral anticoagulation that frequently depend on the duration and intensity of treatment. Major bleeding events, particularly intracerebral hemorrhages, are a serious complication in cases that require the rapid reversal of anticoagulation. Urgent correction of the coagulation defect is also indicated when major emergency surgery is necessary. In addition to vitamin K supplementation, the administration of prothrombin complex concentrates is the most effective measure for the rapid reversal of anticoagulation. Due to the time-consuming administration and increased risk of volume overload, the administration of fresh frozen plasma is less advisable in such instances. The application of prothrombin complex concentrates requires a precautious risk-benefit evaluation, including an estimation of contraindications and repeated laboratory monitoring for dose adjustment.

Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates.

In 1994, shortly after a heat-treated prothrombin complex concentrate (PCC) had been withdrawn from the German market due to transmission of hepatitis B, the license of another brand was withdrawn, due to 3 acute fatalities associated with the use of this product. We report on the clinical data of altogether 5 patients, who died during a 3 month period in Germany after having received this brand of PCC. All patients had surgery, acquired deficiencies of coagulation factors, and underlying diseases predisposing for thrombosis or disseminated intravascular coagulation. PCC was administered for the prevention of bleeding. In three patients, a drug interaction of PCC with aprotinin may also have played a role. Several points, however, are suspicious of a major causative effect of the respective product, (a) the close temporal correlation between administration of the drug and the subsequent clinical as well as laboratory deterioration, (b) the accumulation of these adverse events in a short period of time, when the use and market share of this brand increased due to the shortage of other products, and (c) laboratory abnormalities of this brand which have been consistently observed in several in vitro studies.

[Risk of hepatitis from conventional pooled PPSB preparations]. / Hepatitisrisiko von konventionellen PPSB-Poolpräparaten.

The risk of hepatitis from prothrombin complex (pooled human clotting preparation) was retrospectively analysed. Of 39 patients who had undergone cardiac surgery, 22 (56%) developed hepatitis, while in those had not received pooled preparations the rate was only 5%. Although the proportion of multiple transfusions was significantly higher among the recipients of clotting preparations, it was found that the decisive hepatitis-inducing factor was the pooled preparation, not the transfusion blood. Contrary to earlier results, all cases were of the non-A, non-B type. The frequency of carriers of the causative virus is apparently not different from that with B virus. Thus both virus types must have occurred at similar frequency in earlier pooled clotting preparations. Since, furthermore, there seems to be no difference in their infectivity and their penetration in the population at large is likely to be similarly low, unrecognised double-infections in recipients of pooled clotting preparations were probably frequent before the introduction of recent methods of demonstrating hepatitis B.

Non-mechanical hemorrhage in severe liver injury.

Coagulopathy, or non-mechanical hemorrhage, complicated the operative course of 17 of 33 (51.5%) patients suffering severe liver trauma. The highest incidence of non-mechanical hemorrhage (66.7%) occurred in patients undergoing anatomic lobectomy. Serial hemostatic parameters were assessed and thrombocytopenia was the most striking abnormality in patients with non-mechanical hemorrhage. The degree of thrombocytopenia was directly correlated with the number of blood transfusions administered. The mean operative blood transfusion requirement was significantly greater in patients with non-mechanical hemorrhage, 25.1 +/- 2.87 (S.E.M.) units, than in those without, 12.2 +/- 1.83 units (p < 0.001). The bulk of this transfusion was given before the onset of clinically overt coagulopathy. Massive transfusion of stored blood was felt to be the most important factor in causing non-mechanical hemorrhage. Convincing evidence for disseminated intravascular coagulation was lacking, and abnormal fibrinolysis was infrequent and mild when observed. Although uneventful in most, in six patients non-mechanical hemorrhage resulted in excessive blood transfusion, unnecessary operation or death. Infusions of platelet concentrate, fresh frozen plasma, and fresh blood were used to successfully treat most cases of non-mechanical hemorrhage. In all cases, these components were not started until non-mechanical hemorrhage was clinically apparent. The value of prophylactic use of blood components is stressed. Because of troublesome side effects associated with the use of prothrombin complex concentrates, these agents are contraindicated in patients with severe liver injury. After receiving concentrates, one patient developed severe hypotension leading to ventricular fibrillation, two developed transient thrombocytopenia and two others demonstrated multiple pulmonary microthrombi at autopsy, a finding not observed in autopsied patients not receiving the concentrates.