Recombinant Activated Coagulation Factor VII Research Articles

A bispecific antibody approach for the potential prophylactic treatment of inherited bleeding disorders

Inherited bleeding disorders such as Glanzmann thrombasthenia (GT) lack prophylactic treatment options. As a result, serious bleeding episodes are treated acutely with blood product transfusions or frequent, repeated intravenous administration of recombinant activated coagulation factor VII (rFVIIa). Here we describe HMB-001, a bispecific antibody designed to bind and accumulate endogenous FVIIa and deliver it to sites of vascular injury by targeting it to the TREM (triggering receptor expressed on myeloid cells)-like transcript-1 (TLT-1) receptor that is selectively expressed on activated platelets. In healthy nonhuman primates, HMB-001 prolonged the half-life of endogenous FVIIa, resulting in its accumulation. Mouse bleeding studies confirmed antibody-mediated potentiation of FVIIa hemostatic activity by TLT-1 targeting. In ex vivo models of GT, HMB-001 localized FVIIa on activated platelets and potentiated fibrin-dependent platelet aggregation. Taken together, these results indicate that HMB-001 has the potential to offer subcutaneous prophylactic treatment to prevent bleeds in people with GT and other inherited bleeding disorders, with a low-frequency dosing regimen.

Monozygotic twin cases of endometriosis with Glanzmann thrombasthenia: a case report and review of literature

BackgroundGlanzmann thrombasthenia (GT) is a rare bleeding disorder with a high prevalence in communities where consanguineous marriages are mainstream. Endometriosis is a chronic inflammatory disease, and its risk increases in women with menstrual periods of longer than six days. The phenotypic expression of endometriosis is determined by the frequency and rate of the menstrual flow, as well as genetic and environmental factors.Result and case presentation14-year-old monozygotic twin sisters with GT who developed ovarian endometriosis were referred to Hazrat Rasoul Hospital due to severe dysmenorrhea. In ultrasonic examination, endometrioma cysts were reported in both patients. They both went under endometrioma cystectomy, and the bleeding was managed using antifibrinolytic drugs, followed by recombinant activated coagulation factor VII. Both were discharged after 3 days. In the ultrasound examination performed one year after the surgery, ovaries were normal in the first twin, while the second twin had a 28 × 30 hemorrhagic cyst in the left ovary.Discussion and conclusionMenstrual bleeding and genetic factors are two theories that could be related to GT and endometriosis association, and GT could be considered a risk factor for endometriosis.

Treatment tactics for a patient with acquired hemophilia: continuous infusion of recombinant activated coagulation factor VII and the inhibitor eradication

Introduction. Acquired hemophilia is a rare autoimmune disease caused by an inhibitor to clotting factor VIII (FVIII). It complicates the course of many diseases, in particular autoimmune diseases, and in women is often associated with pregnancy.Aim — to present a case of successful treatment of a patient with acquired hemophilia using long-term continuous infusion of rFVIIa and inhibitor eradication as a result of immunosuppressive therapy.Main findings. A clinical observation of severe hemorrhagic syndrome in a patient with acquired hemophilia associated with pregnancy is presented. Uterine bleeding in the patient after spontaneous delivery, refractory to standard hemorrhagic syndrome treatment, required multiple surgical interventions. Laboratory tests showed prolongation of APTT, CT in the INTEM rotational thromboelastometry test, a decrease in plasma FVIII activity and presence of inhibitor to FVIII. Vacuum-assisted closure was applied to treat infected laparotomy wound. Therapy for acquired hemophilia consisted of hemostatic therapy and the inhibitor eradication. Hemostatic therapy included a continuous infusion of rFVIIa at a rate of 30 μg/kg/h with a gradual decrease up to 9.6 μg/kg/h, as well as its fractional administration before every surgery at a dosage of 80 μg/kg. The effectiveness of the therapy was assessed by the dynamics of CT in the INTEM test and the shortening of the APTT. The inhibitor eradication was achieved by prednisolone therapy, combined immunosuppression with rituximab and azathioprine, followed by its replacement with cyclophosphamide. As a result, the hemorrhage was stopped, reference plasma activity of FVIII and eradication of the inhibitor were reached.

Providing Hemostasis for Long-Term Central Venous Access Device (LTCVAD) Placement in Patients with Factor VIII (FVIII) Inhibitors

Introduction and Objectives: Inhibitors against FVIII can occur in the haemophilic and non-haemophilic patients. Venous access is critical to the treatment of the patients with FVIII inhibitors and the prevention of complications due to bleeding. However, there is no guide to the selection of the most appropriate LTCVADs in these patients. The aim of this study was to investigate the providing hemostasis and the results of the placement of LTVADs in patients with FVIII inhibitors.Patients and Methods: The results of the LTCVADs placement were investigated in 8 patients (7 males, 1 female) with FVIII inhibitors (a median age of 45 years, range 25-73). FVIII inhibitors were revealed in 6 patients with congenital haemophilia A, in the woman with von Willebrand disease and in the patient with acquired idiopathic haemophilia A. In all patients plasma FVIII activity was below 1%, and inhibitor titers were from 120 to 450 BU/ml. Indications, early and delayed complications, hemostatic therapy and implanted period were evaluated. All LTCVADs were monitored from insertion to removal.Results. In total, thirteen LTCVADs were placed. The indications for placement of LTCVADs were Immune tolerance therapy (5 patients), hemostatic therapy (2 patients) and chemotherapy in woman with von Willebrand disease and mammary cancer. Central Venous Port System (Bard Access System) was implanted in hemophilia A patient simultaneously wiht the hip replacement surgery. The hemostasis in this patient was provided by recombinant activated coagulation factor VII (rFVIIa) (Coagil VII, Generium, Russia) 120 mcg/kg every 2 hours for 2 weeks. However, when rFVIIa therapy after surgery was stopped and antibiotic therapy continued extensive hematoma on the breast developed and the port system was removed. In 7 patients 12 peripherally inserted central catheters (PICCs) (GROSHONG PICC CATHETER, Bard Access System) were placed. PICCs were inserted into brachial veins. All patients received rFVIIa (120 mcg/kg) before the procedure, and experienced no bleeding complications. After the procedure, one patient had some bleeding and required repeated administration of rFVIIa (90 mcg/kg). Overall mean PICC dwell time was 176 days (median 120 days; range 5-463). One patient died due to gastrointestinal bleed in 5 days. Occlusions occurred in 3 cases on 30, 120 and 300 days after PICC insertion in two patients. Accidental withdrawals occurred in one patient. At all three patients PICCs have been placed repeatedly. The obstruction rate was 30% (1.9 per 1000 PICC-days). No infection or thrombotic complications were observed. Six patients are still using a catheter without apparent problems for more than 4 months. There were no specific problems in using PICC with immune tolerance therapy and chemotherapy.Conclusion. PICCs appear safe to use in the patients with FVIII inhibitors, with acceptably low rates of infectious or thrombotic complications. Catheter occlusion was the most common complication.Single administration of the rFVIIa provides safe implantation of the PICCs in patients with FVIII inhibitors. PiCCs placement provides significant economic savings (decrease in rFVIIa requirements). DisclosuresNo relevant conflicts of interest to declare.

Patients with haemophilia A with inhibitors in China: a national real‐world analysis and follow‐up

The development of alloantibodies (inhibitors) against coagulation factor VIII (FVIII) is the most serious complication of FVIII replacement therapy in patients with haemophilia A (HA). We carried out a nationwide study focussing on patients with HA with inhibitors in China to evaluate the condition and management of this population. The study retrospectively analysed patient characteristics, clinical history, manifestation, treatment strategy as well as individual haemophilia care of 493 patients with inhibitors (466 with severe HA and 27 with non-severe HA) registered all over China. The median (interquartile range) age at diagnosis of FVIII inhibitors was 13(5-28)years in patients with severe HA and 24(10·5-39·5)years in patients with non-severe HA. Most patients (85%) had high-titre inhibitors. Prothrombin complex concentrate and recombinant activated coagulation factor VII were used respectively in 76·2% and 29·2% of patients for acute bleeding. Only 22·3% of patients underwent immune tolerance induction (ITI) treatment, of whom 64·9% achieved negative inhibitor titre. In patients who did not undergo ITI, the inhibitors turned negative in 17·7%, and patients with low peak inhibitor titre were more likely to acquire negative titre spontaneously (odds ratio 11·524, 95% confidence interval 5·222-25·432; P=0·000). We recorded that 3·2% of the patients died from haemophilia-related life-threatening bleeding.

Опыт применения рекомбинантного активированного фактора свертывания VII в лечении массивных акушерских кровотечений

This article presents the results of a retrospective observational study on the use of recombinant activated coagulation factor VII (Eptacog alfa [activated], Coagil-VII) to evaluate its efficacy and safety in the treatment of massive obstetric hemorrhage (MOH) in 30 women with volume of circulating blood loss over 25%; 90% of women delivered by cesarean section, and 10% of women delivered by vaginal birth. The efficacy and safety of Coagil-VII as a hemostatic agent in intensive therapy for MOH were evaluated using clinical, laboratory and statistical research methods. The administration of Eptacog alfa [activated] (Coagil-VII) helped to significantly reduce the volume of blood loss, duration, time and rate of bleeding, and the amount of blood component transfusion. The total dose of the drug was 3.68 mg. The analysis of laboratory parameters (hemogram, blood biochemistry tests) in patients of the study group with MOH did not reveal any negative effect of Coagil-VII according to the parameters. The results of the hemostatic system assessment showed that after administration of Coagil-VII there was an increase in blood coagulation potential, as evidenced by a decrease in International Normalized Ratio, shortened prothrombin and thrombin time, activated partial thromboplastin time. All parameters were within the reference range, without increasing the risk of thrombotic complications. No thrombotic complications in the early and late postoperative/postpartum period were detected in any patient. Hysterectomy in this study group was performed in 7 (23.3%) patients; the uterus was preserved in 23 (76.7%) women with MOH. The use of modern hemostatic drug Coagil-VII in the complex treatment of MOH under the control of clinical laboratory testing helped to stop (in 86.6% of women) or reduce the intensity of hemorrhage (in 13.3% of patients), reduce the amount of transfused blood components, improve the patients’ condition without thrombotic complications, reduce possible complications associated with transfusions and the cost of therapy, and implement organ preservation tactics in 76.7% of women. Key words: pregnancy, safety, massive hemorrhage, patient blood management, fertility, efficacy

Infusion therapy of traumatic shock

Background. Analysis of all deaths due to military trauma (MT) over the last decade revealed that 1/4 of them could have been prevented. Up to 90 % of these deaths are related to blood loss. Trauma induces acute endogenous coagulopathy within a few minutes in 25 % of patients, which quadruples mortality. The main feature of MT is its combined nature, because in explosive injuries the local action of the explosion is combined with shrapnel wounds and distant damage to organs, and the wound canal goes through several anatomical parts of the body. In case of concomitant injuries, there are several sources of pain impulses, there is a deep endotoxicosis and impaired function of damaged organs. Under MT conditions, it is difficult to determine the nature of the shock due to a combination of hemorrhagic and traumatic shock. Uncontrolled post-traumatic bleeding is the leading cause of preventable death.
 Objective. To describe infusion therapy (IT) of shock.
 Materials and methods. Analysis of literature data on this issue.
 Results and discussion. In approximately 1/3 of hospitalized patients with trauma, the bleeding is coagulopathic. The severity of coagulopathy is determined by the influence of environmental factors, metabolic disorders, therapeutic strategy, the presence of brain and liver injuries, individual characteristics of the patient, the trauma and shock, hemodilution coagulopathy. The primary task of managing a patient with trauma is to eliminate the so-called lethal triad (hypothermia, acidosis, coagulopathy) and ensure perfusion of vital organs. Damage Control Resuscitation (DRC) is a systemic approach to the treatment of severe injuries that combines a resuscitation strategy with a range of surgical techniques from the moment of injury till the end of the treatment. DRC is aimed at blood loss minimization, maximization of tissue oxygenation, and optimization of outcomes. Surgeries performed as part of the DRC approach include an incision from the xiphoid process to the pubis with evacuation of blood and clots from the abdominal cavity, thorough examination and termination of all bleedings. Damaged parenchymal organs are completely resected. Damaged intestine is resected and connected with clips without anastomosis formation. Damaged vessels are ligated. The abdominal cavity is closed with a sterile bandage, but not sutured. After 1-2 days, tampons are removed, anastomoses are formed, and all non-viable tissues are removed. As for examinations, magnetic resonance imaging is the gold standard for assessing the severity of the injury and detecting extraperitoneal bleeding. In patients with closed abdominal trauma, hypotension, or an unknown mechanism of trauma, a rapid ultrasound examination is indicated to look for blood at potential sites of its accumulation. In the treatment of injuries with bleeding and shock, IT is of great importance. Its principles include the restriction of crystalloids use, the use of blood products in the optimal ratio of blood and plasma, and hypotension until the final surgical hemostasis. Reosorbilact (“Yuria-Pharm”) has properties close to an ideal infusion solution. The efficacy of Reosorbilact in shock was demonstrated in a multicenter Rheo-STAT study. In traumatic shock, infusion of 800 ml of Reosorbilact does not affect the coagulation hemostasis system. Instead, administration of a similar volume of 0.9 % NaCl is accompanied by a tendency to hypercoagulation, and 500 ml of hydroxyethyl starch – by hypocoagulation. Reosorbilact has a pronounced rapid hemodynamic effect. The target hemoglobin level in patients with trauma and bleeding is 70-90 g/L. Intravenous iron preparations (Sufer, “Yuria-Pharm”) can be used for its correction. Prehospital plasma transfusion is recommended to normalize coagulogram parameters. Tranexamic acid (Sangera, “Yuria-Pharm”) should be administered to patients with bleeding within 3 hours of injury. The first dose should be given at the prehospital stage of care. The pleiotropic effects of Sangera include antifibrinolytic, anti-allergic and anti-inflammatory. In addition, Sangera 2-3 times lowers the threshold of pain sensitivity. Another recommended component of comprehensive treatment of bleeding is the introduction of calcium chloride. Recombinant activated coagulation factor VII is not recommended for routine administration and is prescribed only when other measures are ineffective. It is recommended to urgently discontinue vitamin K antagonists and use appropriate antidotes. Pulmonary embolism is the third most common cause of death among patients with polytrauma who survived the third day. It is recommended to initiate the pharmacological thromboprophylaxis within 24 hours of bleeding control being achieved.
 Conclusions. 1. A significant proportion of preventable deaths are related to blood loss. 2. The primary task of managing a patient with trauma is to eliminate the lethal triad (hypothermia, acidosis, coagulopathy) and ensure perfusion of vital organs. 3. In the treatment of injuries with bleeding and shock, IT is of great importance. 4. Tranexamic acid should be administered to bleeding patients within 3 hours of injury.

The modern concept of intensive therapy of coagulopathy, which is complicate polytrauma and shock

The statute presents the fourth edition (The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition, 2016) of European recommendations on the treatment of severe blood loss and coagulopathy caused by injury. More than 50% of all trauma patients with a fatal outcome die within 24 hours after injury. After hospitalization in a third of patients with trauma, the bleeding is coagulopathic. They significantly increase the risk of multiple organ failure and death compared with patients with similar trauma in the absence of coagulopathy. Early acute coagulopathy associated with traumatic injury is multifactorial: 1) hemorrhage induced shock; 2) tissue damage with the release of tissue thromboplastin and the development of thrombinemia; 3) activation of anticoagulant and fibrinolytic systems. The severity of coagulation disorders is determined by the influence of environmental factors, metabolic disorders (acidosis, hypothermia, tissue hypoperfusion and consumption coagulopathy) and therapeutic strategy. Coagulopathies can be associated with trauma to the brain, liver, and patient's individual characteristics, which include age, heredity, comorbidities, and medication, especially oral anticoagulants. Coagulation monitoring (internationally normalized ratio (INR) and APTT), characterizes only the beginning of the 2nd phase of blood coagulation, and represents the generation of only the first 4% of thrombin. Therefore, the performance of a normal coagulogram may be normal, although the general condition of the blood coagulation system is pathological. Late diagnosis of traumatic coagulopathy may affect the outcome. A new concept of reanimation of patients with massive bleeding has been presented, the immediate introduction of coagulation components (RBC, native plasma and platelets in a 1: 1: 1 ratio), tranexamic acid, fresh frozen plasma, fibrinogen concentrate, desmopressin, prothrombin complex concentrate, recombinant activated coagulation factor VII (rFVIIa). Currently, the issue of using fresh whole blood for resuscitation in case of injury and massive blood loss is relevant.

Effect of Recombinant Activated Coagulation Factor VII on Hemorrhage Expansion Among Patients With Spot Sign–Positive Acute Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is a devastating stroke type that lacks effective treatments. An imaging biomarker of ICH expansion-the computed tomography (CT) angiography spot sign-may identify a subgroup that could benefit from hemostatic therapy. To investigate whether recombinant activated coagulation factor VII (rFVIIa) reduces hemorrhage expansion among patients with spot sign-positive ICH. In parallel investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trials in Canada ("Spot Sign" Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy [SPOTLIGHT]) and the United States (The Spot Sign for Predicting and Treating ICH Growth Study [STOP-IT]) with harmonized protocols and a preplanned individual patient-level pooled analysis, patients presenting to the emergency department with an acute primary spontaneous ICH and a spot sign on CT angiography were recruited. Data were collected from November 2010 to May 2016. Data were analyzed from November 2016 to May 2017. Eligible patients were randomly assigned 80 μg/kg of intravenous rFVIIa or placebo as soon as possible within 6.5 hours of stroke onset. Head CT at 24 hours assessed parenchymal ICH volume expansion from baseline (primary outcome) and total (ie, parenchymal plus intraventricular) hemorrhage volume expansion (secondary outcome). The pooled analysis compared hemorrhage expansion between groups by analyzing 24-hour volumes in a linear regression model adjusted for baseline volumes, time from stroke onset to treatment, and trial. Of the 69 included patients, 35 (51%) were male, and the median (interquartile range [IQR]) age was 70 (59-80) years. Baseline median (IQR) ICH volumes were 16.3 (9.6-39.2) mL in the rFVIIa group and 20.4 (8.6-32.6) mL in the placebo group. Median (IQR) time from CT to treatment was 71 (57-96) minutes, and the median (IQR) time from stroke onset to treatment was 178 (138-197) minutes. The median (IQR) increase in ICH volume from baseline to 24 hours was small in both the rFVIIa group (2.5 [0-10.2] mL) and placebo group (2.6 [0-6.6] mL). After adjustment, there was no difference between groups on measures of ICH or total hemorrhage expansion. At 90 days, 9 of 30 patients in the rFVIIa group and 13 of 34 in the placebo group had died or were severely disabled (P = .60). Among patients with spot sign-positive ICH treated a median of about 3 hours from stroke onset, rFVIIa did not significantly improve radiographic or clinical outcomes. ClinicalTrials.gov identifier: NCT01359202 and NCT00810888.

Effects of recombinant activated coagulation factor VII on apoptosis and expressions of Bcl-2 and Bax in rats with intracerebral hemorrhage.

To investigate the effects of recombinant activated coagulation factor VII (rFVIIa) on apoptosis and the expressions of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) in rats with intracerebral hemorrhage (ICH). A total of 90 8-week-old male Sprague-Dawley (SD) rats with similar weight were selected and randomly divided into normal group (n=30), ICH control group (n=30), and rFVIIa treatment group (n=30). Five days later, hematoxylin-eosin (HE) staining was applied to observe pathological changes in rat brain in three groups. Cell apoptosis in rat brain was detected at 6 h, 12 h, 24 h, 48 h, 72 h, and 120 h, respectively. The relative expression levels of Bcl-2 and Bax in brain tissues were measured via fluorescence quantitative Polymerase Chain Reaction (qPCR) and Western blotting, respectively. Compared with those in ICH control group, rats in rFVIIa treatment group had fewer degenerated and necrotic nerve cells and milder pathological changes in the marginal zone. The number of apoptotic cells in ICH control group and rFVIIa group was gradually increased in a time-dependent manner, and achieved the peak at 72 h. The number of apoptotic cells in treatment group was significantly lower than that in ICH control group after 24 h (p<0.05). Both fluorescence qPCR and Western blotting results proved that in comparison with ICH control group, rFVIIa group had a higher relative expression level of Bcl-2 (p<0.05) and a lower expression level of Bax (p<0.05). Apoptosis mechanism may be involved in secondary brain injury after ICH. RFVIIa may have an important protective effect on neuronal injury after ICH by promoting the expression of Bcl-2 and inhibiting the expression of Bax protein.

Safety and efficacy of recombinant activated coagulation factor VII in congenital hemophilia with inhibitors in the home treatment setting: A review of clinical studies and registries.

Self-administration of factor and bypassing agents by persons with hemophilia in the home setting is recommended to facilitate earlier intervention after bleeding episodes. The objective of this review was to summarize recombinant activated coagulation factor VII (rFVIIa) safety and efficacy data from clinical trials and patient registries documenting use in the home treatment setting in people with congenital hemophilia with inhibitors (CHwI). A total of 16 studies and registries were identified for inclusion; 14 evaluated on-demand treatment of acute bleeding episodes (865 patients, 9024 bleeding episodes) and 2 evaluated use for secondary prophylaxis (108 patients, 42,861 prophylaxis days). In the on-demand studies, efficacy was consistently high (81%-96%), and thrombotic events were uncommon (n = 3). In the secondary prophylaxis studies, rFVIIa was associated with a 45% to 59% reduction in bleeding episodes and no thrombotic events. These data support the clinical practice of administering rFVIIa in patients in the home treatment setting after initiation under a physician's care.

Recognition and management of platelet-refractory bleeding in patients with Glanzmann's thrombasthenia and other severe platelet function disorders.

Patients with rare qualitative platelet disorders or platelet function disorders (PFDs) may present to the hospital physician with severe bleeding episodes or excessive surgical bleeding. Although standard treatment consists of platelet transfusions, repeated transfusions may result in the development of antiplatelet antibodies (APA) or clinical refractoriness, rendering further platelet therapy ineffective. In such settings, an approved treatment option for patients with Glanzmann’s thrombasthenia (GT), one of the well-known rare PFDs, is recombinant activated coagulation factor VII (rFVIIa). Data regarding the efficacy of rFVIIa in patients with GT and platelet refractoriness are available from a large patient registry, an international survey, and multiple case reports and demonstrate efficacy in patients with and without refractoriness or APA. This article reviews the rFVIIa clinical data in patients with GT and platelet refractoriness and discusses clinical implications relevant to the hospital-based physician. Because uncontrolled bleeding can be life-threatening, hospital physicians should be alert to the signs of platelet refractoriness, be able to recognize continued internal or external bleeding, and know how to adapt treatment regimens for the effective management of bleeding. The management of patients who receive rFVIIa should occur in consultation with a hematologist with experience in PFDs, and patients with suspected platelet refractoriness should be referred to such a hematologist as early as possible. A critical unmet need is the development of a definition of an adequate response to platelet transfusion, which would facilitate early recognition of platelet refractoriness in patients with PFDs who exhibit a normal platelet count.

Safety and efficacy of recombinant factor VIIa by pediatric age cohort: reassessment of compassionate use and trial data supporting US label.

The relative safety and efficacy of recombinant activated coagulation factor VII (rFVIIa, NovoSeven® RT) across pediatric age cohorts is poorly defined. The objective of this analysis was to assess the safety and efficacy of rFVIIa in pediatric patients with congenital hemophilia with inhibitors (CHwI) in the clinical studies supporting the U.S. labeling. Pediatric data were derived from seven studies (five acute and two perioperative treatments) and pooled. All data were stratified by age (<2, 2 to <6, 6 to <12, and 12-16 years) and study category (acute treatment of bleeding episodes or surgery). The pediatric dataset included 172 patients; 144 received rFVIIa for the treatment of bleeding episodes and 28 for the control of bleeding perioperatively. Recombinant FVIIa was effective for 95.4% (1,026/1,076) of the evaluable bleeding episodes and had similar treatment effectiveness across pediatric age groups (range, 94.1-97.2%). The majority received doses of 90 mcg/kg. rFVIIa was effective in achieving perioperative hemostasis across pediatric age groups (range, 91-100%), with greater efficacy observed with the recommended (90 mcg/kg) versus lower dose (35 mcg/kg). A total of 88 pediatric patients experienced a total of 285 adverse drug reactions, similar in type to those reported among adult patients. A total of seven thrombotic events were recorded in seven pediatric patients; only one was confirmed related to rFVIIa upon individual case review. rFVIIa is safe and effective in the treatment of bleeding episodes and prevention of periprocedure bleeding in CHwI with no apparent differences observed among pediatric age groups.

Safety of recombinant factor VIIa in patients under extracorporeal membrane oxygenation

To address the safety (rate of thromboembolic events and circuit complications) and efficacy (rate of bleeding control) of recombinant activated coagulation factor VII (rFVIIa) to treat severe bleeding refractory to all surgical and medical treatments in patients under veno-arterial (VA) or veno-venous (VV) extracorporeal membrane oxygenation (ECMO) support. In a tertiary referral University Cardiothoracic Surgery Centre including three intensive care units, 30 patients received the rFVIIa during ongoing VA or VV ECMO support (8.6% of ECMO activity from 2005 to 2014; N = 347). Early and late clinical results were analysed (retrospective analysis of prospectively collected data). In a substudy, a case-matching procedure was performed among ECMO patients who received (Group A) or did not receive (Group B) rFVIIa treatment. The mediastinum was the most common site of refractory bleeding (after heart transplantation or other cardiac surgery; 90%); 90% (n = 27) of patients were on VA ECMO and the remainder on VV ECMO. The survival rate at ECMO explantation and at the 30th post-implantation day was 67 and 50%, respectively. The final efficacy rate of rFVIIa in stopping bleeding was 93.3%. The rate of thromboembolic events was 3.3% (1 case) and the rate of circuit change was 16.7% (without instances of overt circuit clotting). After case-matching, Group A comprised 23 patients and Group B included 43 patients. No statistically significant differences were observed among groups in terms of thromboembolic events (P = 0.99), circuit change, ventilation time (P = 0.71), infectious complications (P = 06) and survival at both ECMO explantation and the 30th post-implantation day. Late survival was comparable (Kaplan-Meier analysis; P = 0.42). In case of life-threatening bleeding refractory to all conventional therapies, rFVIIa presents an acceptable safety profile in patients under ECMO support. No circuit dysfunctions and limited rates of thromboembolism are observed.

Pharmacokinetics of Multiple Doses of rFVIIa in Patients with Hemophilia With and Without Inhibitors

Introduction:Recombinant activated coagulation factor VII (rFVIIa, NovoSeven®) has a well-established efficacy and safety profile, and is currently the only recombinant by-passing agent globally available for the treatment of bleeding episodes in patients with hemophilia and inhibitors. In clinical trials with on-demand treatment of mild and moderate bleeding episodes, both the 3×90 µg/kg repeat dose and the 270 µg/kg single dose dosing regimens have proven to be efficacious with success rates around 90%. This clinical trial is the first direct comparison of the PK of 3x90 µg/kg and 270 µg/kg in patients with hemophilia using two PK assays, and the trial also includes an evaluation of other coagulation parameters, to allow for a comparison of the two regimens from a PK perspective.Aim:To evaluate and compare the pharmacokinetics of rFVIIa administered intravenously after a single 270 µg/kg dose and three 90 µg/kg doses given at three hour intervals to hemophilia patients, using two PK assays (FVIIa activity assay and FVII antigen). In addition, a series of plasma coagulation tests (PT, aPTT, F1+F2, and D-dimer) was performed and correlated to the exposure of rFVIIa.Methods:Six patients with severe hemophilia A and B, with and without inhibitors, were included in a single center randomized cross-over clinical trial. Each patient was randomized to receive both a single injection of 270 µg/kg rFVIIa and 3x90 µg/kg rFVIIa (one administration every three hours; the maximum interval for the treatment of a bleed according to the EU label) in a non-bleeding state. Blood samples were collected pre-dose and 10 min, 1, 3, 6, 9, 12, and 24 hours post-dose. For the multiple-dose regimen, the same post-dose samples were collected after the first 90 µg/kg dose and in addition, 10 min after the 2nd dose, and 10 min and 1 hour after the 3rd dose. The trial was conducted according to ICH GCP and the declaration of Helsinki.Results:The PK based on FVIIa activity was comparable for the two dosing regimens, with AUC of 429.5 and 455.4 IUxh/mL and a half-life of 2.6 and 2.8 hours for the 3x90 and 270 µg/kg dosing regimens, respectively, results which are comparable to previously reported studies (Tiede et al. 2011, Morfini et al. 2012). For the 90 µg/kg dose administered every 3 hours, an accumulation ratio of 1.8 was observed, which resulted in a higher peak activity following the last dose (Figure 1).For rFVIIa PK based on FVII antigen, the results were somewhat different compared to the FVIIa activity results, with a reduced clearance. Previous data (Agersø et al. 2011) have shown that this discrepancy is due to the formation of FVIIa-AT complexes as part of the FVIIa clearance pathway.For PT, aPTT, and D-Dimer, no apparent differences between the two treatment regimens were observed. For both regimens, a rapid reduction of PT followed the first administration of rFVIIa. The PT remained reduced for the duration of sampling, with a slow return towards baseline beginning 9 hours after administration.F1+2 showed a transient increase following rFVIIa administration. The increase was most pronounced after the 270 µg/kg dose, with the peak 1 hour after the injection. In the 3x90 µg/kg dose regime, the F1+2 response was lower, and the most pronounced response was seen 1 hour following the last of the 3 doses of 90 µg/kg (Figure 2.) [Display omitted] [Display omitted] Conclusions:The PK parameters of rFVIIa are consistent and comparable between the two dosing regimens, with low inter-subject variation.The accumulation ratio following 3 doses of 90 µg/kg rFVIIa of 1.8 resulted in a 50% increase in peak activity following the last dose.PK results using the FVII antigen assay showed reduced clearance compared to FVIIa activity, confirming the involvement of AT complexes in rFVIIa clearance.F1+2 followed the FVIIa activity, with the highest peak following administration of 270 µg/kg, and an increase in F1+2 concentration with multiple doses of rFVIIa, but with a delayed response. DisclosuresStenmo:Novo Nordisk: Employment. Fernandez-Bello:Novo Nordisk: Research Funding. Ezban:Novo Nordisk: Employment. Butta:Novo Nordisk: Research Funding. Jiménez-Yuste:novo Nordisk: Consultancy.

Use of Prothrombin Complex Concentrate in Patients during Heart Transplantation after Implantation of a Left Ventricular Mechanical Support System

Heart transplantation in patients after implantation of mechanical cardiac support devices entails an extremely high risk for perioperative bleeding. Recombinant activated coagulation factor VII is presently used to reduce the volume of bleeding in this patient group. There are parallel data on its administration-induced thromboembolic events in the literature. This paper describes a case of using a prothrombin complex concentrate in a patient during explantation of a left ventricular bypass system and subsequent orthotopic heart transplantation in the presence of significant hypocoagulation. At the end of a surgery, 1200 IU of the agent was used at a remaining bleeding rate of more than 1000 ml/hour. Within the first 24 hours after surgery, the rate of discharge drainage was less than 100 ml/hour. A control plain chest X-ray study revealed massive left-sided hydrothorax on day 2 postsurgery. The left pleural cavity was revised under thoracoscopic guidance and 1000 ml of blood clots were evacuated. Although the administration of prothrombin complex concentrate did not guard against re-intervention, its use seems a promising strategy in life-threatening bleedings in patients after explantation of mechanical cardiac support devices. Further multicenter investigations are required to determine the efficacy and safety of prothrom-bin complex concentration in cardiac surgery. Key words: Recombinant activated coagulation factor VII, prothrombin complex concentration, mechanical cardiac support device, orthotopic heart transplantation.

Behandlung der traumainduzierten Koagulopathie - Was ist die Evidenz?

The increasing understanding of trauma-induced coagulopathy has led to an expansion of treatment strategies in the acute management of trauma patients. The aim of this manuscript is to give a summary of current recommendations for the treatment of trauma-induced coagulopathy based on current literature and valid guidelines. Thetrauma-induced coagulopathyis an independentacutemultifactorial diseasewith significantimpact on the mortalityof severelyinjured patients. Largely responsible for the occurrence and severity of trauma-induced coagulopathy seems to be tissue trauma and shock-induced hypoperfusion. Coagulopathy is amplified by accompanying factors such as hypothermia or dilution. Diagnosis and therapy of deranged coagulation should start as soon as possible. Routinely tested coagulation parameters are of limited use to confirm diagnosis. Therapy follows the concept of "damage control resuscitation". Infusion of large volumes should be avoided and a mean arterial pressure of 65mmHg (in consideration of contraindications!) may be aimed.A specific protocol for massive transfusion should be introduced and continued.Acidaemia should be prevented and treated by appropriate shock therapy.Loss of body temperature should be prevented and treated. Hypocalcaemia <0.9 mmol/l should be avoided and may be treated. For actively bleeding patients, packed red blood cells (pRBC) may be given at haemoglobin<10g/dl(0,62mmol/l). If massive transfusion is performed using fresh frozen plasma (FFP), a ratio of FFP to pRBC of 1:2 to 1:1 should be achieved.For treatment of hyperfibrinolysis after severe trauma the use of tranexamic acid should be considered at an early stage. Fibrinogen should be substituted at levels <1,5g/l (4,41μmol/l). Prothrombin complex concentrates may be helpfull for treatment of diffuse bleeding or anticoagulativemedikation. In acute bleeding, platelets may be transfused at a platet count <100000/μl. For diffuse bleeding or thrombocytopathic patients desmopressin might be a therapeutic option.If a factor XIII (FXIII) measurement is not promptly available, a factor XIII blind-dose should be considered in severe ongoing bleeding. The use of recombinant activated coagulation factor VII (rFVIIa) be considered if major bleeding persists despite standard attempts to control bleeding and best practice use of blood components.

The expanding role of prophylaxis with recombinant activated factor VII.

The expanding role of prophylaxis with recombinant activated factor VII.

Rationaler Einsatz von Blutprodukten - Reduzierung des Blutprodukteverbrauchs durch ein modernes Gerinnungsmanagement

Evaluating the patient's individual bleeding history with a standardized questionnaire, using "point-of-care" - methods for coagulation analyses and providing autologous transfusion techniques are preconditions of a modern coagulation management. Therapy of coagulopathic patients should be based on structured hemotherapy algorithms. Surgical haemostasis and the maintenance of the basic conditions for haemostasis are elementary requirements for an effective therapy. In cases of diffuse bleeding, early antifibrinolytic therapy should be considered. Coagulation factor deficiencies should be corrected "goal-directed" using coagulation factor concentrates. Transfusion of fresh frozen plasma is only indicated in the clinical setting of massive transfusions. DDAVP and transfusion of platelet concentrates are options to optimize primary haemostasis. In cases of on-going bleeding, recombinant activated coagulation factor VII represents an option for "ultima-ratio" therapy.

Recombinant factor VIIa as last‐resort treatment of desperate haemorrhage

Studies are inconclusive regarding clinical outcomes after administration of recombinant activated coagulation factor VII (rFVIIa) during severe haemorrhage. The circumstances encountered during desperate haemorrhage make it difficult to include the most critically ill patients that could possibly benefit the most from such treatment into randomized controlled trials. We report our experience with rFVIIa as last-resort treatment of desperate haemorrhage when all standard treatment has failed. Hospital charts of all consecutive patients treated with rFVIIa for desperate non-haemophilic bleeding over a 10-year period at the single institution administering rFVIIa were surveyed for treatment indications, clinical outcome, transfusion need and coagulation profiles. Fifty-five rFVIIa treatment occasions of desperate bleeding were identified in 54 patients (median age 54 years). A single rFVIIa dose was used in 86%, and haemorrhage was considered effectively contained by immediate clinical response on 81% of occasions. Overall, 38 patients (71%) survived for over 30 days. Two thromboembolic events occurred (3.6%). The 24-h mortality in 45 rFVIIa immediate clinical responders and 10 non-responders was 2% and 50%, respectively (P = 0.0004), and the 30-day mortality was 25% and 60%, respectively (P = 0.05). Blood product use decreased with rFVIIa (P < 0.01) as did the prothrombin time (20.0-13.3 s, P < 0.0001). The majority of unselected consecutive patients receiving rFVIIa as last-resort treatment for desperate haemorrhage were considered to have immediate clinical response as well as reduced transfusion requirements and correction of coagulation parameters. An immediate clinical response to rFVIIa may possibly be predictive of survival.