Administration Of rFVIIa Research Articles

Changes in coagulation potential over time after administration of recombinant activated factor VII in an emicizumab-treated hemophilia A patient with inhibitors.

We describe a 67-year-old patient with hemophilia A and inhibitors (PwHA-I) receiving emicizumab prophylaxis who underwent surgical treatment for pseudoaneurysm. He was treated with a bolus infusion of recombinant factor VIIa (rFVIIa; 79μg/kg) immediately before surgery, and a second dose of rFVIIa after an initial treatment on day 1. A third rFVIIa bolus was infused 17h after the second dose on day 2, and the treatment was continued every 24h on day 3 and day 4. Treatment with rFVIIa was discontinued on day 4. No perioperative bleeding or thrombotic events were observed. Coagulation potentials at 8h after rFVIIa administration determined by clot waveform analysis (CWA) and thrombin generation assay (TGA) were within near-normal ranges, and results at 17h after rFVIIa administration showed coagulation function comparable to that in the patient without rFVIIa. Our experimental data suggest that the coagulation potential in FVIII-deficient plasma spiked with both 0.28µg/mL (11.2μg/kg) rFVIIa and emicizumab was equivalent to or greater than that spiked with 2.2µg/mL (90μg/kg) rFVIIa alone. Thus, administration of rFVIIa every 8h may be feasible for managing perioperative treatment in emicizumab-treated PwHA-I.

Antifibrinolytic and Adjunct Hemostatic Agents: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

To derive systematic-review informed, modified Delphi consensus regarding antifibrinolytic and adjunct hemostatic agents in neonates and children supported with extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE consensus conference. A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. Use of antifibrinolytics (epsilon-aminocaproic acid [EACA] or tranexamic acid), recombinant factor VII activated (rFVIIa), or topical hemostatic agents (THAs). Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Eleven references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form. Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements for the management of bleeding and thrombotic complications in pediatric ECMO patients. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. One weak recommendation and three consensus statements are presented. Evidence supporting recommendations for administration of antifibrinolytics (EACA or tranexamic acid), rFVIIa, and THAs were sparse and inconclusive. Much work remains to determine effective and safe usage strategies.

Rationale for the Potential Use of Recombinant Activated Factor VII in Severe Post-Partum Hemorrhage.

Severe post-partum hemorrhage (PPH) is a major cause of maternal mortality worldwide. Recombinant activated factor VII (rFVIIa) has recently been approved by the European Medicines Agency for the treatment of severe PPH if uterotonics fail to achieve hemostasis. Although large randomized controlled trials are lacking, accumulated evidence from smaller studies and international registries supports the efficacy of rFVIIa alongside extended standard treatment to control severe PPH. Because rFVIIa neither substitutes the activity of a missing coagulation factor nor bypasses a coagulation defect in this population, it is not immediately evident how it exerts its beneficial effect. Here, we discuss possible mechanistic explanations for the efficacy of rFVIIa and the published evidence in patients with severe PPH. Recombinant FVIIa may not primarily increase systemic thrombin generation, but may promote local thrombin generation through binding to activated platelets at the site of vascular wall injury. This explanation may also address safety concerns that have been raised over the administration of a procoagulant molecule in a background of increased thromboembolic risk due to both pregnancy-related hemostatic changes and the hemorrhagic state. However, the available safety data for this and other indications are reassuring and the rates of thromboembolic events do not appear to be increased in women with severe PPH treated with rFVIIa. We recommend that the administration of rFVIIa be considered before dilutional coagulopathy develops and used to support the current standard treatment in certain patients with severe PPH.

Intrapulmonary administration of recombinant activated factor VII in pediatric, adolescent, and young adult oncology and hematopoietic cell transplant patients with pulmonary hemorrhage.

Diffuse alveolar hemorrhage (DAH) is a devastating disease process with 50-100% mortality in oncology and hematopoietic cell transplant (HCT) recipients. High concentrations of tissue factors have been demonstrated in the alveolar wall in acute respiratory distress syndrome and DAH, along with elevated levels of tissue factor pathway inhibitors. Activated recombinant factor VII (rFVIIa) activates the tissue factor pathway, successfully overcoming the tissue factor pathway inhibitor (TFPI) inhibition of activation of Factor X. Intrapulmonary administration (IP) of rFVIIa in DAH is described in small case series with successful hemostasis and minimal complications. We completed a single center retrospective descriptive study of treatment with rFVIIa and outcomes in pediatric oncology and HCT patients with pulmonary hemorrhage at a quaternary hematology/oncology hospital between 2011 and 2019. We aimed to assess the safety and survival of patients with pulmonary hemorrhage who received of IP rFVIIa. We identified 31 patients with pulmonary hemorrhage requiring ICU care. Thirteen patients received intrapulmonary rFVIIa, while eighteen patients did not. Overall, 13 of 31 patients (41.9%) survived ICU discharge. ICU survival (n=6) amongst those in the IP rFVIIa group was 46.2% compared to 38.9% (n=7) in those who did not receive IP therapy (p=0.69). Hospital survival was 46.2% in the IP group and 27.8% in the non-IP group (p=0.45). There were no adverse events noted from use of IP FVIIa. Intrapulmonary rFVIIa can be safely administered in pediatric oncology patients with pulmonary hemorrhage and should be considered a viable treatment option for these patients.

Role of recombinant factor VIIa in the clinical management of severe postpartum hemorrhage: consensus among European experts

Objectives There have been significant advances in the medical management of severe postpartum hemorrhage (sPPH) over recent decades, which is reflected in numerous published guidelines. To date, many of the currently available national and international guidelines recommend recombinant factor VIIa (rFVIIa) to be used only at a very late stage in the course of sPPH, as a “last resort”, before or after hysterectomy. Based on new safety data, rFVIIa has recently been approved by the European Medicines Agency (EMA) and Swissmedic for use in sPPH, if uterotonics are insufficient to achieve hemostasis, which in fact is significantly earlier in the course of postpartum hemorrhage (PPH). We therefore aimed to develop expert consensus guidance as a step toward standardizing care with the use of rFVIIa for clinicians managing women experiencing life-threatening sPPH. Methods The consensus process consisted of one face-to-face meeting with a group of nine experts, including eight obstetrician-gynecologists and a hematologist highly experienced in sPPH care in tertiary care perinatal centers. The panel was representative of multidisciplinary expertise in the European obstetrics community and provided consensus opinion in answer to pre-defined questions around clinical practice with rFVIIa in the management of sPPH. Recommendations have been based on current national and international guidelines, extensive clinical experience, and consensus opinion, as well as the availability of efficacy and new safety data. Results The expert panel developed 17 consensus statements in response to the 13 pre-defined questions on the use of rFVIIa in the management of sPPH including: available efficacy and safety data and the need for interdisciplinary expertise between obstetricians, anesthesiologists, and hematologists in the management of sPPH. Based on novel data, the experts recommend: (1) earlier administration of rFVIIa in patients with sPPH who do not respond to uterotonic administration to optimize the efficacy of rFVIIa; (2) the importance of hematological parameter prerequisites prior to the administration of rFVIIa to maximize efficacy; and (3) continued evaluation or initiation of further invasive procedures according to standard practice. Furthermore, recommendations on the timing of rFVIIa treatment within the sPPH management algorithm are outlined in a range of specified clinical scenarios and settings, including vaginal delivery, cesarean section, and smaller birthing units before transfer to a tertiary care center. The panel agreed that according to available, and new data, as well as real-world experience, there is no evidence that the use of rFVIIa in patients with sPPH increases the risk of thromboembolism. The authors acknowledge that there is still limited clinical effectiveness data, as well as pharmacoeconomic data, on the use of rFVIIa in sPPH, and recommend further clinical trials and efficacy investigation. Conclusions This expert panel provides consensus guidance based on recently available data, clinical experience, and expert opinion, augmented by the recent approval of rFVIIa for use in sPPH by the EMA. These consensus statements are intended to support clinical care for sPPH and may help to provide the impetus and a starting point for updates to existing clinical practice guidelines.

Retrospective Comparison of Recombinant Activated Factor VII Versus 4-Factor Prothrombin Complex Concentrate in Cardiac Surgical Patients

ObjectivesTo compare the incidence of postoperative thrombotic complications, transfusion of blood products, and chest tube output in congenital cardiac surgical patients who received either recombinant activated factor VII (rFVIIa) or four-factor prothrombin complex concentrate (4F-PCC) DesignRetrospective analysis SettingTertiary academic hospital ParticipantsPediatric patients who underwent cardiac surgery. InterventionsNone Measurements and Main ResultsData were obtained from the Society of Thoracic Surgeons and the Pediatric Cardiac Critical Care Consortium databases, as well as from manual chart review. Adjusted p-values were obtained from multivariable regression using age (days), surgeon (number), cardiopulmonary bypass time (minutes), and need for deep hypothermic circulatory arrest (yes/no). We included 55 patients in the 4F-PCC group and 89 in the rFVIIa group. The median dose of rFVIIa was 77 mcg/kg (46-88) and the median dose of 4F-PCC was 31 IU/kg (24-43). The incidence of thrombotic complications was 8% in the 4F-PCC group and 30% in the rFVIIa group (adjusted P= 0.023). No difference was reported between the group in terms of chest tube output on day 1 and 2, or transfusion of blood products. Using a sensitivity analysis with propensity matching, the incidence of thrombosis was 10% in the 4F-PCC group (n=38) and 31% in the rFVIIa group (n=39) (P=0.036). No difference was reported in term of bleeding or transfusion. ConclusionsThis retrospective study suggests that the administration of rFVIIa is associated with a higher risk of thrombotic complications when compared to 4F-PCC without benefits in term of bleeding and transfusions.

Use of Recombinant Activated Factor VII in Bleeding Lung Transplant Patients Undergoing Perioperative ECMO Therapy.

Hemostasis in critically ill patients represents a fragile balance between hypocoagulation and hypercoagulation, and is influenced by various factors. Perioperative use of extracorporeal membrane oxygenation (ECMO)-increasingly used in lung transplantation-further destabilizes this balance, not least due to systemic anticoagulation. In the case of massive hemorrhage, guidelines recommend considering recombinant activated Factor VII (rFVIIa) as an ultima ratio treatment only after several preconditions of hemostasis have been established. These conditions are calcium levels ≥ 0.9 mmol/L, fibrinogen levels ≥ 1.5 g/L, hematocrit ≥ 24%, platelet count ≥ 50 G/L, core body temperature ≥ 35 °C, and pH ≥ 7.2. This is the first study to examine the effect of rFVIIa on bleeding lung transplant patients undergoing ECMO therapy. The fulfillment of guideline-recommended preconditions prior to the administration of rFVIIa and its efficacy alongside the incidence of thromboembolic events were investigated. In a high-volume lung transplant center, all lung transplant recipients receiving rFVIIa during ECMO therapy between 2013 and 2020 were screened for the effect of rFVIIa on hemorrhage, fulfillment of recommended preconditions, and incidence of thromboembolic events. Of the 17 patients who received 50 doses of rFVIIa, bleeding ceased in four patients without surgical intervention. Only 14% of rFVIIa administrations resulted in hemorrhage control, whereas 71% of patients required revision surgery for bleeding control. Overall, 84% of all recommended preconditions were fulfilled; however, fulfillment was not associated with rFVIIa efficacy. The incidence of thromboembolic events within five days of rFVIIa administration was comparable to cohorts not receiving rFVIIa.

Comparison of Prothrombin Complex Concentrate with Activated Factor VII Use for Bleeding Following Cardiopulmonary Bypass in Children.

This study aims to compare the efficacy and safety of activated recombinant factor VII (rFVIIa) and prothrombin complex concentrate (PCC) in the treatment of bleeding complications following surgery requiring cardiopulmonary bypass (CPB) in children. This is a retrospective chart review of a single institution comprising patients aged 0 to 18 years old with congenital heart disease. Patients must have received either PCC or rFVIIa after coming off CPB. Our primary efficacy endpoint is time in the operating room from off-CPB to pediatric intensive care unit admission. Our primary safety endpoint is thrombosis through 30 days. Our primary efficacy outcome was significantly shorter in the PCC group compared with the rFVIIa group (P < .0001). Similarly, secondary efficacy outcomes of packed red blood cell administration, chest tube output, and transfusion exposures all significantly favored PCC administration. However, CPB time was significantly longer, and body temperatures were significantly lower, in the rFVIIa group. Safety outcomes, including our primary safety outcome of thrombosis through 30 days, were similar between the two groups. This study questions whether PCC could be favored over rFVIIa for hemostasis in children with congenital heart disease following CPB surgery. In addition, this study has found no difference when comparing PCC and rFVIIa in terms of safety outcomes, particularly thrombosis events. There are several limitations to this study due to the retrospective nature of the design and the differences between the two study groups. Despite the limitations, this study suggests that relatively early administration of PCC could be favored over delayed administration of rFVIIa to control recalcitrant post-CPB bleeding in the operating room.

Comparative study of predisposition to thrombosis with administration of known systemic hemostatic agents and fibrin monomer in the experiment

Aim. To compare predisposition to thrombosis caused by administration of known systemic hemostatic agents and fibrin monomer under the conditions of normal coagulation versus drug-induced hypocoagulation in the experiment.Materials and methods. The prothrombotic effect of intravenous (IV) administration of various systemic hemostatic agents was compared in a series of in vivo experiments. These agents included fibrin monomer (FM) (0.25 mg / kg), prothrombin complex concentrate (PCC) (40 IU / kg) or recombinant factor VIIa (rFVIIa) (270 mcg / kg). The studies were conducted under the conditions of hypocoagulation induced by the administration of warfarin (per os at a dose of 0.4–0.5 mg / kg / day for 14 days) or dabigatran etexilate (per os at a single dose of 15–20 mg / kg). Hemostatic system parameters were evaluated using thromboelastometry and calibrated automated thrombography.Results. It was found that PCC reversed anticoagulant effects and led to an overcompensated increase in the density characteristics of the blood clot along with an excessive increase in thrombin generation in the groups of animals with warfarin-induced coagulopathy. The use of PCC and rFVIIa in the groups of animals with dabigatran-induced hypocoagulation also resulted in an increase in blood thrombogenic properties. In the administration of PCC, it was manifested though an increased D-dimer level and in administration of rFVIIa – through an increase in the clot density characteristics. At the same time, replacement of these hemostatic agents with FM did not affect the hemostatic system parameters.Conclusion. FM at a dose of 0.25 mg / kg, as opposed to PCC and rFVIIa, is safer in terms of the risk of thrombosis.

Local pulmonary administration of factor VIIa (rFVIIa) in massive pulmonary haemorrhage in post-operative cardiac infant.

Diffuse pulmonary haemorrhage is an ominous condition that has a high paediatric mortality rate. Recombinant activated factor VIIa (rFVIIa) is a powerful haemostatic agent which has been used intravenously in life-threatening haemorrhage in variety of conditions in which conventional medical or surgical therapy are unsuccessful. We report off-label successful use of endotracheal rFVIIa for massive life-threatening respiratory haemorrhage following aspiration and cardiopulmonary resuscitation in a 3-month-old infant who was anticoagulated with enoxaparin following corrective cardiac surgery with other comorbidities. Off-label administration of endotracheal rFVIIa permitted rapid safe control of massive pulmonary haemorrhage and prevented further detrimental decline in respiratory function with satisfactory outcome.

Thromboelastometry as an Ancillary Tool for Evaluation of Coagulation Status after rFVIIa Therapy in a Pregnant Woman with Severe Hypoproconvertinemia-A Case Series and Review of the Literature.

Introduction: Factor VII (FVII) deficiency is a rare hemorrhagic diathesis. In females, heavy menstrual and postpartum bleeding can appear as a consequence of its deficiency. Supplementation of the recombinant FVIIa is widely accepted. The supplementation effect in FVII-deficient subjects is difficult to predict, and severe hemorrhage has been described even when FVII levels after supplementation were within normal ranges. The aim of this report is to present the application of thromboelastometry to control the coagulation status in a patient with severe FVII deficiency during pregnancy and delivery, supplemented by rFVIIa per protocol complicated with life-threatening venous thromboembolism. Methods: Rotational thromboelastometry (ROTEM) was performed in 16 pregnant women: in one 28 year old primigravida at 35 weeks of pregnancy with congenital FVII deficiency after rFVIIa administration and 15 healthy women at 38 gestational weeks. The results were compared. Results: The thromboelastometry results showed significant shortening of the clotting time in the extrinsic and the intrinsic pathway in the hypoproconvertinemia patient after rFVIIa administration in relation to healthy pregnant women. A significant reduction in maximum lysis of the clot after FVII supplementation was observed. Conclusions: The thromboelastometry results showed a significant hypercoagulable state with hypoproconvertinemia. Thrombotic complications after delivery might be prevented by the reduction in rFVIIa guided by thromboelastometry. Thromboelastometry performed on a pregnant woman with factor VII deficiency during the supplementation of rFVIIa in peripartum time might be helpful in order to determine an individual, effective dosage regimen of rFVIIa to ensure full correction of clotting disorders without the tendency to develop thrombosis, but further studies are needed.

Perioperative management for patient with congenital factor VII deficiency who underwent laparoscopic cholecystectomy: Case report.

Introduction and importanceIn patients with congenital factor VII (FVII) deficiency, perioperative bleeding events are concern, so recombinant activated factor VII (rFVIIa) is favorably used, but the optimal dosage regimen has not clearly established. We report management of a patient with congenital FVII deficiency who underwent laparoscopic cholecystectomy.Case presentationA 70-year-male with congenital FVII deficiency was diagnosed as acute cholecystitis, so we planned laparoscopic cholecystectomy. FVII activity and prothrombin time international normalized ratio (PT-INR) were intraoperatively monitored as scheduled. At the start of surgery, FVII activity was 3.1% (75–130%) and PT-INR was 3.37 (0.8–1.2), so 1 mg of rFVIIa was administered. Both of these values then improved to 325.0% and 0.73, respectively. Laparoscopic cholecystectomy was successfully completed without unexpected bleeding or oozing. When FVII activity and PT-INR was re-checked 6 h after the first administration of rFVIIa, these values were 23.9% and 1.53, respectively. Additional 1 mg of rFVIIa was used only once after the operation. The patient was discharged on the sixth day after surgery without postoperative complication.Clinical discussionIn this case, rFVIIa was used just twice and there were no bleeding events during the perioperative period. Previous reports suggested using 15–30 μg/kg of rFVIIa before surgery and subsequent every 4–6 h in the first 24 h, then increasing the interval to 8–12 h. It is necessary to evaluate optimal dose of rFVIIa based on the risk and surgical invasiveness for each case.ConclusionOur patient with congenital FVII deficiency uneventfully underwent laparoscopic cholecystectomy.

Acute arterial thrombosis in hemophilia with inhibitory antibodies

The authors demonstrate an importance of personalized approach to perioperative hemostatic therapy in a 48-year-old patient with hemophilia A and inhibitory antibodies. Laparoscopic hernia repair and extraction of 15 decayed teeth were performed. Hemostatic therapy included AICC and rFVIIa. Postoperative period was complicated by acute thrombosis of splenic artery and partial spleen infarction. An essential factor in splenic artery thrombosis was increase in blood coagulation potential under rFVIIa administration and depletion of fibrinolytic system (prolongation of XIIa-dependent fibrinolysis from 25 to 75 min) and antithrombin III decrease up to 81%. Cancellation of hemostatic therapy under TEG control ensured fast regression of arterial thrombosis and preservation of spleen. Individual characteristics of patients (compensatory mechanisms of coagulation, comorbidities, clinical changes) should be considered when prescribing hemostatic therapy in hemophilia patients. Perioperative control of all possible coagulation tests (routine and integral) is required for individual selection of hemostatic therapy and decrease of the risk of hemorrhagic and thrombotic complications.

Management of diffuse alveolar hemorrhage in the hematopoietic stem cell transplantation population: A systematic review.

Pulmonary complications post-hematopoietic stem cell transplantation (HSCT) such as diffuse alveolar hemorrhage (DAH) can occur in 2% to 14% of HSCT patients and have a mortality greater than 80%. Diffuse alveolar hemorrhage is considered to be an inflammatory response; therefore, HSCT patients are primarily treated with different types of systemic corticosteroids with varying dosages. Other treatments currently reported in the literature in conjunction with corticosteroids include aminocaproic acid, recombinant factor VIIa (rFVIIa), and etanercept. This review highlights appropriate frontline and adjunctive treatment options for HSCT patients with DAH and outcomes for each intervention. To perform the review, the PubMed database was searched from inception through March 19, 2021, to identify potential studies using the search terms DAH and HSCT, DAH and hematopoietic cell transplant (HCT), DAH and stem cell, lung injury and HSCT, and lung injury and HCT. When applicable, references from articles identified in the search were also reviewed for inclusion. Much of the data identified were limited to retrospective cohort studies and case series. Based on the data available, the treatment approach should consist of corticosteroid therapy with a suggested methylprednisolone dose of 250mg daily followed by a 50% taper every 3days. Intrapulmonary administration of rFVIIa and intravenous administration of aminocaproic acid could be considered as adjunctive agents in those patients who do not promptly respond to corticosteroid therapy. Due to a lack of data specific to HSCT patients who develop DAH and the risk of infectious complications, etanercept should be avoided. Future studies should be designed as randomized controlled trials and examine the use of adjunctive therapies in the upfront setting for HSCT patients with DAH.

Safety and Efficacy of Recombinant Factor VIIa (NovoSeven) Use during ECMO Support in Patients after Cardiac Surgery

Background: Acute postoperative bleeding in cardiac surgical patients is a major cause of morbidity and mortality. Substitution of coagulatory factors may not always provide optimal hemostasis and off label, use of recombinant FVIIa has been proposed. When on ECMO, extra care must be taken during coagulatory substitution as clotting of the system may cause cardiovascular complications and possible ECMO failure, leading to death. In this paper, we examined the safety and efficacy of rFVIIa during ECMO support in postoperative cardio-surgical patients. Methods: We retrospectively examined all patients receiving rFVIIa postoperatively from December 2005 and January 2020. Clinical characteristics, demographics, bleeding, thrombotic complications, mortality, and rFVIIa administration were analyzed. Results: A total of 74 patients received rFVIIa postoperatively due to uncontrollable bleeding after cardiac surgery on our ICU. Of these patients, 23 patients were on ECMO treatment. Twelve patients received rFVIIa during, but not prior to the initiation of ECMO therapy. Six patients (50%) were male; mean age was 46 years (30-72 years). Eleven patients (91.7%) were on venoarterial ECMO, one patient was on central ECMO (8.3%). Dose of administered rFVIIa was corrected for body weight; mean dosage was 82μg/kg. We saw a significant reduction in need for red packed cells, fresh frozen plasma and thrombocyte transfusion after rFVIIa administration. There was no impact on the functionality of the ECMO system, especially regarding the oxygenator after rFVIIa administration. One patient suffered a stroke due thromboembolism (8.3%). One patient developed late thromboembolism in the leg (8.3%), and two cases of pulmonary embolism (16.7%) were recorded. Overall survival was 25% and there was no significant difference in survival between ECMO and non-ECMO patients. Weaning from ECMO could be achieved successfully in 41.7% of our patients. Conclusion: Recombinant Factor VIIa is an effective agent in reducing blood loss during ongoing ECMO therapy in patients with refractory bleeding. Although no direct relation between rFVIIa application and thromboembolic events could be established, its use should be done with the utmost care and in selected patients. However, rFVIIa therapy did not impact ECMO function in our cohort.

Evaluation of the Thrombophilic Response to rFVIIa-Induced Hemostasis Activation in Factor V Leiden Carriers By Monitoring of Activated Protein C (APC) In Vivo

Background: The majority of patients with unprovoked venous thromboembolism (VTE) does not exhibit laboratory risk factors. Monitoring a limited and standardized activation of the hemostatic system in these patients might help to identify prothrombotic phenotypes in VTE. Promising biomarkers to monitor subclinical changes of the hemostatic activation status are plasma levels of active enzymes including thrombin and APC. Aim of this study was to characterize the prothrombotic phenotype in factor V (FV) Leiden carriers as a prerequisite for the identification of novel prothrombotic mechanisms.Methods: Subclinical activation of extrinsic hemostasis was induced by i.v. injection of recombinant activated factor VII (rFVIIa, 15 µg/kg) into 14 asymptomatic FV Leiden carriers (thereof 12 heterozygous, five males) and 12 healthy FV wild type (WT) carriers (six males). rFVIIa-induced hemostatic activation was monitored by measuring plasma levels of free thrombin and APC at baseline and repeatedly during an eight-hour follow-up period using oligonucleotide-based enzyme capture assays (OECA). In addition, prothrombin fragment F1+2 (F1+2), thrombin-antithrombin complex, plasmin-α2-antiplasmin complex, soluble fibrin monomer, and D-dimer were determined.Results: Administration of rFVIIa was well tolerated in all subjects. Its pharmacokinetics showed an expected course with no differences between FV Leiden carriers and WT carriers (Figure 1A). At baseline, median (interquartile range, IQR) APC plasma levels were 0.081 (0.068-0.117) ng/ml in heterozygous FV Leiden carriers and 0.035 (0.028-0.067) ng/ml in WT carriers. Following rFVIIa injection, a significant (p<0.05) elevation of APC levels from baseline was observed between t=10 min and t=5 h (3 h for WT carriers). Peaks of 0.509 (0.431-0.721) ng/ml (p=10-4) in heterozygous FV Leiden carriers and of 0.164 (0.139-0.194) ng/ml (p=3·10-4) in WT carriers were observed at t=1 h (Figure 1B). In addition to higher peaks (p=2·10-4) in heterozygous FV Leiden carriers than in WT carriers, the area under the APC generation curve (AUC) was greater (p=4·10-6) with 2.40 (1.84-2.84) vs. 0.77 (0.63-0.97) ng/ml·h. Interestingly, the AUC of both homozygous FV Leiden carriers (2.82 and 2.67 ng/ml·h) and their APC peak levels (0.717 and 1.123 ng/ml) lay within the ranges of the heterozygous cohort. Among the other biomarkers, only F1+2 showed an increase from baseline (0.178, 0.122-0.197 nmol/l in heterozygous FV Leiden carriers; 0.125, 0.087-0.188 nmol/l in WT carriers) that became statistically significant at t=2 h (0.229, 0.187-0.264 nmol/l, p=0.001), t=3 h (0.230, 0.190-0.281 nmol/l, p=0.006), and t=5 h (0.230, 0.172-0.274 nmol/l, p=0.02) in heterozygous FV Leiden carriers, and at t=2 h (0.179, 0.111-0.200 ng/ml, p=0.03) in WT carriers. All other biomarkers remained unchanged, and no statistically significant differences were observed between FV carriers and WT carriers.Conclusion: Increased thrombin generation rates are counterbalanced by increased APC generation rates in clinically asymptomatic FV Leiden carriers after subclinical activation of extrinsic coagulation. Furthermore, the data presented demonstrate that subclinical activation of the hemostatic system by rFVIIa combined with serial APC testing is a new diagnostic tool to assess the functionality of the anticoagulant APC pathway in vivo. [Display omitted] DisclosuresRühl:Grifols: Research Funding; Sobi: Consultancy. Winterhagen:Sobi: Consultancy.

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.

Impact of Early, Low-Dose Factor VIIa on Subsequent Transfusions and Length of Stay in Cardiac Surgery

Recombinant factor VII (rFVIIa) is used to treat cardiac surgical bleeding in an off-label manner. However, optimal dosing and timing of administration to provide efficacious yet safe outcomes remain unknown. Retrospective, observational study. Tertiary care academic center. Cardiac surgical patients (N = 214) who received low-dose rFVIIa for cardiac surgical bleeding. Patients were allocated into one of three groups based on timing of rFVIIa administration during the course of bleeding resuscitation based on the number of hemostatic products given before rFVIIa administration: group one = ≤one products (n = 82); group two = two-to-four products (n = 73); and group three= ≥five products (n = 59). Patients who received low-dose rFVIIa later in the course of bleeding resuscitation (group three) had longer intensive care unit stays (p = 0.014) and increased incidence of postoperative renal failure when compared with group one (p = 0.039). Total transfusions were lowest in patients who received rFVIIa early in the course of resuscitation (group one) (median, two [interquartile range (IQR), 1-4.75]) and highest in group three (median, 11 [IQR, 8-14]; p < 0.001). Subsequent blood product transfusions after rFVIIa administration were highest in group two (p = 0.003); however, the median for all three groups was two products. There were no differences in thrombosis, reexplorations, or mortality in any of the groups. This study identified no differences in adverse outcomes based on timing of administration of low-dose rFVIIa for cardiac surgical bleeding defined by stage of resuscitation, but the benefits of early administration remain unclear.

The features of the mode of delivery in patients with congenital deficiency of coagulation factor VII: case reports

Congenital deficiency of clotting factor VII (FVII) — refers to rare hemorrhagic diatheses, for which no unified approaches to the management of pregnancy and childbirth have been developed. The analysis of hemostasiological management of four pregnant women with congenital hypoproconvertinemia is presented. Cases reports. All patients had no or minimal history of hemorrhagic syndrome. In two cases, the diagnosis was made during the actual pregnancy. Provision of hemostasis during delivery (two — vaginal delivery, two — cesarean section) was carried out with recombinant activated FVII (rFVIIa): in two cases, once at a dose of 15–30 mcg/kg, in one twice with repeated administration after 12 hours, in another one tranexamic acid was used. There were no hemorrhagic or thrombotic complications. The thromboelastography (TEG) during pregnancy did not correspond to the severity of hypoproconvertinemia: at FVII activity &lt; 5%, the TEG parameters indicated hypercoagulation. Discussion. There is a weak correlation between the level of FVII activity in plasma and the severity of hemorrhagic syndrome. The decision on the mode of delivery in patients with FVII deficiency is made according to obstetric criteria. In most cases, a single administration of rFVIIa is sufficient at a dose of 15–30 mcg/kg at the beginning of labor or before performing a caesarean section.

Ex Vivo Prediction of Comprehensive Coagulation Potential Using Simulated Blood Concentrations of Emicizumab in Patients with Acquired Hemophilia A.

Emicizumab prophylaxis improves coagulation function in congenital hemophilia A, regardless of inhibitor presence. We recently reported that emicizumab enhanced the coagulant potentials, ex vivo, in plasmas from patients with acquired hemophilia A (PwAHAs) at diagnosis. However, coagulant effects of emicizumab in PwAHAs during the clinical course remain unclear. To assess ex vivo coagulant effects of emicizumab in PwAHAs during the clinical course. Blood samples were obtained from 14 PwAHAs on (median) days 0 and 6 during a severe-bleeding phase, and days 27 and 59 during a reduced-bleeding phase with elevated endogenous factor VIII (FVIII) and decreased inhibitor titers. If administered a single dose of 3 or 6 mg/kg, or two doses at 6 mg/kg followed by 3 mg/kg, estimated plasma emicizumab concentrations (10/5/2.5, 20/10/5, and 30/15/7.5 µg/mL on days 0-7/30/60, respectively) could be used to represent potential changes, based on the half-life (T 1/2: ∼30 days). Emicizumab concentrations that covered maximum plasma concentrations of each dosage were used for spiking on day 0. Ex vivo addition of estimated emicizumab to PwAHA's plasma containing endogenous FVIII and/or inhibitor, without and with recombinant (r)FVIIa administration during immunosuppressive therapy, increased the calculated Ad|min1| values, assessed by clot waveform analysis, and their coagulant potentials were below normal levels. Rotational thromboelastometry revealed that ex vivo emicizumab addition resulted in the further improvement of coagulant potentials in whole bloods when combined with rFVIIa administration. Based on ex vivo and in vitro data, emicizumab has the potential to be effective in clinical situations for PwAHAs.