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Background: Recombinant factor VIIa (rFVIIa) and prothrombin concentrate complex (PCC) are used for uncontrolled bleeding in cardiac surgery (CS), however, there are limited direct comparisons of these agents. Objective: To evaluate the efficacy and safety of rFVIIa and PCC in CS related bleeding. Methods: This retrospective study included adult CS patients who received either low dose rFVIIa ( < 30 mcg/kg) or 4-factor PCC. The primary outcome was transfusion requirements of packed red blood cells (pRBC) within 6 hours of factor administration. Secondary efficacy outcomes included transfusion requirements 0-18 hours, doses of additional factor product, thrombotic events, and acute kidney injury (AKI). Results: A total of 179 patients were included (n = 78 rFVIIa; n = 101 PCC). Of patients who received blood products, there was no difference in the requirement of pRBCs within 6 hours (73.8 vs 68.9%, P = .5359) or in the median amount of pRBC transfused (500 mL vs 640 mL, P = .0723) in the rFVIIa and PCC groups respectively. Patients in the PCC group were more likely to require additional factor products (24.4% vs 47.5%, P = .0015), develop AKI (12.8% vs 25.7%, P = .0325), have longer ICU lengths of stay [2 (IQR 1-5) vs 4 (IQR 2-6), P = .0487] and greater in-hospital mortality (2.6% vs 10.9%, P = .033). There was no difference in thrombotic events. Conclusion: Although, there was no difference in pRBC transfusion requirements between PCC and rFVIIa, more patients in the PCC group required additional factor products and had increased adverse effects. Further comparisons of PCC and rFVIIa are warranted., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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; 79 μg/kg) immediately before surgery, and a second dose of rFVIIa after an initial treatment on day 1. A third rFVIIa bolus was infused 17 h after the second dose on day 2, and the treatment was continued every 24 h 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 8 h after rFVIIa administration determined by clot waveform analysis (CWA) and thrombin generation assay (TGA) were within near-normal ranges, and results at 17 h 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 0.28 µg/mL (11.2 μg/kg) rFVIIa and emicizumab was equivalent to or greater than that spiked with 2.2 µg/mL (90 μg/kg) rFVIIa alone. Thus, administration of rFVIIa every 8 h may be feasible for managing perioperative treatment in emicizumab-treated PwHA-I., (© 2024. Japanese Society of Hematology.)

Objectives: 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., Data Sources: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021., Study Selection: Use of antifibrinolytics (epsilon-aminocaproic acid [EACA] or tranexamic acid), recombinant factor VII activated (rFVIIa), or topical hemostatic agents (THAs)., Data Extraction: 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., Measurements and Main Results: 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., Conclusions: 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., Competing Interests: The Executive Committee (Drs. Alexander, Muszynski, Bembea, Cheifetz, Steiner, and Barbaro) served as arbitrators for conflict of interest management. Dr. Alexander’s institution received funding from Novartis (Prospective Trial to Assess the Angiotensin Receptor Blocker NeprilysinInhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatmentof Pediatric HF [PANORAMA-HF]). Dr. Ryerson received an honorarium from the Instrumentation Laboratory for consultation work. Dr. Ryerson disclosed the off-label product use of antifibrinolytic agents (epsilon-aminocaproic acid and tranexamic acid) and topical hemostatic agents. Drs. Alexander and Muszynski’s institutions received funding from the National Institutes of Health (NIH) and received support for article research from the NIH. Dr. Alexander’s institution received funding from the Extracorporeal Life Support Organization and Novartis. Dr. Steiner’s institution received funding from the Department of Defense; she received funding from Octapharma and Medtronic; she disclosed she was on the Data Safety and Monitoring Board for the Pumps for Kids, Infants and Neonates (PumpKIN) Trial; she disclosed the off-label product use of rFVIIa, Kcentra, antithrombin, tranexamic acid, and Amicar. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Glanzmann thrombasthenia is a rare congenital thrombocytopathy. The first-line treatment in severe life-threatening bleeding is a transfusion of platelet concentrate or recombinant factor VIIa in the case of platelet transfusion refractoriness. We present the case of a 16-year-old boy with Glanzmann thrombasthenia who was admitted to hospital with severe bleeding into the quadriceps femoris muscle. At the age of 15 years, he was hospitalized again because of chronic bleeding into the right ankle joint, resulting in joint destruction. Here we give a scheme of management and treatment of this patient. Hemostatic therapy followed by radiosynovectomy of the right ankle joint and introduction of secondary preventive treatment with recombinant factor VIIa proved to be efficacious and safe., Competing Interests: The author declares no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hemophilia A (HA) is an inherited X-linked bleeding disease with costly treatment, especially for high titer inhibitory patients. Emicizumab, a new humanized bispecific antibody, has been approved for use to prevent or reduce the frequency of bleeding episodes in HA patients with inhibitors. This study evaluated the cost-utility of emicizumab prophylaxis (EP) in comparison with recombinant factor VII activated on-demand treatment in HA patients with inhibitors., Methods: A life-time Markov model with payer and societal perspectives was developed in different age groups with different annual bleeding rates (ABR). Efficacy of treatments were extracted from HAVEN trials. Utilities were retrieved from published evidence. Costs were calculated based on Iran food and drug administration official website, national tariff book for medical services and hospital data. One-way deterministic sensitivity analysis was performed., Results: EP was dominant choice in comparison with on-demand administration of recombinant factor VII activated in all age groups with ABR 20 and 25, and it remained dominant in patients with age 2 and age 12 at start point with ABR 16 and 17. The reported incremental cost-effectiveness ratio for the group with ABR 18 at the age 20, was 12,936 United States Dollars which is lower than the acceptable threshold of cost-effectiveness in Iran (1-3 gross domestic product per capita) and EP can be considered as cost-effective choice in this scenario., Conclusion: EP was found to be a dominant and cost-effective choice for Iranian HA patients with factor VIII inhibitors with ABR 18 and above with considerable cost saving., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Outcomes following administration of very-low-dose recombinant activated factor VIIa (vld-rFVIIa) for cardiac surgical bleeding remain debatable. We sought to determine the association of vld-rFVIIa and adverse surgical outcomes. Retrospective, cohort matching of patients undergoing cardiac surgery who received vld-rFVIIa (median 13.02 μg/kg) for perioperative bleeding were matched to cardiac surgical patients who had bleeding and received standard of care for bleeding without Factor VIIa administration. Of the 362 matched patients (182 in each group), patients who received rFVIIa required significantly less red blood cell transfusions [median 3 units (range 0--60, IQR = 4 units) versus 4 units (range 2-34, IQR = 4 units); P = 0.0004], decreased length of hospital stay (median 8 versus 9 days; P = 0.0158) and decreased renal risk (P < 0.0001). Incidence of renal failure, postoperative infection, postoperative thrombosis, prolonged ventilation, total ICU hours and 30-day mortality were not different between the two groups. Vld-rFVIIa for cardiac surgical bleeding was associated with decreased red blood cell transfusion, renal risk and length of hospital stay without increased thromboembolism or mortality when compared to patients who had cardiac surgical bleeding and received standard of care without Factor VIIa., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Glanzmann thrombasthenia is an inherited disease causing bleeding episodes due to platelet dysfunction. The standard treatment for moderate-severe bleeding is platelet transfusion. Recombinant factor VIIa (rFVIIa) is successfully used in bleeding episodes and invasive procedures. Here, we present a patient with Glanzmann thrombasthenia, whose bleeding episodes could only be controlled by rFVIIa. The patient is a 28 years old male, who has had frequent bleeding episodes unresponsive to local hemostatic agents and tranexamic acid and had an anaphylactoid reaction to platelet transfusion. We started the patient on a low-dose (20 μg/kg) rFVIIa once a week. The patient has no spontaneous bleeding since then. This is the first case report of a Glanzmann thrombasthenia patient on routine prophylaxis with low-dose rFVIIa., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Emicizumab reduces bleeding in patients with hemophilia A and inhibitors (PwHA-I). Coagulation potential during the perioperative period in emicizumab-treated PwHA-I undergoing surgery remains to be evaluated. We describe a 14-year-old boy with HA-I receiving emicizumab prophylaxis who experienced arthroscopic synovectomy. He was treated with a bolus infusion of recombinant factor VIIa (rFVIIa; 80 μg/kg) immediately before surgery, and treatment continued at the same dose every 3 h on day 1, every 4 h on day 2, and every 6 h on day 3. Treatment with rFVIIa was discontinued on day 4. No perioperative bleeding or thrombotic events were observed. Coagulation potential throughout the perioperative period was retrospectively assessed with an easy-to-use clot waveform analysis (CWA). Measurements from CWA returned to within or near the normal range, suggesting successful hemostatic management. Coagulation potentials assessed by CWA showed a significant correspondence with those from a thrombin generation assay (TGA) that is already in use. CWA and TGA could both provide useful data for assessing coagulation potential in the perioperative hemostatic management of emicizumab-treated PwHA-I.

Background and Objectives: IL-6 (interleukin 6) is a proinflammatory cytokine and an established biomarker in acute brain injury. We sought to determine whether admission IL-6 levels are associated with severity and functional outcome after spontaneous intracerebral hemorrhage (ICH)., Methods: We performed an exploratory analysis of the recombinant activated FAST trial (Factor VII for Acute ICH). Patients with admission serum IL-6 levels were included. Regression analyses were used to assess the associations between IL-6 and 90-day modified Rankin Scale. In secondary analyses, we used linear regression to evaluate the association between IL-6 and baseline ICH and perihematomal edema volumes., Results: Of 841 enrolled patients, we included 552 (66%) with available admission IL-6 levels (mean age 64 [SD 13], female sex 203 [37%]). IL-6 was associated with poor outcome (modified Rankin Scale, 4-6; per additional 1 ng/L, odds ratio, 1.30 [95% CI, 1.04-1.63]; P =0.02) after adjustment for known predictors of outcome after ICH and treatment group. IL-6 was associated with ICH volume after adjustment for age, sex, and ICH location, and this association was modified by location (multivariable interaction, P =0.002), with a stronger association seen in lobar (β, 12.51 [95% CI, 6.47-18.55], P <0.001) versus nonlobar (β 5.32 [95% CI, 3.36-7.28], P <0.001) location. IL-6 was associated with perihematomal edema volume after adjustment for age, sex, ICH volume, and ICH location (β 1.22 [95% CI, 0.15-2.29], P =0.03). Treatment group was not associated with IL-6 levels or outcome., Conclusions: In the FAST trial population, higher admission IL-6 levels were associated with worse 90-day functional outcome and larger ICH and perihematomal edema volumes.

Rationale: Acquired hemophilia A (AHA) is a rare bleeding disorder with prolonged activated partial thromboplastin time (aPTT). Severe hemorrhage may occur, especially in refractory AHA., Patient Concerns: We reported a 63-year-old man who suffered from life-threatening bleeding after the onset in lower limbs., Diagnoses: The patient was diagnosed as AHA which was related to pemphigoid., Interventions: The patient had no response to the first-line treatment with corticosteroid and cyclophosphamide. Meanwhile, fatal hemorrhage occurred successively in thoracic cavity and right frontal lobe. rFVIIa and rituximab were administered., Outcomes: The patient survived from the life-threatening hemorrhage with a normal aPTT. His aPTT and FVIII:C level was normal during the follow-up of 6 months., Lessons: Rituximab and rFVIIa can play a critical role in rescuing AHA that is refractory to the first-line treatment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Acquired haemophilia A (AHA) is a rare autoimmune disorder, characterized by bleeds of varying severity caused by autoantibodies against factor VIII (FVIII)., Aim: Identify risk factors associated with AHA-related deaths/relapses and assess the effect of increased corticosteroid doses., Methods: AHA patients treated across two specialist centres in the Czech Republic, generally receiving first-line haemostatic therapy with rFVIIa and immunosuppression with corticosteroids/cyclophosphamide, were included. We analysed the association between early death (within 8 weeks of diagnosis [considered disease-related]) and age, malignancy, FVIII levels and bleeding severity. Risk factors associated with reduced 2-year survival and relapse incidence, and the effect of increased corticosteroid doses on early death and remission were also assessed., Results: The demographics of the described cohort (n = 66) were similar to other AHA registries. Early death occurred in 20% of cases. Unlike age and malignancy, FVIII levels <1% and severe bleeding were associated significantly with early death (P = .010 and P = .046, respectively). Patients with underlying malignancy or requiring continued haemostatic therapy exhibited significantly decreased 2-year survival compared with those without these risk factors (P = .007 and P = .006, respectively). Patients with an underlying autoimmune disease relapsed significantly more than those without (P = .015). Higher corticosteroid doses were associated with a significantly increased incidence of early deaths (P < .001), but also with early remission (P < .001)., Conclusion: Based on this rather large patient cohort, we were able to evaluate the significance of several risk factors associated with treatment outcomes in AHA and the effect of initial treatment with corticosteroids on survival and time to remission., (© 2020 John Wiley & Sons Ltd.)

Introduction: Haemophilic pseudotumour (HP) is an encapsulated haematoma in patients with haemophilia (PWH) which has a tendency to progress and produce clinical symptoms related to its anatomical location., Aim: To show the experience of one surgeon who has been using mini-invasive technique to treat pseudotumours of limbs in PWH with and without inhibitors at one centre for 28 years., Materials and Methods: Thirty-three patients with 39 HP were treated. All patients had haemophilia A. Twenty-four patients had no inhibitors (72.8%), and 9 had inhibitors (27.2%). The mean follow-up was 16 years (1-25). All patients had x-rays and MRIs. All of them received Buenos Aires protocol as conservative treatment for 6 weeks. MRIs were repeated after 6 weeks' treatment to assess response to treatment. Surgery was performed in patients who did not respond to conservative treatment., Results: After Buenos Aires protocol, four pseudotumours did not shrink (10.24%), 33 (84.61%) shrank, and two (5.12%) healed. Thirty-seven pseudotumours had surgery, 35 pseudotumours (94.59%) healed with minimally invasive treatment, and two did not heal (5.41%). No infection was observed with this treatment. The mortality rate for the series was 0%., Conclusion: The minimally invasive treatment of pseudotumours was effective in 95% of the cases and resulted in no mortality in this series after 28 years., (© 2020 John Wiley & Sons Ltd.)

Objectives: This study estimated the cost of prophylaxis with activated prothrombin complex concentrate (aPCC) and recombinant activated factor VIIa (rFVIIa) in surgical patients with haemophilia A and inhibitors in Spain., Methods: A decision-analytic model was developed to estimate the cost to the Spanish National Health System of providing haemostatic coverage in this haemophilia population, with age distribution and average weight derived from the literature, and the annual number of surgeries (0.33 per patient) from local data. Drug costs were calculated from official ex-factory prices with a 7.5% mandatory deduction and recommended dosing regimens., Results: The estimated average costs per patient were €10 100.73 (aPCC) and €14 265.89 (rFVIIa) for dental extraction, €24 043.88 (aPCC) and €62 301.08 (rFVIIa) for minor surgery and €126 595.81 (aPCC) and €347 731.09 (rFVIIa) for major surgery. Assuming an estimated 23 annual surgeries in this population (N = 69), distributed as 19% dental extraction, 50% minor surgery and 31% major surgery, the total annual cost of prophylaxis was €1 209 682.35 with aPCC and €3 221 929.28 with rFVIIa., Conclusions: aPCC costs were 62.5% lower than rFVIIa. Assuming potential clinical equivalence, aPCC is a potentially cost-saving option for surgical patients with haemophilia A and inhibitors., (© 2020 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)

Acquired hemophilia A in postoperative patients can cause major bleeding and an accurate diagnosis is required for effective treatment. Standard treatment is costly, difficult to obtain, and takes 4 to 6 weeks to be effective. This article describes a patient successfully treated with recombinant factor VIIa, porcine factor VIII, plasmapheresis, rituximab, and high-dose corticosteroids.

Objective: Recent studies showed that FVIIa (factor VIIa), upon binding to EPCR (endothelial cell protein C receptor), elicits endothelial barrier stabilization and anti-inflammatory effects via activation of PAR (protease-activated receptor)-1-mediated signaling. It is unknown whether FVIIa induces PAR1-dependent cytoprotective signaling through cleavage of PAR1 at the canonical site or a noncanonical site, similar to that of APC (activated protein C). Approach and Results: Mouse strains carrying homozygous R41Q (canonical site) or R46Q (noncanonical site) point mutations in PAR1 (QQ41-PAR1 and QQ46-PAR1 mice) were used to investigate in vivo mechanism of PAR1-dependent pharmacological beneficial effects of FVIIa. Administration of FVIIa reduced lipopolysaccharide-induced inflammation, barrier permeability, and VEGF (vascular endothelial cell growth factor)-induced barrier disruption in wild-type (WT) and QQ46-PAR1 mice but not in QQ41-PAR1 mice. In vitro signaling studies performed with brain endothelial cells isolated from WT, QQ41-PAR1, and QQ46-PAR1 mice showed that FVIIa activation of Akt (protein kinase B) in endothelial cells required R41 cleavage site in PAR1. Our studies showed that FVIIa cleaved endogenous PAR1 in endothelial cells, and FVIIa-cleaved PAR1 was readily internalized, unlike APC-cleaved PAR1 that remained on the cell surface. Additional studies showed that pretreatment of endothelial cells with FVIIa reduced subsequent thrombin-induced signaling. This process was dependent on β-arrestin1., Conclusions: Our results indicate that in vivo pharmacological benefits of FVIIa in mice arise from PAR1-dependent biased signaling following the cleavage of PAR1 at the canonical R41 site. The mechanism of FVIIa-induced cytoprotective signaling is distinctly different from that of APC. Our data provide another layer of complexity of biased agonism of PAR1 and signaling diversity.

Background: Recombinant factor VIIa (rFVIIa) (Novoseven®) is utilized for the reversal of anticoagulation-associated bleeding and refractory bleeding in cardiac surgery. In August 2015, rFVIIa was transferred from the blood bank to the pharmacy at New York University (NYU) Langone Health. Concordantly, an off-label dosing guideline was developed. The objective of this study was to describe utilization and cost of rFVIIa and assess compliance to our dosing guideline., Methods: We performed a retrospective, observational review of rFVIIa administrations post-implementation of an off-label dosing guideline. All patients who received rFVIIa between September 2015 and June 2017 were evaluated. For each rFVIIa administration, anticoagulation and laboratory values, indications for use, dosing, ordering and administration times, concomitant blood products, and adverse events were collected. Adverse events included venous thromboembolism, stroke, myocardial infarction, and death due to systemic embolism and mortality. The primary endpoint was the utilization of rFVIIa in accordance with the off-label dosing guideline. Secondary endpoints included hemostatic efficacy of rFVIIa, adverse events, blood products administered, and cost-effectiveness of rFVIIa transition to pharmacy., Results: A total of 63 patients [pediatric ( n  = 6), adult ( n  = 57)] received rFVIIa, with the majority of use for refractory bleeding after cardiac surgery. The utilization of rVIIa decreased after development of the off-label dosing guideline and transition from blood bank to pharmacy. The total incidence of thromboembolic events within 30 days was 19.6%; 17.6% arterial and 2% venous; 70% of patients with an adverse event were over 70 years of age. Use of rFVIIa reduced the median number of units of blood products administered., Conclusion: Administration of rFVIIa for cardiac surgery appears to be effective for hemostasis. Transitioning rFVIIa from the blood bank to pharmacy and implementation of a dosing guideline appears to have reduced utilization. Patients receiving rFVIIa should be monitored for thromboembolic events. Elderly patients may be at higher risk for thromboembolic events.

Background:  Factor XI (FXI) deficiency is a rare autosomal bleeding disorder. The rarity of spontaneous bleeding and absence of optimal tools to predict the bleeding risk in FXI-deficient patients hamper the standardization of prophylactic treatment enabling them to undergo major surgeries without blood products., Objectives:  We explored the effectiveness of a single and very low dose of recombinant factor VIIa (rFVIIa) along with tranexamic acid (TXA) as prophylactic treatment for FXI-deficient patients undergoing various types of surgery at various sites of injury. We studied the potential use of thrombin generation (TG) as a surrogate tool for predicting thrombogenicity., Patients and Methods:  Our cohort consisted of 10 patients with severe FXI deficiency undergoing 12 interventions. Patients received a single dose of 10 to 15 μg/kg rFVIIa at the end of surgery in addition to TXA initiated 2 hours before surgery at the dose of 4 g/day for 3 to 5 days. TG was tested before and 30 minutes after rFVIIa administration., Results:  All operations were uneventful and none of the patients bled excessively or required blood products. No thrombotic event was reported, and the postoperative hospitalization duration was comparable to that of patients without bleeding disorders. TG performed at the peak of rFVIIa was below the curve of healthy controls, thus confirming that the administered dose was not thrombogenic., Conclusion:  A single very low dose of rFVIIa along with TXA is a simple and safe treatment to control hemostasis in severe FXI-deficient patients undergoing diverse type of surgical procedure at various sites., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Recombinant FVIIa (rFVIIa) is widely used to manage bleeding risk during and after surgery in patients with haemophilia complicated by inhibitors. In the postoperative period, rFVIIa must be delivered frequently and regularly to maintain haemostasis, considering its short half-life. Preparation and manual administration of bolus doses of rFVIIa at regular intervals may place a strain on available nursing resources. A programmable mini-pump may offer an approach to facilitate regular administration of bolus doses of rFVIIa at specified intervals., Aim: To investigate if a mini-pump is a practical and effective way to deliver rFVIIa in the postoperative period., Methods: It was first necessary to establish that rFVIIa remains stable and sterile in the mini-pump reservoir for an extended period. Four days after loading the mini-pump under sterile conditions no evidence of bacterial or fungal growth was observed and in vitro procoagulant activity of rFVIIa remained stable. The mini-pump was used to deliver rFVIIa as bolus doses to two patients with inhibitors who had undergone surgery. Nurses were asked to report their satisfaction with the use of the mini-pump using a specific questionnaire., Results: Haemostasis was evaluated as excellent in both cases; nurses were satisfied with use of the mini-pump., Conclusion: This pilot study shows that intermittent delivery of rFVIIa at fixed intervals using an automated mini-pump offers accurate and reliable administration in the postoperative setting. This approach may reduce burden on nursing staff, potentially minimize the risk of human error and avoid delay in administration of rFVIIa., (© 2019 John Wiley & Sons Ltd.)

Background: Recombinant activated factor VII (rFVIIa; eptacog alfa activated, NovoSeven ® , Novo Nordisk A/S) is a bypassing agent used in congenital hemophilia A patients with inhibitors. Emicizumab (Hemlibra ® ; F Hoffmann-La Roche Ltd) is a recombinant, humanized, bispecific monoclonal antibody used for routine prophylaxis in patients with congenital hemophilia A with inhibitors. Concomitant use of the hemostatic agents rFVIIa and emicizumab carries a theoretical increased risk of thrombotic complications. Roche and Novo Nordisk collaboratively analyzed all available data on the use of rFVIIa in patients receiving emicizumab prophylaxis in the Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors (HAVEN) clinical development program., Objective: Obtain further insights into the concomitant clinical use and safety of rFVIIa and emicizumab., Methods: The initial individual rFVIIa dose, dosing intervals and cumulative dosing were evaluated in the HAVEN 1, HAVEN 2, and HAVEN 4 trials. All adverse events reported in each of the three trials in patients treated with rFVIIa, including available narratives, were assessed., Results: The vast majority of bleeds occurred in HAVEN 1. When rFVIIa was used to treat a bleeding episode, a 100 ± 20 μg/kg dose was used to initiate treatment in the majority of cases. The dosing interval, as well as cumulative dosing were consistent with prescribing information and current practice. No serious adverse events, no thrombotic microangiopathy cases, or thromboembolic events were assessed to be associated with rFVIIa when used in conjunction with emicizumab prophylaxis in the HAVEN trials., Conclusion: rFVIIa use in the context of emicizumab prophylaxis does not change the rFVIIa safety profile as described in the product information., (© 2019 F. Hoffman La-Roche AG. Journal of Thrombosis and Haemostasis published by Wiley Periodicals Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Objective: Activated recombinant factor VII (rFVIIa) has been used to treat cardiac surgical bleeding in an off-label manner. This observational report analyzes the outcomes with use of a low dose and early administration of rFVIIa for cardiac surgical bleeding., Design: A retrospective, observational study., Setting: Single-center, tertiary care cardiothoracic surgical setting., Participants: A total of 6,862 patients underwent cardiac surgery from January 2012 to January 2018. Of those, 372 patients received rFVIIa perioperatively., Interventions: An institutional policy directed low-dose, incremental aliquots of intravenous rFVIIa (0.5-1 mg). Characteristics and outcomes were compared among patients who survived (n = 328) and patients who died (n = 44)., Measurements and Main Results: The median dose of rFVIIa was low at 13.29 μg/kg. Higher doses were given to patients who died (15.79 μg/kg v 12.99 μg/kg; p = 0.0133). Patients who died received more blood and component transfusions (median 9 products in those who died v 6 products in survivors; p = 0.0022), although the median transfusion requirement for all patients was 6 units per patient. The rate of reoperation was not different in the 2 groups. Mortality was associated with emergent/urgent surgical procedures (p = 0.0282), type of surgical procedure with aortic procedures being highest risk (p = 0.0014), cardiogenic shock (p = 0.0028), postoperative renal failure (p = 0.0035), postoperative cardiac arrest (p = 0.0006), and ischemic stroke (p = 0.0084)., Conclusion: Mortality after life-threatening cardiac surgical bleeding treated with rFVIIa was more common in aortic procedures and emergent and urgent surgeries. Lower doses of rFVIIa than previously reported may achieve bleeding cessation because overall blood component transfusions were low in this cohort., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Our earlier studies showed that recombinant human factor VIIa (rhFVIIa) administered intravascularly in mice disappeared rapidly from the circulation. However, a small fraction of rhFVIIa that entered extravascular remained functionally active for an extended period. The present study aims to investigate the dose-dependency of rhFVIIa accumulation and retention in mouse knee joints and test whether the hemophilic condition affects rhFVIIa sequestration in joints. Wild-type and FVIII -/- mice were injected with three doses of rhFVIIa (eptacog beta, 90, 250, and 500 μg/kg) via the tail vein. At varying times following rhFVIIa administration, blood and knee joints were collected to measure FVIIa activity and antigen levels in plasma and joint tissues. Joint tissue sections were analyzed by immunohistochemistry for the presence of rhFVIIa. Vascular permeability was assessed by either Evans Blue dye or fluorescein dextran extravasation. The study showed that rhFVIIa accumulated in knee joints of wild-type and FVIII -/- mice in a dose-dependent manner. rhFVIIa antigen and FVIIa activity could be detectable in joints for at least 7 days. Significantly higher levels of rhFVIIa accumulation were observed in knee joints of FVIII -/- mice compared with that of wild-type mice. Immunohistochemical analyses confirmed higher levels of rhFVIIa retention in FVIII -/- mice compared with wild-type mice. Additional studies showed that FVIII -/- mice were more permissible to vascular leakage. In conclusion, the present data demonstrate a dose-dependent accumulation of rhFVIIa in knee joints, and the hemophilic condition enhances the entry of rhFVIIa from circulation to the extravascular. The present data will be useful in improving rhFVIIa prophylaxis., Competing Interests: J.G. is an employee of LFB USA, a subsidiary company of LFB S.A. that produced activated eptacog beta. rhFVIIa-eptacog beta is currently under clinical evaluation in patients with congenital hemophilia A or B with inhibitors. The project is partly funded by the subsidiaries of the manufacturer of rhFVIIa-eptacog beta. J.M., U.P., S.V.M., and L.V.M.R. declare no competing financial interests in the study., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To evaluate the effect of recombinant activated factor VII (rFVIIa) administration on outcomes in pediatric cardiac surgery patients with postoperative bleeding., Design: A propensity score-matched retrospective study., Setting: Single tertiary medical center., Participants: The study comprised 151 patients who received treatment with rFVIIa and were matched with control patients at a 1:2 ratio., Interventions: None., Measurements and Main Results: The primary endpoints were thrombotic events, renal replacement therapy (RRT), and mortality. The secondary endpoints were length of intensive care unit stay and the reexploration rate. Patients in the rFVIIa group showed no significant differences in thrombotic events (odds ratio [OR] 1.03; 95% confidence interval [CI] 0.48-2.21; p = 0.948), mortality (OR 0.94; 95% CI 0.42-2.13; p = 0.891), and RRT (OR 1.38; 95% CI 0.73-2.58; p = 0.319). However, patients in the rFVIIa group experienced a prolonged length of intensive care unit stay (5.65 [3.00-12.28] d v 3.91 [1.83-6.77] d) and an increased reexploration rate (8.2% v 3.1%). High-dose rFVIIa was an independent risk factor of thrombotic events (OR 5.17; 95% CI 1.19-22.49; p = 0.029)., Conclusion: This study found that rFVIIa is not associated with increased risks of postoperative thrombotic events, mortality, or RRT in pediatric patients undergoing cardiac surgery. Nevertheless, rFVIIa was associated with longer intensive care unit stay and increased reexploration rate. Furthermore, the risk for thrombotic events may increase with high-dose rFVIIa., (Copyright © 2019. Published by Elsevier Inc.)

Essentials Hemophilia patients on concizumab prophylaxis may need rFVIIa to treat breakthrough bleeds. Effect and safety of concizumab + rFVIIa were tested in vitro and in vivo. Concizumab + rFVIIa had no additive effects on bleeding in hemophilic rabbits. High steady-state levels of concizumab did not affect the safety of rFVIIa in cynomolgus monkeys. SUMMARY: Background Concizumab is a monoclonal antibody (mAb) against tissue factor pathway inhibitor (TFPI), currently in clinical development as a subcutaneous prophylactic therapy for hemophilia A/B with and without inhibitors. In patients with inhibitors, the treatment choice for breakthrough bleeding will comprise bypassing agents, e.g. activated recombinant FVIIa (rFVIIa) or activated prothrombin complex concentrates. Objectives To explore the effect and safety of concizumab and rFVIIa when they are simultaneously present. Methods Human blood made hemophilic with a FVIII antibody was spiked with increasing concentrations of concizumab, rFVIIa, or concizumab and rFVIIa in combination, and this was followed by thrombin generation test or thromboelastography. Blood loss in hemophilic rabbits was measured when concizumab, rFVIIa or concizumab + rFVIIa was administered either before or during cuticle bleeding. In a safety study, cynomolgus monkeys were exposed to high steady-state concizumab concentrations and given three doses of rFVIIa, and then subjected to full necropsy and histopathological examination. Results In human blood, concizumab + rFVIIa had more pronounced procoagulant effects under hemophilic conditions than the sum of individual responses. In contrast, concizumab + rFVIIa had no additional effects on blood loss in hemophilic rabbits as compared with rFVIIa or concizumab alone. In cynomolgus monkeys, the macroscopic and microscopic pathological examinations revealed no thrombi or other signs of excessive coagulation activation. Both rFVIIa and concizumab caused increases in thrombin-antithrombin and D-dimer concentrations; this effect tended to be additive with concomitant administration. Conclusions Concizumab did not affect the potency or safety of rFVIIa in vivo. These results support a clinical evaluation of rFVIIa at standard dose (90 μg kg -1 ) to treat breakthrough bleeds in concizumab clinical trials., (© 2019 International Society on Thrombosis and Haemostasis.)

Background: Recombinant activated factor VII (rFVIIa) has been used off-label to treat or prevent severe bleeding in patients for whom conventional treatments are unsuccessful. However, studies in children remain limited., Procedure: To examine the efficacy and safety of rFVIIa, we performed a retrospective analysis of rFVIIa off-label use in a pediatric hematology/oncology cohort at a single center from 2006 to 2014., Results: Of 58 patients identified, 46 (79.3%) received rFVIIa to treat bleeding and 12 (20.7%) to prevent bleeding. Thirty-three (71.7%) patients had life-threatening bleeding. In the treatment group, 63.0% patients were responders (ie, bleeding decreased or stopped) and 37.0% were nonresponders (ie, bleeding did not change). Blood products usage was similar between responders and nonresponders. After rFVIIa administration, prothrombin time, partial thromboplastin time and lactate were significantly lower, but fibrinogen was significantly higher in responders than nonresponders. Venous thromboembolism developed in 5.2% (3/58) patients, but its relation to rFVIIa remains unclear. Responders had significantly lower mortality than nonresponders (17.2% vs. 82.4%, P<0.0001)., Conclusions: rFVIIa controlled most bleeding events in this cohort, despite predominance of life-threatening bleeding, suggesting good efficacy. Venous thromboembolism rate was low. Further studies are warranted to identify predictors of favorable response to rFVIIa in similar patients.

Introduction: Primary blast lung injury causes intrapulmonary haemorrhage. A number of case reports have suggested the efficacy of recombinant activated factor VII (rFVIIa) in the treatment of diffuse alveolar haemorrhage from a range of medical causes, but its efficacy in blast lung is unknown. The aim of this study was to investigate whether nebulised rFVIIa attenuates the haemorrhagic effects of blast lung injury in an animal model., Methods: Terminally anaesthetised rabbits subjected to blast lung injury were randomised to receive either rFVIIa or placebo via a nebuliser. The primary outcome was the level of blood iron-transferrin complex, a marker of the extent of blast lung injury, analysed using low temperature electron paramagnetic resonance spectroscopy., Results: Blast exposure led to a significant fall in iron-bound transferrin in both groups of animals (p<0.001), which remained depressed during the study. There were no significant differences in iron-transferrin between the rFVIIa and placebo treatment groups over the duration of the study (p=0.081), and there was no trend towards elevated iron-transferrin in the rFVIIa-treated group once drug treatment had started. There was suggestive evidence of systemic absorption of rFVIIa given via the inhaled route., Conclusion: A single dose of nebulised rFVIIa did not attenuate pulmonary haemorrhage in a rabbit model of blast lung injury. As there was some evidence of systemic absorption, the inhaled route does not avoid the concern about potential thromboembolic complications from administration of rFVIIa., Competing Interests: Competing interests: None declared., (© Crown copyright (2018), Dstl.)

Organ transplant in patients with congenital bleeding disorders is a challenge requiring an integrated approach of various specialists. Inherited factor VII deficiency is the most common of the rare bleeding disorders, with a wide set of hemorrhagic features. Although a kidney allograft is the most frequent type of solid-organ transplant, it is rarely performed in individuals with congenital hemorrhagic disorders. Here, we highlight the course of a patient with coagulation factor VII deficiency who underwent successful kidney transplant without significant coagulopathy. Our patient was a 19-year-old man with end-stage kidney disease and congenital coagulation factor VII deficiency. Perioperative bleeding was successfully prevented by administration of recombinant factor VII, confirming its safety in solid-organ transplants. Success requires evaluation of doses and therapeutic schedules, as well as a multidisciplinary approach.

Introduction:  Glanzmann thrombasthenia (GT) is a rare bleeding disorder. The disease is caused by the lack or dysfunction of platelet membrane glycoprotein IIb/IIIa (integrin αIIbβ3) which is essential for platelet aggregation. Bleeding episodes are usually managed by platelet transfusions. Recombinant activated factor VII (rFVIIa) is a common adjunct or alternative treatment option., Objective:  This article evaluates GT patients' response to increasing concentrations of rFVIIa using an ex vivo thrombin generation assay to elaborate the knowledge in which rFVIIa treats a platelet dysfunction for bleeding episodes and preoperative management., Materials and Methods:  Twenty-four GT patients in a non-bleeding state were enrolled into the study. Thrombin generation was measured in platelet-rich plasma (PRP) in the presence of 0.7 to 7.0 µg/mL rFVIIa. Clinical data of rFVIIa used to treat GT patients' bleeding episodes was collected, and patients' follow-up course was documented., Results:  Thrombin generation was significantly decreased in GT patients compared with controls. An individual response to rFVIIa spiking was noted in GT patients' PRP. In the majority of patients, a significant improvement in thrombin generation was already demonstrated with low concentrations (0.7 µg/mL) of rFVIIa., Conclusion:  Thrombin generation is improved in the majority of GT patients following ex vivo spiking with rFVIIa. The magnitude of this improvement is individual and was noted at low concentrations of rFVIIa. There is a need for a prospective clinical trial to find the optimal doses or rFVIIa for treatment of GT patients., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

In cardiac surgery, supplementation with recombinant factor VIIa is the treatment of choice for patients with factor VII deficiency, but overzealous administration can be associated with thromboembolic side-effects. A 53-year-old man with factor VII activity 15.2%, international normalized ratio 2.9, and acute thrombotic critical coronary anatomy, underwent coronary artery bypass surgery and a thoracotomy with decortication 5 months later. He was managed successfully without recombinant factor VIIa supplementation. This case demonstrates that current bedside and laboratory tests such as thromboelastography, prothrombin time or international normalized ratio, and factor VII activity may not predict replacement therapy in these patients.

This case illustrates a 36-year-old man who presented with a factor VIII (FVIII) inhibitor (acquired haemophilia A) with cutaneous bleeding and a significant thigh haematoma. No traditional risk factors for the development of a FVIII inhibitor were identified. However, previous treatment with alemtuzumab for multiple sclerosis was noted in the patient's history. Alemtuzumab is an anti-CD52 monoclonal antibody and is known to be associated with the development of a number of autoimmune conditions, with a delay in onset of these conditions as long as 5 years after the cessation of treatment. To our knowledge, there have only been three previously documented cases of a FVIII inhibitor in the setting of alemtuzumab therapy. This case adds further evidence to the current body of literature suggesting alemtuzumab as a causative agent for the development of an FVIII inhibitor., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Essentials Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII. A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia. MarzAA was safe and tolerated at intravenous doses up to 30 μg kg -1 Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX., Summary: Background Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia. Objectives To investigate the safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending intravenous bolus doses of MarzAA in non-bleeding patients with congenital hemophilia A or B with or without inhibitors. Methods This international, phase 1, open-label study (NCT01439971) enrolled males aged 18-64 years with severe hemophilia A or B, with or without FVIII or FIX inhibitors. Subjects were assigned to single-dose MarzAA cohorts (0.5, 4.5, 9, 18 or 30 μg kg -1 ). Blood sampling was performed predose and postdose, and subjects were monitored for 60 days postdose. Safety endpoints included adverse events, vital sign changes, electrocardiograms, laboratory abnormalities, and immunogenicity; secondary endpoints included evaluation of PK and PD. Results Overall, in 25 patients, MarzAA was well tolerated at all dose levels tested, and was not associated with dose-limiting toxicity. No treatment-emergent severe or serious adverse events occurred. MarzAA showed linear dose-response PK across the 4.5-30 μg kg -1 dose range, with a terminal half-life of ⁓ 3.5 h. Dose-dependent shortening of the activated partial thromboplastin time and prothrombin time, and evidence of an increase in peak thrombin as determined with a thrombin generation assay, were observed at all doses. Conclusions MarzAA was tolerated at doses up to 30 μg kg -1 . The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors., (© 2018 International Society on Thrombosis and Haemostasis.)

Objectives: Although off-label use of recombinant activated factor VII against refractory bleeding is incorporated in current guideline recommendations, safety concerns persist predominantly with respect to thromboembolic complications. We analyzed the safety and efficacy of recombinant activated factor VII at a very low dose in cardiosurgical patients with refractory bleeding., Methods: This prospective study includes 1180 cardiosurgical patients at risk of bleeding. Goal-directed substitution was based on real-time laboratory testing and clinical scoring of the bleeding intensity. All patients who fulfilled the criteria for enhanced risk of bleeding (n = 281) were consequently included in the present analysis. Patients in whom refractory bleeding developed despite substitution with specific hemostatic compounds (n = 167) received a single shot of very low-dose recombinant activated factor VII (≤20 μg/kg). Mortality and risk of thromboembolic complications, and freedom from stroke and acute myocardial infarction in particular, were analyzed (vs patients without recombinant activated factor VII) by multivariable logistic and Cox regression analyses, as well as Kaplan-Meier estimates., Results: There was no increase in rates of mortality (30-day mortality 4.2% vs 7.0% with P = .418; follow-up survival 85.6% at 13.0 [interquartile range, 8.4-15.7] months vs 80.7% at 10.2 [interquartile range, 7.2-16.1] months with P = .151), thromboembolic complications (6.6% vs 9.6% with P = .637), renal insufficiency, need for percutaneous coronary intervention, duration of ventilation, duration of hospital stay, or rehospitalization in patients receiving very low-dose recombinant activated factor VII compared with patients not receiving recombinant activated factor VII. Complete hemostasis without any need for further hemostatic treatment was achieved after very low-dose recombinant activated factor VII administration in the majority of patients (up to 88.6% vs 0% with P < .001). The key results were confirmed after adjustment by propensity score-based analyses., Conclusions: When combined with early and specific restoration of hemostatic reserves after cardiac surgery, very low-dose recombinant activated factor VII treatment of refractory bleeding is effective and not associated with any apparent increase in adverse events., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Even though vitamin K antagonists (VKAs) have been employed for >50 years, there is still some uncertainty about the best strategy to reverse anticoagulation due to VKAs in cases of major bleeding. Furthermore, there is also scarce evidence about the most appropriate way to treat serious bleeding associated with non-vitamin K antagonist oral anticoagulants. This review analyses the main advantages and disadvantages of the various forthcoming therapeutic options to restore a normal coagulation status in anticoagulated patients with ongoing serious bleeding. It discusses the role of fresh frozen plasma, prothrombin complex concentrates and recombinant factor VII activated. Moreover, we report updated evidence on antidotes currently available or in development. Finally, this article proposes a comprehensive algorithm that summarizes major bleeding management during treatment with oral anticoagulants., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Severe postpartum hemorrhage (sPPH) is an obstetric emergency that needs prompt and effective therapy to reduce the risk of complications. In this study, women who developed sPPH (study cohort, n = 27) were treated according to a standardized management protocol prescribing sequential administration of uterotonic drugs, crystalloids, tranexamic acid, labile blood products, low-dose fibrinogen, and recombinant activated factor VII (rFVIIa). This group was compared to patients treated with different strategies during 2 preceding periods: an in-house guideline regulating the administration of rFVIIa (historical cohort 1, n = 20) and no specific guideline (historical cohort 2, n = 27). The management protocol was used over 33 months. The study cohort had a lower estimated blood loss ( P = .004) and required less red blood cell concentrates ( P = .007), fresh frozen plasma units ( P = .004), and platelet concentrates ( P = .020) compared to historical cohort 1 and historical cohort 2, respectively. The necessity of emergency postpartum hysterectomy was lower in the study group ( P = .012). In conclusion, in patients with sPPH treated with this standardized management protocol, we observed a decreased requirement of labile blood products and lower need to proceed to emergency postpartum hysterectomy.

Introduction: Recombinant FVIIa (rFVIIa) is an effective treatment for haemophilia through frequent administration. However, the short half-life of rFVIIa decreases its prophylactic ability to reduce bleeding. Carboxy-terminal peptide (CTP)-modified FVIIa (MOD-5014) is a long-acting rFVIIa developed for on-demand treatment of haemophilia using either an intravenous or subcutaneous injection with the aim of less frequent administrations, as well as for prophylactic use., Aim: The comprehensive evaluation of the activity MOD-5014 vs commercially available rhFVIIa, as well as their interaction with cofactors and inhibitors., Methods: The in vitro characterization included clotting activity, affinity by surface plasmon resonance, cleavage of synthetic substrates, thrombin generation (TG) and rotation thromboelastometry., Results: Reduced specific activity was obtained for MOD-5014 compared to rhFVIIa, while both compounds demonstrated comparable affinity to tissue factor (TF). MOD-5014 showed reduced TG when spiked at a similar concentration as rhFVIIa, suggesting that an increased concentration might be needed in a clinical setting to provide initial haemostatic effect. MOD-5014 demonstrated a slightly lower affinity for binding to activated platelets and slightly lower proteolytic activity on the platelet surface, possibly as the fusion of CTP has the potential to sterically hinder binding to both the platelet membrane and to protein substrates. Both compounds showed a similar dose-dependent stimulatory effect on clot formation, and both showed a similar deactivation pattern following incubation with TF pathway inhibitor (TFPI), antithrombin and heparin., Conclusion: The comparable in vitro activity of MOD-5014 and rhFVIIa paves the way for in vivo pharmacology evaluations of MOD-5014 in preparation for clinical studies., (© 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Background: Blood transfusions and fractionated products are not without risk and may lead to acute and long-term adverse events. The objective of this study was to evaluate the appropriateness of usage of frozen plasma (FP), cryoprecipitate (CRYO), and recombinant factor VIIa (rVIIa) in a pediatric setting., Methods: All orders for FP, CRYO, and rVIIa were prospectively audited over 6 weeks. Data collected included demographics, laboratory values, indication, and adverse reactions. The appropriateness of each order was independently evaluated using adjudication criteria rated by two hematologists., Results: Two hundred sixty-five products were ordered; 67% of the orders were issued to operating rooms or intensive care units. The most common indication for all products was cardiac surgery. FP was ordered as fluid replacement (15/215; 7%) to correct abnormal coagulation tests (23/215; 11%) and for patients with minor or no bleeding (111/242; 46%). FP was more likely to alter the international normalized ratio (INR) if the INR was over 2.0 (P < 0.0001). The rate of inappropriate products was judged as FP 19%, CRYO 21%, and rVIIa 91%., Conclusion: FP, CRYO, and rVIIa are most commonly used in the operating room and intensive care units. FP was often used for fluid resuscitation and for patients with mild to no bleeding. FP was only effective in lowering the INR when the INR was over 2.0. Use of rVIIa was rarely ordered for an appropriate indication. Results of this study inform its readers where trials of pediatric transfusion should be performed to clarify how these products should be used in clinical practice., (© 2017 Wiley Periodicals, Inc.)

Recombinant, activated factor VIIa (rFVIIa) is used during cardiac surgeries to mitigate refractory coagulopathic bleeding. The purpose of this study was to examine whether rFVIIa use in orthotopic heart transplant (OHT) recipients was associated with a higher incidence of thromboembolic (TE) events compared to patients who did not. A single-center, retrospective, cohort study was performed on OHT recipients who received rFVIIa for refractory coagulopathic bleeding from January 2013 to December 2015. Patients were evaluated for up to 6 months after transplantation and assessed for TE events, rejection, readmissions, graft survival, and patient survival. Categorical variables were analyzed using the Chi square test while student's t or ANOVA testing was utilized for continuous variables. Of the 62 patients who met inclusion criteria, 27 patients received rFVIIa, and 35 patients were selected for the control group. The overall incidence of TE events was not significantly different between patients who received rFVIIa compared to patients in the control group (14.8% vs 11.4%) (p = 0.69). Within 14 days, 14.81% of rFVIIa patients suffered a TE event compared to 5.7% of the control group (p = 0.23). Rejection, readmissions, graft survival, and patient survival were not significantly different at any time points. Use of rFVIIa in heart transplantation showed no difference in the overall rate of TE events, however, there was a nonsignificant trend toward higher risk of early TE development in the rFVIIa group compared to the control group.

Background: Prasugrel is a thienopyridine that inhibits platelet aggregation more rapidly and effectively than clopidogrel, with an increased bleeding risk., Objective: The current study aimed to evaluate the efficacy of three nonspecific haemostatic drugs - recombinant activated factor VII (rFVIIa), tranexamic acid and desmopressin (DDAVP) - to limit blood loss after administration of prasugrel in a rabbit model of bleeding while also evaluating any prothrombotic effects., Design: Randomised, placebo-controlled study., Setting: Faculty of Medicine, University of Geneva, Switzerland, in 2013., Animals: Anaesthetised and artificially ventilated rabbits (n=56)., Interventions: Animals were randomly allocated to one of five groups: control (placebo-placebo), prasugrel-placebo, rFVIIa (prasugrel-rFVIIa 150 μg kg), tranexamic acid (prasugrel-tranexamic acid 20 mg kg) or DDAVP (prasugrel-DDAVP 1 μg kg). Two hours after an oral prasugrel loading dose (4 mg kg), a stenosis and an injury were inflicted on the carotid artery to induce cyclic flow reductions (CFRs) due to thrombosis. Haemostatic drugs were administered during the ensuing observation period., Main Outcome Measures: Standardised hepatosplenic sections were performed to evaluate the primary endpoint of blood loss, monitored for 15 min. Ear-immersion bleeding time and incidence of CFRs were secondary endpoints., Results: Prasugrel decreased ADP-induced platelet aggregation (light transmission method) from 66 ± 4% (mean ± SD) to 41 ± 7% (P < 0.001) and doubled blood loss: 10.7 g (10.1 to12.7) [median (interquartile range)] vs. 20.0 g (17.0 to 24.4), P = 0.003 in the control and prasugrel-placebo groups, respectively. rFVIIa, tranexamic acid and DDAVP reduced neither hepatosplenic blood loss [19.7 g (14.0 to 27.6), 25.2 g (22.6 to 28.7) and 22.9 g (16.8 to 28.8), respectively] nor bleeding time compared with placebo. Regarding safety, rVIIa induced three or more CFRs in 5/12 rabbits, vs. 0/12 in the prasugrel-placebo group (P = 0.037), whereas tranexamic acid and DDAVP did not increase them., Conclusion: The three studied haemostatic drugs rFVIIa, tranexamic acid and DDAVP failed to reduce prasugrel-related bleeding in this model. rFVIIa-treated rabbits were more prone to arterial thrombotic events., Trial Registration: NA.

Factor XI deficiency is associated with significant bleeding in the setting of trauma and surgery. We present a patient with FXI deficiency and multiple red blood cell allo-antibodies requiring repeat aortic root replacement and discuss the perioperative management of patients with FXI deficiency undergoing cardiac surgery., (© 2018 Wiley Periodicals, Inc.)

Objective: To compare outcomes following inactive prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) administration during cardiac surgery., Design: Retrospective propensity-matched analysis., Setting: Academic tertiary-care center., Participants: Patients undergoing cardiac surgery requiring cardiopulmonary bypass who received either rFVIIa or the inactive 3-factor PCC., Interventions: Outcomes following intraoperative administration of rFVIIa (263) or factor IX complex (72) as rescue therapy to treat bleeding., Measurements and Main Results: In the 24 hours after surgery, propensity-matched patients receiving PCC versus rFVIIa had significantly less chest tube outputs (median difference -464 mL, 95% confidence interval [CI] -819 mL to -110 mL), fresh frozen plasma transfusion rates (17% v 38%, p = 0.028), and platelet transfusion rates (26% v 49%, p = 0.027). There were no significant differences between propensity-matched groups in postoperative stroke, deep venous thrombosis, pulmonary embolism, myocardial infarction, or intracardiac thrombus. Postoperative dialysis was significantly less likely in patients administered PCC versus rFVIIa following propensity matching (odds ratio = 0.3, 95% CI 0.1-0.7). No significant difference in 30-day mortality in patients receiving PCC versus rFVIIa was present following propensity matching., Conclusions: Use of rFVIIa versus inactive PCCs was significantly associated with renal failure requiring dialysis and increased postoperative bleeding and transfusions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We describe the successful use of recombinant factor VIIa (rFVIIa) in the control of massive haemoptysis in a 17-year-old patient with a Fontan circulation. The patient was intubated and ventilated in the ICU with deteriorating gas exchange. Conventional methods to control the haemoptysis were ineffective, and rFVIIa was successfully administered as a rescue therapy. rFVIIa is a powerful pro-thrombotic agent, which is only licensed in haemophiliacs with acquired inhibitors to anticoagulation. It has been used off-license in the treatment of massive haemorrhage, although a Cochrane review did not show any significant benefit; however, it may have a role as a rescue therapy where alternatives options have been exhausted after careful risk-benefit analysis.

Severe sepsis with multi-organ failure is associated with a high mortality rate. This case report highlights the challenges and modalities available in the management of a lady with refractory shock and disseminated intravascular coagulation (DIC) due to toxic shock syndrome (TSS) from genital tract sepsis. Early surgical intervention to remove the source of infection, the use of recombinant activated factor VII to treat intractable disseminated intravascular coagulation and intravenous immunoglobulin to neutralise the circulating exotoxins, have been employed and shown to drastically improve outcomes.

Introduction: Haemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis., Aim: Evaluate the dose-dependent efficacy, safety and immunogenicity of activated eptacog beta (rhFVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes (BEs)., Methods: A Phase 3, randomized, cross-over study of initial dose regimens (IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on-demand treatment of mild/moderate BEs. Intravenous 75 μg/kg or 225 μg/kg initial doses with 75 μg/kg subsequent doses by schedule were administered until clinical response., Results: The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 μg/kg IDR, 84.9% (95% CI; 74.0%, 95.7%) of mild/moderate BEs at 12 hours were successfully treated compared to 93.2% (95% CI; 88.1%, 98.3%) treated in the 225 μg/kg IDR. Efficacy between the IDRs was statistically different (P<.020) in mild/moderate bleeding episodes. Both IDRs were well tolerated with no detectable immunogenic or thrombotic responses to rhFVIIa or host cell proteins., Conclusion: The dose-dependent efficacy seen in this study supports individualizing the initial dose of eptacog beta to optimize clinical response. By reducing uncertainty, the PERSEPT 1 results should increase the adoption of early haemostasis as a treatment goal for clinicians who treat haemorrhage in the inhibitor population., (© 2017 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Background: Acquired hemophilia A (AHA) is a rare bleeding disease caused by autoantibodies against factor VIII. Spontaneous bleeding symptoms usually affect the skin and muscle, while pericardial effusion is an extremely rare manifestation. In the elderly, anticoagulant treatment is frequent and bleeding symptoms are usually associated with this., Clinical Findings: We report a hemorrhagic pericardial effusion as the AHA debut in a patient with untreated chronic lymphocytic leukemia and anticoagulated with apixaban for atrial fibrillation and chronic arterial ischemia. The patient was treated with recombinant activated factor VII to control the active bleeding and corticosteroids and cyclophosphamide to eradicate the inhibitor. In addition, a briefly review of hematological malignancies associated to acquired hemophilia was performed. PARTICULARITIES:: a) anticoagulant treatment may confuse the suspicion of AHA and its diagnosis; b) hemorrhagic pericardial effusion is an extremely rare presentation; c) bypassing agents raise the risk of thromboembolism; d) hematological malignancies rarely cause AHA (<20% of cases)., Conclusion: A multidisciplinary team is needed to diagnose and manage AHA effectively. The use of anticoagulants may lead to the misdiagnosis of clinical symptoms. Chronic lymphocytic leukemia is one of the main causes of hematological malignancies associated. The specific treatment of CLL is still recommended in the event of active disease., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

: Severe hereditary factor VII deficiency is a rare bleeding disorder and may be associated with a severe bleeding phenotype. We describe a pregnancy in a 33-year-old woman with compound heterozygous factor VII deficiency and a history of severe menorrhagia and mucocutaneous bleedings. After discontinuation of contraceptives, menstruation was covered with recombinant activated factor VII (rFVIIa), and during pregnancy, rFVIIa had to be administered in first trimester in doses ranging from 15 to 90 μg/kg per day because of recurrent retroplacental hematomas and vaginal bleedings. Thrombin generation was measured in first trimester at different doses of rFVIIa and showed an increase in lag time when doses of less than 30 μg/kg/day were administered, whereas time to thrombin peak and peak thrombin were not influenced. A low-dose rFVIIa prophylactic treatment of 15 μg/kg every other day in the late second and in the third trimester was sufficient to allow a successful childbirth in this patient with severe factor VII deficiency.