Recombinant Factor VIIa Research Articles

Oral invasive procedures in Glanzmann Thrombasthenia: a retrospective observational study

BackgroundGlanzmann Thrombasthenia (GT) is a very rare inherited autosomal bleeding disease affecting megakaryocyte lineage with impacts on oral health such as gingival bleeding and requiring specific management protocols. Only very few clinical cases have been published in the dental and hematological literature. ObjectivesThis study focuses on a series of 21 patients affected specifically by GT and their hemorrhagic prophylaxis management with the use of recombinant factor VIIa (rFVIIa) for dental extractions and full-mouth debridement. Results41 full-mouth debridement and 176 dental extractions were performed along 102 sessions of dental care in outpatient setting. A total of 226 injections of rFVIIa was delivered. The mean of injection was 2.2 (range 1 to 4) per dental procedure. The overall rate of bleeding complication was 5.9% (n = 6). All of these six hemorrhagic complications were classified as minor bleeding. No thromboembolic event was observed nor allergic reaction. ConclusionThe data presented in this retrospective observational study support the efficacy and safety of rFVIIa for the prevention of bleeding for invasive dental procedures in patients affected by GT. rFVIIa protocol presented here seems to be a safe and efficient protocol for the prevention of bleeding for invasive oral procedures.

Saliva of persons with hemophilia A triggers coagulation via extrinsic tenase complexes

AbstractHuman saliva contains extracellular vesicles (EVs). These EVs expose extrinsic tenase complexes of tissue factor (TF) and activated factor VII (FVIIa), and trigger blood coagulation. Here, we show that EVs exposing extrinsic tenase complexes are also present in saliva of persons with severe hemophilia A, that is, persons with FVIII deficiency. Addition of these salivary EVs to autologous FVIII-deficient blood results in FXa generation, thereby compensating for the lack of FXa generation via intrinsic tenase (FVIIIa/FIXa) complexes. Consistently, in our retrospective analysis of persons with severe hemophilia A who do not receive prophylactic FVIII substitution, oropharyngeal mucosal bleedings are infrequent and self-limited. Conversely, in saliva of persons with severe FVII deficiency, in whom oropharyngeal bleedings are prevalent, functional extrinsic tenase complexes are absent, because EVs lack FVII. Saliva of persons with severe FVII deficiency is unable to restore blood coagulation, which is because of the absence of FVII in both their saliva and blood. Picomolar levels of recombinant FVIIa can restore the coagulant potential of saliva of persons with FVII deficiency. Taken together, our findings may explain the paucity of oropharyngeal bleedings in persons with hemophilia A as well as the occurrence of such bleedings in persons with severe FVII deficiency.

Real-world insights into the management of hemophilia A in Italy: treatment patterns and healthcare resource utilization

PurposeThis real-world analysis described the Hemophilia A (HA) population in Italy, evaluating drug utilization and consumption of factor VIII (FVIII) products of patients under prophylaxis and on-demand therapy.MethodsFrom Jan-2017 to Jun-2022, male patients with HA were identified through prescriptions of FVIII products [extended half-life FVIII, standard half-life recombinant FVIII, and plasma-derived FVIII (EHL FVIII, SHL rFVIII, and pdFVIII, respectively)], or emicizumab or FVIII plus von Willebrand factor or HA-related hospitalization using administrative flows of Italian healthcare entities. Patients on treatment with FVIII products during 2021–2022 were stratified by treatment regimen (prophylaxis/on-demand). The mean annual consumption expressed in International Units (IU) of EHL FVIII and SHL FVIII in patients treated during 2021–2022 having at least 12-month follow-up were assessed.ResultsAmong included HA patients, 145 (39.5%) received EHL FVIII and 222 (60.5%) SHL FVIII. Of 165 patients on prophylaxis, 105 (64%) received an EHL FVIII and 60 (36%) an SHL FVIII. The mean annual consumption of FVIII was 336,700 IU (median 319,000 IU) for EHL FVIII and 440,267 IU (median 360,500 IU) for SHL FVIII. Specifically, for patients on EHL FVIII, the most common drugs were efmoroctocog alfa (N = 51) and damoctocog alfa pegol (N = 50), followed by turoctocog alfa pegol (N = 25) and rurioctocog alfa pegol (N = 19). Of 702 HA patients initially treated with FVIII products, 74 (10.5%) switched to emicizumab during follow-up.ConclusionThese findings revealed an extensive use of EHL FVIII products, suggesting growing efforts from clinicians to optimize prophylactic strategies and achieve better bleeding protection.

The anticoagulant effects of milvexian, a novel small molecule factor XIa inhibitor, are neutralized by activated prothrombin complex concentrates and recombinant factor VIIa in human plasma and whole blood in vitro

BackgroundThe development of anticoagulants that provide antithrombotic efficacy without a concomitant bleeding risk remains an unmet clinical need in thrombosis. Although direct oral anticoagulants (DOACs) have a reduced incidence of major bleeding compared with warfarin, they still carry a bleeding risk, resulting in a suboptimal therapeutic index. Epidemiologic data suggest that inhibiting activated factor (F)XI may offer an improved safety profile with respect to bleeding risk compared with current-generation DOACs. Additionally, a phase II trial of milvexian in patients undergoing elective total knee replacement demonstrated robust dose-dependent efficacy with no statistically significant increase in bleeding. Nevertheless, the ability to rapidly and effectively correct FXIa inhibitor–induced anticoagulation may still be important in situations where patients experience uncontrolled bleeding or require emergency surgery. ObjectivesWe assessed the ability to normalize the anticoagulant effects of the novel small molecule FXIa inhibitor milvexian (BMS-986177/JNJ-70033093) in vitro using commercially available prohemostatic agents. MethodsMilvexian-associated anticoagulation and correction was evaluated in activated partial thromboplastin time clotting assays, thromboelastography, and kaolin-initiated thrombin generation assays. ResultsActivated prothrombin complex concentrates (PCCs) and recombinant factor (rF)VIIa corrected the anticoagulant effects of milvexian in activated partial thromboplastin time clotting assays, thromboelastography, and kaolin-initiated thrombin generation assays. In contrast, other agents including PCCs, rFIX, and rFVIII demonstrated either modest or no correction of milvexian-associated anticoagulation. ConclusionThis study demonstrated that currently available activated PCCs and rFVIIa normalize anticoagulation induced by milvexian in vitro. The clinical utility of these agents remains to be established.

Acquired hemophilia A as a disease of the elderly: A comprehensive review of epidemiology, pathogenesis, and novel therapy

AbstractAcquired hemophilia A (AHA) is a rare autoimmune bleeding disorder characterized by the development of neutralizing autoantibodies (inhibitors) against coagulation factor VIII (FVIII). This review provides an in-depth exploration of AHA, covering its epidemiology, pathogenesis, clinical presentation, diagnosis, complications, and treatment strategies, focusing on recent advancements. AHA can manifest in both men and women with no prior bleeding history. The annual incidence is estimated to be approximately 1 case per million individuals in the general population. The incidence increases significantly with age: the incidence among individuals aged 60 years or older is approximately 3 to 4 cases per million individuals per year. Typically, patients present with an acquired bleeding disorder that is characterized by an isolated, prolonged activated partial thromboplastin time stemming from FVIII deficiency. Diagnosis relies on the detection of neutralizing antibodies using the Nijmegen-modified Bethesda assay. Hemostatic control strategies involve bypassing agents like recombinant activated factor VII, activated prothrombin complex concentrate, and recombinant porcine FVIII for bleeding patients. Emicizumab, a novel bypassing agent, exhibits several potential advantages. In the realm of immunosuppressive treatment for inhibitor eradication, the CyDRi regimen emerged as a remarkable advancement, significantly enhancing the outlook for the management of AHA even in the elderly frail population.

Real‐world effectiveness of eptacog beta in patients with haemophilia and inhibitors: A multi‐institutional case series

AbstractIntroductionThe management of bleeding events (BEs) in haemophilia A (HA) and B (HB) patients with inhibitors necessitates the use of bypassing agents. The recombinant factor VIIa bypassing agent eptacog beta has demonstrated efficacy at treating BEs and managing perioperative bleeding in adults in phase three clinical studies.AimTo provide real‐world descriptions of eptacog beta use for BE treatment in patients on emicizumab or eptacog beta prophylaxis.MethodsThis is a retrospective case series of 14 patients who received eptacog beta at seven haemophilia treatment centres, with HA (n = 11) or HB (n = 3) and inhibitors or anaphylaxis to factor replacement.ResultsTwenty‐four spontaneous and traumatic BEs are described (muscle hematomas, joint hemarthroses, port site, and epistaxis) involving 11 subjects. Eptacog beta was effective for acute bleed treatment as both first‐line therapy and for treatment of BEs refractory to eptacog alfa in 23/24 events. When eptacog beta was used for prophylaxis, 2/3 patients reported a decreased frequency of breakthrough BEs compared with prophylactic eptacog alfa and one patient experienced a similar frequency of breakthrough BEs compared with prophylactic activated prothrombin complex concentrate. Eptacog beta provided effective bleed control for three subjects who underwent minor surgical procedures. Treatment with eptacog beta was estimated to be 46%–72% more cost‐effective than eptacog alfa. No safety concerns or adverse events were reported.ConclusionsIn this case series, eptacog beta was safe, effective, and economical as first‐line therapy, treatment of refractory BEs, management of perioperative bleeding, or prophylaxis in haemophilia patients with inhibitors.

Clinical, Laboratory, and Molecular Aspects of Factor VII Deficiency.

Congenital factor VII (FVII) deficiency, the most frequent among the recessively inherited disorders of blood coagulation, is characterized by a wide range of symptoms, from mild mucosal bleeds to life-threatening intracranial hemorrhage. Complete FVII deficiency may cause perinatal lethality. Clinically relevant thresholds of plasma levels are still uncertain, and modest differences in low FVII levels are associated with large differences in clinical phenotypes. Activated FVII (FVIIa) expresses its physiological protease activity only in a complex with tissue factor (TF), which triggers clotting at a very low concentration. Knowledge of the FVIIa-TF complex helps to interpret the clinical findings associated with low FVII activity as compared with other rare bleeding disorders and permits effective management, including prophylaxis, with recombinant FVIIa, which, however, displays a short half-life. Newly devised substitutive and nonsubstitutive treatments, characterized by extended half-life properties, may further improve the quality of life of patients. Genetic diagnosis has been performed in thousands of patients with FVII deficiency, and among the heterogeneous F7 mutations, mostly missense changes, several recurrent variants show geographical distribution and identity by descent. In the general population, common F7 polymorphisms explain a large proportion of FVII level variance in plasma through FVII-lowering effects. Their combination with pathogenic variants may impact on the frequent detection of FVII coagulant levels lower than normal, as well as on mild bleeding conditions. In the twenties of this century, 70 years after the first report of FVII deficiency, more than 200 studies/reports about FVII/FVII deficiency have been published, with thousands of FVII-deficient patients characterized all over the world.

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.

Severe acquired hemophilia A associated with COVID-19 vaccination: A case report and literature review.

Acquired hemophilia A (AHA) is a rare autoimmune disease caused by an antibody that inhibits coagulation factor VIII activity. More than half of patients with AHA cannot identify underlying disorders. The remaining patients are associated with malignancies, autoimmune diseases, skin diseases, infections, and medications. Here, we present a case of 56-year-old Korean man with underlying hypertension, dyslipidemia, and diabetes mellitus who developed AHA following the second dose of BNT162b2 COVID-19 vaccination. He presented with a large 20 × 30 cm-sized hematoma along the psoas muscle and intracranial hemorrhage, necessitating intensive care with mechanical ventilation and continuous renal replacement therapy. Laboratory testing demonstrated that activated partial thromboplastin time and prothrombin times were 74.7 seconds (normal range 29-43 seconds) and 17.2 seconds (normal range 12.5-14.7 seconds), respectively. Laboratory tests confirmed AHA with undetectable factor VIII activity (<1.5%) and a positive factor VIII antibody with a titer of 8.49 Bethesda units/mL. Recombinant factor VIIa (NovoSeven®) was administered every 2 hours to control the bleeding, alongside immunosuppression with methylprednisolone 1 mg/kg daily and cyclophosphamide 2 mg/kg daily to eliminate the autoantibody. Despite the treatments, the patient developed sepsis and succumbed 14 weeks after admission. This rare case underscores the importance of monitoring for AHA following COVID-19 vaccination. Although the benefits outweigh the risks of vaccination, AHA should be considered in the differential diagnosis of unusual bleeding following the vaccinations. Early diagnosis and management before severe bleeding are critical for successfully controlling life-threatening bleeding.

Acquired hemophilia successfully treated with recombinant factor VIIa: A case report

Acquired Hemophilia A (AHA) is a disorder characterized by the impaired clotting ability of the blood, primarily resulting from a deficiency in factor VIII, a crucial clotting protein. It is an infrequent disorder that affects a minority of individuals. This condition can pose a life-threatening risk, with reported mortality rates reaching as high as 22%. The diagnosis of AHA is challenging owing to its non-specific presentation and low prevalence rate. The primary objectives of treatment for AHA encompass the cessation and prevention of bleeding episodes, eradication of the inhibitor, and management of the underlying disease in secondary cases. This case report summarizes the successful treatment of a patient with AHA and major bleeding with the repeated use of prednisolone, recombinant factor VIIa, and rituximab.

Glanzmann's thrombasthenia: A nightmare for hernia surgeons.

Glanzmann's thrombasthenia is a rare inherited disorder affecting one in one million. It is characterised by a lack of platelet aggregation due to a defect in the platelet membrane receptor complex (αIIb/βIIIa), which mediates the aggregation of platelets at the site of vessel injury. We report here the first case of successful perioperative haemostatic management of a male patient with Glanzmann's thrombasthenia, who underwent an elective laparoscopic hernia repair. The patient was posted for elective surgery considering the availability of expertise in minimally invasive surgery and accessibility to recombinant activated factor VII. The patient was operated using the extended-view totally extraperitoneal technique for inguinal hernia repair. The patient recovered successfully and reported no complication during follow-up. We conclude that with proper perioperative haematological consultation, and careful coordination between anaesthetists and surgeons, elective laparoscopic procedure can be done in patients with Glanzmann's thrombasthenia, with only recombinant factor VIIa support.

A Scoping Review of Military Combat Casualty Data on Submassive, Massive, and Supermassive Transfusions.

Blood transfusions are common during combat casualty care, aiming to address the loss of blood volume that often accompanies severe battlefield injuries. This scoping review delves into the existing military combat casualty data to analyze the efficacy, challenges, and advances in the use of massive and super-massive transfusions in the management of critically injured warfighters. We performed a scoping review of combat-related literature published between 2006 and 2023 pertaining to massive transfusions used during combat deployments. We utilized PubMed to identify relevant studies and utilized the PRISMA-ScR Checklist to conduct the review. We identified 53 studies that met the inclusion criteria with the majority being retrospective studies from registries used by the United States, British, French, and Dutch Militaries. Most of the studies focused on transfusion ratios, the movement of blood transfusions to more forward locations, implementation of massive transfusions with different fibrinogen-to-red blood cell ratios, the addition of recombinant factor VII, and the use of predictive models for transfusion. Lastly, we identified reports of improved survival for casualties with the rapid implementation of various blood products (warm fresh whole blood, cold-stored low titer group O blood, freeze-dried plasma, and component therapy) and literature relating to pediatric casualties and submassive transfusions. Notable findings include the establishment of hemodynamic and cell blood count parameters as predictors of the requirement for massive transfusions and the association of higher fibrinogen-to-red blood cell ratios with decreased mortality. We identified 53 studies focused on blood transfusions from the Global War on Terrorism conflicts. The majority were related to transfusion ratios and the movement of blood transfusions to more forward locations. We highlight key lessons learned on the battlefield that have been translated into scientific developments and changes in civilian trauma methods.

Diagnosis and management of factor XI alloinhibitors in patients with congenital factor XI deficiency-A large single-centre experience.

Factor (F) XI deficiency is an inherited bleeding disorder with increased prevalence in Ashkenazi Jews where it is mainly caused by two variants, p.Glu135* (type II, leading to a null allele) and p.Phe301Leu (type III, missense variant). Inhibitor development is rare, and only seen in severe FXI deficiency (<20IU/dL) upon exposure to plasma-based products. We report our experience of a large cohort of patients with severe FXI deficiency, including seven patients who developed FXI alloinhibitors, their presentation, natural history and subsequent perioperative management. A single-centre retrospective database review of patients with FXI deficiency, including those who have subsequently developed inhibitors, and extraction of clinical, laboratory and genotype data, including operative management records. A total of 682 patients were identified with FXI deficiency, of whom 113 had FXI<20IU/dL and 42 had FXI≤1IU/dL. Factor XI inhibitors were seen in seven patients, six of whom were homozygous for the type II variant (prevalence of inhibitor with this genotype of 30%, risk of inhibitor upon plasma exposure 50%). FXI inhibitors were not seen, despite similar exposures, in patients with other genotypes. No alteration in bleeding phenotype occurred after inhibitor development and subsequent surgery was managed on 13 occasions with recombinant factor VIIa (rFVIIa), including low doses (15-30µg/kg), with good haemostasis. The inhibitor spontaneously disappeared in four of seven patients over 1-22 years. FXI inhibitors were only observed in severe FXI deficient patients homozygous for p.Glu135* (null allele) upon plasma or FXI concentrate exposure, with a 30% prevalence. The bleeding phenotype was not altered and inhibitors may disappear with time. Adequate haemostasis in the perioperative setting is achievable with low doses of rFVIIa.

Kinetic Modeling for BT200 to Predict the Level of Plasma-Derived Coagulation Factor VIII in Humans.

Lack of Factor VIII (FVIII) concentrates is one of limiting factors for Hemophilia A prophylaxis in resource-limited countries. Rondaptivon pegol (BT200) is a pegylated aptamer and has been shown to elevate the level of von Willebrand Factor (VWF) and FVIII in previous studies. A population pharmacokinetic model for BT200 was built and linked to the kinetic models of VWF and FVIII based on reasonable assumptions. The developed PK/PD model for BT200 described the observed kinetic of BT200, VWF, and FVIII in healthy volunteers and patients with mild-to-moderate hemophilia A from two clinical trials. The developed model was evaluated using an external dataset in patients with severe hemophilia A taking recombinant FVIII products. The developed and evaluated PK/PD model was able to describe and predict concentration-time profiles of BT200, VWF, and FVIII in healthy volunteers and patients with hemophilia A. Concentration-time profiles of FVIII were then predicted following coadministration of plasma-derived FVIII concentrate and BT200 under various dosing scenarios in virtual patients with severe hemophilia A. Plasma-derived products, that contain VWF, are more accessible in low-resource countries as compared to their recombinant counterparts. The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week.

Evaluating the Effectiveness of Recombinant Factor VIIa in Nonhemophilic Pediatric Cancer Patients with Acute Severe Bleeding

Abstract Context: Despite recombinant factor VIIa (rFVIIa) being approved for treating bleeding in hemophilia patients, there has been limited research on its efficacy in nonhemophilic cases, particularly, in pediatric cancer patients who are vulnerable to bleeding. Aim: Our objective is to assess rFVIIa’s effectiveness in managing severe bleeding in pediatric nonhemophilic cancer patients. Settings and Design: We conducted a retrospective study at a comprehensive cancer center. Materials and Methods: It involves reviewing cases of nonhemophilic pediatric cancer patients treated with rFVIIa for acute severe bleeding during hospitalization between 2013 and 2022 using the pharmacy electronic system. Patients without a cancer diagnosis were excluded. The primary outcome assessed was the cessation of bleeding within 48 h post the last administered rFVIIa dose. Statistical Analysis Used: Descriptive statistics were used to report the outcomes. Results: The results revealed that our analysis encompassed 22 nonhemophilic pediatric cancer patients experiencing acute severe bleeding. The mean age was 7 ± 16.9 (SD) years, with 18 (81.8%) being male. Among them, 7 (31.8%) had leukemia and 5 (22.7%) had neuroblastoma. Thrombocytopenia was prevalent in 21 (95.5%) patients, and 7 (31.8%) underwent bone marrow transplantation. On average, patients received 85 ± 10 (SD) µg/kg of rFVIIa for one to two doses per bleeding episode. Bleeding cessation was achieved in 13 (59%) patients. Conclusion: Our findings suggest that rFVIIa could serve as a viable therapeutic option for managing acute severe bleeding in nonhemophilic pediatric cancer patients.

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.

Comparing the Yield of Recombinant Human Factor VII Protein Expressed by the rDNA-Promoter with the CMV-Promoter in Iranian Lizard Leishmania.

Iranian Lizard Leishmania (I.L.L) is a nonpathogenic Leishmania strain. Due to its advantages, several recombinant proteins have been produced in this host. However, I.L.L shows a lower yield of recombinant protein expression compared to other commercial hosts. Considering the role of protease enzymes in protein digestion, we selected cysteine protease B (CPB) to investigate its impact on recombinant protein yield in I.L.L. we generated gene knockouts by utilizing homologous recombination (HR) and CRISPR methods. To assess the efficacy of the designed construct, we compared the yield of recombinant human factor VII (rhFVII) production between cells transfected with the pLEXSY-hyg2-FVII vector and the CMV-promoter-based construct (pF7cmvneo). The knockout of a single CPB gene allele through the HR method or the complete knockout of all alleles through the CRISPR method led to cell death. This outcome suggests that even the deletion of a single CPB gene allele diminishes the protein to a level insufficient for the survival of I.L.L, indicating a critical dependency on the presence of this protein for the organism's viability. rhFVII exhibited a greater expression yield with the pLEXSY construct compared to the pF7cmvneo construct in I.L.L. The lower expression rate of pF7cmvneo may be influenced by epigenetic factors related to the CPC gene or the RNA polymerase used for the expression of that promoter. Therefore, considering alternative integration targets for CMV-promoter-based constructs and incorporating UTR sequences of I.L.L high-expression proteins in the vector may enhance recombinant protein expression rates.

Case Report: Effective management of adalimumab-induced acquired hemophilia A with the CyDRI protocol

IntroductionAcquired Hemophilia A (AHA) is a rare autoimmune disorder characterized by the emergence of inhibitors that specifically target coagulation Factor VIII, frequently resulting in severe bleeding episodes.MethodsWe conducted a retrospective analysis of the medical records of a 68-year-old male patient who presented with adalimumab-induced AHA.ResultsThe patient received adalimumab, a tumor necrosis factor inhibitor antibody, as part of his treatment for rheumatoid arthritis. The patient’s clinical journey, characterized by intense bleeding and coagulopathy, was effectively managed with the application of recombinant Factor VIIa (rFVIIa) and the CyDRi protocol.DiscussionThe case emphasizes the importance of prompt coagulation assessment in patients with bleeding symptoms receiving disease-modifying therapy for rheumatoid arthritis that includes adalimumab therapy, considering the rare yet life-threatening nature of AHA. Additionally, this report provides an extensive review of the existing literature on drug-induced AHA, with a special emphasis on cases linked to immunomodulatory medications. Through this two-pronged approach, our report aims to enhance understanding and awareness of this severe complication among healthcare providers, promoting timely diagnosis and intervention.

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.

Additional Factor X Enhances Emicizumab-Driven Coagulation Function in Patients with Hemophilia A and Hemophilia A Mice.

Bypassing agents are used for breakthrough bleedings in patients with hemophilia A with inhibitor (PwHAwI) receiving emicizumab prophylaxis. Previous study demonstrated a weak binding affinity between emicizumab and factor (F)X (K d; 1.85 μM), and that this value was much greater than the plasma FX concentration (∼130 nM). We speculated that increased FX levels could enhance coagulation potential in emicizumab-treated patients with hemophilia A (PwHA). To investigate the relationship between FX concentrations and emicizumab-driven coagulation. Plasma FX (up to 1,040 nM) and emicizumab (50 µg/mL) were added to FVIII-deficient plasmas, and plasma-derived FX (520 nM) or recombinant (r)FVIIa (2.2 µg/mL) was added to plasmas from three emicizumab-treated PwHAwI. The adjusted maximum coagulation velocity (Ad|min1|) by clot waveform analysis and peak thrombin (PeakTh) by thrombin generation assay in them were evaluated. Emicizumab (3.0 mg/kg), human (h)FIX (100 IU/kg), and various doses of hFX (100-500 IU/kg) were intravenously administered to HA mice. Clotting time/clot formation time (CT/CFT) were assessed using rotational thromboelastometry, and blood loss was estimated by a tail-clip assay. The addition of FX to FVIII-deficient plasma with emicizumab increased Ad|min1| and PeakTh. The coagulation parameters in emicizumab-treated PwHAwI spiked with additional FX remained within the normal range as well as the additional rFVIIa. In animal models, hFX injection shortened the CT and CT + CFT. The shorter CT and CT + CFT, and the lower blood loss were evident after 200 or 500 IU/kg hFX administration, and those indices were comparable to those in wild-type mice. Supplementation with FX may improve emicizumab-driven hemostasis in PwHA.