Factor VII Coagulant Activity Research Articles

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

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

Acquired isolated factor VII deficiency in a patient with myxoid pleomorphic liposarcoma, case report

Introduction: Acquired factor VII (FVII) deficiency is a rare condition with various causes, including acquired inhibitors to FVII, liver disease, and malignancies. Myxoid pleomorphic liposarcoma is a rare and aggressive form of soft tissue sarcoma that can cause a range of clinical manifestations, including bleeding and clotting disorders. Patient concerns and diagnosis: We present a case report of a 21-year-old man with severe acquired FVII deficiency due to mediastinal myxoid pleomorphic liposarcoma. The patient presented with elevated International normalized ratio (INR) and a severe reduction in FVII coagulant activity, unresponsive to conventional therapy. While an acquired inhibitor to FVII was initially suspected, negative results from laboratory testing, including protein G sepharose adsorption and a Bethesda assay using Immunoglobulin G purified from patient plasma, made the diagnosis of an acquired inhibitor to FVII uncertain. Interventions and outcome: The patient underwent surgical resection of the tumor, supported by recombinant FVII infusion, leading to the normalization of coagulation parameters. However, a relapse of the disease was detected 6 months later when he was noted to have a decline in FVII levels. Conclusion: This case highlights the importance of considering rare causes of bleeding and clotting disorders, particularly in unresponsive or atypical presentations. It also underscores the need for close monitoring and follow-up in patients with acquired FVII deficiency, even after successful treatment.

A Prospective, Observational, Multi-Center Study of Rurioctocog Alfa Pegol Pharmacokinetic-Guided Prophylaxis Using Mypkfit in Severe Hemophilia a Patients in Taiwan (ATTRACT-HA Study): An Interim Analysis

Background Rurioctocog alfa pegol is a polyethylene glycol (PEG)-ylated recombinant antihemophilic factor VIII (FVIII) with an extended half-life, which allows prolonged dosing intervals. Using myPKFiT, the first and only FDA-cleared PK dosing software, healthcare professionals can simulate dosing regimens using patients' pharmacokinetic profiles. According to 2020 WFH Guidelines for the Management of Hemophilia, the trough level is suggested to be increased from >1% to 3-5% or higher to improve patient care (Srivastava et al. Haemophilia 2020). The Phase 3b Continuationstudy demonstrated that maintaining trough levels ≥3% with PK-guided prophylaxis in patients with severe haemophilia A reduced spontaneous annual bleeding rate (sABR), and thus led to the resolution of target joints (Chowdary et al. Haemophilia 2020). The ATTRACT-HA study will provide the first multi-center real-world evidence in Taiwan whether maintaining a predicted trough level of ≥3% using rurioctocog alfa pegol PK-guided prophylaxis using myPKFiT in severe hemophilia A patients can result in improved clinical outcomes as well as a better quality of life.This interim analysis will focus on the hemophilia-related characterization of the enrolled patients. Methods We enrolled patients, ≥12 years old with body weights of ≥30 kg and ≤140 kg, diagnosed with severe hemophilia A (FVIII clotting activity <1%). The enrolled patients were required to be on prophylaxis with rurioctocog alfa pegol for more than a month before the baseline visit and their historical bleeding data, 6 months prior to the screening visit, was also collected. Patients with a stable dosing regimen at the baseline underwent a myPKFiT PK assessment to determine if a patient was in the trough level <3% or ≥3% group (Figure 1). The primary endpoint of this study was to evaluate the clinical outcomes based on ABR and AJBR. Secondary endpoints included the scores of clinical outcomes with haemophilia early arthropathy detection with ultrasound (HEAD-US), the Haemophilia Quality of Life Questionnaire, and the international physical activity questionnaire (IPAQ) assessing patients' daily activity level performed at the baseline visit and in month 12. The date of data cut-off for this interim analysis was 5 th of January 2023. Results A total of 16 patients with severe hemophilia A were enrolled and stratified by myPKFiT PK assessment into two groups, with a trough level either <3% or ≥3%. There were 7 patients (median age: 23.0 y/o; Q1-Q3 15-29) in the trough level <3% group and 9 patients (median age: 43.0 y/o; Q1-Q3 35-55) in the trough level ≥3% group. Within 6 months prior to enrollment, 71.43% of the patients in the trough level <3% group experienced episodic bleeding, while only 44.44% of the patients experienced episodic bleeding in the trough level ≥3% group (Table 1). The median baseline HEAD-US score was numerically lower in the trough level <3% compared to the trough level ≥3% group (4.29 vs 24.11). The median score of Haem-A-QoL was 25.93 (Q1-Q3; 16.67-47.28) in the trough level <3% group and 42.93 (Q1-Q3; 28.89-48.37) in the trough level ≥3% group. Prospective 1-year follow-up assessments will be performed thereafter. Conclusion The ATTRACT-HA study is the first prospective, multi-center, observational study currently ongoing in Taiwan to provide real-world evidence of the effectiveness of rurioctocog alfa pegol PK-guided prophylaxis using myPKFiT app in patients with severe hemophilia A. In this interim report, we described the clinical features and factors of the study participants at the beginning of this real-world study. Between the two trough levels, we observed a higher percentage of patients experiencing episodic bleeding prior to PK-guided prophylaxis and lower baseline HEAD-US scores in the <3% trough level group, which may be in part due to the younger median age in this group. Acknowledgments The authors thank Dr. Brenden Chen for his contribution of clinical insight and editorial support during the abstract development. This study was funded by Takeda Pharmaceuticals Taiwan, Ltd. Disclosures Yi-Rou Lei, Chieh-Min Chen, Melody Cheng, Brenden Chen are employees of Takeda Pharmaceuticals Taiwan, Ltd. All the other authors disclose no relevant conflicts of interest.

A Phase 1/2, First-in-Human, Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of HMB-001 in Participants with Glanzmann Thrombasthenia

Background & Significance: Glanzmann thrombasthenia (GT) is a rare bleeding disorder resulting from a deficiency of integrin αIIbβ3 (also known as glycoprotein [GP] IIb/IIIa), a receptor for fibrinogen on platelets. Fibrinogen binding to αIIbβ3 bridges platelets and is a required step for normal platelet aggregation and hemostasis. GT is considered a severe bleeding disorder with approximately 50% of the patients reporting 1 bleed every day, and 13% reporting over 500 bleeds per year. The current standard of care for bleeding in patients with GT is reactive and on-demand, with no approved therapies for primary prophylaxis. HMB-001 is a bispecific antibody being developed by Hemab for prophylactic treatment to prevent and reduce bleeding events in patients with GT that can be administered subcutaneously. One arm of HMB-001 binds to and accumulates endogenous activated coagulation factor VII (FVIIa) while the second arm binds to the TREM-like transcript 1 receptor (TLT-1) on activated platelets. The combined effect of FVIIa accumulation and targeting to the surface of activated platelets via HMB-001 brings the activity of FVIIa to levels that are considered therapeutically effective based on clinical experience with recombinant FVIIa (rFVIIa). This is a first-in-human, Phase 1/2, dose escalation, safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy study of HMB-001 in participants with Glanzmann thrombasthenia. Study Design and Methods: The study consists of 3 parts. Part A is a Phase 1, open-label, single ascending dose study, which will evaluate the safety, tolerability, PK, and PD of HMB-001 in participants with GT.Part B is a Phase 2, open-label, multiple ascending dose study evaluating the safety, tolerability, PK, PD, and preliminary effects on bleeding of repeat doses of HMB-001 monotherapy.Part C is a Phase 2, open-label, treatment extension portion study. It will be open to participants who have fulfilled the requirements of Part B and are considered eligible to continue by the Investigator. Part C will evaluate longer term safety, and preliminary efficacy of repeat doses of HMB-001 monotherapy for 9 months. Study Population: Male and female participants 18 to 65 years of age with GT. Part A is single-center, while Part B/C will be a multicenter study in various countries. Major inclusion and exclusion criteria include: Criteria for Inclusion: Part A and B Age 18 to 65Diagnosis of GTVital signs within normal rangeNegative pregnancy testMust meet the following baseline organ function eGFR >45 mL/min/1.73m 2LFTs within normal rangeHgb >85 g/L and platelet count >150 x 10 9/L Part B only 2 bleeding events per week on average of any severity and type and at least 1 spontaneous or traumatic bleed within the last 12 months requiring treatment with rFVIIa, platelets, medical or surgical procedure Criteria for Exclusion: Part A Active severe infection or inflammationHistory of clinically significant hypersensitivity associated with monoclonal antibody therapies.Personal or family history of venous or arterial thrombosis or thromboembolic disease.Other risk factors that substantially increase risk of venous or arterial thrombosisCongenital or acquired bleeding disorders other than GTConcurrent disease, treatment, medications, or abnormality in clinical laboratory tests that may pose additional riskAddiction or other diseases that prevent the participant from appropriately assessing the nature and scope of the clinical study or participating in study procedures Participants included in Part B are eligible for Part C following completion of their dosing in Part B.

Current status and future prospects of activated recombinant coagulation factor VIIa, NovoSeven®, in the treatment of haemophilia and rare bleeding disorders.

rFVIIa, a human recombinant activated coagulation factor VII, has been used worldwide for more than two decades for the treatment of bleeding episodes and prevention of bleeding in patients undergoing surgery/invasive procedures with congenital haemophilia A or B with inhibitors (CHwI A or B), acquired haemophilia (AH), congenital factor VII deficiency and Glanzmann thrombasthenia (GT), refractory to platelet transfusion. The approved dosage, administration and indication of rFVIIa in the US, Europe and Japan differ, depending on the needs of the patient population and regulatory practices. This review presents an overview of the current status and future prospects, including that from a Japanese perspective, of using rFVIIa in the treatment of approved indications. The efficacy and safety of rFVIIa in the approved indications has been demonstrated in several randomised and observational studies and data from registries. The overall incidence of thrombosis across all approved indications in a retrospective safety assessment of clinical trials and registries, prelicensure studies and postmarketing surveillance studies of rFVIIa use was 0.17%. Specifically, the risk of thrombotic events was 0.11% for CHwI, 1.77% for AH, 0.82% for congenital factor VII deficiency and 0.19% for GT. Emerging non-factor therapies such as emicizumab have changed the treatment landscape of haemophilia A, including preventing bleeding in patients with CHwI. However, rFVIIa will continue to play a significant role in the treatment of such patients, particularly during breakthrough bleeding or surgical procedures.

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

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

Low Value of Activated Coagulation Factor VII in Young Primary Spontaneous Pneumothorax

Low Value of Activated Coagulation Factor VII in Young Primary Spontaneous Pneumothorax

Mutations of TFPI-binding exosites on factor VII cause bleeding phenotypes in factor VII deficiency

AbstractTissue factor (TF) pathway inhibitor (TFPI) is a Kunitz-type anticoagulation protein that inhibits activated factor VII (FVIIa)/TF complex. Incidentally, many different F7 gene variants, including TFPI-binding exosite mutations, have been reported in patients with congenital FVII deficiency and clinical bleeding variabilities. Here, TFPI-binding exosites (R147 and K192) on FVII zymogen were selectively disrupted to understand their roles in the pathogenesis of bleeding phenotypes. Expression of recombinant FVII variants (R147A, K192A, and R147A/K192A) demonstrated markedly reduced secretion of FVII owing to intracellular retention in the endoplasmic reticulum, as demonstrated by upregulation of the unfolded protein response genes in all FVII variants. FVII variants showed a similar FVII activation pattern and FVIIa amidolytic activity than FVII wild-type (WT). In contrast to FVII activation, R147A and K192A showed a 90% reduction in FX activation relative to WT, whereas the R147A/K192A variant demonstrated a 99% decrease in FX activation. The clotting time was markedly prolonged with R147A and K192A than WT, and no FVII coagulant activity was detected in R147A/K192A. In addition, the thrombin generation assay revealed a significant prolongation of lag time in all FVII variants. Our study explains how mutations of TFPI-binding exosites of FVII can lead to bleeding phenotypes in individuals carrying these aberrancies.

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

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

Clinical phenotype and F7 gene genotype in 40 Tunisian patients with congenital factor VII deficiency.

Congenital factor VII (FVII) deficiency is an autosomal recessive bleeding disorder characterized by a weak phenotypic and genotypic correlation. This study aimed to determine the genetic alterations of 40 Tunisian patients and to evaluate their relationships with the collected clinical and biological data. Forty FVII-deficient Tunisian patients have been included in this study. First, diagnosis of the FVII deficiency was made on the basis of FVII coagulant activity (FVII:c) levels performed using the prothrombin time assay. Then, clinical and anamnesis data were set up and filed out from the regional registry of bleeding disorders and the medical file of each patient. Finally, genetic alterations were determined by direct sequencing of the coding regions, intron/exons boundaries of the F7 gene. Clinical heterogeneity was noticed, and the direct sequencing allowed the identification of 13 F7 gene mutations of which one was a novel mutation. The clinical manifestations are variably associated with FVII activity FVII:c levels. Lack of relations between severity of clinical manifestations and genotypes was observed; however, a relationship between the nonpathogeneous mutations and clinical phenotypes was noticed. A wide phenotypic inter-individual variability was detected, which suggests the presence of other extra-genetic components influencing the expressivity of the deficiency.

An engineered activated factor V for the prevention and treatment of acute traumatic coagulopathy and bleeding in mice

AbstractAcute traumatic coagulopathy (ATC) occurs in approximately 30% of patients with trauma and is associated with increased mortality. Excessive generation of activated protein C (APC) and hyperfibrinolysis are believed to be driving forces for ATC. Two mouse models were used to investigate whether an engineered activated FV variant (superFVa) that is resistant to inactivation by APC and contains a stabilizing A2-A3 domain disulfide bond can reduce traumatic bleeding and normalize hemostasis parameters in ATC. First, ATC was induced by the combination of trauma and shock. ATC was characterized by activated partial thromboplastin time (APTT) prolongation and reductions of factor V (FV), factor VIII (FVIII), and fibrinogen but not factor II and factor X. Administration of superFVa normalized the APTT, returned FV and FVIII clotting activity levels to their normal range, and reduced APC and thrombin-antithrombin (TAT) levels, indicating improved hemostasis. Next, a liver laceration model was used where ATC develops as a consequence of severe bleeding. superFVa prophylaxis before liver laceration reduced bleeding and prevented APTT prolongation, depletion of FV and FVIII, and excessive generation of APC. Thus, prophylactic administration of superFVa prevented the development of ATC. superFVa intervention started after the development of ATC stabilized bleeding, reversed prolonged APTT, returned FV and FVIII levels to their normal range, and reduced TAT levels that were increased by ATC. In summary, superFVa prevented ATC and traumatic bleeding when administered prophylactically, and superFVa stabilized bleeding and reversed abnormal hemostasis parameters when administered while ATC was in progress. Thus, superFVa may be an attractive strategy to intercept ATC and mitigate traumatic bleeding.

Hemophilia: The Past, the Present, and the Future.

Hemophilia: The Past, the Present, and the Future.

The von Willebrand factor A-1 domain binding aptamer BT200 elevates plasma levels of von Willebrand factor and factor VIII: a first-in-human trial.

von Willebrand factor (VWF) and factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary hemostasis and clotting, respectively. A new VWF A1-domain binding aptamer, BT200, demonstrated good subcutaneous bioavailability and a long half-life in non-human primates. This first-in-human, randomized, placebo-controlled, double-blind trial tested the hypothesis that BT200 is well tolerated and has favorable pharmacokinetic and pharmacodynamic effects in 112 volunteers. Participants received one of the following: a single ascending dose of BT200 (0.18-48 mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterized, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin-induced aggregation, platelet function under high shear rates, and thrombin generation. The mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dose-dependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagen-adenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (P<0.001), without increasing VWF propeptide levels, indicating decreased VWF/FVIII clearance. This, in turn, increased thrombin generation and accelerated clotting. Desmopressin-induced VWF/FVIII release had additive effects on a background of BT200. Tolerability and safety were generally good, but exaggerated pharmacology was seen at saturating doses. This trial identified a novel mechanism of action for BT200: BT200 dose-dependently increases VWF/FVIII by prolonging half-life at doses well below those which inhibit VWF-mediated platelet function. This novel property can be exploited therapeutically to enhance hemostasis in congenital bleeding disorders.

Diagnosis and Treatment of Acquired Hemophilia: One Single-Center Experience from PR. China

Objective: To deepen the understanding of the clinical manifestations of acquired hemophilia A for timely and correctly treatment.Methods: The clinical data of the acquired hemophilia A patients diagnosed in the hospital from Jan 2006 to Mar 2021 were retrospectively analyzed, and the relevant literature was reviewed.Results: 17 patients with acquired hemophilia A, male: female =10: 7, median age 61 years (19 to 78 years), were diagnosed and treated in the hospital with the median time from the onset to diagnosis 21 days (2 days to 6 months). Six patients had comorbidity, including hepatitis B carrying, chronic myelomonocytic leukemia, diabetes, hypertension and positive autoantibodies, pemphigoid and gastric cancer, respectively. Other 11 patients were healthy before the onset. All patients had large large ecchymosis of skin, and one case was combined with hematuria, and one case with retroperitoneal hematoma. All patients had APTT extension (45s-144.7s) and the prolonged APTT could not be corrected with normal mixed plasma with and without incubation at 37℃ for 2 hours. FVIII activity was 1% - 8.9% and inhibitor titer 2 - 128 Bu/ml. All patients with bleeding were with prothrombin complex/recombinant activated coagulation factor VII, some of them with pd-coagulation factor FVIII preparations. Inhibitors were removed with prednisone acetate (1 case) + chemotherapy (1 case), prednisone acetate / + CTX (11 cases) + chemotherapy (1 case), prednisone acetate/prednisolone + mabthera (2 cases) + CTX (1 case), respectively. The removal time of inhibitor was from 8 days to 4 years. During the treatment process, two patients developed lower extremity venous thrombosis, and one patient was complicated with lung infection.Conclusion: Patients with unexplained bleeding and prolonged APTT should be conducted normal mixed plasma correction test, coagulation factor activity and inhibitor titer examination. After correctly diagnosis, bypass agents /coagulation factor VIII preparations should be given timely for hemostasis, protocol based on glucocorticoid + CTX/mabthera to remove the inhibitor and symptomatic treatment for patients with primary comorbidity disease at the same time. DisclosuresNo relevant conflicts of interest to declare.

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

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

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

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

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

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

Infusion therapy of traumatic shock

Background. Analysis of all deaths due to military trauma (MT) over the last decade revealed that 1/4 of them could have been prevented. Up to 90 % of these deaths are related to blood loss. Trauma induces acute endogenous coagulopathy within a few minutes in 25 % of patients, which quadruples mortality. The main feature of MT is its combined nature, because in explosive injuries the local action of the explosion is combined with shrapnel wounds and distant damage to organs, and the wound canal goes through several anatomical parts of the body. In case of concomitant injuries, there are several sources of pain impulses, there is a deep endotoxicosis and impaired function of damaged organs. Under MT conditions, it is difficult to determine the nature of the shock due to a combination of hemorrhagic and traumatic shock. Uncontrolled post-traumatic bleeding is the leading cause of preventable death.&#x0D; Objective. To describe infusion therapy (IT) of shock.&#x0D; Materials and methods. Analysis of literature data on this issue.&#x0D; Results and discussion. In approximately 1/3 of hospitalized patients with trauma, the bleeding is coagulopathic. The severity of coagulopathy is determined by the influence of environmental factors, metabolic disorders, therapeutic strategy, the presence of brain and liver injuries, individual characteristics of the patient, the trauma and shock, hemodilution coagulopathy. The primary task of managing a patient with trauma is to eliminate the so-called lethal triad (hypothermia, acidosis, coagulopathy) and ensure perfusion of vital organs. Damage Control Resuscitation (DRC) is a systemic approach to the treatment of severe injuries that combines a resuscitation strategy with a range of surgical techniques from the moment of injury till the end of the treatment. DRC is aimed at blood loss minimization, maximization of tissue oxygenation, and optimization of outcomes. Surgeries performed as part of the DRC approach include an incision from the xiphoid process to the pubis with evacuation of blood and clots from the abdominal cavity, thorough examination and termination of all bleedings. Damaged parenchymal organs are completely resected. Damaged intestine is resected and connected with clips without anastomosis formation. Damaged vessels are ligated. The abdominal cavity is closed with a sterile bandage, but not sutured. After 1-2 days, tampons are removed, anastomoses are formed, and all non-viable tissues are removed. As for examinations, magnetic resonance imaging is the gold standard for assessing the severity of the injury and detecting extraperitoneal bleeding. In patients with closed abdominal trauma, hypotension, or an unknown mechanism of trauma, a rapid ultrasound examination is indicated to look for blood at potential sites of its accumulation. In the treatment of injuries with bleeding and shock, IT is of great importance. Its principles include the restriction of crystalloids use, the use of blood products in the optimal ratio of blood and plasma, and hypotension until the final surgical hemostasis. Reosorbilact (“Yuria-Pharm”) has properties close to an ideal infusion solution. The efficacy of Reosorbilact in shock was demonstrated in a multicenter Rheo-STAT study. In traumatic shock, infusion of 800 ml of Reosorbilact does not affect the coagulation hemostasis system. Instead, administration of a similar volume of 0.9 % NaCl is accompanied by a tendency to hypercoagulation, and 500 ml of hydroxyethyl starch – by hypocoagulation. Reosorbilact has a pronounced rapid hemodynamic effect. The target hemoglobin level in patients with trauma and bleeding is 70-90 g/L. Intravenous iron preparations (Sufer, “Yuria-Pharm”) can be used for its correction. Prehospital plasma transfusion is recommended to normalize coagulogram parameters. Tranexamic acid (Sangera, “Yuria-Pharm”) should be administered to patients with bleeding within 3 hours of injury. The first dose should be given at the prehospital stage of care. The pleiotropic effects of Sangera include antifibrinolytic, anti-allergic and anti-inflammatory. In addition, Sangera 2-3 times lowers the threshold of pain sensitivity. Another recommended component of comprehensive treatment of bleeding is the introduction of calcium chloride. Recombinant activated coagulation factor VII is not recommended for routine administration and is prescribed only when other measures are ineffective. It is recommended to urgently discontinue vitamin K antagonists and use appropriate antidotes. Pulmonary embolism is the third most common cause of death among patients with polytrauma who survived the third day. It is recommended to initiate the pharmacological thromboprophylaxis within 24 hours of bleeding control being achieved.&#x0D; Conclusions. 1. A significant proportion of preventable deaths are related to blood loss. 2. The primary task of managing a patient with trauma is to eliminate the lethal triad (hypothermia, acidosis, coagulopathy) and ensure perfusion of vital organs. 3. In the treatment of injuries with bleeding and shock, IT is of great importance. 4. Tranexamic acid should be administered to bleeding patients within 3 hours of injury.

Prostasin and hepatocyte growth factor B in factor VIIa generation: Serine protease knockdowns in zebrafish

BackgroundBlood clotting in humans is initiated by the binding of tissue factor to activated coagulation factor VII (FVIIa) in the plasma. Previous studies have reported that hepsin and factor VII (FVII)‐activating protease are responsible for generating FVIIa. ObjectivesWe aimed to identify other proteases that may activate FVII using zebrafish as a model. MethodsWe screened 179 genes encoding serine protease domains using the piggyback knockdown method to identify genes involved in the activation of zebrafish Fvii. A prolonged kinetic prothrombin time (kPT) assay was used to detect gene knockdown effects. ResultsIn the primary screen, 21 genes showed prolonged kPT. In the secondary screen, 14 of 21 genes showed positive results. In the tertiary screen, all 14 genes showed prolonged kPT. These 14 genes were knocked down again to estimate relative levels of zebrafish Fviia. Six genes, including known genes, such as f10 and novel prostasin and hepatocyte growth factor B (hgfb), showed lower Fviia levels. Fvii levels were affected only by the knockdown of f7 and not by the knockdown of the other five genes. ConclusionsProstasin and hgfb are involved in generating Fviia. We hypothesize that prostasin exerts serine protease activity directly or indirectly to activate Fvii. As Hgfb has a mutated serine protease domain, it may not cleave Fvii but may bind to Fvii to induce autoactivation. The approach developed here may be extended to design other large‐scale knockdown screens.

Congenital Deficiency in Factor VII Revealed by Menorrhagia: Case Report

Factor VII (FVII) deficiency is the most common among rare inherited autosomal recessive bleeding disorders. It is a multifaceted disease because of the lack of a direct correlation between plasma levels of coagulation FVII and bleeding manifestations. Clinical phenotypes range from asymptomatic condition—even in homozygous subjects—to severe, life-threatening bleedings (e.g., central nervous system and gastrointestinal bleeding). Menorrhagia is a frequent type of bleeding in FVII deficiency, with a prevalence rate of two in three women aged 10 to 50 years and with a peak prevalence in teenagers. When menorrhagia is observed and once the gynecological causes are excluded, it is important to carry out a hemostasis assessment because, if an anomaly is found, specific treatment can be administered and preventive measures taken. Basic diagnostic work-up includes routine assays, prothrombin level, activated partial thromboplastin time and platelet count, followed by FVII coagulant activity measurement for isolated decreased prothrombin level. To confirm the diagnosis, FVII assay should be repeated at least once. Several treatment options are currently available for FVII deficiency: Recombinant activated Factor VII (rFVIIa), plasma-derived Factor VII, fresh frozen plasma and prothrombin complex concentrates. rFVIIa is the most used replacement therapy. Other medical therapies of menorrhagia includes hemostatic agents and hormonal treatments (combined oral contraceptives, levonorgestrel intrauterine devices), in combination or not with rFVIIa.&#x0D; We report the case of a fourteen-and-a-half-year-old girl who presented menorrhagia of great abundance at the age of thirteen, the exploration of which revealed a congenital deficit in FVII.