Background. There is a continued search for effective and safe drugs with systemic hemostatic effects. Experimental data from previous studies show that low-dose fibrin monomer (FM) can reduce posttraumatic bleeding without causing activation of clotting in the circulating blood.Aim. To study the systemic hemostatic and hemostasiological effects of prophylactic intravenous administration of FM on the background of fibrinolysis activation by streptokinase.Methods. In a placebo-controlled study using male rabbits, fibrinolysis was activated by intravenous administration of streptokinase at a dose of 150,000 IU/kg. One hour before liver injury, FM was administered intravenously at a dose of 0.25 mg/kg. Tranexamic acid (TXA) was administered intravenously at a dose of 15 mg/kg 30 min before injury as a reference drug. After metered-dose injuring, blood loss was estimated as % of the circulating blood volume and by the rate of blood loss (mg/s). The study of blood platelet count, activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen concentration and the results of rotational blood thromboelastometry were taken into consideration.Results. Administration of FM and TXA before fibrinolysis activation by streptokinase reduced the blood loss volume by 11.0 and 15.4 times, respectively. FM and TXA both reduced the blood loss rate by 3.8 times compared to the placebo group that received the same fibrinolytic. The administration of streptokinase in all cases was accompanied by 23–30% a decrease in the fibrinogen concentration without affecting APTT and TT. The hemostatic effects of FM and TXA were observed in vivo while preserving the density properties of the blood clot (according to the parameters of α angle, MCF and A10 in thromboelastometry) despite the administration of streptokinase, whereas a significant decrease in these parameters was observed in the placebo group.Conclusion. The systemic hemostatic effects of FM at a dose of 0.25 mg/kg with fibrinolysis activation by streptokinase were close to the effects of TXA. Thus, FM administration can be considered a promising hemostatic therapy for the reduction of thrombolysis-associated bleeding. Received 18 December 2019. Accepted 22 January 2020. Funding: The study was supported by a grant from the Russian Foundation for Basic Research (No. 18-415-220001), Altai State Medical University. Conflict of interest: Authors declare no conflict of interest. Author contributionsConception and study design: A.P. Momot, V.M. Vdovin, I.I. ShakhmatovData collection: V.M. Vdovin, D.A. Orekhov, V.O. Krasyukova, N.A. Lycheva, D.A. Momot, V.E. Chernus, V.V. TerjaevData analysis: A.P. Momot, V.M. VdovinDrafting the article: V.M. Vdovin, A.P. MomotCritical revision of the article: A.P. Momot, В V.M. VdovinStatistical analysis: V.M. VdovinFinal approval of the version to be published: V.M. Vdovin, A.P. Momot, D.A. Orekhov, V.O. Krasyukova, I.I. Shakhmatov, N.A. Lycheva, D.A. Momot, V.E. Chernus, V.V. Terjaev

IntroductionOctanate® is a human, plasma‐derived, von Willebrand factor‐stabilized coagulation factor VIII (FVIII) concentrate with demonstrated haemostatic efficacy in previously treated patients with haemophilia A.AimThis prospective, open‐label study aimed to assess the immunogenicity of octanate® in previously untreated patients (PUPs).MethodsThe study monitored development of FVIII inhibitors in 51 PUPs. Tolerability, viral safety, FVIII recovery and efficacy of octanate® for the prevention and treatment of bleeds and in surgical procedures were also assessed.ResultsFive (9.8%) of the 51 patients developed inhibitors during the study, 4 of which (7.8%) were high titre. Three inhibitor cases (5.9%) were considered clinically relevant; 2 were transient inhibitors that disappeared during regular octanate® treatment without a change in dose or treatment frequency. Amongst 45 patients with FVIII:C <1% at baseline and who received ≥20 exposure days (EDs) or had <20 EDs but developed an inhibitor, inhibitor incidence was 11.1% (6.7% clinically relevant). All clinically relevant inhibitors developed within 20 EDs of on‐demand treatment. No inhibitors developed in PUPs receiving prophylaxis. All patients who developed inhibitors had either intron 22 inversions or large deletions. Irrespective of the reason for administration, haemostatic efficacy was rated as “excellent” in 99.6% of all infusions (4700 of 4717 infusions), and no complications were reported in 23 surgical procedures. Mean incremental in vivo recovery was 2.0%/IU/kg (±0.7) and 1.9%/IU/kg (±0.5) for the first and second assessments, respectively. Tolerability was rated “very good” in 99.9% of infusions.ConclusionIn PUPs with severe haemophilia A, octanate® demonstrated haemostatic efficacy with a low rate of inhibitor development.

IntroductionNuwiq® (human‐cl rhFVIII, simoctocog alfa) is a 4th generation recombinant human FVIII, without chemical modification or fusion with any other protein, produced in a human cell line.Aim/MethodsThis study (GENA‐13) was an extension of the GENA‐03 study in which previously treated children aged 2‐12 years with severe haemophilia A received Nuwiq® prophylaxis for ≥6 months. GENA‐13 examined long‐term tolerability, immunogenicity and efficacy of Nuwiq® prophylaxis in children.ResultsOf 59 patients enrolled in GENA‐03, 49 continued Nuwiq® prophylaxis in GENA‐13 for a median (range) of 30.0 (9.5‐52.0) months. No patient withdrew due to drug‐related adverse events or developed inhibitors. Only 2 of 20 518 infusions were associated with possibly related adverse events (dyspnoea, fever). The estimated annualized bleeding rate (ABR) was 0.67 (95% CI: 0.44, 1.02) for spontaneous and 2.88 (95% CI: 1.86, 4.46) for all bleeds. Younger children (2‐5 years) had lower ABRs than children aged 6‐12 years. Annualized bleeding rates were reduced in GENA‐13 vs GENA‐03, especially for spontaneous bleeds in younger children (71% reduction; ABR ratio 0.29 [95% CI: 0.11, 0.74]). Nuwiq® efficacy was rated as excellent/good in the treatment of 83.0% of 305 evaluated breakthrough bleeds. Surgical prophylaxis with Nuwiq® was rated as excellent for all 17 assessed procedures.ConclusionLong‐term treatment with Nuwiq® for the prevention of bleeds in children with severe haemophilia A was well tolerated, effective and reduced spontaneous bleeding by up to 70% compared with GENA‐03.

Nuwiq® (Human‐cl rhFVIII) is a fourth generation recombinant FVIII, produced in a human cell line, without chemical modification or protein fusion. No inhibitors developed in studies with Nuwiq® in 201 previously treated patients with haemophilia A (HA). The immunogenicity, efficacy and safety of Nuwiq® in previously untreated patients (PUPs) with severe HA are being assessed in the ongoing NuProtect study.

Development of neutralizing inhibitors against factor VIII (FVIII) is a major complication of haemophilia A treatment.

SummaryRecombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open‐label, non‐controlled trial investigated the safety, efficacy and pharmacokinetics (PK) of turoctocog alfa, a new rFVIII product, in a paediatric population. The primary objective was to evaluate safety. A total of 31 younger children (0–5 years) and 32 older children (6–11 years), with ≥50 exposure days to any factor VIII (FVIII) product and no history of inhibitors, received prophylaxis with turoctocog alfa (25–50 IU kg−1 every second day or 25–60 IU kg−1 three times weekly). PK assessments of turoctocog alfa and the patients’ previous FVIII product were performed in 28 patients. Mean exposure to turoctocog alfa was 60 exposure days per patient. This corresponds to approximately 4.5 months in the trial. None of the patients developed inhibitors (≥0.6 BU) and no safety concerns were raised. A total of 120 bleeding episodes (95%) were controlled with 1–2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as ‘excellent’ or ‘good’ haemostatic response) for treatment of bleeding episodes was 92%. Overall, the median annualized bleeding rate was 3.0 (interquartile range: 8.5) bleeds patient−1 year−1. PK parameters were comparable between the two age groups. In conclusion, the present large global clinical trial showed that turoctocog alfa was safe, effective in treatment of bleeding episodes and had a prophylactic effect in paediatric patients.