Prevention Of Bleeding In Patients Research Articles

Prophylaxis and Treatment of Bleeding or Thrombosis with Fibrinogen Concentrate (Fibryga) in Patients with Congenital Hypofibrinogenemia or Dysfibrinogenemia

Congenital fibrinogen disorders (CFDs) are rare and make up approximately 0.6% of all inherited bleeding disorders. Two subtypes include a quantitative deficiency of fibrinogen, congenital afibrinogenemia (CA), congenital hypofibrinogenemia (CH), and qualitative defect of the fibrinogen molecule, congenital dysfibrinogenemia (CD). Patients with CD may have a thrombotic as well as a hemorrhagic disease phenotype. In the past, fresh frozen plasma or cryoprecipitate were the only options available for treatment and prevention of bleeding in patients with CFD. Today in the US, human plasma-derived concentrates (FIBRYGA, Octapharma, Lachlen, Switzerland, and RiaSTAP, CSL, Melbourne, Australia) are available and considered safe and effective treatment options for CD and CH. Guidelines for the treatment and prevention of bleeding is not established for CFDs, and especially for CD. We present eight clinical cases of patients with hypo- or dysfibrinogenemia that were effectively treated with a pooled, plasma-derived fibrinogen concentrate (FIBRYGA) either prophylactically for elective or urgent surgery, or post-traumatic injury. The mean age of patients treated was 34 years (min-max 8-70 years). Three patients were male and five, female. Four patients had CH and four, CD. FIBRYGA was used to prophylactically treat a total of ten surgical procedures and two post-traumatic events in these patients. Dosing of FIBRYGA was based on the goal peak plasma fibrinogen concentration and the manufacturer's prescribing information, but modified to align with local laboratory reference ranges for the functional fibrinogen test. No acute or delayed infusion reactions (nausea, fever, rigors, headache) and no hypersensitivity reactions were noted. One patient developed two adverse events, one thrombotic and one hemorrhagic. This patient underwent left, above the knee amputation (AKA) and had a complicated postoperative period due to her multiple comorbidities including type 2 diabetes, hypertension, and long standing, poorly-controlled, severe peripheral arterial disease. She presented nineteen days after receiving FIBRGYA with a PE and multiple DVTs. Fifty-nine days later she presented with wound dehiscence and underwent an extensive excisional debridement with postoperative bleeding deemed to be secondary to her strap sliding during surgery and acting as a tourniquet for venous blood flow. For the majority (86%) of our patients described here with CH and CD, FIBRYGA was well tolerated and effective in preventing post procedural or post traumatic bleeding complications. The post procedural bleeding noted in one patient may have been due to inadequate fibrinogen concentration or other comorbid conditions. Further clinical studies are needed to determine the role of FIBRGYA and other HFC in the treatment of patients with CFD, especially those with CD.

Liposomal Resveratrol Alleviates Platelet Storage Lesion via Antioxidation and the Physical Buffering Effect.

Platelet transfusion is essential in the treatment of platelet-related diseases and the prevention of bleeding in patients with surgical procedures. Platelet transfusion efficacy and shelf life are limited mainly by the development of platelet storage lesion (PSL). Mitigating PSL is the key to prolonging the platelet shelf life and reducing wastage. Excess intracellular reactive oxygen species (ROS) are one of the main factors causing PSL. In this study, we explored a nanomedicine strategy to improve the quality and functions of platelets in storage. Resveratrol (Res), a natural plant product, is known for its antioxidative effect. However, medical applications of Res are limited due to its low water solubility and stability. Therefore, we used a resveratrol-loaded liposomal system (Res-Lipo) to better utilize the antioxidant effect of the drug. This study aimed to evaluate the effect of Res-Lipo on platelet oxidative stress and alleviation of PSL during the storage time. Res-Lipo scavenged intracellular ROS and inhibited platelet apoptosis and activation during storage. Res-Lipo not only maintained mitochondrial function but also improved platelet aggregation in response to adenosine 5'-diphosphate. These results revealed that Res-Lipo ameliorated PSL and prolonged the platelet survival time in vivo. The strategy provides a potential method for extending the platelet storage time and might be considered a potential and safe additive to alleviate PSL.

The use of endoscopic band ligation in the primary prevention of bleeding in patients with ascites listed in the liver transplantation waiting list

Background. Saving lives and preventing patients from dropping out of the waiting list for liver transplantation due to the progression of portal hypertension and the development of complications is an urgent task of transplantology in conditions of a donor organ shortage, which causes long waiting times for this operation. Aim. To study the efficacy of endoscopic band ligation versus no intervention in the primary prevention of upper gastrointestinal bleeding and assess the impact on survival of patients with ascites listed in the liver transplantation waiting list. Material and methods. A retrospective comparative study was conducted in patients with decompensated liver diseases with severe ascites and varicose veins, without a history of bleeding, when included in the waiting list for liver transplantation. Primary prevention of bleeding from varices was carried out in patients by means of endoscopic ligation of varicose veins (n=92, group 1); this intervention was not performed in other patients (n=89, group 2). Results. The compared groups were comparable in demographics, clinical parameters, MELD and Child-TurcottePugh scores, or the incidence of severe ascites. The study groups of patients did not have significant differences in the numbers of medium-size and large varices. The incidence of bleeding was significantly lower in the group of patients with endoscopic band ligation as a method of primary prevention than in the group of patients without this intervention (23.9% and 78.7%, respectively, p=0.0001). Patient survival was significantly higher in the group of patients who underwent endoscopic band ligation than in the group of patients without interventions, which was established using the Kaplan-Meier method (Log Rank=0.0001). Conclusion. Primary prevention of bleeding from the upper digestive tract through endoscopic band ligation is an effective method of saving lives and preventing patients with ascites from dropping out of the liver transplantation waiting list in conditions of a donor organ shortageб which causes a long waiting period for surgery.

Timing of intra-abdominal aortic balloon occlusion for prevention of hemorrhage in patients with placenta previa and placenta accreta spectrum.

Placenta accreta spectrum (PAS) has been linked to severe negative maternal-fetal pregnancy outcomes, including a high risk of maternal death. The goal of this study was to determine whether an abdominal aortic balloon block performed before fetal birth lowered intraoperative bleeding and the risk of severe bleeding, as opposed to a block performed after fetal birth. In this retrospective cohort study, patients who underwent pre-delivery or post-delivery inflation were compared for intraoperative hemorrhage, transfusion rate, hysterectomy rate, intensive care unit (ICU) hospitalization, and newborn indices. To ensure the robustness of our findings, we applied multivariate logistic regression, propensity score analysis, and an inverse probability-weighting model. This study included 168 patients who underwent balloon occlusion (62 pre-delivery, 106 post-delivery). The overall probability of major bleeding was 56.5% (95/168), and the pre-delivery and post-delivery probabilities for major bleeding were 64.5% (40/62) and 51.9% (55/106) (P = 0.112), respectively. In the multivariable-adjusted model, post-delivery inflation was associated with a 33% numerically higher probability of massive bleeding (odds ratio 1.33, 95% confidence interval 0.54-3.25, P = 0.535). However, the difference was not statistically significant. According to our findings, pre-delivery inflation did not significantly reduce the risk or amount of severe bleeding.

Oral tranexamic acid in the treatment of hyperpigmentation disorder beyond melasma: A review.

Tranexamic acid, a synthetic derivative of the amino acid lysine, is an antifibrinolytic, procoagulant agent approved by the Food and Drug Administration for the treatment of cyclic heavy menstrual bleeding and prevention of bleeding in patients with hemophilia undergoing tooth extraction. Oral tranexamic acid has been used off-label in dermatology in the treatment of melasma and other hyperpigmentation disorders. In a recent study, oral tranexamic acid was reviewed thoroughly in treating melasma, and its effectiveness was demonstrated. Their role in treating other hyperpigmentation disorders has also been tried in several studies. To review the evidence regarding the use of tranexamic acid in treating different types of hyperpigmentation disorders other than melasma. A comprehensive literature review was searched using the electronic online database "PubMed" and "google scholar" using key words "Postinflammatory hyperpigmentation," "lichen planus pigmentosus," "ashy dermatosis," "riehl melanosis". After that, a full-text review of the studies was performed. Oral tranexamic acid has been used in different types of hyperpigmentation disorder, including postinflammatory hyperpigmentation treatment and prevention, lichen planus pigmentosus, ashy dermatosis, and Riehl melanosis in a dose range from 250 mg per day to 1500 mg per day for a period range from 2 weeks to 6 months with variable efficacy and a good safety profile. Oral tranexamic acid is a promising treatment option in a different type of hyperpigmentation disorders refractory to topical treatment. However, more evidence from blinded randomized controlled trials and case-control studies is needed to determine their efficacy in treating various hyperpigmentation disorders.

Prevention of Bleeding in Patients with Moderate and Severe Hemophilia A Playing Sports: A Comparison between Factor VIII and Emicizumab Prophylaxis (STEP: SporTs Emicizumab Prophylaxis)

Prevention of Bleeding in Patients with Moderate and Severe Hemophilia A Playing Sports: A Comparison between Factor VIII and Emicizumab Prophylaxis (STEP: SporTs Emicizumab Prophylaxis)

Emicizumab prophylaxis in infants with severe haemophilia A without inhibitors: Illustrative real-world cases to support shared decision-making.

Emicizumab has been shown to be safe and effective for prevention of bleeds in patients with severe haemophilia A (SHA), both with and without inhibitors. The subcutaneous administration and long half-life make emicizumab an attractive option for prophylaxis in infants with SHA, however data to inform treatment decisions in this younger age group are almost absent. The aim of this report is to share real world experience to illustrate how the availability of emicizumab has shifted the prophylaxis paradigm in the management of infants with SHA. We selected four cases from our own cohort of infants with SHA to outline the rationale for emicizumab prophylaxis in a range of scenarios familiar to paediatric haemophilia treaters. In Case 1 emicizumab was commenced at 7 days following initial treatment of neonatal ICH with a FVIII infusion. In Case 2 emicizumab was commenced at 5weeks due to parental anxiety regarding the potential for ICH during infancy. Case 3 commenced emicizumab at 15 months in lieu of standard primary prophylaxis. Case 4 switched to emicizumab prophylaxis at 14 months after a period of primary prophylaxis with FVIII concentrates to alleviate parental anxiety regarding future inhibitor development. No patient had any bleeding events after commencement of emicizumab (median follow up 12 months), and no drug-related adverse effects were observed. Despite the paucity of data in infants with SHA the potential role of emicizumab prophylaxis should be discussed with families when clinically relevant, with decisions tailored to individual need.

EVALUATION OF THE QUALITY OF LIFE OF PATIENTS WITH CIR-RHOSIS AFTER SURGICAL PREVENTION OF BLEEDING FROM VARI-COSEVEINS OF THE ESOPHAGUS

The scientific work is based on the experience of endoscopic ligation of varicose veins of the esophagus (EVV) in 65 patients with liver cirrhosis with portal hypertension syndrome. The degree of ERVP was established in accordance with the classification of K.J. Paquet (1982). Varicose veins of the esophagus of III and IV degrees were recorded in 58 (89.2%) patients. For a comprehensive assessment of the degree of liver failure, the Child-Pugh scale was used (1973). 11 (16.9%) patients were assigned to class A, 23 (35.4%) to class B, 31 (47.7%) patients to class C. The effectiveness of endoscopic ligation in the prevention of bleeding was 92.2%. Recurrence of esophageal-gastric bleeding in the immediate period occurred in 3 patients. Hospital mortality was 4.6%. In the long-term period after endoscopic eradication, recurrence of esophageal varicose veins was diagnosed in 27.8% of patients. Endoscopic ligation of varicose veins of the esophagus is an effective method for stopping and preventing bleeding in patients with liver cirrhosis.

Assessment of rVWF Pharmacokinetics in Overweight and Obese VWD Patients Using a Population Pharmacokinetic Model

Introduction: Adequate treatment and prevention of bleeding in patients with von Willebrand disease (VWD) requires replacement of von Willebrand factor (VWF) to thresholds often dictated by the clinical situation. While weight (WT)-based dosing is widely used for calculation of clotting factor dose, its validity in all populations has been debated. Further questions have arisen regarding the use of ideal vs actual body weight to calculate dose, likely driven by the large interindividual variability between factor concentrations and associated pharmacokinetics (PK). Understanding the relationship between body size and VWF PK in overweight and obese patients could contribute to optimization of dosing in these populations. Here, we aimed to understand the relationship between body size metrics (body mass index [BMI] and WT) and PK parameters of recombinant VWF (rVWF) in overweight and obese patients, using a population model that described von Willebrand Ristocetin Cofactor (VWF:RCo) PK following rVWF administration. Methods: A previously developed 2-compartment population PK model, capturing the influence of body size on VWF:RCo PK by WT-based allometric scaling (Bauer A et al, Res Pract Thromb Haemost 2020;4[Suppl 1]), was utilized to investigate rVWF PK in overweight and obese VWD patients. VWF:RCo data used for model development originated from two phase 1 (study 070701 and 071104) and two phase 3 (study 071001 and 071101) VWD trials, for a total of 79 patients with a BMI and WT range of 16.6-47.8 kg/m2 and 43.8-144.8 kg, respectively. The model performance in the target subgroup of patients was qualified by means of visual predictive checks (VPC). The relationship between BMI/WT and individual PK parameters was then investigated graphically. Finally, an exposure-matching exercise was performed to assess whether VWF:RCo exposure following rVWF administration in overweight subjects was comparable to that of the reference population (Food and Drug Administration, Guidance for Industry, Exposure-Response Relationships: Study Design, Data Analysis, and Regulatory Applications, 2003); to this end, VWF:RCo area under the curve from time zero to infinity (AUCinf) for patients of 45-150 kg was simulated following a rVWF dose of 50 IU/kg. The AUCinf was then compared to the target AUCinf range, defined as the AUCinf of a 74-kg patient receiving 50 IU/kg rVWF +/- 20% (Weiner D, Improving the Drug Company Information to Real World Patient Drug Dosing: a Rivaroxaban AF Case Study, American College of Pharmacometrics 2019 Meeting). Results: The VPC stratified by BMI and WT showed satisfactory predictive performance of the model in overweight patients, with a slight underprediction of peak VWF:RCo activity in patients with BMI >25 kg/m2. As expected, graphical analyses indicated an increase in VWF:RCo clearance and volume of distribution with rising BMI and WT, whereas half-life (t1/2), incremental recovery (IR) and mean residence time appeared to be independent of body size. Trends in PK parameters vs. WT or BMI were similar because of the high correlation between the two body size indices (r=0.94 in the present data set). The simulations of VWF:RCo PK revealed that, for the typical patient, AUCinf was within the target exposure across the weight range of 45-150 kg. Deviations from the target AUCinf were observed when inter-individual variability was considered. Conclusions: The available PK model adequately described VWF:RCo activity in overweight patients with VWD. Overall, t1/2 and IR remained the same even as BMI or WT increased. Model-simulations indicated that, on average, WT-based dosing in patients of < 150 kg led to an AUCinf of VWF:RCo within the pre-defined target. These results support calculation of rVWF dosing based on actual WT in a patient population similar to the one included in the current analysis (BMI ≤ 47.8 kg/m2). However, PK assessments should remain regularly utilized by physicians to address any potential interindividual variability. Disclosures Hale: Takeda Pharmaceutical Company Limited: Current Employment. Bauer:Baxalta Innovations GmbH, a Takeda company, Vienna, Austria: Current Employment, Current equity holder in publicly-traded company. Smania:Pharmetheus: Current Employment; Baxalta/Takeda: Consultancy. Friberg-Hietala:Pharmetheus: Current Employment, Current equity holder in private company; Baxalta/Takeda: Consultancy. Wolfsegger:Baxalta Innovations GmbH, a Takeda company: Current Employment, Current equity holder in publicly-traded company.

An Open-Label Extension Study to Assess the Long-Term Efficacy and Safety of a Plasma-Derived von Willebrand Factor (VWF)/Factor VIII (FVIII) Concentrate in Patients with von Willebrand Disease (SWIFT-VWDext Study).

ObjectivePlasma-derived von Willebrand factor/factor VIII (pdVWF/FVIII; VONCENTO®, CSL Behring) is a high-concentration, low-volume, high-purity concentrate, which contains a high level of high-molecular-weight multimers and a VWF/FVIII ratio of ~2.4:1. The SWIFT (“Studies with von Willebrand factor/Factor VIII”) program is evaluating pdVWF/FVIII in patients with von Willebrand disease (VWD). The long-term efficacy and safety profile of pdVWF/FVIII was investigated in this multicenter, open-label, extension study.MethodsPediatric, adolescent, and adult patients with VWD who required treatment of non-surgical bleeds (NSBs), treatment during surgical events or who were receiving prophylaxis and who had completed one of two previous clinical trials of pdVWF/FVIII were included. Efficacy and safety analyses were performed for on-demand (n=10), prophylaxis (n=8), or on-demand and prophylaxis (n=2) treatment in patients pre-treated with pdVWF/FVIII for ≥12 months.ResultsSeven patients experienced a total of 402 NSBs in the on-demand arm, of which 77 required treatment and nine NSB events in three patients were considered major. Nine patients reported 118 NSBs in the prophylaxis arm, with 96 events requiring treatment and seven patients experiencing 12 major NSB events. Excellent or good hemostatic efficacy was reported by the investigator for 98.7% (on-demand) and 97.9% (prophylaxis) of NSB events treated with pdVWF/FVIII, without relevant differences between subgroups by age. pdVWF/FVIII was well tolerated, and the adverse events seen were mild-moderate and consistent with the safety profile for this product seen in other studies. There were no cases of anaphylactic reactions and angioedema, development of VWF/FVIII inhibitors, thromboembolic events, or viral infections.ConclusionThis contemporary comprehensive development program evaluating pdVWF/FVIII across all ages demonstrates long-term safety and efficacy for treatment and prevention of bleeds in patients with severe VWD, supporting the benefit–risk profile of pdVWF/FVIII.

The effect of adjunctive intravitreal conbercept at the end of diabetic vitrectomy for the prevention of post-vitrectomy hemorrhage in patients with severe proliferative diabetic retinopathy: a prospective, randomized pilot study

BackgroundTo investigate the effect of intravitreal conbercept (IVC) injections on the incidence of postoperative vitreous hemorrhage (VH) in eyes undergoing surgery for severe proliferative diabetic retinopathy.MethodsThis was a pilot prospective, comparative, and randomized study. Thirty patients, who underwent vitrectomy for severe proliferative diabetic retinopathy, were assigned randomly to either group 1 (intravitreal conbercept [IVC] injection at the end of pars plana vitrectomy) or group 2 (no IVC injection). Postoperative follow-up was performed on the first day, first week, first month, third month, sixth month and first year after surgery. The primary outcome was the incidence of postoperative VH. Secondary outcomes were the initial time of vitreous clearing (ITVC), best-corrected visual acuity (BCVA) and central retinal thickness (CRT) after surgery.ResultsA total of 30 eyes, from 30 patients, were included. Fifteen eyes were enrolled in the IVC group and fifteen in the control group. The incidence of early and late postoperative VH was not significantly different between the control and IVC groups. ITVC was shorter in the IVC group than that in the control group, but this was not significant (7.38 ± 10.66 vs 13.23 ± 17.35, P = 0.31). Final BCVA, 1 year after surgery, showed significant improvement compared to baseline in both groups. However, analysis of the BCVA at any postoperative visit after surgery showed no significant differences between the two groups. There were two cases of recurrent VH identified at 3 and 6 months after surgery in each group, requiring a second round of surgery. Foveal thickness was significantly different between the two groups at the 3-month, 6-month and 1-year follow-up visits.ConclusionsIn this pilot study, the effect of IVC injection in reducing the incidence of postoperative VH after diabetic vitrectomy at the end of vitrectomy was not shown.Trial registrationThe study was registered with the Chinese Clinical Trial Registry. (Reference Number: ChiCTR1800015751).

Real Life Experience in Clinical Practice with Recombinant Coagulation FVIII-Fc Fusion Protein

Introduction: Efmoroctocog alfa (Elocta®) is a recombinant coagulation FVIII-Fc (rFVIIIFc), a fully recombinant fusion protein produced in human embryonic kidney cells, with an extended half-life used for the treatment and prevention of bleeding in patients with severe hemophilia A. Using rFVIIIFc for the treatment of severe hemophilia A patients received the approval of reimbursement in Spain at the end of 2016. Therefore, there are no many comparative data published about real life use of rFVIIIFc. Objective: This work aims to describe characteristics of the treatment of severe hemophilia A patients with rFVIIIFc and to compare its results with those previously obtained employing other FVIII products. Methods: This was an open-label non-interventional retrospective study reviewing patient characteristics and treatment outcomes before and after the use of rFVIIIFc. The La Paz University Hospital Ethics Committee approved the experimental protocol. Patients with severe hemophilia A without inhibitors being treated with rFVIIIFc since at least six months before study approval by Ethics Committee were included. The following data were collected for patients included in the study: dose (IU/kg) and prophylaxis treatment regimen, number of spontaneous and traumatic bleedings, annual bleeding rate (ABR) and FVIII trough level. The statistical analysis on the variables listed above comparing before and after rFVIIIFc usage was performed by the Biostatistics Unit of La Paz University Hospital with the statistical package SPSS v.18.0 (SPSS Inc., Chicago, IL, USA). Results: Twenty two severe hemophilia A patients (median age: 20 years old, ranging from 6 to 63 years) on prophylaxis with rFVIIIFc were considered to be included in this study, but two were excluded due to lack of data. Median follow-up period was 14 months (ranging from 6 to 28 months). Nineteen severe hemophilia A patients have been previously treated with rFVIII (two of them with other extended half-life product) and one with plasma-derived FVIII. Eight of the ten severe hemophilia A patients who presented an ABR greater than 0 with previous treatments reduced their ABR when treated with rFVIIIFc (Table 1). Among those patients with an ABR=0 with previously used FVIII products, only one increased to an ABR=1 when treated with Elocta® due to a traumatic bleeding. Table 1 shows ABR across all patients before and after rFVIIIFc. There was no difference in dose per injection between other FVIII products and rFVIIIFc (median dose for patients treated with other FVIII products: 46.0 IU/kg, ranging from 26 to 65 IU/kg; median dose for patients treated with rFVIIIFc: 46.5 IU/kg, ranging from 26 to 65 IU/kg). Nevertheless, a reduction was observed in administration frequency. Among the twelve patients who received treatment with other FVIII products every 48 hours, eleven came to receive rFVIIIFc 3 times a week and the one previously receiving a plasma-derived FVIII, to twice a week. Five of the patients receiving treatment 3 times a week reduced its frequency to twice per week. Three patients maintained the same schedule of administration. To note, one of the two patients receiving another prolonged half-life product maintained the schedule of treatment and the other reduced its frequency from every 48 hours to 3 times a week. FVIII trough level in plasma (% of FVIII), expressed as median (25th-75th percentile), was 1.1 (0.1-4.0) for rFVIIIFc treatment and 0.2 (0.0-1.9) for other FVIII products (p=0.06). Conclusions: 85% of the severe hemophilia A patients from our cohort reduced the weekly dose administration after beginning treatment with rFVIIIFc. Most of the patients increased plasma trough level of FVIII with rFVIIIFc. 45% of patients reduced and 40% kept their ABR=0 when they changed rFVIIIFc. These data suggest that treatment with rFVIIIFc gives a higher protection to severe hemophilia A patients. However, further research with larger sample size is required to investigate this. This work was supported by SOBI. NB holds a tenure track grant from FIS-FONDOS FEDER (CP14/00024). Disclosures Álvarez Roman: Takeda: Research Funding; Amgen: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau. Fernandez-Bello:Novartis, Pfizer, ROCHE, Stago: Speakers Bureau. Martín:SOBI: Research Funding; Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau. Rivas Pollmar:Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau; SOBI: Research Funding. García Barcenilla:Bayer, Pfizer, Takeda, Novartis: Speakers Bureau; SOBI: Research Funding. Canales:SOBI: Research Funding; iQone: Honoraria; Karyopharm: Honoraria; Novartis: Honoraria; Takeda: Speakers Bureau; Gilead: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Sandoz: Honoraria. Butta:Roche, Pfizer: Speakers Bureau; Novartis: Consultancy. Jimenez-Yuste:Bayer, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, Shire: Consultancy, Honoraria, Other: reimbursement for attending symposia/congresses , Research Funding, Speakers Bureau.

Fibrinogen concentrates in hereditary fibrinogen disorders: Past, present and future.

Hereditary fibrinogen disorders (HFD) are rare coagulation disorders. Even if the spectrum of symptoms is broad depending on the sub-type, bleeding is the most common complication. Of the available sources of fibrinogen replacement, fibrinogen concentrate provides a safer and more effective option to treat and prevent bleeding. Recent clinical trials on established and new fibrinogen concentrates have increased our knowledge on the clinical pharmacology of these products, pointing out possible age and weight differences for dose adjustment. The efficacy of fibrinogen infusions has been demonstrated, especially for the management of acute bleeding with an excellent response based on investigator rating. The target fibrinogen levels in the setting of both minor and major surgeries have been better specified. The safety has been confirmed with a low number of adverse events but there still remains concern over possible thrombotic risks. Pharmacological, clinical aspects and future perspectives on the utilization of fibrinogen concentrates in the treatment and prevention of bleeding in patients with HFD are reviewed.

Prevention of gastrointestinal bleeding in patients receiving oral anticoagulants: focus on proton pump inhibitors

The review addresses the issue of the gastrointestinal bleeding (GIB) development in patients receiving oral anticoagulants, and the proton pump inhibitors (PPIs) efficiency in reducing of such complications. Epidemiological data on the prevalence of GIB in the presence of nonwarfarin oral anticoagulants (NOACs) and warfarin intake are presented. The factors that increase the risk of bleeding associated with the use of anticoagulants are discussed, including the potential drug-drug interactions and patients’ dietary habits. A description of the scales that assess the bleeding risks during anticoagulant therapy is given. In the second part of the article the principles of prevention and minimization of the GIB risks in the presence of oral anticoagulants treatment are presented. In the context of evidence-based medicine, the PPIs’ role in reducing the risk of GIB is fully discussed. The results of recent large-scale randomized clinical trials and meta-analyses are described in detail, suggesting the benefits of PPIs in the decreasing the risk of the upper gastrointestinal tract bleeding when NOACs and warfarin are prescribed, especially with concomitant therapy with acetylsalicylic acid. So, PPIs can be considered as one of the effective drug prevention “tools” of these complications.

Correction of bleeding in experimental severe hemophilia A by systemic delivery of factor VIII-encoding mRNA.

The treatment or prevention of bleeding in patients with hemophilia A relies on replacement therapy with different factor VIII (FVIII)-containing products or on the use of by-passing agents, i.e., activated prothrombin complex concentrates or recombinant activated factor VII. Emerging approaches include the use of bispecific anti-factor IXa/factor X antibodies, anti-tissue factor pathway inhibitor antibodies, interfering RNA to antithrombin, and activated protein C-specific serpins or gene therapy. The latter strategies are, however, hampered by the short clinical experience and potential adverse effects including the absence of tight temporal and spatial control of coagulation and the risk of uncontrolled insertional mutagenesis. Systemic delivery of mRNA allows endogenous production of the corresponding encoded protein. Thus, injection of erythropoietin-encoding mRNA in a lipid nanoparticle formulation resulted in increased erythropoiesis in mice and macaques. Here, we demonstrate that a single injection of in vitro transcribed B domain-deleted FVIII-encoding mRNA to FVIII-deficient mice enables endogenous production of pro-coagulant FVIII. Circulating FVIII:C levels above 5% of normal levels were maintained for up to 72 h, with an estimated half-life of FVIII production of 17.9 h, and corrected the bleeding phenotype in a tail clipping assay. The endogenously produced FVIII did however exhibit low specific activity and induced a potent neutralizing IgG response upon repeated administration of the mRNA. Our results suggest that the administration of mRNA is a plausible strategy for the endogenous production of proteins characterized by poor translational efficacy. The use of alternative mRNA delivery systems and improved FVIII-encoding mRNA should foster the production of functional molecules and reduce their immunogenicity.

Experience in the treatment of immune thrombocytopenia in the Department of Oncohematology of the Voronezh Regional Children’s Clinical Hospital № 1

Introduction. Immune thrombocytopenia (ITP) is a benign hematological disease characterized by an isolated decrease in platelet count, with different course options requiring both an urgent therapeutic decision and clinical observation of patients. At the present stage in the treatment of children with immune thrombocytopenia, especially with the chronic form, significant success has been achieved. Therapeutic options are determined by an individual approach to the patient and are based on the experience of a hematologist. Materials and methods. For the period from 01.01.2013 to 12.31.2017, in the Oncohematological Department of Chemotherapy of the Voronezh Regional Children’s Clinical Hospital № 1, 153 children with various forms of ITP, aged between 1 and 6 months to 17 years, received treatment. Diagnosis and stage of the disease were carried out on the basis of modern clinical guidelines and ITP classification. The analysis of the severity of hemorrhagic syndrome in the diagnosis of ITP was carried out. The principles of patient therapy were based on the pathogenetic aspects of ITP, the stage of the disease. Patients with newly diagnosed ITP (n = 106; 69.4 %), persistent form (n = 26; 16.9 %) received different lines of therapy, provided for by clinical guidelines, some patients were only under the supervision of a hematologist. The chronic form of the course of the disease was formed in 21 (14 %) children out of 153, regardless of the type of treatment. Children with the chronic form received various lines of therapy, including thrombopoietin agonists. The decision to manage such patients was based on a joint discussion with specialists from the largest federal centers. Splenectomy for the above period was performed for 1 child with a pronounced and chronic “wet” component of the disease. Discussion. Treatment of ITP in children, despite the emergence of a new class of drugs with a targeted effect, in some cases is a difficult task for a hematologist. The adoption of a specific therapeutic decision is based on the severity of the clinical and hematological data of the patient, the search for a possible cause of the thrombocytopenic condition, as well as the individual experience of the doctor. Prevention and prevention of bleeding in patients with different ITP, in particular with chronic ITP, with the absence or minimal manifestation of hemorrhagic syndrome according to the principle “0 bleeding per year” is the ultimate therapeutic task. Conclusion. ITP in children, in particular its chronic form, belongs to orphan diseases, therefore, the experience of managing such patients may be useful in determining the overall tactics of treating patients.

Treatment and prevention of arresive bleeding in patients with pancreonecrosis.

The article is devoted to the study of acute necrotizing pancreatitis, which leads to the development of various fluid pathologies different in pathogenesis and time, which in turn can lead to an arrosive bleeding. Diagnostic-treatment is p resented algorithm with the active use of modern methods of hemostasis in patients with arrosive bleeding developed against the background of pancreatonecrosis.

Emicizumab for the Prevention of Bleeding in Patients with Hemophilia A

Most individuals with severe hemophilia A infuse factor VIII concentrates two or three times per week to prevent hemorrhages. Emicizumab, a

Hemostatic efficacy of pathogen-inactivated vs untreated platelets: a randomized controlled trial

AbstractPathogen inactivation of platelet concentrates reduces the risk for blood-borne infections. However, its effect on platelet function and hemostatic efficacy of transfusion is unclear. We conducted a randomized noninferiority trial comparing the efficacy of pathogen-inactivated platelets using riboflavin and UV B illumination technology (intervention) compared with standard plasma-stored platelets (control) for the prevention of bleeding in patients with hematologic malignancies and thrombocytopenia. The primary outcome parameter was the proportion of transfusion-treatment periods in which the patient had grade 2 or higher bleeding, as defined by World Health Organization criteria. Between November 2010 and April 2016, 469 unique patients were randomized to 567 transfusion-treatment periods (283 in the control arm, 284 in the intervention arm). There was a 3% absolute difference in grade 2 or higher bleeding in the intention-to-treat analysis: 51% of the transfusion-treatment periods in the control arm and 54% in the intervention arm (95% confidence interval [CI], −6 to 11; P = .012 for noninferiority). However, in the per-protocol analysis, the difference in grade 2 or higher bleeding was 8%: 44% in the control arm and 52% in the intervention arm (95% CI −2 to 18; P = .19 for noninferiority). Transfusion increment parameters were ∼50% lower in the intervention arm. There was no difference in the proportion of patients developing HLA class I alloantibodies. In conclusion, the noninferiority criterion for pathogen-inactivated platelets was met in the intention-to-treat analysis. This finding was not demonstrated in the per-protocol analysis. This trial was registered at The Netherlands National Trial Registry as #NTR2106 and at www.clinicaltrials.gov as #NCT02783313.

PRIMARY PREVENTION OF BLEEDING FROM ESOPHAGEAL AND GASTRIC VARICES IN PATIENTS WITH PORTAL HYPERTENSION

The problem of primary prevention of bleeding from esophageal and gastric varices in patients with portal hypertension is discussed in the review. It was analyzed main views on the mechanisms of bleeding whose study is important to define pathogenetic primary prevention. The role of accurate diagnosis of the esophageal and gastric varices state is presented to predict the risk of bleeding. It was reviewed the variants of primary prevention of bleeding using medical, endoscopic, surgical and X-ray endovascular techniques. Also different drugs for primary prevention of bleeding were characterized depending on main disease nature and degree of compensation. Minimally invasive methods for primary prevention including endoscopic, endovascular techniques and medical therapy were compared. The authors discuss some unsolved problems of primary prevention of bleeding in patients with intrahepatic and extrahepatic portal hypertension, as well as in primary distribution of varices in stomach.