Clotting Factor Concentrates Research Articles

CHIEF: A retrospective self-control study of children with severe hemophilia A without inhibitors comparing emicizumab to FVIII prophylaxis.

Hemophilia A (HA) is an X-linked bleeding disorder diagnosed by a deficiency in factor VIII (FVIII). For severe HA (SHA), prophylaxis clotting factor concentrates (CFC) has become the standard of care; however, it imparts a high treatment burden and typically results in an annualized bleeding rate (ABR) of 2-6. Emicizumab, a subcutaneously administered FVIII substitute, has become the de facto standard-of-care prophylaxis for children with SHA in many countries. Previous clinical trials of emicizumab have assessed ABR in patients greater than 12years without inhibitors, and in children less than 12years with inhibitors; however, there is little information published regarding the ABR of emicizumab compared to CFC in non-inhibitor SHA children. Using a retrospective electronic medical record chart review, we conducted a self-control analysis of 15 patients less than 12years of age during equivalent periods of CFC versus emicizumab prophylaxis. The mean ABR on CFC and emicizumab was 1.79 and 1.13 (p=.092), respectively, with a substantially decreased rate of joint bleeds (CFC 0.94; emicizumab 0.33; p=.001) and spontaneous bleeds (CFC 0.79; emicizumab 0.23; p=.008). No safety events were recorded for patients while administering emicizumab. The mean annual cost of CFC prophylaxis was $515,340 (SD $199,540), compared to $328,410 (SD $137,230) for emicizumab prophylaxis (p<.001). Emicizumab resulted in an improved ABR compared to CFC, especially for joint and spontaneous bleeds, had fewer administration complications, and was substantially less expensive compared to CFC prophylaxis; however, more research is necessary for a complete understanding of the effect of emicizumab on joint health and muscle bleeds.

Real-World Amount of Clotting Factor Products and Non-Factor Products Dispensed and Annual Medical Expenditures for Japanese Patients with Haemophilia A.

Treatment for haemophilia A has expanded from plasma-derived factor VIII (pdFVIII) and standard half-life (SHL) recombinant FVIII (rFVIII) to extended half-life (EHL) rFVIII and non-factor products that mimic FVIII activity. To determine amounts of clotting factor concentrates (CFCs) and emicizumab dispensed and associated healthcare expenditures in Japanese patients with haemophilia A. This retrospective, non-interventional, observational study analysed data from 2016 to 2020 from a large-scale, hospital-based administrative database. Patients had haemophilia A without inhibitors and ≥ 2 prescriptions of the same CFC or emicizumab. In total, 974 patients with haemophilia A (median age, 30.0 years; median follow-up, 3.7 years) were included. Outpatient use of EHL rFVIII and emicizumab increased, although pdFVIII/SHL rFVIII were still used over the study. Median annual total healthcare expenditures/patient increased from ¥9,200,230 in 2016 to ¥19,748,221 in 2020. Overall, the median annual drug expenditure/patient increased from ¥8,723,120 in 2016 to ¥18,051,689 in 2020. Drug expenditure was highest with emicizumab, with an increase in median annual expenditure/patient from 2018 (n = 4, ¥26,030,206) to 2020 (n = 107, ¥45,430,408). Overall, 233 patients (23.9%) switched from an SHL to an EHL product. Although amounts of FVIII prescribed increased in the 3 months after switching, overall, there was no noticeable difference before and after switching. Median total healthcare and FVIII product expenditures increased following switching. Prescribing of EHL products increased over the study and healthcare expenditures increased for patients who switched from SHL to EHL rFVIII products.

Cancer-associated thrombosis: the role of inherited thrombophilia.

Cancer-associated thrombosis (CAT) is a common complication and a major cause of morbidity and mortality in patients with active cancers. CAT is common in various malignancies, particularly pancreatic, ovarian, gastric, colorectal, and hematologic cancers. In fact, CAT is a complicated multifactorial complication that may be influenced by the type of cancer as well as by the genetic background and inheritance of thrombophilic variants and elevated concentrations of coagulation factors. Several studies have shown the prominent role of inherited thrombophilias, such as prothrombin 20210, factor V Leiden, factor XIII Val34Leu, MTHFR C677T, in the occurrence of CAT, while others have found no correlation between them and CAT. In the present review, we have attempted to investigate the possible role of inherited thrombophilia in the occurrence of CAT.

Efficacy of a 1:1 ratio VWF/FVIII concentrate in patients with von Willebrand disease.

Patients with von Willebrand disease (VWD) require administration of von Willebrand factor (VWF) concentrates peri-operatively. Concerns about FVIII accumulation after repetitive injections of a 1:1 ratio VWF/FVIII clotting factor concentrate (CFC) led this study to explore the recovery and FVIII accumulation over time. This monocentre study examined patients with VWD receiving perioperative 1:1 ratio CFC infusions. CFC dosing was based on body weight and endogenous VWF/FVIII activity. FVIII and VWF activity was monitored at T0 (baseline), T1 (15 min postinfusion), and trough levels at T2-T6 (24-120h). We included 125 patients, undergoing 125 procedures (63 major surgeries, 62 minor), with a median of two CFC infusions (IQR 1-3). With a mean administered dose of 35.7IU/kg CFC, recovery rates of FVIII and VWF were 2.6IU/dL per IU/kg and 2.4IU/dL per IU/kg, respectively. Mean FVIII levels at T0 were 62 (SD 51.9), T1: 164 (SD 80.4), T2: 155 (SD 62.8), T3: 162 (SD 59.8), T4: 124 (SD 78.4), and T5: 120 (SD 65.3) IU/dL. Mean VWF activity levels at T0 were 29 (SD 25.0), T1: 133 (SD 43.7), T2: 92 (SD 37.2), and T3: 86 (SD 37.5) IU/dL. Subgroup analysis in 47 patients with more than three infusions, showed no accumulation of mean FVIII levels. This perioperative study demonstrated excellent FVIII and VWF recovery of a 1:1 ratio VWF product in patients with VWD. Stable FVIII and VWF activity levels were observed after repeated infusions, without accumulation. Most major surgeries required only three CFC infusions.

Combined coagulation and inflammation markers as predictors of venous thrombo-embolism and death in COVID-19.

The COVID-19 pandemic related to SARS-CoV-2 virus was responsible for global pandemic. The severe form of the disease was linked to excessive activation of immune pathways together with a systemic cytokine storm response and thrombotic venous or arterial complications. Factors predicting severe outcomes including venous and/or pulmonary thrombosis (VT) and death were identified, but the prognostic role of their combination was not addressed extensively. We investigated the role of prognostic factors from the coagulation or inflammatory pathways to better understand the outcome of the disease. For this, we prospectively studied 167 SARS-CoV-2-positive patients from admission in intensive care units (ICU) or emergency departments from four academic hospitals over a 14-month period. Besides standard biology, we assessed serum concentrations of inflammatory markers, coagulation factors and peripheral blood cells immunophenotyping. Thirty-nine patients (23.3%) developed VT and 30 patients (18%) died. By univariate analysis, C-reactive protein (CRP) level > 150 mg/L, interleukin-6 (IL-6) ≥ 20 pg/mL, D-dimers > 1,500 μg/L, ADAMTS13 activity ≤ 50%, Von. A combination of coagulation and inflammatory markers can refine the prognostication of severe outcome in COVID-19, and could be useful for the initial evaluation of other types of viral infection.

#409 Correlation between ha factor concentration and urinary syndrome in patients with chronic glomerulonephritis when using rivaroxaban

Abstract Background and Aims Considering the pathogenetic role of factor X of the coagulation system in the formation and progression of chronic glomerulonephritis (CGN), as well as the mechanism of action of rivaroxaban, this study examined the concentration of coagulation factor X in peripheral blood. Aim of our study to reveal the pathogenetic relationship between the concentration of Xa factor and the severity of urinary syndrome in patients with CGN on the background of basic therapy with the inclusion of rivaroxaban. Method 108 CGN patients, on the background of 3-month baseline therapy with inclusion of rivaroxaban (AC+ group, 55 patients) and without anticoagulant (AC- group, 53 patients). Initially and after 3 months of the study the concentration of coagulation factor Xa in peripheral blood was studied. Results In CGN patients the concentration of Xa factor was significantly higher than in CG (122.17 ± 2.23% vs. 104.28 ± 6.54% in CG, p &amp;lt; 0.05). On the background of 3-month therapy including antiaggregant, corticosteroid hormone and cytostatic, the concentration of Xa factor decreased by 18.82 ± 0.64% (p &amp;lt; 0.001 reliability of difference with initial data). The use of rivaroxaban, as expected, was associated with a more significant decrease in Xa factor level—by 38.76 ± 1.40% (p &amp;lt; 0.001 significance of difference with baseline data; significance of difference in relative dynamics of Xa factor concentration between groups depending on anticoagulant use, p &amp;lt; 0.001). Correlation analysis revealed a significant positive strong correlation between the initial concentration of Xa factor in peripheral blood of CGN patients and the severity of hematuria (r = 0.83, p &amp;lt; 0.01) and a positive weak correlation between the concentration of Xa factor and cylindruria as a manifestation of proteinuria (r = 0.30, p &amp;lt; 0.01), as well as a positive weak correlation between the concentration of Xa factor and cylindruria at the end of the 3rd month of observation (r = 0.33, p &amp;lt; 0.01). There was also found a significant negative weak correlation between the initial concentration of Xa factor and the relative dynamics of hematuria (r = −0.48, p &amp;lt; 0.01) and cylindruria (r = −0.33, p &amp;lt; 0.01). Conclusion The study confirmed the pathogenetic relationship between the concentration of Xa factor and the severity of urinary syndrome in CGN patients. It was also found that initially high concentration of Xa factor is associated with less positive dynamics of urinary syndrome parameters.

Mechanism of Panax notoginseng saponins modulation of miR-214-3p/NR1I3 affecting the pharmacodynamics and pharmacokinetics of warfarin

BackgroundWith the prevalence of dietary supplements, the use of combinations of herbs and drugs is gradually increasing, together with the risk of drug interactions. In our clinical work, we unexpectedly found that the combination of Panax notoginseng and warfarin, which are herbs that activate blood circulation and remove blood stasis, showed antagonistic effects instead. The purpose of this study was to evaluate the drug interaction between Panax notoginseng saponins (PNS) and warfarin, the main active ingredient of Panax notoginseng, and to explore the interaction mechanism. MethodsThe effects and mechanisms of PNS on the pharmacodynamics and pharmacokinetics of warfarin were explored mainly in Sprague–Dawley rats and HepG2 cells. Elisa was used to detect the concentrations of coagulation factors, HPLC-MS to detect the blood concentrations of warfarin in rats, immunoblotting was employed to examine protein levels, qRT-PCR to detect mRNA levels, cellular immunofluorescence to detect the localization of NR1I3, and dual luciferase to verify the binding of miR-214-3p and NR1I3. ResultsPNS significantly accelerated warfarin metabolism and reduced its efficacy, accompanied by increased expression of NR1I3 and CYP2C9. Interference with NR1I3 rescued the accelerated metabolism of warfarin induce by PNS co-administration. In addition, we demonstrated that PNS significantly reduced miR-214-3p expression, whereas miR-214-3p overexpression reduced NR1I3 and CYP2C9 expression, resulting in a weakened antagonistic effect of PNS on warfarin. Additionally, we found that miR-214-3p bound directly to NR1I3 3′-UTR and significantly downregulated NR1I3 expression. ConclusionOur study demonstrated that PNS accelerates warfarin metabolism and reduces its pharmacodynamics by downregulating miR-214-3p, leading to increased expression of its target gene NR1I3, these findings provide new insights for clinical drug applications to avoid adverse effects.

Haemophilia and Cancer: A Literature Review.

Opinions in the literature on the impact of cancer on patients with haemophilia are contradictory. There is a lack of data on the clinical presentation and management of cancer in patients with haemophilia (PWH). Papers were found following a comprehensive search in PubMed, Google Scholar, and Scopus using the terms "cancer" and "haemophilia" without time limits and using the English language as a filter. The references from all the retrieved original articles and reviews were assessed for additional relevant articles. The emergence of malignancies is one of the important causes of morbidity and mortality in PWH. In the past decade, the literature mainly focused on the epidemiology and outcome of blood-borne cancers in the haemophilia patient group, as the incidence of hepatitis B virus (HBV), hepatitis C (HCV), and HIV infection were high among them. However, with the introduction of recombinant clotting factor concentrates (CFCs), physicians now pay attention to non-virus-related malignancies. Bleeding and thrombotic complications are important causes of morbidity and mortality in critically ill patients with cancer; replacement therapy with factor VIII or IX or others should be maintained during antitumour treatment. Overall, managing cancer in patients with haemophilia requires careful evaluation and individualised planning involving a multidisciplinary team of physicians experienced in haematology, oncology, and surgery.

Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial

AbstractFitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This phase 3, open-label study evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary end point was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary end points included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor, n = 19; noninhibitor, n = 46) were eligible for ABR analyses. Observed median ABRs were 6.5 (interquartile range [IQR], 2.2-19.6)/4.4 (IQR, 2.2-8.7) with BPA/CFC prophylaxis vs 0.0 (IQR, 0.0-0.0)/0.0 (IQR, 0.0-2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = .0021) and 46.4% (P = .0598) vs BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced 0 treated bleeds with fitusiran vs 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events vs BPA/CFC prophylaxis in PwHA/B, with or without inhibitors, and reported adverse events were generally consistent with previously identified risks of fitusiran. This trial was registered at www.ClinicalTrials.gov as #NCT03549871.

Evaluation of the efficacy and safety of lyophilized plasma

Objective. To assess the hemostatic potential, preclinical safety and in vitro efficacy of lyophilized plasma in patients and blood donors.Materials and methods. The study of acute toxicity was carried out on outbred mice of both sexes (n=120), pyrogenicity – on rabbits of both sexes (n=30), abnormal toxicity – on mice (n=25) and guinea pigs (n=6). Histopathological studies were carried out on preparations of five fragments of the middle part of the mouse tail after intravenous administration of the maximum dose (4500 mg/kg) lyophilized plasma (LP), physiological solution, fresh frozen plasma (FFP) and pathogen-reduced FFP (PRFFP) using the Intercept system. The proand anticoagulant activity was investigated by clotting and chromogenic method to evaluate the hemostatic potential of PL. The effect on hemostasis was studied in vitro by thromboelastometry when FFP and LP were added to blood samples of patients (n = 23) and donors (n = 20). Results. Acute toxicity study showed the absence of death and clinical signs of intoxication in all series. On the 14th day, body weight gain was observed in animals of all series. Regardless of the used LP dosage, no development of effusion and adhesions in the thoracic and abdominal cavities, as well as macroscopically detectable pathologic changes of the main organs were observed in animals. The analysis of the relative weight of internal organs of animals did not reveal statistically significant differences in experimental and control series relative to the values of similar indicators in intact animals. The studied hemostatic potential showed that LP was not inferior to PRFFP in the content of coagulation factors of the blood system. Evaluation of the effect of LP application in vitro in female patients showed statistically significant correction of CT (clotting time) index, which indicates the effectiveness of its application for replenishment of blood coagulation factors (BCF).Conclusion. Preclinical animal studies of LP have proven its safety and efficacy compared to FFP.

Advancing Hemophilia Prophylaxis: Personalized Low-Dose CFC and Emicizumab in Resource-Limited Settings

Introduction: Hemophilia, a congenital bleeding disorder resulting from clotting factor deficiency, significantly impacts the lives of persons due to recurrent bleeding. Prophylaxis, involving clotting factor replacement, has been recognized as a vital approach to reduce complications and to improve the quality of life in people with hemophilia. However, access to this remains limited, in low-income countries like India. This study examines the effectiveness of personalized low-dose clotting factor concentrates (CFC) prophylaxis and Emicizumab in children with hemophilia, aiming to achieve zero annual bleed rates (ABR), thereby enhancing their well-being and reducing healthcare burden. Patients and Methods: This retrospective observational study was conducted at the Hemophilia Treatment Centre (HTC) in Aluva, Kerala, India, spanning from May 31, 2022, to June 1, 2023. Study included children under 18 years with hemophilia A/B, with or without inhibitors, who had commenced prophylaxis with personalized low-dose CFC since 2015 and completed one year of prophylaxis. The total sample size was 31. Data on ABR, Annual Joint Bleed Rate (AJBR), Hemophilia Joint Health Status (HJHS) score, and Functional Independence Score Hemophilia (FISH) were extracted from the HTC registry.Standard half-life CFCs were used for prophylaxis, with a starting frequency of twice a week for Factor VIII and once a week for Factor IX. Patients were regularly followed up in the Hemophilia Clinic, and the frequency/doses of prophylaxis were increased in case of breakthrough bleeds. Additionally, children were advised to organize peak activities to coincide with the days of CFC injections. Personalization of doses was not based on pharmacokinetic software but was determined through close monitoring and individual adjustments.Health education on identifying and managing bleeding episodes followed ISTH guidelines. Prophylaxis outcomes were assessed with changes in ABR and AJBR during the last year of prophylaxis and compared to the bleed rates in the one year prior to prophylaxis. Changes in HJHS and FISH were documented for older children. All analysis were done using SPSS version24. For quantitative variables results were presented as mean with standard deviation and for qualitative variables, results were presented in percentages. Comparison achieved with standard paired t-test, and p value &amp;lt; 0.05 considered as significant. Results: Out of 36 children receiving prophylaxis, 31 met the inclusion criteria. Among them,10 (32%) received Emicizumab prophylaxis, while 21 (68%) were managed with personalized low-dose CFC prophylaxis. Hemophilia A constituted 24(77%) of cases, mostly classified as severe disease-29 (94%). Table :1 summarises the patient characteristics, prophylaxis dose, cost and outcome measures of the study population.The personalized low-dose CFC prophylaxis had significant measurable improvements, reducing the ABR from 14.90 to 2.90( p 0.000) and the AJBR from 4.95 to 1.43( p 0.004). Additionally, HJHS improved from 3.30 to 0.95( p 0.102), and FISH increased from 29.90 to 32.00( p 0.020).Children on Emicizumab achieved exceptional results, with all reporting zero ABR ( p 0.027), and AJBR ( p 0.131) even with lower than recommended doses(1.02mg/kg/week). In contrast, personalized low-dose CFC prophylaxis (Factor VIII: 36.35/kg/week, Factor IX:32/kg/week) showed varied outcomes, with only 4(19%) achieving zero ABR. HJHS and FISH were not evaluated in Emicizumab group as 7(70%) were belonging to the age group of less than 5 years. Conclusion: This study highlights the effectiveness of personalized low-dose CFC prophylaxis and Emicizumab in reducing bleeding rates and improving musculoskeletal health and functional independence in children with hemophilia. Emicizumab prophylaxis demonstrated remarkable outcomes, achieving zero bleeds even with lower doses. However, personalized low-dose CFC prophylaxis struggled to achieve zero bleed rates for most of them. The findings underscore the need for alternative strategies and increased accessibility to Emicizumab and other newer drugs to achieve the goal of zero bleed rates for children with hemophilia in resource-limited settings. The study's results provide hope for achieving zero bleed rates, ultimately enhancing the well-being of children with hemophilia in resource-limited regions.

Treatment of dermal ulcer with autologous fibrin glue: Two case reports of an exploratory prospective pilot study.

The healing of recurrent and refractory skin ulcers requires a long time, during which there is risk of infection, and hospital admission is occasionally required for surgical or daily conservative treatment. Therefore, the development of promising treatments that promote faster, uneventful healing is a must. Composed of cryoprecipitate and thrombin, fibrin glue has a history of surgical use for preventing bleeding and spinal fluid leakage. Moreover, in-house cryoprecipitates contain higher concentrations of coagulation factors and cytokines that may enhance wound healing than commercially available products. However, the efficacy of completely autologous fibrin glue (AFG) in tissue repair has not yet been fully demonstrated. This study aimed to evaluate the efficacy of AFG in the treatment of refractory skin ulcers in comparison with the conventional treatment. Two patients with skin ulcer on their lower extremities due to trauma or scleroderma who showed resistance to conventional treatment were included in the study. Both study participants were diagnosed with refractory skin ulcer and were ineligible for autologous skin transplantation. AFG was prepared following autologous blood donation using a Cryoseal® system. Subsequently, AFG was administered to 50% of the area of each ulcer and observed for 4 weeks in comparison with recombinant basic fibroblast growth factor with bucladesine sodium treatment that was administered to the rest of the ulcer. The skin ulcer after trauma in participant 1 showed better improvement in the AFG-treated area. Although AFG did not show superiority regarding the ulcer area of a patient with scleroderma, it guarded the continuous exudation from the edge of the swollen skin surrounding the ulcer. AFG showed effective and beneficial results for wound healing of refractory skin ulcer and prevented exudation without any severe adverse events.

Estimating the impact of improved management of haemophilia a on clinical outcomes and healthcare utilisation and costs

ObjectiveHaemophilia A (HA) is associated with high clinical and healthcare burden. We developed an Excel-based model comparing current practice to improved management in severe HA patients currently managed on demand (OD). Outcomes included short- and long-term bleed events. Expected annual bleeds were estimated based on locally-derived OD annualised bleed rate (ABR), adjusted by relative prophylaxis-related ABRs (published literature). The objective of our study was to explore the impact of improving HA prophylaxis in target countries with limited published data (Algeria, Argentina, Chile, India, Malaysia, Mexico, Taiwan and Thailand). Bleed-related healthcare resource use (HCRU) and costs were estimated as a function of bleed type, with inputs obtained from local expert estimates. Clotting factor concentrates (CFC) consumption related to treatment and prophylaxis was estimated based on locally relevant dosing. CFC costs were not included.ResultsWhen 20% of OD patients were switched to prophylaxis, projected reduction in bleeds was estimated between 3% (Taiwan) through 14% (Algeria and India); projected reductions in hospitalisations ranged from 3% (Taiwan) through 15% (India). Projected HCRU-related annual cost savings were estimated at USD 0.45 m (Algeria), 0.77 m (Argentina), 0.28 m (Chile), 0.13 m (India), 0.29 m (Malaysia), 2.79 m (Mexico), 0.15 m (Taiwan) and 0.78 m (Thailand). Net change in annual CFC consumption ranged from a 0.05% reduction (Thailand) to an overall 5.4% increase (Algeria). Our model provides a flexible framework to estimate the clinical and cost offsets of improved prophylaxis. Modest increase in CFC consumption may be an acceptable offset for improvements in health and healthcare capacity in resource constrained economies.

Overcoming Hurdles in Hemophilia Care: The Impact of World Federation of Hemophilia Humanitarian Aid on Arthroplasties and Orthopedic Surgeries in Low-Middle-Income Setting

Introduction: Hemophilia is a hereditary bleeding disorder characterized by the absence or deficiency of clotting factors, leading to prolonged bleeding and joint damage. In lower-middle-income countries (LMICs) like India, access to standard care for hemophilia has been limited, resulting in many children not receiving prophylaxis and developing severe joint disease in young adulthood. This significantly impacts their quality of life and productivity. Arthroplasty has offered hope for hemophiliacs with established joint disease, but its accessibility in LMICs faces numerous hurdles, including lack of laboratory diagnostics and monitoring facilities, shortage of hematologists, absence of advanced orthopedic surgical teams, limited insurance coverage, and inadequate access to clotting factor concentrates (CFCs) to support surgeries. Comprehensive care centers can address some challenges, but the availability of CFCs remains crucial for effective corrective arthroplasties and other orthopedic surgeries. Aim: This retrospective analysis aims to assess the impact of the World Federation of Hemophilia (WFH) humanitarian aid in facilitating effective corrective arthroplasties and other orthopedic surgeries at a comprehensive care center in a lower-middle-income country. Methods: The study was conducted at a comprehensive care center in India that previously lacked access to CFCs until the initiation of WFH humanitarian aid. Clinical data of patients with hemophilia who underwent major orthopedic surgeries and received CFC support from WFH humanitarian aid between November 2017 and June 2023 were reviewed. Patients with inhibitor-positive status were excluded. Patients were assessed in a comprehensive clinic prior to the elective arthroplasty. The analysis evaluated the utilization of CFCs in orthopedic surgeries, immediate surgical outcomes, and the effect of regulating CFC dose guided by lab monitoring. Additionally, the study audited the impact on CFC utilization when performing two surgeries in one sitting. Data analysis was performed using SPSS version 20.Continuous variables are depicted as mean±SD or median with range. Percentages represent categorical variables. Results: The study included 21 patients with Hemophilia {19 Hemophilia A(90%) and 2 Hemophilia B(10%)} who underwent orthopedic surgeries with CFC support from WFH humanitarian aid.There were 18(85%) patients with severe Hemophilia.Elective arthroplasty was done in 17 patients (81%) and 4 patients(19%) underwent emergency internal fixation. The median age of patients who underwent surgery was 31(range 18-75) years. Elective unilateral knee arthroplasty was done in 7(33%)patients, hip arthroplasty in 2(10%)patients and elbow arthroplasty in 1(5%)patient.Bilateral knee arthroplasty was done in a single surgical setting for efficient CFC utilization in 7 (33%) patients. Extended Half-life (EHL)CFC was used in 10 patients (48%), Standard half-life (SHL) CFC in 2 patients (10%), while the others received a combination of both. Mean use of CFC was 410(Range 270-767) units/kg in Hemophilia A and 650(range 500-800)units/kg in Hemophilia B. The mean EHL FVIII utilization in Bilateral TKR was 400 (Range 322-536) units/kg. None of the patients experienced major intraoperative bleeding or post-operative thromboembolism.No patient developed inhibitor positivity when tested post operatively. Notably, CFC utilization in all patients was found to be less than the empirically recommended levels in WFH guidelines for resource-constrained settings. Table 1 demonstrates the demographics, Type of surgery, CFCs used and immediate outcomes of orthopaedic surgeries done using WFH Humanitarian Aid. Conclusion: The findings of this retrospective analysis demonstrate the transformative impact of WFH humanitarian aid in a comprehensive care center for hemophiliacs in a lower-middle-income country. With access to CFCs, effective corrective arthroplasties and orthopedic surgeries were made possible, providing hope and improved quality of life for patients with established joint disease. The study underscores the vital role of WFH humanitarian aid in enhancing care outcomes for hemophiliacs in resource-limited settings and emphasizes the need for continued support and collaboration to advance hemophilia care globally.

Comparison of hemodynamic features and thrombosis risk of membrane oxygenators with different structures: A numerical study

PurposeThe geometric structure of the membrane oxygenator can exert an impact on its hemodynamic features, which contribute to the development of thrombosis, thereby affecting the clinical efficacy of ECMO treatment. The purpose of this study is to investigate the impact of varying geometric structures on hemodynamic features and thrombosis risk of membrane oxygenators with different designs. MethodsFive oxygenator models with different structures, including different number and location of blood inlet and outlet, as well as variations in blood flow path, were established for investigation. These models are referred to as Model 1 (Quadrox-i Adult Oxygenator), Model 2 (HLS Module Advanced 7.0 Oxygenator), Model 3 (Nautilus ECMO Oxygenator), Model 4 (OxiaACF Oxygenator) and Model 5 (New design oxygenator). The hemodynamic features of these models were numerically analyzed using the Euler method combined with computational fluid dynamics (CFD). The accumulated residence time (ART) and coagulation factor concentrations (C[i], where i represents different coagulation factors) were calculated by solving the convection diffusion equation. The resulting relationships between these factors and the development of thrombosis in the oxygenator were then investigated. ResultsOur results show that the geometric structure of the membrane oxygenator, including the location of the blood inlet and outlet as well as the design of the flow path, has a significant impact on the hemodynamic surroundings within the oxygenator. In comparison to Model 4, which had the inlet and outlet located in the center position, Model 1 and Model 3, which had the inlet and outlet at the edge of the blood flow field, exhibited a more uneven distribution of blood flow within the oxygenator, particularly in areas distant from the inlet and outlet, which was accompanied with lower flow velocity and higher values of ART and C[i], leading to the formation of flow dead zones and an elevated risk of thrombosis. The oxygenator of Model 5 is designed with a structure that features multiple inlets and outlets, which greatly improves the hemodynamic environment inside the oxygenator. This results in a more even distribution of blood flow within the oxygenator, reducing areas with high values of ART and C[i], and ultimately lowering the risk of thrombosis. The oxygenator of Model 3 with circular flow path section shows better hemodynamic performance compared to the oxygenator of Model 1 with square circular flow path. The overall ranking of hemodynamic performance for all five oxygenators is as follows: Model 5 > Model 4 > Model 2 > Model 3 > Model 1, indicating that Model 1 has the highest thrombosis risk while Model 5 has the lowest. ConclusionThe study reveals that the different structures can affect the hemodynamic characteristics inside membrane oxygenators. The design of multiple inlets and outlets can improve the hemodynamic performance and reduce the thrombosis risk in membrane oxygenators. These findings of this study can be used to guide the optimization design of membrane oxygenators for improving hemodynamic surroundings and reducing thrombosis risk.

Comparison of Activity and Safety of DSPAα1 and Its N-Glycosylation Mutants.

DSPAα1 is a potent rude thrombolytic protein with high medicative value. DSPAα1 has two natural N-glycan sites (N153Q-S154-S155, N398Q-K399-T400) that may lead to immune responses when administered in vivo. We aimed to study the effect of its N-glycosylation sites on DSPAα1 in vitro and in vivo by mutating these N-glycosylation sites. In this experiment, four single mutants and one double mutant were predicted and expressed in Pichia pastoris. When the N398Q-K399-T400 site was mutated, the fibrinolytic activity of the mutant was reduced by 75%. When the N153Q-S154-S155 sites were inactivated as described above, the plasminogen activating activity of its mutant was reduced by 40%, and fibrin selectivity was significantly reduced by 21-fold. The introduction of N-glycosylation on N184-G185-A186T and K368N-S369-S370 also considerably reduced the activity and fibrin selectivity of DSPAα1. The pH tolerance and thermotolerance of all mutants did not change significantly. In vivo experiments also confirmed that N-glycosylation mutations can reduce the safety of DSPAα1, lead to prolonged bleeding time, non-physiological reduction of coagulation factor (α2-AP, PAI) concentration, and increase the risk of irregular bleeding. This study ultimately demonstrated the effect of N-glycosylation mutations on the activity and safety of DSPAα1.

Cryopreserved platelets and amotosalen-treated plasma in an experimental clot formation set-up.

Amotosalen treatment of plasma and cryopreservation of platelets affect the quality and potentially the interplay between platelets and coagulation factors. We set up an experimental clot formation study to test the hypothesis that amotosalen treatment of plasma affects the interaction with different platelet preparations. Pooled plasma units (n=16) were subjected to coagulation tests before and after pathogen inactivation with amotosalen treatment (PI) and aliquots were frozen at -80°C. Fresh and cryopreserved platelets were analyzed for phenotypic and activity markers. Finally, coagulation properties of different combinations of platelets and plasma, before and after PI, were analyzed by viscoelastography (ROTEM). PI of plasma reduced the concentration of several coagulation factors (p<0.01). Cryopreservation altered phenotypic expression and reduced the platelets' ability to respond to agonists (p<0.0001). The interplay between all plasma derivatives and cryopreserved platelets resulted in shortened coagulation time (p<0.0001) but prolonged clot formation time and reduced clot strength (p<0.0001) as compared to the interaction between fresh platelets with different plasma variants. PI of the plasma does not seem to have a major impact on coagulation time, clot formation time or clot strength. Our data show that the reduced concentration of coagulation factors after PI treatment of plasma are negligible measured by viscoelastography, with fresh and cryopreserved platelets in this experimental clot formation setup, and that platelets play a more pronounced role. Cryopreserved platelets are more activated and result in reduced clot stability.

Evaluation of Changes in Coagulation Factors in Cryoprecipitate Plasma During Storage at Kisii Teaching and Referral Hospital

Background: Cryoprecipitate is used without knowing the concentration of coagulation factors it contains which might cause circulatory overload with no any improvement if several bags are transfused with low factor levels. Objective: The objective was to assess the changes in coagulation factors in cryoprecipitate plasma during storage at -18°C for 5 weeks at Kisii Teaching and Referral Hospital. Methods: The study involved time series analysis design involving analysis of cryoprecipitate during storage at -18°C for 5 weeks. Blood collected from the Kisii satellite blood transfusion center was received at Hematology laboratory where factor assays were performed on Erba Mannheim ECL 105 semi-automated coagulation analyzer. Thawing for subsequent coagulation factor analysis and serial testing was done using Stericox Plasma Thawing Bath at 37°C, for 45 mins. Data were entered into Excel and analyzed by SPSS version 25. Results: The mean rank for cryoprecipitate from week one to week five was in a decreasing trend with 3.00, 1.99 and 1.01 respectively. This confirms a steady statistical significant difference in mean ranks for the time period. Conclusion: There was a significant reduction in coagulation factors in cryoprecipitate plasma during storage at -18°C for 5 weeks at Kisii Teaching and Referral Hospital.

Nonreplacement therapy for hemophilia in low-income countries: experience from a prospective study in Ivory Coast

BackgroundHemophilia management has fundamentally evolved over the last decades with the development of ground-breaking therapies. Because of their mode of action and biochemical properties, these innovative therapies that are available in developed countries could be readily implemented among people from low-income countries who are either not or inadequately treated with clotting factor concentrates (CFCs). ObjectivesWe aimed at evaluating the impact of prophylaxis with emicizumab, a bispecific monoclonal antibody mimicking the FVIII activity administered subcutaneously, among boys with severe hemophilia A (HA) from the Ivory Coast, where access to CFCs is limited to humanitarian aid. MethodsWe prospectively collected data on the implementation and outcomes of prophylaxis with emicizumab, in 33 Ivorian boys aged 2 to 13 years with severe HA (with and without inhibitors). Bleeds, CFC consumption, quality of life and satisfaction of the patients and their parents were assessed. ResultsOverall, 12 months after initiating emicizumab, a 99% reduction in bleeding rates was observed, with a raise from 18% to 100% of boys having zero spontaneous joint bleeds. Three boys required a single FVIII infusion following a traumatic bleed. Health-related quality of life measures significantly improved, and perception of treatment efficacy was positively rated in children and parents. Acceptance, tolerance, and adherence were excellent. Emicizumab was instrumental in successfully implementing uninterrupted, highly efficacious, and well-tolerated prophylaxis in 72% of the Ivorian children aged ≤ 13 years identified with severe hemophilia A. ConclusionThese data illustrate how innovative and disruptive nonreplacement therapies that are already accessible in developed countries could potentially provide equity in care by profoundly and rapidly modifying hemophilia burden with a magnified impact in low-income countries.

Impact of SMS Text-Messaging on Patient-Provider Communication, Protocol Adherence, and Clinical Outcomes in Adult Patients with Bleeding Disorders Undergoing Surgery or Procedures: A Real-World Feasibility Study

Background: Adult patients with bleeding disorders (PWBD), such as hemophilia or von Willebrand Disease (VWD), frequently require surgeries and procedures. In order to achieve and maintain hemostasis throughout the peri-operative period, clotting factor concentrates (CFCs) are prescribed. Patients then adhere to a detailed CFC treatment plan (TP), which outlines exact doses to take, when to take them, and for how long. However, despite following the TP, non-adherence sometimes occurs. Importantly, if inadequate amounts of CFC are prescribed or taken, and under-treatment leads to bleeding complications, even simple procedures could result in death. As a result, the ability to evaluate clinical effectiveness in real-time is urgently needed. However, most post-procedure-related recovery happens outside of the hospital or clinic setting. Therefore, little is known about clinical outcomes post-procedurally. A baseline study at our institution showed only 51% of PWBD answered their phone when clinic staff called to assess the effectiveness of and adherence to the TP. A better understanding of CFC adherence and bleeding rates may improve cost-effectiveness of and patient satisfaction with CFC use peri-procedurally. Our aims were to assess feasibility of 2-way SMS text messaging (TM) between our clinic and PWBD, establish peri-operative CFC adherence rates, evaluate for post-operative bleeding, and to determine patient-preferred methods of communication during peri-operative management. Design/Methods: The Utah Center for Bleeding & Clotting Disorders at the University of Utah follows approximately 500 PWBD, all of whom were eligible for participation. Patients were consented using Adobe Sign software. Webtext.com served as the TM platform. Mobile devices were provided to patients free-of-charge using grant funding. HIPAA-compliant, templated TMs were sent by clinic staff to participants each day CFCs were prescribed to assess adherence to the TP, and incidence and severity of post-procedural bleeding. A patient satisfaction survey was emailed on the final day of CFC therapy. Study data, captured using REDCap, included baseline demographics, bleeding disorder type and severity, procedure type, factor therapy prescribed, and TM responses. Descriptive analyses were used for all study endpoints. The primary endpoint was to compare the ability to reach patients using TMs vs. phone call (feasibility). Secondary endpoints included: doses taken vs. prescribed, incidence of post-operative bleeding, overall patient satisfaction with TM, and average total cost of CFC therapy. Results: To date, 50 PWBD consented. Average age: 37 years (range: 18 - 81); 28 PWBD had hemophilia (19 HA, 9 HB), 20 had VWD, and 2 had unconfirmed bleeding disorders; 50% were women. Eleven PWBD lived ≥ 50 miles from the HTC. Ten were taking CFC prophylaxis. Of the 50 PWBD, 10 have undergone surgery (Table 1). The remaining PWBD have yet to undergo their planned procedure. The average cost of CFC procured per PWBD per procedure exceeded $100,000. In total, PWBDs responded to 121/142 (85%) of TMs sent. All PWBD (n=10; 100%) responded to at least one text message sent. Daily communication (time from first text sent to time when last response received) lasted roughly 8 minutes. Protocol adherence: In total, 87% (55/63) of CFC doses prescribed were taken (Table 1). Post-op bleeding occurred in 3 PWBD (30%). Patient satisfaction survey results showed 70% (7/10) of PWBD preferred TM to communication via chart messaging, 90% (9/10) chose to use TM again for their care, and no PWBD was dissatisfied with TM communication. Conclusion: This is the first study to assess the impact and feasibility of using TM to determine protocol adherence and clinical outcomes in adult PWBD undergoing surgery or procedures in a real-world setting. Compared to phone calls, the response rate to TM was 34% higher. This study identified both PWBD that were non-adherent to the TP, and those who experienced post-operative bleeding at home. Most PWBD (90%) elected to continue using TM to communicate with clinic staff. These data may help improve the cost-effective management of future procedures for PWBD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal