Baseline Factor Research Articles

Baseline Clinical Factors Associated with Cessation of Growth Hormone Therapy in Patients with Severe Growth Hormone Deficiency - Real World Evidence

Background: Growth hormone replacement is indicated in adults with severe growth hormone (GH) deficiency, adult growth hormone deficiency assessment (AGHDA) score of at least 11 and are receiving treatment for other pituitary hormone deficiencies. There are no data looking at the cessation of GH replacement in adult patients with severe GH deficiency and the factors that predict the likelihood of patients continuing or stopping growth hormone replacement. Methods: We audited patients on the GH register between January 2006 and January 2023 in Hull University Teaching Hospitals NHS foundation Trust, a UK tertiary hospital. Baseline characteristics, the cause of GH deficiency, AGHDA score at diagnosis and the reason for stopping GH were collected. Proportions were compared between patients adhering to GH replacement and those who had ceased it. Logistic regression analysis was used to identify factors independently associated with cessation of GH. Results: The study comprised 141 adult patients with a mean age of 52 years, of which 75 (53%) were female. 54 (38%) individuals had discontinued GH replacement therapy. Predominant reasons for discontinuation were lack of therapeutic benefit (46%) and a change in clinical indication (26%). Among patients who discontinued GH therapy, the most frequent cause of GH deficiency was idiopathic (57%), while for those on GH replacement, pituitary surgery was the leading cause of GH deficiency (53%). Logistic regression analysis showed no baseline factor was statistically significantly associated with GH cessation, except female gender which had a borderline significance (P = 0.05). Conclusions: In this real-world investigation of patients with severe GH deficiency, over two in five individuals who discontinued GH therapy cited the absence of perceived benefits. We show a borderline association of female gender with GH cessation and large population-based studies will be needed to investigate this and other causes of GH cessation.

Haemophilia testing of young girls in Canada: Describing the current recommendations for factor level and genetic testing and the experiences of Canadian parents.

It is widely acknowledged that haemophilia affects women and girls, yet current testing recommendations for factor level and genetic testing vary and do not universally incorporate updated research. Canadian parents have expressed frustration at inconsistent recommendations and reported instances where delayed testing led to missed diagnosis and preventable bleeding. Study aim was to explore and describe the practice of haemophilia-related testing of young girls in Canada. A mixed methods study was carried out with two populations: (1) Nurses working in haemophilia care completed a survey regarding the current testing recommendations of their Haemophilia Treatment Centre (HTC), (2) Parents of obligate or potential haemophilia carriers completed a structured interview with questions about their family experience of haemophilia and testing decisions for daughters. Twenty-six survey responses were received and showed wide variation in the usual recommendations of Canadian HTCs. Different factor level testing recommendations may be given to obligate and potential carriers despite no difference in bleeding risk. Only a minority of HTCs currently recommend an early baseline factor level (<10 years) to obligate carriers (27%) or potential carriers (15%). For genetic testing of potential carriers, 70% of HTC would approve a family request for genetic testing of a minor with specific conditions. The majority of parents interviewed felt dissatisfied with their testing experience (58%) and highlighted many issues related to delayed testing recommendations. Updated, nationally affirmed testing recommendations are needed that align with research on bleeding in women and girls affected by haemophilia.

Association of plasma VEGF with futile recanalization and intracranial angiogenesis in ischemic stroke post-endovascular treatment

ObjectiveThis study aimed to compare baseline and subsequent vascular endothelial growth factor (VEGF) levels in predicting futile recanalization (FR) in acute ischemic stroke (AIS) patients undergoing endovascular treatment (EVT), and to explore the association between angiogenesis and VEGF. Methods84 participants were recruited, including 46 AIS in the EVT group, 20 AIS in the conventional treatment group, and 18 healthy controls. Plasma VEGF levels were measured at different time points. FR was defined as a modified Rankin scale score of 3–6 at 3 months. Multivariable analysis evaluated whether VEGF levels at different time points independently predicted FR, and receiver operating characteristic (ROC) curves assessed their predictive value. Using intracranial lesion side vascular imaging, the Maas scoring system assessed angiogenesis post-onset, with scores of 4 to 5 indicating angiogenesis. ResultsIn the conventional treatment group, VEGF levels significantly decreased by day 7, while in the EVT group, reduction was observed as early as day 3. After adjusting for potential confounders, only VEGF levels on day 3 emerged as an independent predictor of FR. The combined model incorporating VEGF levels on day 3 with other factors effectively predicted FR (area under the curve = 0.916; sensitivity = 84.21 %; specificity = 100 %, P<0.0001). Plasma VEGF levels were notably higher in patients with angiogenesis in specific brain regions compared to those without angiogenesis at days 1, 3, 7, and 14 (P<0.05). ConclusionVEGF levels on the 3rd day post-EVT demonstrate superior predictive value for FR. Elevated VEGF levels correlate with angiogenesis, suggesting its potential as a therapeutic target.

One-year evaluation of people recovering from COVID-19 receiving allied primary healthcare: A nationwide prospective cohort study

BackgroundA Dutch nationwide prospective cohort study was initiated to investigate recovery trajectories of people recovering from coronavirus disease 2019 (COVID-19) and costs of treatment by primary care allied health professionals. ObjectivesThe study described recovery trajectories over a period of 12 months and associated baseline characteristics of participants recovering from COVID-19 who visited a primary care allied health professional. It also aimed to provide insight into the associated healthcare and societal costs. MethodsParticipants completed participant-reported standardized outcomes on participation, health-related quality of life, fatigue, physical functioning, and costs at baseline (ie, start of the treatment), 3, 6, 9 and 12 months. ResultsA total of 1451 participants (64 % women, 76 % mild/moderate severity) with a mean (SD) age of 49 (12) years were included. Linear mixed models showed significant and clinically relevant improvements over time in all outcome measures between baseline and 12 months. Between 6 and 12 months, we found significant but not clinically relevant improvements in most outcome measures. Having a worse baseline score was the only baseline factor that was consistently associated with greater improvement over time on that outcome. Total allied healthcare costs (mean €1921; SEM €48) made up about 3% of total societal costs (mean €64,584; SEM €3149) for the average participant in the cohort. ConclusionsThe health status of participants recovering from COVID-19 who visited an allied health professional improved significantly over a 12-month follow-up period, but nearly the improvement occurred between baseline and 6 months. Most participants still reported severe impairments in their daily lives, and generated substantial societal costs. These issues, combined with the fact that baseline characteristics explained little of the variance in recovery over time, underscore the importance of continued attention for the management of people recovering from COVID-19. Trial registrationclinicaltrials.gov (NCT04735744)

#3052 mTOR inhibitors in kidney transplant recipients with high immunological risk: practical insights from clinical experience

Abstract Background and Aims The use of mTOR inhibitors (mTORi) is not usually considered in high immunological risk kidney transplant recipients (KTR) for a perceived increased risk of rejection. However, in most of the studies that examined the combination of mTORi with calcineurin inhibitors (CNI), hypersensitized patients have been excluded from enrollment. The aim of the present study is to analyze our clinical experience with the use of mTORi in association with calcineurin inhibitors (CNI) in this subset of patients. Method Analysis of 212 consecutive kidney transplant recipients with a baseline calculated panel reactive antibody (cPRA) ≥50% who received a graft from June 2013 to December 2019. Immunosuppression was based on tacrolimus, steroids and, alternatively, mycophenolic acid (MPA; n = 96) or mTORi (either sirolimus or everolimus, target trough levels 3-8 ng/ml, n = 116) depending on the active Institution's protocol at the time of transplantation. The outcomes chosen included rejection-free, graft and patient survival and were analyzed by means of Cox-regression analysis. Results Demographic and immunological characteristics were similar between groups, apart from the higher number of living donors in the MPA group (42.7% vs 14.7%%, P &amp;lt; 0.001). Baseline cPRA was 92.5 [76-98]% for the MPA and 94 [77.25-98]% for the mTORi group, respectively (P = 0.882). Induction therapy with lymphocyte-depleting agents was employed in the majority of patients (91.7% in the MPA group and 88.8% in the mTORi group, P = 0.898). Median follow-up time was 2.6 [1.45-4.05] years. Biopsy-proven rejection (either cellular or humoral) occurred in 33.3% of the MPA and in 19.8% of the mTORi group, respectively. Cox-regression analysis of rejection-free survival revealed better rejection-free survival with mTORi versus MPA (HR [95% CI], 0.54 [0.32-0.98], P = 0.028). The only other baseline factor associated with rejection was previous transplantation (HR [95% CI] 1.96 [1.07-3.60], P = 0.030). When entered into a bivariable Cox-regression analysis, both mTORi and previous transplantation maintained a statistical significant association with rejection (mTORi versus MPA HR [95% CI] 0.53 [0.31-0.91], P = 0.023, and previous transplantation HR [95% CI] 2.01 [1.09-3.69], P = 0.024). No differences between mTORi and MPA were noted for graft (HR [95% CI] 0.90 [0.40-2.02], P = 0.807) and patient survival (HR [95% CI] 1.23 [0.60-2.50, P = 0.606). Median creatinine 1 year after transplantation was 1.45 [1.11-1.98]mg/dl for the MPA group and 1.51 [1.09-2.06]mg/dl for the mTORi group (P = 0.917). Conclusion This retrospective study suggests that hypersensitized KTRs can receive safely a maintenance immunosuppression based on a combination of CNI with mTORi, without an increased risk of rejection.

Incidence and Predictors of Ventricular Arrhythmia after Cardiac Resynchronization Therapy Device Implantation

Background: Cardiac resynchronization therapy (CRT) serves as a pivotal therapeutic modality for patients with heart failure with reduced ejection fraction and biventricular dyssynchrony. The implementation of CRT not only mitigates the risk of sudden cardiac death but also enhances the overall quality of life. Knowledge concerning the incidence and predictive factors of ventricular arrhythmia (VA) following CRT implantation is invaluable for optimizing future CRT protocols and assessing cost-effectiveness. Materials and Methods: The present research constituted a retrospective cohort analysis with a nested case-control study, conducted between January 2005 and April 2018. Inclusion criteria encompassed patients who experienced heart failure with a left ventricular ejection fraction (LVEF) of less than 35%, displayed a QRS complex duration exceeding 120 milliseconds on electrocardiography, which underwent optimized pharmacological treatment, and subjected to a minimum one-year follow-up post-implantation. Results: One hundred forty-six CRT patients were included, and 47.9% (95% confidence interval [CI] 39.9 to 55.9) VA was detected. The average age at the time of implantation was 64 years. Only male, at 68.5%, was the baseline factor to increase the risk of VA (odds ratio [OR] 2.20, 95% CI 1.07 to 4.53, p=0.031). The other significant predictors for VA included fewer improvements in QRS width or LVEF post-implantation (p&lt;0.001 and 0.001, respectively). Conversely, a reduction of at least 7 milliseconds in QRS width following implantation correlated with a significant decline in VA events (p&lt;0.001), exhibiting a sensitivity of 80.3% and a specificity of 65.7%. Conclusion: In patients who underwent CRT implantation, the risk factors determining the occurrence of VAs included male gender and minimal post-procedural improvements in QRS width or LVEF. On the contrary, a narrowing of the QRS width by more than 7 milliseconds post-implantation was significantly associated with a reduced incidence of ventricular arrhythmic events.

Kinetics of the hepatitis B core-related antigen and treatment responses in chronic hepatitis B patients treated with tenofovir alafenamide.

An association between hepatitis B core-related antigen (HBcrAg) kinetics and hepatocarcinogenesis during nucleoside (t)id analog (NA) treatment has recently been reported. HBcrAg kinetics and factors associated with HBcrAg response during tenofovir alafenamide (TAF) administration remain unclear. In this multicenter retrospective study, we aimed to clarify the efficacy and safety of TAF in treatment-naïve patients with chronic hepatitis B, focusing on the reduction in HBcrAg levels. Patients were treated with TAF monotherapy for 96weeks, and the kinetics of HBcrAg during treatment and the factors associated with HBcrAg response (defined as a change in HBcrAg of -1logIU/mL from baseline) were evaluated. The study population comprised 241 patients, 36.9% of whom were HBeAg-positive. The median baseline HBcrAg level was 4.7logIU/mL. The median change in HBcrAg from baseline was -1.1logIU/mL at 96weeks after treatment. The HBcrAg response rate at 96weeks was 56.6% (43/76). Multivariate analysis revealed high alanine transaminase level as an independent baseline factor associated with HBcrAg response at 96weeks of treatment (p=4.53×10-6). No correlation was found between the HBcrAg and hepatitis B surface antigen kinetics in patients treated with TAF monotherapy. In TAF monotherapy for patients with chronic hepatitis B, HBcrAg levels were significantly decreased and baseline alanine transaminase level is an important factor associated with HBcrAg reduction. As no correlation was found between HBcrAg and reduced hepatitis B surface antigen levels in this study, HBcrAg kinetics in addition to hepatitis B surface antigen may need to be monitored during TAF treatment.

Assessment of Temporary Warfarin Reversal in Patients With Left Ventricular Assist Devices: the KVAD Study*

Patients with left ventricular assist devices (LVADs) require interruption of warfarin for invasive procedures, but parenteral bridging is associated with many complications. Four-factor prothrombin complex concentrate (4F-PCC) can temporarily restore hemostasis in patients undergoing anticoagulation with warfarin. This pilot study evaluated the strategy of using variable-dose 4F-PCC to immediately and temporarily reverse warfarin before invasive procedures without holding warfarin in patients with LVADs. The duration of effect of 4F-PCC on factor levels and time to reestablish therapeutic anticoagulation post procedure were assessed. Adult patients with LVADs and planned invasive procedures were enrolled from a single center. Warfarin was continued uninterrupted. The 4F-PCC dose administered immediately pre-procedure was based on study protocol. International normalized ratio (INR)- and vitamin K-dependent factor levels were collected before and during the 48 hours after 4F-PCC administration. The use of parenteral bridging, International Society for Thrombosis and Haemostasis major and clinically relevant nonmajor bleeding (CRNMB) and thromboembolic events at 7 and 30 days were collected. In 21 episodes of 4F-PCC reversal, median baseline INR was 2.7 (IQR 2.2-3.2). The median dosage of 4F-PCC administered was 1794 units (IQR 1536-2130). At 24 and 48 hours post 4F-PCC administration, median INRs were 1.8 (IQR 1.7-2.0) and 2.0 (IQR 1.9-2.4). Two patients required postoperative bridging. One patient experienced major bleeding within 72 hours, and 2 experienced CRNMB within 30 days. There were no thromboembolic events. Baseline and post 4F-PCC vitamin K-dependent factor levels corresponded with changes in INR values. The median time to achieve therapeutic INR post-procedure was 2.5 days (IQR, 1-4). Administration of 4F-PCC for temporary reversal of warfarin for invasive procedures in patients with LVADs allowed for continued warfarin dosing with minimal use of post-intervention bridging, limited bleeding and no thromboembolic events.

270 Radiologic diagnosis of Extranodal Extension (ENE) in patients with HPV-positive oropharyngeal cancer: consensus diagnosis and influence on prognosis

Tumor often progresses through the weakest part of any surrounding tissues. The extent of tumor invasion depends on: a. Aggressiveness of the tumor cells (e.g. number and invasive character of stem cells), b. robustness of the surrounding tissues and their composition (e.g. vessels), and c. time to allow the tumor to proliferate. The lymph node (LN) capsule comprises dense connective tissue stroma and collagenous fibers, and is a natural barrier that generally prevents further tumor progression. Permeation of tumor through the nodal capsule into surrounding tissues is termed “extranodal extension”. The idiosyncratic and inconsistent mechanism of ENE is imprecisely understood, but it is thought to be due to either tumor cell proliferation that outpaces the capacity of nodal capsular expansion (“ruptures” the LN capsule), or factors within the tumor or tumor microenvironment that facilitate the “breach” of the capsule. The latter might explain ENE in small LNs, or a “neglected” tumor (lengthy intranodal tumor growth with eventual “rupture” through an expanded nodal capsule). Several biomarkers (e.g. podoplanin) that are often associated with tumor aggressiveness have been reported to have a high expression in ENE+ LN. ENE represents a spectrum of tumor nodal invasion. The early sign of ENE can only be visible under the microscope (pathologic ENE); when ENE progresses further, the radiographic signal changes become apparent, making it visible on imaging (iENE). Most advanced ENE causes emergence of clinical surrogates (e.g. peau d'orange, or a “fixed” nodal mass), rendering it detectable by regular clinical examination (ENEc). iENE has been reported to be one of the strongest anatomic prognostic factors for overall survival (mainly due to increased risk of distant metastasis) in HPV-positive oropharyngeal carcinoma (HPV+ OPC), and is able to identify a subgroup of stage I disease with poor prognosis. Several deintensification trials (NRG-HN002, ORATOR, ORATOR2, E3311) have excluded HPV+ OPC with some form of iENE from trial enrolment. Several authors have proposed that iENE be included in future clinical N classification for HPV+ OPC. However, adoption of iENE in clinical care remains challenging because it is not a well-defined radiologic feature among the radiology community. Various definitions / descriptions of iENE have been used in literature. There is also insufficient awareness of the prognostic importance of this parameter in head and neck oncology community. The international iENE Expert Panel was convened under the HNCIG comprised expert internationally renowned neuroradiologists and clinicians. Several rounds of Delphi process were conducted to consolidate iENE definition. The consensus recommendations on the terminology and diagnostic criteria for iENE were generated. The experts in the consensus process recognized the following as criteria for the diagnosis of iENE: clear evidence of irregular or indistinct nodal margin/border; extension into perinodal fat; extension into adjacent structures, and conglomerate/matted/coalescent nodes. These recommendations have been endorsed by 19 national organisations, representing 34 countries. With increased awareness and consolidated definition as well as training, iENE could become an important baseline factor for risk stratification and staging in HPV+ OPC.

Expert United Kingdom consensus on the preservation of joint health in people with moderate and severe haemophilia A: A modified Delphi panel.

For people with haemophilia A (PwHA), bleeding in the joints leads to joint damage and haemophilia-related arthropathy, impacting range of motion and life expectancy. Existing guidelines for managing haemophilia A support healthcare professionals (HCPs) and PwHA in their efforts to preserve joint health. However, such guidance should be reviewed, considering emerging evidence and consensus as presented in this manuscript. Fifteen HCPs experienced in the management of PwHA in the UK participated in a three-round Delphi panel. Consensus was defined at ≥70% of panellists agreeing or disagreeing for Likert-scale questions, and ≥70% selecting the same option for multiple- or single-choice questions. Questions not reaching consensus were revised for the next round. 26.8% (11/41), 44.8% (13/29) and 93.3% (14/15) of statements reached consensus in Rounds 1, 2 and 3, respectively. HCPs agreed that prophylaxis should be offered to patients with a baseline factor VIII (FVIII) level of ≤5 IU/dL and that, where there is no treatment burden, the aim of prophylaxis should be to achieve a trough FVIII level ≥15 IU/dL and maintain a longer period with FVIII levels of ≥20-30 IU/dL to provide better bleed protection. The aspirational goal for PwHA is to prevent all joint bleeds, which may be achieved by maintaining normalised (50-150 IU/dL) FVIII levels. The panel of experts were largely aligned on approaches to preserving joint health in PwHA, and this consensus may help guide HCPs.

Factors contributing to the development of choroidal microvasculature dropout in glaucoma suspects and patients with glaucoma

Aims/Purpose: We aimed to characterize and compare the occurrence of MvD between glaucoma suspects and patients with glaucoma. In addition, the factors related to the development of parapapillary MvD in glaucoma suspects and patients with glaucoma were investigated.Methods: Total 150 eyes, 68 eyes of glaucoma suspects and 82 eyes of glaucoma patients were analysed in this study. Disc photography, VF, OCT, HRT, OCTA examinations were performed every year. Student's t‐test and the χ2 test were used to compare continuous and categorical variables, respectively. Slope of OCT, HRT, and VF parameters were calculated as change per year using linear regression. Univariate and multivariate logistic regression analyses were used to identify factors associated with MvD development.Results: Comparison between group who developed MvD and group without MvD, there was a significant difference in the slope of cup volume by OCT, central VF progression, and ONH surface depression measured by HRT. Thinner baseline GCIPL thickness, central VF progression, and the slope of cup shape measures by HRT were found to be significant associated factors to MvD development in multivariate analysis in total subjects. In the regression analysis of glaucoma suspect group, greater axial length and baseline cup volume among the baseline factors and the slope of GCIPL thickness and central VF progression among follow‐up factors were significantly associated with the MvD development. In the glaucoma group, central VF progression and ONH depression among follow‐up elements were observed as significant factors and the baseline factor had little relationship.Conclusions: MvD appears not only as a result of the progression of axonal loss of RGC in glaucoma but may also be developed by structural changes and mechanical susceptibility of the ONH associated with baseline characteristics, including myopia, thin central corneal thickness, and higher baseline IOP. Analysing the structural susceptibility of the ONH can predict the occurrence of MvD, which is can be helpful in predicting the progression of glaucoma.

Factors Contributing to the Development of Choroidal Microvasculature Dropout in Glaucoma Suspects and Patients with Glaucoma.

We aimed to characterize and compare the occurrence of peripapillary microvasculature dropout (MvD) between glaucoma suspects and patients with glaucoma. In addition, the factors related to the development of parapapillary MvD in glaucoma suspects and patients with glaucoma were investigated. Of a total 150 eyes, 68 eyes of glaucoma suspects and 82 eyes of glaucoma patients were analyzed in this study. Univariate and multivariate logistic regression analyses were used to identify factors associated with MvD development. The classification of glaucoma patients or glaucoma suspects was not significantly associated with MvD development (beta 1.368, 95% CI, 0.718-2.608, p = 0.341). In the regression analysis of the glaucoma suspect group, greater axial length (beta 1.520, 95% CI, 1.008-2.291, p = 0.046) and baseline cup volume (beta 3.993, 95% CI, 1.292-12.345, p = 0.035) among the baseline factors and the slope of ganglion cell-inner plexiform layer (GCIPL) thickness (beta 0.027, 95% CI, 0.072-0.851, p = 0.027) and central visual field (VF) progression (beta 7.040, 95% CI, 1.781-16.306, p = 0.014) among follow-up factors were significantly associated with MvD development. In the glaucoma group, central VF progression (beta 5.985, 95% CI, 1.474-24.083, p = 0.012) and ONH depression (beta 3.765, 95% CI, 1.301-10.895, p = 0.014) among follow-up elements were observed as significant factors and the baseline factor had little relationship. MvD appears not only as a result of the progression of axonal loss of RGC in glaucoma but may also be developed due to structural changes and mechanical susceptibility of the ONH associated with baseline characteristics. Analyzing the structural susceptibility of the ONH can predict the occurrence of MvD, which can be helpful in predicting the progression of glaucoma.

Efficacy, Safety, and Pharmacokinetics by Body Mass Index Category in Phase 3/3b Long-Acting Cabotegravir Plus Rilpivirine Trials.

Cabotegravir plus rilpivirine (CAB + RPV) is a guideline-recommended long-acting (LA) injectable regimen for the maintenance of human immunodeficiency virus-1 (HIV-1) virologic suppression. This post hoc analysis summarizes CAB + RPV LA results by baseline body mass index (BMI) category among phase 3/3b trial participants. Data from CAB + RPV-naive participants receiving every 4 or 8 week dosing in FLAIR, ATLAS, and ATLAS-2M were pooled through week 48. Data beyond week 48 were summarized by study (FLAIR through week 96 and ATLAS-2M through week 152). HIV-1 RNA <50 and ≥50 copies/mL, confirmed virologic failure (CVF; 2 consecutive HIV-1 RNA ≥200 copies/mL), safety and tolerability, and plasma CAB and RPV trough concentrations were evaluated by baseline BMI (<30 kg/m2, lower; ≥30 kg/m2, higher). Among 1245 CAB + RPV LA participants, 213 (17%) had a baseline BMI ≥30 kg/m2. At week 48, 92% versus 93% of participants with lower versus higher BMI had HIV-1 RNA <50 copies/mL, respectively. Including data beyond week 48, 18 participants had CVF; those in the higher BMI group (n = 8) all had at least 1 other baseline factor associated with CVF (archived RPV resistance-associated mutations or HIV-1 subtype A6/A1). Safety and pharmacokinetic profiles were comparable between BMI categories. CAB + RPV LA was efficacious and well tolerated, regardless of baseline BMI category. NCT02938520, NCT02951052, and NCT03299049.

Real-World Use of Recombinant Von Willebrand Factor in People with Clinically Severe Congenital Von Willebrand Disease: Interim Analysis of Athn 9: A Natural History Study for People with Severe VWD

Background: People with von Willebrand disease (VWD) present with a spectrum of bleeding patterns and clinical symptoms, independent of subtype (Rugeri. Haematologica. 2007; Kalot. Haemophilia. 2021). In certain situations, prophylaxis may be appropriate, particularly when there is recurrent and severe bleeding (Connell, Blood Advances, 2021). There are limited real-world data on the use of recombinant von Willebrand factor (rVWF) in the United States. Aim: To characterize the safety and real-world effectiveness of routine prophylaxis with rVWF in people with clinically severe congenital VWD. Study Design and Methods:This is an interim analysis of a phase 4, longitudinal, prospective, observational cohort study (NCT03853486). Participants with severe VWD types 1, 2, and 3 (≤30% of normal) or “clinically severe VWD” (≤40% of normal with severe bleeding and requiring prophylaxis with factor concentrates) were identified from the ATHNdataset. The American Thrombosis &amp; Hemostasis Network (ATHN) is the steward of the ATHNdataset, a Health Insurance Portability and Accountability Act-compliant, de-identified patient health dataset containing data from individuals with bleeding disorders receiving care through ATHN affiliates who opt in to contribute. Treatment regimens were at the discretion of each participant's respective bleeding disorder provider. Participants are followed for 2 years from the time of enrollment. Safety was measured using definitions from the European Haemophilia Safety Surveillance program. Bleeding events (BEs) were measured by individual bleeding components and calculated per the International Society on Thrombosis and Haemostasis Bleed Assessment Tool and/or the Pictorial Bleeding Assessment Chart. Health-related quality of life measures, including an ATHN9 rVWF substudy form, were used to describe real-world effectiveness of rVWF treatment. Descriptive statistics were used to analyze study outcomes. This study was not designed to detect differences in safety or efficacy between individual treatment products. Interim Results:As of June 16, 2023, 23 participants enrolled in the ATHN9 study were receiving rVWF; 14 participants have been prescribed rVWF for at least 1 full year, 13 of whom received continuous prophylaxis. This abstract reports on those 13 participants in the first year of the study. Mean (SD) age was 42.9 (29.2) years; 69.2% (n=9) of participants were female. Most participants had no comorbidities. As expected, most participants had a family history of VWD (84.6%; n=11) and no documented VWF inhibitors (84.6%; n=11); inhibitor status for the remaining 2 participants was unknown. Baseline VWF and factor VIII measurements were reported for most participants ( Table 1). The majority had type 2 VWD (84.6%; n=11), 92.3% (n=12) had identifiable genetic sequence defects in VWF, and 30.8% (n=4) had an abnormal VWF multimer profile. As dictated by the local investigator, rVWF prophylactic regimens ranged from 36.6 IU/kg once weekly to 57.6 IU/kg every 3 days; 7 (53.8%) participants received 40-60 IU/kg at a frequency of 2-3 times per week. Twenty-one BEs occurred in 5 (38.5%) of the participants receiving rVWF prophylaxis during the first year ( Table 2). Most BEs were spontaneous (61.9%; 13/21), occurring in the nose (n=7), gastrointestinal tract (n=5), or ankle (n=1). The remaining BEs were associated with activity with no known trauma (n=4), trauma (n=2), or unknown cause (n=2). One participant reported 3 rVWF treatment-unrelated adverse events (AEs) of humerus shaft closed fracture, metabolic encephalopathy, and acute exacerbation of chronic obstructive airways disease. When surveyed about their experience with rVWF, participants reported very or extremely satisfied as follows: 76.9% (n=10) with infusion time, 84.6% (n=11) with breakthrough bleed control time, 46.2% (n=6) with number of infusions required for breakthrough bleed control, and 69.2% (n=9) with frequency of achieving bleed control without concomitant hemostatic medication. Discussion:In participants with clinically severe congenital VWD, continuous prophylaxis with rVWF was associated with minimal AEs. Most participants receiving rVWF prophylaxis experienced no BEs during the first year of the study. Most participants expressed overall satisfaction with the use of rVWF.

Characterization of Joint Disease in Women with Hemophilia: The Carriers Ultrasound Project (CUP) Study

Introduction: Women with hemophilia (WWH) are at risk for bleeding despite normal or mildly reduced plasma factor VIII (FVIII) or IX (FIX) activity levels. Subclinical joint bleeds can contribute to longstanding and irreversible joint damage. Although joint health has been well-studied among men with hemophilia, there is currently a gap in knowledge on the prevalence, clinical characteristics, and natural history of joint health in women with hemophilia. No prior studies have utilized point-of-care musculoskeletal ultrasound (POC-MSKUS) to assess the presence and characteristics of joint changes in carrier women. Aim: This multi-institutional, cross-sectional study primarily aimed to evaluate and compare the prevalence and extent of joint-related symptoms and joint changes in WWH compared to age-matched controls utilizing validated clinical tools including the Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) protocol. We also aimed to examine the relationship between innate FVIII and FIX levels and presence of joint disease changes in this population. Methods: Between 2017-2023, women aged 18 to 40 years were enrolled and divided in 2 cohorts. The “carrier cohort” included women with a confirmed hemophilia A or B diagnosis, regardless of factor activity level. The “control cohort” included women without personal or family history of a bleeding disorder. Individuals were excluded if they had history of joint trauma or surgery within 12 months prior to enrollment or any history of joint replacement. Collected clinical information included presence of bleeding symptoms, joint-related symptoms, and historical use of hemostatic medications. Participants underwent clinical and radiological assessment of bilateral elbows, knees, and ankles using the Hemophilia Joint Health Score (HJHS) and HEAD-US protocol. Factor activity levels were measured in the carrier cohort. Descriptive and interferential statistics were performed using SPSS software with p&amp;lt;0.05 considered statistically significant. Results: Fifty-eight women, including 30 controls (51.7%) and 28 carriers (48.3%) were enrolled. The mean age at enrollment was 30.7 years (range: 19-39 years). Most women were White (79.3%) and Hispanic (51.7%). Of the 28 carriers, 85.6% (n=24) were hemophilia A carriers and 14.3% (n=4) hemophilia B carriers, respectively ( TABLE 1). Among carriers, the mean and median factor activity levels were 56% and 54% (range 20-120%) respectively. Carriers reported significantly higher prevalence of bleeding symptoms when compared to controls, including heavy menstrual bleeding (64.3% vs. 10%, p&amp;lt;0.001), epistaxis (25% vs. 3.3%, p=0.017), gingival bleeding (25% vs. 3.3%, p=0.017), and easy bruising (50% vs. 3.3%, p&amp;lt;0.001). The majority (53.5%, n=15) of carriers reported presence of joint-related symptoms when compared to controls, including joint pain (50% vs. 3.3%, p&amp;lt;0.001) and joint swelling (28.6% vs. 0%, p=0.02). Three (10.7%) carriers reported history of overt joint bleeds. Carriers had significantly higher mean HJHS scores (4.7 vs. 1.5, p&amp;lt;0.001) than did controls, however no significant changes in HEAD-US scores were found. A high body mass index (BMI) (&amp;gt;25kg/m2) was significantly associated with an increased prevalence of joint bleeding (25% vs. 0%, p=0.03) among carriers. When dividing carriers in 2 groups based on their baseline factor activity level (&amp;gt;40% versus &amp;lt;40%), the prevalence of bleeding manifestations and joint-related symptoms were similar ( TABLE 2). Carriers with factor levels &amp;lt;40% were more likely to require factor replacement on-demand (60% vs. 17.4%, p=0.046) and anti-fibrinolytics (60% vs. 17.4%, p=0.046) than carriers with factor levels &amp;gt;40%. There were no changes in mean HJHS or mean HEAD-US scores among the two groups. Conclusions: Women with hemophilia are at increased risk of bleeding manifestations and joint-related symptoms, regardless of factor activity levels. This population also seems to have poorer joint health than do non-carrier women as assessed by HJHS. Dedicated follow-up to help prevent and treat joint-related complications among WWH seems imperative. Our study did not detect significant ultrasonographic joint changes in the carrier cohort. However, joint findings may become more evident later in life or when assessed with magnetic resonance imaging. Further long-term studies are needed to support our hypothesis.

Descriptive and Epidemiological Study of Joint Damage in Non-Severe Hemophilia: Update of the Damage Study of the Mediterranean Group

Introduction: There is growing evidence indicating joint damage (JD) in non-severe hemophilia (nSH) patients. Although age and baseline factor (F) VIII/FIX levels have been proposed as good predictors of JD in mild hemophilia (MiH), data are scarce and in moderate hemophilia (MoH) are lacking. Besides, global hemostatic capacity (GHC) in this population and its contribution to JD has not been assessed. Methods: We designed a cross-sectional, observational and multicenter study carried out in 12 Spanish hospitals (Mediterranean Group). We evaluated JD in nSH patients and its correlation with age, baseline FVIII/FIX and GHC. JD was defined as a HEAD-US score &amp;gt;0. Baseline FVIII (chromogenic assay), FIX (clotting assay) and GHC (assessed by thrombin generation test, TGT, Genesia ®, Stago) were evaluated in a central laboratory. Results were expressed as median (25 th-75 th percentiles). Categorical variables were expressed with percentage. A p value&amp;lt;0.05 was considered statistically significant. Results: A total of 98 nSH patients were included: 10 (10.2%) MoH (9 HA: age= 35.6 [21.7-45.0] years old (YO); FVIII = 4.0 [4.0-5.0] IU/dL; 1 HB: FIX= 2 IU/dL) and 88 MiH (84 HA: age= 38.6 [19.0-52.1 YO]; FVIII= 15.5 [11.0-24.0] IU/dL; 4 HB: FIX= 30.0 [16.8-35.4] IU/dL). Target joints were observed in patients with MiH (7/88: 8.6% of the MiH patients). HEAD-US score was obtained in 73 patients (74.5% of the total participating patients): nine MoH patients presented a HEAD-US= 1 (0-6) (age: 32.7 [21.7-42.9] YO) while 64 MiH patients presented a HEAD-US= 0 (0-3) (age: 37.9 [17.8-48.7] YO) (comparison between MoH and MiH patients: HEAD-US: p=0.427, age: p= 0.614). Only 55.5% (5/9) MoH patients and 45.3% (29/64) MiH patients, presented JD (p=0.725). Baseline FVIII/FIX was 13.0 (7.0-20.0) IU/dL and 16.0 (11.0-22.5) IU/dL in patients with or without JD respectively (p= 0.311). These mild difference of number of patients with JD and degree of JD between MiH and MoH were corroborated by not detecting correlation between baseline FVIII/FIX levels and JD (r= -0.095; p= 0.426) (Figure 1). JD increased with age (r= 0.380; p= 0.001) reinforcing previous findings. GHC correlated with baseline FVIII/FIX (Table 1) but not with the degree of JD, suggesting that thrombin generation, with the used conditions, might not be helpful to predict JD in this population. Conclusions: Around 50% of patients with nSH presented JD. This JD increased with age, supporting previous data. Although there was a correlation between baseline FVIII/FIX levels and thrombin generation, none of the TGT parameters were predictive of the degree of JD, enhancing that other variables might be influencing the development of JD in nSH patients. Of note, MiH individuals may develop severe JD due to presence of target joints. In summary, our results highlight the importance of evaluating JD in nSH in order to determine whether new protocols are required for the diagnosis, prevention, and treatment of JD in nSH patients.

Treatment-Related Clinical and Humanistic Unmet Needs in Hemophilia A without Inhibitors

Introduction: Patients with hemophilia still experience significant burden of disease despite the growing availability of efficacious treatment options. Presented here are the final patient-reported data from a non-interventional study of treatment and disease burden in US patients with hemophilia A without inhibitors (HAwoI). Methods: Patients with HAwol were recruited to the PicnicHealth research platform using digital marketing, referrals and community partnerships. PicnicHealth collects and extracts medical records on behalf of the patient, provides them with their records and invites them to participate in recurring patient-reported outcome surveys. Hemophilia severity reported here was based on baseline factor values and medical records. Two validated questionnaires, Hemophilia Treatment Experience Measure (Hemo-TEM)(Brod, M. et al., J Patient Rep Outcomes. 2023) and Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Profile v2.0 (Hays, R.D., et al., Qual Life Res. 2018)were used to collect data on treatment and disease burden. Patients were also asked about their prophylactic medication, if any, as well as two independent questions on anxiety and/or worry concerning bleed protection with current treatment. All surveys were administered between April 2022 and April 2023, with the most recent survey included in this analysis for patients who completed multiple surveys during the study period. Hemo-TEM domain scores were transformed onto a 0 to 100-point scale with higher scores indicating greater burden. PROMIS-29 scores were transformed into T-scores, based on a reference sample with a mean of 50 and standard deviation of 10, except for the pain intensity score, which was rated 0-10. The directionality of impact was specific for each domain (Hays, R.D., et al., Qual Life Res. 2018). Results are presented as proportions, median and interquartile range (IQR, Q1-Q3). Informed consent was obtained. Results: Out of 230 patients with HAwol (91% male; median age: 33.3 years; IQR: 23.9-41.7), 147 (64%) had severe, 41 (18%) had moderate and 42 (18%) had mild hemophilia. Use of prophylactic FVIII was reported by 74 (50%), 16 (39%) and 13 (31%) patients with severe, moderate and mild hemophilia, respectively, while prophylactic non-factor replacement therapy use was reported by 64 (44%), 8 (20%) and 5 (12%) patients, respectively (treatment classes are not mutually exclusive). Treatment class was unspecified (includes patients who did not report prophylactic medication use) for 58 (25%) patients. Treatment burden was observed through Hemo-TEM scores across all subgroups of disease severity and treatment class (n=223), with the strongest drivers being physical impact (median: 25 [IQR: 12-38]), treatment bother (21 [9-32]) and emotional impact (21 [6-38]) domains (Table 1). The PROMIS-29 scores and its directionality shown in Figure 1 demonstrated comparable disease burden in all domains regardless of disease severity or treatment class (n=228). Patients with severe disease on prophylactic FVIII/prophylactic non-factor replacement therapy reported scores of 42 (37-50)/46 (39-57) in physical functioning and 51 (49-61)/49 (46-55), 57 (52-64)/56 (42-60) and 52 (48-56)/52 (46-56) in domains of fatigue, pain interference and sleep disturbance, respectively. Impact on mental well-being for these patients were shown by scores of 56 (49-61)/54 (41-59) and 58 (51-63)/56 (51-61) in domains of depression and anxiety, respectively. Pain intensity for all patients with severe disease was 4 (2-6) out of 10. In response to two independent survey questions, patients with severe HAwol reported feeling anxious (42%) and/or worried (39%) at least sometimes that their current treatment might not adequately protect them from bleed. Conclusion: Patients with HAwoI continue to experience treatment and disease burden, across treatment class and disease severity subgroup. Despite improved outcomes with current treatment strategies, there remains a need to continue to address disease burden. Greater understanding is required of the driving factors behind similar treatment and disease burden between the subgroups to facilitate individualized care.

Coagulation profiles during and after anabolic androgenic steroid use: data from the HAARLEM study

BackgroundAnabolic androgenic steroids (AAS) are thought to increase venous thromboembolism (VTE) risk. ObjectivesWe investigated whether AAS influence coagulation parameters associated with VTE by assessing their changes during and after AAS use. MethodsThe HAARLEM study enrolled 100 male amateur athletes voluntarily starting an AAS cycle between 2015 and 2018. We measured procoagulant and anticoagulant protein levels, D-dimer levels, endogenous thrombin potential (ETP), and clot lysis time (CLT) at baseline and during 2 years of follow-up. Changes in coagulation during AAS cycle, 3 months after its discontinuation, and 1 year after its inclusion compared with baseline were estimated using linear mixed models. The associations between AAS dose and duration of use with these outcomes were studied through adjusted multivariable linear regression. ResultsParticipants used AAS for a median of 13 weeks (IQR: 10-23) with a median weekly dose of 901 mg (IQR: 634-1345 mg). Mean levels of multiple coagulation factors (F) increased during use compared with baseline, whereas FVIII and von Willebrand factor levels remained unchanged. Protein S and D-dimer showed the biggest increase (22% [95% CI: 15-29] and 1.3-fold [95% CI: 1.2-1.5], respectively). CLT was 8 minutes longer (95% CI: 5-10) and ETP was 165 nM∗min (95% CI: −205 to −124) lower during the AAS cycle. A high weekly AAS dose and short cycle duration were associated with changes in protein S and ETP during use. All parameters returned to baseline values 3 months after discontinuation and remained similar after. ConclusionDuring AAS use, procoagulant and anticoagulant protein levels increased in a reversible manner. The overall balance did not suggest a clear procoagulant state.

Risk factors for coagulation inhibitor development in children with severe hemophilia A

Aim of the study: to examine the role of potential risk factors in inhibitor development in previously untreated patients (PUPs) (or minimally treated patients) with severe hemophilia A. The study was approved by the Independent Ethics Committee and the Scientific Council of the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus). The study included 89 boys who underwent regular follow-up for severe hemophilia A at the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus) from 1998 to 2022. The median age (10th–90th percentile) at diagnosis of hemophilia was 8.0 (1.0–21.0) months, the baseline factor VIII activity was 0.7% (0.4–0.95%). Age at first exposure to factor VIII concentrate was 11.0 (1.0–31.0) months. Out of 89 patients, 23 children had severe hemophilia A with inhibitors. The cumulative incidence of inhibitors in the whole group of PUPs was 31.0 ± 5.6%. The cumulative incidence of hemophilia A with inhibitors was higher in the patients with null mutations (37.0 ± 6.9%) than in the patients with non-null mutations (6.5 ± 6.0%) (the log-rank test, p = 0.041). The use of plasma-derived FVIII concentrate (approved for use in neonates and for prophylaxis) from one manufacturer was associated (c2 = 8.53; p = 0.004) with a lower incidence of factor VIII inhibitors (up to 21.3 ± 8.5%) compared with the incidence in the group of patients treated with FVIII concentrates from different manufacturers (45.2 ± 7.8%). Age (&gt; 1 year old or &lt; 1 year old) at first exposure to FVIII had no effect on the formation of inhibitors (the log-rank test, p = 0.746). Such factors as age at diagnosis of hemophilia (odds ratio (OR) 0.99; 95% confidence interval (CI) 0.93–1.024; p = 0.991) and baseline factor VIII activity (OR 0.99; 95% CI 0.8–1.06; p = 0.09) were not associated with inhibitor development. The first measurements of activated partial thromboplastin time (APTT) ratio (patient APTT value over the APTT reference value) (OR 1.89; 95% CI 0.72–5.09; p = 0.21) and FVIII recovery in vivo (OR 0.74; 95% CI 0.27–2.01; p = 0.55) were not associated with inhibitor development either. We have confirmed that one of the main risk factors for FVIII inhibitor development is F8 gene mutations. The incidence of inhibitors among the patients who received plasma-derived FVIII concentrates (recommended for use in PUPs in the neonatal period) from one manufacturer was lower than among those who received FVIII from different manufacturers.

Association between acute complications in PMM2-CDG patients and haemostasis anomalies: Data from a multicentric study and suggestions for acute management

ObjectivesPatients with PMM2-CDG develop acute events (stroke-like episodes (SLEs), thromboses, haemorrhages, seizures, migraines) associated with both clotting factors (factor XI) and coagulation inhibitors (antithrombin, protein C and protein S) deficiencies. The aim of the study was to correlate acute events to haemostasis and propose practical guidelines. MethodsIn this multicentric retrospective study, we evaluated clinical, radiological, haemostasis and electroencephalography data for PMM2-CDG patients hospitalized for acute events. Cerebral events were classified as thrombosis, haemorrhage, SLE, or “stroke mimic” (SM: normal brain imaging or evoking a migraine). ResultsThirteen patients had a total of 31 acute episodes: 27 cerebral events with 7 SLEs, 4 venous thromboses, 4 haemorrhages (3 associated with thrombosis), 15 SMs at a mean age of 7.7 years; 4 non-cerebral thromboses, one of which included bleeding. A trigger was frequently involved (infection, head trauma). Although sometimes normal at baseline state, factor XI, antithrombin and protein C levels decreased during these episodes. No correlation between haemostasis anomalies and type of acute event was found. DiscussionAcute events in PMM2-CDG are not negligible and are associated with haemostasis anomalies. An emergency protocol is proposed for their prevention and treatment (https://www.filiere-g2m.fr/urgences). For cerebral events, brain Magnetic Resonance Imaging with perfusion weight imaging and diffusion sequences, electroencephalogram and haemostasis protein levels guide the treatment: anticoagulation, antithrombin or fresh frozen plasma supplementation, antiepileptic therapy. Preventing bleeding and thrombosis is required in cases of surgery, prolonged immobilization, hormone replacement therapy. ConclusionAcute events in PMM2-CDG are associated with abnormal haemostasis, requiring practical guidance.