Objective:
The Indiana Sickle Cell Data Collection (IN-SCDC) program aims to provide timely, reliable, and locally relevant information on the sickle cell disease (SCD) population in Indiana to ...inform public health interventions, research, and policy development. We describe the development of the IN-SCDC program and report the prevalence and geographic distribution of people with SCD in Indiana using an integrated data collection approach.
Methods:
Using multiple integrated data sources and case definitions established by the Centers for Disease Control and Prevention, we classified cases of SCD in Indiana during 2015-2019. We calculated the prevalence and incidence of SCD and described characteristics of people with SCD.
Results:
We identified 1695 people living with SCD in Indiana during the study period. The median age of people living with SCD was 21 years, and 1474 (87.0%) were Black or African American. Most (n = 1596, 91%) resided in metropolitan counties. The age-adjusted prevalence of SCD was 24.7 cases per 100 000 people. The prevalence of SCD among Black or African American people was 209.3 per 100 000 people. The incidence was 1 in 2608 live births overall and 1 in 446 live births among Black or African American people. Eighty-six deaths were confirmed in this population during 2015-2019.
Conclusions:
Our results establish a baseline for the IN-SCDC program. Baseline and future surveillance program efforts will help accurately inform standards of care for treatments, identify gaps in coverage and access to care, and provide guidance for legislators and community-based organizations.
Congenital plasminogen deficiency is caused by mutations in PLG, the gene coding for production of the zymogen plasminogen, and is an ultrarare disorder associated with abnormal accumulation or ...growth of fibrin-rich pseudomembranous lesions on mucous membranes. Left untreated, these lesions may impair organ function and impact quality of life. Plasminogen replacement therapy should provide an effective treatment of the manifestations of congenital plasminogen deficiency. An open-label phase 2/3 study of human Glu-plasminogen administered IV at 6.6 mg/kg every 2 to 4 days in 15 patients with congenital plasminogen deficiency is ongoing. Reported here are data on 14 patients who completed at least 12 weeks of treatment. The primary end point was an increase in trough plasminogen activity levels by at least an absolute 10% above baseline. The secondary end point was clinical success, defined as ≥50% improvement in lesion number/size or functionality impact from baseline. All patients achieved at least an absolute 10% increase in trough plasminogen activity above baseline. Clinical success was observed in all patients with clinically visible (conjunctiva and gingiva), nonvisible (nasopharynx, bronchus, colon, kidney, cervix, and vagina), and wound-healing manifestations of the disease. Therapeutic effects were rapid, as all but 2 lesions resolved or improved after 4 weeks of treatment. Human Glu-plasminogen was well tolerated in both children and adults. This study provides critical first evidence of the clinical utility of ongoing replacement therapy with human Glu-plasminogen for the treatment of children and adults with congenital plasminogen deficiency. This trial was registered at www.clinicaltrials.gov as #NCT02690714.
•This is the first trial to evaluate the clinical utility of Glu-plasminogen in children and adults with congenital plasminogen deficiency.•Glu-plasminogen achieves physiological levels of plasminogen activity coinciding with improved clinical efficacy and disease management.
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This study aimed to comprehensively analyze inflammatory and autoimmune characteristics of patients with sickle cell disease (SCD) at a steady-state condition (StSt) compared to healthy controls ...(HCs) to explore the pathogenesis of StSt and its impact on patients' well-being. The study cohort consisted of 40 StSt participants and 23 HCs enrolled between July 2021 and April 2023. StSt participants showed elevated white blood cell (WBC) counts and altered hematological measurements when compared to HCs. A multiplex immunoassay was used to profile 80 inflammatory cytokines/chemokines/growth factors in plasma samples from these SCD participants and HCs. Significantly higher plasma levels of 35 analytes were observed in SCD participants, with HGF, IL-18, IP-10, and MCP-2 being among the most significantly affected analytes. Additionally, autoantibody profiles were also altered, with elevated levels of anti-SSA/Ro60, anti-Ribosomal P, anti-Myeloperoxidase (MPO), and anti-PM/Scl-100 observed in SCD participants. Flow cytometric analysis revealed higher rates of red blood cell (RBC)/reticulocyte-leukocyte aggregation in SCD participants, predominantly involving monocytes. Notably, correlation analysis identified associations between inflammatory mediator levels, autoantibodies, RBC/reticulocyte-leukocyte aggregation, clinical lab test results, and pain crisis/sensitivity, shedding light on the intricate interactions between these factors. The findings underscore the potential significance of specific biomarkers and therapeutic targets that may hold promise for future investigations and clinical interventions tailored to the unique challenges posed by SCD. In addition, the correlations between vaso-occlusive crisis (VOC)/pain/sensory sensitivity and inflammation/immune dysregulation offer valuable insights into the pathogenesis of SCD and may lead to more targeted and effective therapeutic strategies.
ClinicalTrials.gov, Identifier: NCT05045820.
Life expectancy for persons with hemophilia has increased over recent decades due to advances in treatment practice and patient care. Those with hemophilia are now more likely to be affected by ...conditions associated with aging, such as myocardial infarction, hemorrhagic/ischemic stroke, deep vein thrombosis, pulmonary embolism, and intracranial hemorrhage. Here, we describe the results of a literature search designed to summarize current data on the prevalence of the above selected bleeding and thrombotic events in persons with hemophilia vs the general population. A total of 912 articles published between 2005 and 2022 were identified in a search of BIOSIS Previews, Embase, and MEDLINE databases conducted in July 2022. Case studies, conference abstracts, review articles, studies focusing on hemophilia treatments or surgical outcomes, and studies examining patients with inhibitors only were excluded. After screening, 83 relevant publications were identified. The prevalence of bleeding events was consistently higher in hemophilia populations vs reference populations (hemorrhagic stroke, 1.4%-5.31% vs 0.2%-0.97%; intracranial hemorrhage, 1.1%-10.8% vs 0.04%-0.4%). Serious bleeding events showed a high rate of mortality with standardized mortality ratios for intracranial hemorrhage ranging from 3.5 to 14.88. Although 9 studies reported lower prevalence of arterial thrombosis (myocardial infarction/stroke) in hemophilia vs general populations, 5 studies reported higher or comparable prevalence in hemophilia. Prospective studies are therefore needed to understand the prevalence of bleeding and thrombotic events in hemophilia populations, particularly with the observed increases in life expectancy and availability of novel treatments.
•We compare the prevalence of bleeding/thrombotic events in hemophilia vs general population.•Bleeding event prevalence was consistently higher in persons with hemophilia than those without hemophilia.•Data suggest that the prevalence of thrombotic events is not always lower in populations with hemophilia.•Prospective cohort studies are needed to examine bleeding/thrombosis prevalence in hemophilia.
Introduction
Deficiencies of plasminogen and plasminogen activator inhibitor type 1 (PAI‐1) are rare disorders of fibrinolysis. Current laboratory assays for analysis of activity of plasminogen and ...PAI‐1 do not provide an accurate correlation with clinical phenotype.
Methods
The Nijmegen Hemostasis Assay (NHA) was used to simultaneously measure thrombin and plasmin generation in 5 patients with plasminogen deficiency (PLGD) and 10 patients with complete PAI‐1 deficiency. Parameters analysed included: lag time ratio, thrombin peak time ratio, thrombin peak height, thrombin potential (AUC), fibrin lysis time, plasmin peak height and plasmin potential. Parameters were expressed as a percentage compared to a reference value of 53 healthy normal controls.
Results
Patients with PLGD demonstrated a short lag time and thrombin peak time, with normal thrombin peak height but an increased AUC. Plasmin generation was able to be detected in only one (23% plasminogen activity) of the five PLGD patients. All ten PAI‐1 deficient patients demonstrated a short lag and thrombin peak time, low thrombin peak height with normal AUC. Plasmin generation revealed an increased plasmin peak and plasmin potential; interestingly, there was a large variation between individual patients despite all patients having the same homozygous defect.
Conclusion
Patients with either PLGD or PAI‐1 deficiency show distinct abnormalities in plasmin and thrombin generation in the NHA. The differences observed in the propagation phase of thrombin generation may be explained by plasmin generation. These results suggest that disorders of fibrinolysis also influence coagulation and a global assay measuring both activities may better correlate with clinical outcome.
Approximately 100,000 persons with sickle cell disease (SCD) live in the United States, including 15,000 in the Midwest. Unfortunately, many patients experience poor health outcomes due to limited ...access to primary care providers (PCPs) who are prepared to deliver evidence-based SCD care. Sickle Treatment and Outcomes Research in the Midwest (STORM) is a regional network established to improve care and outcomes for individuals with SCD living in Indiana, Illinois, Michigan, Minnesota, Ohio, and Wisconsin.
STORM investigators hypothesized that Project ECHO
®
methodology could be replicated to create a low-cost, high-impact intervention to train PCPs in evidence-based care for pediatric and young adult patients with SCD in the Midwest, called STORM TeleECHO. This approach utilizes video technology for monthly telementoring clinics consisting of didactic and case-based presentations focused on the National Heart, Lung and Blood Institute (NHLBI) evidence-based guidelines for SCD.
Network leads in each of the STORM states assisted with developing the curriculum and are recruiting providers for monthly clinics. To assess STORM TeleECHO feasibility and acceptability, monthly attendance and satisfaction data are collected. Changes in self-reported knowledge, comfort, and practice patterns will be compared with pre-participation, and 6 and 12 months after participation.
STORM TeleECHO has the potential to increase implementation of the NHLBI evidence-based guidelines, especially increased use of hydroxyurea, resulting in improvements in the quality of care and outcomes for children and young adults with SCD. This model could be replicated in other pediatric chronic illness conditions to improve PCP knowledge and confidence in delivering evidence-based care.
Background
The factor V east Texas bleeding disorder (FVETBD) is caused by increased plasma tissue factor pathway inhibitor‐α (TFPIα) concentration. The underlying cause is a variant in F5 causing ...alternative splicing within exon 13 and producing FV‐short, which tightly binds the C‐terminus of TFPIα, prolonging its circulatory half‐life.
Objectives
To diagnose a family presenting with variable bleeding and laboratory phenotypes.
Patients/Methods
Samples were obtained from 17 family members for F5 exon 13 sequencing. Plasma/platelet TFPI and platelet FV were measured by ELISA and/or western blot. Plasma thrombin generation potential was evaluated using calibrated automated thrombography.
Results
The FVET variant was identified in all family members with bleeding symptoms and associated with elevated plasma TFPIα (4.5‐ to 13.4‐fold) and total TFPI (2‐ to 3‐fold). However, TFPIα and FV‐short were not elevated in platelets. TF‐initiated thrombin generation in patient plasma was diminished but was restored by a monoclonal anti‐TFPI antibody or factor VIIa. TFPIα localized within vascular extracellular matrix in an oral lesion biopsy from an affected family member.
Conclusions
Factor V east Texas bleeding disorder was diagnosed in an extended family. The variant was autosomal dominant and highly penetrant. Elevated plasma TFPIα, rather than platelet TFPIα, was likely the primary cause of bleeding. Plasma FV‐short did not deplete TFPIα from extracellular matrix. In vitro thrombin generation was restored with an anti‐TFPI antibody or factor VIIa suggesting effective therapies may be available. Increased awareness of, and testing for, bleeding disorders associated with F5 exon 13 variants and elevated plasma TFPI are needed.
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