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BioRxiv : the Preprint Server For... May 2024Platelets are highly reactive fragments of megakaryocytes that play a fundamental role in thrombosis and hemostasis. Predictably, all conventional anti-platelet...
Platelets are highly reactive fragments of megakaryocytes that play a fundamental role in thrombosis and hemostasis. Predictably, all conventional anti-platelet therapies elicit bleeding, raising the question whether the thrombotic activity of platelets can be targeted separately. In this study, we describe a novel approach of inhibiting platelet activation through the use of bispecific single-chain variable fragments (bi-scFvs), termed cis-acting platelet receptor inhibitors (CAPRIs) that harness the immunoreceptor tyrosine-based inhibition motif (ITIM)-containing co-inhibitory receptor G6b-B (G6B) to suppress immunoreceptor tyrosine-based (ITAM)-containing receptor-mediated platelet activation. CAPRI-mediated hetero-clustering of G6B with either the ITAM-containing GPVI-FcR γ-chain complex or FcγRIIA (CD32A) inhibited collagen- or immune complex-induced platelet aggregation. G6B-GPVI CAPRIs strongly and specifically inhibited thrombus formation on collagen under arterial shear, whereas G6B-CD32A CAPRI strongly and specifically inhibited thrombus formation to heparin-induced thrombocytopenia, vaccine-induced thrombotic thrombocytopenia and antiphospholipid syndrome complexes on Von Willebrand Factor-coated surfaces and photochemical-injured endothelial cells under arterial shear. Our findings provide proof-of-concept that CAPRIs are highly effective at inhibiting ITAM receptor-mediated platelet activation, laying the foundation for a novel family of anti-thrombotic therapeutics with potentially improved efficacy and fewer bleeding outcomes compared with current anti-platelet therapies. .
PubMed: 38798354
DOI: 10.1101/2024.05.10.593500 -
International Journal of Molecular... May 2024Cardiovascular diseases, among which includes coronary artery disease, represent one of the most important causes of mortality and morbidity worldwide. Research aimed at... (Review)
Review
Cardiovascular diseases, among which includes coronary artery disease, represent one of the most important causes of mortality and morbidity worldwide. Research aimed at determining the risk factors involved recognizes a group of "traditional" risk factors, but also more recent studies identified over 100 "novel" ones which may have a role in the disease. Among the latter is the thrombophilia profile of a patient, a pathology well-established for its involvement in venous thromboembolism, but with less studied implications in arterial thrombosis. This paper reviews the literature, explaining the pathophysiology of the thrombophilia causes associated most with coronary thrombosis events. Results of several studies on the subject, including a meta-analysis with over 60,000 subjects, determined the significant involvement of factor V Leiden, prothrombin G20210A mutation, plasminogen activator inhibitor-1 and antiphospholipid syndrome in the development of coronary artery disease. The mechanisms involved are currently at different stages of research, with some already established and used as therapeutic targets.
Topics: Humans; Coronary Artery Disease; Thrombophilia; Thrombosis; Factor V; Prothrombin; Plasminogen Activator Inhibitor 1; Risk Factors; Genetic Predisposition to Disease; Mutation
PubMed: 38791267
DOI: 10.3390/ijms25105228 -
Innovations in Pharmacy 2024: Warfarin has many indications; however, it is the only anticoagulant that is indicated for mechanical mitral value and antiphospholipid syndrome. Management may be...
: Warfarin has many indications; however, it is the only anticoagulant that is indicated for mechanical mitral value and antiphospholipid syndrome. Management may be conducted by pharmacists in medical clinic settings. : To evaluate the percentage difference in the international normalized ratio (INR) target range when managed by a community-based pharmacist with a collaborative practice agreement (CPA) versus a physician and to analyze patient satisfaction of an anticoagulation clinic when managed by a community-based pharmacist with a CPA versus a physician. : Independent community-based pharmacy. : Community-based pharmacist managed anticoagulation clinic. Pharmacist provides anticoagulation services under a collaborative practice agreement or conducts INR testing and reporting with physician management of anticoagulation. : Quasi-experiment study design with retrospective and prospective evaluation of warfarin management and patient satisfaction. A retrospective chart review was conducted of patients enrolled in the anticoagulation clinic from January 1 2020 to June 30 2022. Patients, 18 years or older with an indication for warfarin and attendance of at least 3 anticoagulation appointments were included. The Time in Therapeutic Range (TTR) was determined using the traditional method. TTR differences across the two groups were reported using descriptive, bi-variate, and multivariate statistics. All statistical tests were conducted using SAS 9.0. Patient satisfaction was collected for 6 months using a survey created by the investigators. Survey consisted of 18 questions using a 3-point Likert scale. Survey was assessed using descriptive statistics. : Thirty-seven patients met the inclusion criteria, 26 were in the pharmacist management group with 609 appointments, and 11 patients were in the physician management group with 123 appointments. There was no statistical significance for the time in the therapeutic range between the pharmacist-managed group (60.7%) and the physician-managed group (59.4%); p-value of <0.829. Results of the satisfaction survey suggest that patients slightly prefer management by a pharmacist over a physician. : Community-based pharmacist warfarin management of time in therapeutic range was equivalent to physician management and with similar patient satisfaction.
PubMed: 38779104
DOI: 10.24926/iip.v15i1.5929 -
Annals of the Rheumatic Diseases May 2024To analyse the new evidence (2018-2022) for the management of systemic lupus erythematosus (SLE) to inform the 2023 update of the European League Against Rheumatism...
OBJECTIVES
To analyse the new evidence (2018-2022) for the management of systemic lupus erythematosus (SLE) to inform the 2023 update of the European League Against Rheumatism (EULAR) recommendations.
METHODS
Systematic literature reviews were performed in the Medline and the Cochrane Library databases capturing publications from 1 January 2018 through 31 December 2022, according to the EULAR standardised operating procedures. The research questions focused on five different domains, namely the benefit/harm of SLE treatments, the benefits from the attainment of remission/low disease activity, the risk/benefit from treatment tapering/withdrawal, the management of SLE with antiphospholipid syndrome and the safety of immunisations against varicella zoster virus and SARS-CoV2 infection. A Population, Intervention, Comparison and Outcome framework was used to develop search strings for each research topic.
RESULTS
We identified 439 relevant articles, the majority being observational studies of low or moderate quality. High-quality randomised controlled trials (RCTs) documented the efficacy of the type 1 interferon receptor inhibitor, anifrolumab, in non-renal SLE, and belimumab and voclosporin, a novel calcineurin inhibitor, in lupus nephritis (LN), when compared with standard of care. For the treatment of specific organ manifestations outside LN, a lack of high-quality data was documented. Multiple observational studies confirmed the beneficial effects of attaining clinical remission or low disease activity, reducing the risk for multiple adverse outcomes. Two randomised trials with some concerns regarding risk of bias found higher rates of relapse in patients who discontinued glucocorticoids (GC) or immunosuppressants in SLE and LN, respectively, yet observational cohort studies suggest that treatment withdrawal might be feasible in a subset of patients.
CONCLUSION
Anifrolumab and belimumab achieve better disease control than standard of care in extrarenal SLE, while combination therapies with belimumab and voclosporin attained higher response rates in high-quality RCTs in LN. Remission and low disease activity are associated with favourable long-term outcomes. In patients achieving these targets, GC and immunosuppressive therapy may gradually be tapered. Cite Now.
PubMed: 38777375
DOI: 10.1136/ard-2023-225319 -
Thrombosis Journal May 2024This study aimed to evaluate the association of antiphospholipid antibodies (aPL) and conventional markers of coagulation with ischemic and bleeding risk in patients...
BACKGROUND
This study aimed to evaluate the association of antiphospholipid antibodies (aPL) and conventional markers of coagulation with ischemic and bleeding risk in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI).
METHODS
In this prospective two-center observational cohort study, patients with AF and an indication for oral anticoagulation (OAC) were enrolled after PCI. Blood was drawn on day 1-3 after PCI. Dilute Russell's viper venom time was used to determine lupus anticoagulant (LA) in OAC-free plasma. Anti-cardiolipin (aCL) IgG, IgM, and anti-β2-Glycoprotein 1 (aβ2GP1) IgG were analyzed by enzyme-linked immunosorbent assay (ELISA). Fibrinogen (FIB), d-dimer, and prothrombin fragment 1 and 2 (PF 1 + 2) were measured in citrated plasma. The primary ischemic outcome was time to major adverse cardiovascular events (MACE; death, myocardial infarction, or stroke) assessed at 6 months. Bleeding was defined according to International Society on Thrombosis and Haemostasis.
RESULTS
158 patients were enrolled between May 2020 and May 2021 on day 1-3 after PCI. The median age was 78 years (interquartile range [IQR] 72-82), 111 (70%) were male, and 39 (25%) presented with acute coronary syndrome. D-dimer was elevated in 74 (47%) patients, FIB was increased in 40 (25%) and PF1 + 2 in 68 (43%) patients. 32 (20%) patients had ≥ 1 antiphospholipid antibody elevated (aPL; LA: 19 [12%], aCL: 14 [9%], aβ2GP1: 2 [1%]). The presence of aPL was neither significantly associated with MACE (HR 1.46, 95% CI [0.39-5.49], p = 0.579), nor bleeding (HR 1.07 [0.30-3.84], p = 0.917). Elevated d-dimer was significantly associated with higher risk for MACE (HR 5.06 [1.09-23.41], p = 0.038) and major bleeding (HR 7.04 [1.58-31.47], p = 0.011). Elevated D-dimer increased the predictive capacity of HAS-BLED for major bleedings (HAS-BLED: AUC 0.71 [0.60-0.83] vs. HAS-BLED + d-dimer: AUC 0.79 [0.70-0.88]; p = 0.025). Increased levels of FIB were associated with higher risk for MACE (HR 3.65 [1.11-11.96], p = 0.033).
CONCLUSION
Biomarkers of coagulation might be suitable to assess ischemic and bleeding risk in patients with AF following PCI.
PubMed: 38773510
DOI: 10.1186/s12959-024-00610-x -
CASE (Philadelphia, Pa.) Apr 2024• CTD and SLE with APS-associated thrombogenesis can lead to RA thrombi formation. • In CTD, a large inferior RA chamber thrombi can cause severe inflow obstruction....
• CTD and SLE with APS-associated thrombogenesis can lead to RA thrombi formation. • In CTD, a large inferior RA chamber thrombi can cause severe inflow obstruction. • TTE and TEE are essential in defining the hemodynamic impact of CTD and RA thrombi. • TEE is key in guiding successful surgical resection of CTD and RA thrombi.
PubMed: 38765628
DOI: 10.1016/j.case.2024.01.004 -
La Revue de Medecine Interne May 2024Q fever is a zoonosis caused by Coxiella burnetii. Acute infection is mainly asymptomatic. In other cases it mainly causes a flu-like illness, a pneumonia, or an...
INTRODUCTION
Q fever is a zoonosis caused by Coxiella burnetii. Acute infection is mainly asymptomatic. In other cases it mainly causes a flu-like illness, a pneumonia, or an hepatitis. We present an atypical case of an acute Q fever revealed by a massive pleural effusion.
CASE REPORT
We report the case of a 43-year-old man referred to our hospital for an acute respiratory distress. Further analyses showed an exudative eosinophilic pleural effusion, associated with a pulmonary embolism and a deep femoral vein thrombosis. Aetiologic explorations revealed an acute Q fever (IgM and IgG against C. burnetii phase II antigens) associated with anti-phospholipids. The outcome was favorable with vitamin K antagonists, doxycycline, and hydroxychloroquine, till the negativation of the anti-phospholipid antibodies.
DISCUSSION AND CONCLUSION
During acute C. burnetii infections, anti-phospholipid antibodies are highly prevalent but thrombotic complications are rare. The 2023 ACR/EULAR APS criteria restricts the diagnosis of APS, as in our case of acute severe infection. In front of an atypical pneumonia and/or thrombotic events, screening of C. burnetii and anti-phospholipid antibodies could be useful. Given its low level of evidence, prolongated treatment by doxycycline, hydroxychloroquine ± anticoagulant for C. burnetii's associated anti-phospholipid syndrome is discussed, but succeeded in our case.
PubMed: 38762438
DOI: 10.1016/j.revmed.2024.05.006 -
Scientific Reports May 2024With its increasing use in the treatment of thrombocytopenia, avatrombopag's associated adverse events (AEs) pose a major challenge to its clinical application. This...
With its increasing use in the treatment of thrombocytopenia, avatrombopag's associated adverse events (AEs) pose a major challenge to its clinical application. This study aims to comprehensively study AEs associated with avatrombopag by using real-world evidence. We curated AE reports for avatrombopag from the first quarter of 2018 to the fourth quarter of 2023 in the US Food and Drug Administration's Adverse Event Reporting System (FAERS) database. AEs were coded using the Medical Dictionary for Regulatory Activities of Preferred Terms and System Organ Classes. The reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item Gamma-Poisson Shrinker were used to investigate the relationship between avatrombopag and AE reports. Among 9,060,312 reported cases in the FAERS database, 1211 reports listed avatrombopag as "primary suspected" drug. Disproportionality analysis identified 44 preferred terms across 17 organ systems met the criteria for at least one of the four algorithms. The most commonly reported AEs were platelet count decreased (20.2%), headache (16.7%), platelet count increased (11.9%), platelet count abnormal (6.3%), contusion (2.7%), pulmonary embolism (2.3%), and deep vein thrombosis (2.1%). Unexpected AEs such as seasonal allergy, rhinorrhea, antiphospholipid syndrome, ear discomfort, and photopsia were also observed. Excluding the other serious outcomes, hospitalization (34.6%) was the most frequently reported serious outcome, followed by death (15.4%). Most reported AEs occurred within the first 2 days of initiating avatrombopag therapy, and the median onset time was 60 days. We identified new and unexpected AEs with clinical use of avatrombopag, and our results may provide valuable information for clinical monitoring and identifying risks associated with avatrombopag.
Topics: Humans; Pharmacovigilance; United States Food and Drug Administration; United States; Adverse Drug Reaction Reporting Systems; Retrospective Studies; Data Mining; Male; Female; Middle Aged; Aged; Adult; Thrombocytopenia; Databases, Factual; Thiazoles; Young Adult; Adolescent; Child; Thiophenes
PubMed: 38760419
DOI: 10.1038/s41598-024-62129-5 -
Journal of Autoimmunity Jun 2024To evaluate the effectiveness of the 2023 ACR/EULAR criteria for antiphospholipid syndrome (APS) in a Chinese cohort, and compare them with the Sapporo and revised...
OBJECTIVES
To evaluate the effectiveness of the 2023 ACR/EULAR criteria for antiphospholipid syndrome (APS) in a Chinese cohort, and compare them with the Sapporo and revised Sapporo criteria.
METHODS
A cohort comprising 436 patients diagnosed with APS and 514 control subjects was enrolled, including 83 with seronegative APS and 86 classified as antiphospholipid antibody (aPL) carriers. We assessed IgG and IgM anticardiolipin antibodies (aCL) and anti-β2-glycoprotein I (aβ2GPI) antibodies using ELISA, along with a systematic collection of lupus anticoagulant data. Subsequently, we compared the sensitivity and specificity across the three classification criteria.
RESULTS
The 2023 ACR/EULAR criteria exhibited improved specificity at 98 %, surpassing the revised Sapporo (90 %) and original Sapporo (91 %) criteria. However, this came with decreased sensitivity at 82 %, in contrast to higher sensitivities in the revised Sapporo (98 %) and Sapporo (91 %) criteria. Examining individual components sheds light on the scoring system's rationale within the new criteria. The inclusion of microvascular thrombosis, cardiac valve disease, and thrombocytopenia improved the identification of nine patients previously classified as "probable APS". Insufficient scoring in 78 previously diagnosed APS individuals was linked to traditional risk factor evaluations for thrombotic events, the emphasis on determining whether obstetric events are linked to severe preeclampsia (PEC) or placental insufficiency (PI), and the lower scores assigned to IgM aCL and/or aβ2GPI antibody. Seronegative APS remained a challenge, as non-criteria aPL and other methods were not included.
CONCLUSIONS
The new criteria presented notable advancements in specificity. This study provides detailed insights into the strengths and possible challenges of the 2023 ACR/EULAR criteria, enhancing our understanding of their impact on clinical practice.
Topics: Humans; Antiphospholipid Syndrome; Female; Male; Adult; Middle Aged; Antibodies, Antiphospholipid; beta 2-Glycoprotein I; Antibodies, Anticardiolipin; China; Pregnancy; Cohort Studies; Lupus Coagulation Inhibitor; Sensitivity and Specificity; Immunoglobulin M; Asian People; East Asian People
PubMed: 38749076
DOI: 10.1016/j.jaut.2024.103237