Fibrinogenolysis and fibrinolysis in vaccine-induced immune thrombocytopenia and thrombosis.

BACKGROUND: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterized by thrombosis, anti-platelet factor 4 (PF4) antibodies, thrombocytopenia, high D-dimer, and hypofibrinogenemia. OBJECTIVES: To investigate abnormalities in fibrinolysis that contribute to the clinical features of VITT. METHODS: Plasma samples from 18 suspected VITT cases were tested for anti-PF4 by ELISA and characterized as meeting criteria for VITT (11/18) or deemed unlikely (7/18; non-VITT). Antigen levels of PAI-1, factor XIII (FXIII), plasmin-α2antiplasmin (PAP), and inflammatory markers were quantified. Plasmin generation was quantified by chromogenic substrate. Western blotting was performed with antibodies to fibrinogen, FXIII-A, and plasminogen. RESULTS: VITT patients 10/11 had scores indicative of overt disseminated intravascular coagulation, while 0/7 non-VITT patients met the criteria. VITT patients had significantly higher levels of inflammatory markers, IL-1ß, IL-6, IL-8, TNFα, and C-reactive protein. In VITT patients, both fibrinogen and FXIII levels were significantly lower, while PAP and tPA-mediated plasmin generation were higher compared to non-VITT patients. Evidence of fibrinogenolysis was observed in 9/11 VITT patients but not in non-VITT patients or healthy controls. Fibrinogen degradation products were apparent, with obvious cleavage of the fibrinogen α-chain. PAP complex was evident in those VITT patients with fibrinogenolysis, but not in non-VITT patients or healthy donors. CONCLUSION: VITT patients show evidence of overt disseminated intravascular coagulation and fibrinogenolysis, mediated by dysregulated plasmin generation, as evidenced by increased PAP and plasmin generation. These observations are consistent with the clinical presentation of both thrombosis and bleeding in VITT.

S100A8/A9 drives the formation of procoagulant platelets through GPIbα.

S100A8/A9, also known as "calprotectin" or "MRP8/14," is an alarmin primarily secreted by activated myeloid cells with antimicrobial, proinflammatory, and prothrombotic properties. Increased plasma levels of S100A8/A9 in thrombo-inflammatory diseases are associated with thrombotic complications. We assessed the presence of S100A8/A9 in the plasma and lung autopsies from patients with COVID-19 and investigated the molecular mechanism by which S100A8/A9 affects platelet function and thrombosis. S100A8/A9 plasma levels were increased in patients with COVID-19 and sustained high levels during hospitalization correlated with poor outcomes. Heterodimeric S100A8/A9 was mainly detected in neutrophils and deposited on the vessel wall in COVID-19 lung autopsies. Immobilization of S100A8/A9 with collagen accelerated the formation of a fibrin-rich network after perfusion of recalcified blood at venous shear. In vitro, platelets adhered and partially spread on S100A8/A9, leading to the formation of distinct populations of either P-selectin or phosphatidylserine (PS)-positive platelets. By using washed platelets, soluble S100A8/A9 induced PS exposure but failed to induce platelet aggregation, despite GPIIb/IIIa activation and alpha-granule secretion. We identified GPIbα as the receptor for S100A8/A9 on platelets inducing the formation of procoagulant platelets with a supporting role for CD36. The effect of S100A8/A9 on platelets was abolished by recombinant GPIbα ectodomain, platelets from a patient with Bernard-Soulier syndrome with GPIb-IX-V deficiency, and platelets from mice deficient in the extracellular domain of GPIbα. We identified the S100A8/A9-GPIbα axis as a novel targetable prothrombotic pathway inducing procoagulant platelets and fibrin formation, in particular in diseases associated with high levels of S100A8/A9, such as COVID-19.

The suboptimal fibrinolytic response in COVID-19 is dictated by high PAI-1.

BACKGROUND: Severe COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. This study investigates whether the hemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system. METHODS: This prospective study analyzed fibrinolytic profiles of 113 patients hospitalized with COVID-19 disease with 24 patients with non-COVID-19 respiratory infection and healthy controls. Antigens were quantified by Ella system or ELISA, clot lysis by turbidimetric assay, and plasminogen activator inhibitor-1 (PAI-1)/plasmin activity using chromogenic substrates. Clot structure was visualized by confocal microscopy. RESULTS: PAI-1 and its cofactor, vitronectin, are significantly elevated in patients with COVID-19 disease compared with those with non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in patients with COVID-19 disease relative to healthy controls. PAI-1 and tissue plasminogen activator (tPA) were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fiber length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID-19 disease, while PAI-1 activity was elevated. Clot lysis time significantly correlated with PAI-1 levels. Stratification of COVID-19 samples according to PAI-1 levels reveals significantly faster lysis when using the PAI-1 resistant (tPA) variant, tenecteplase, over alteplase lysis. CONCLUSION: This study shows that the suboptimal fibrinolytic response in COVID-19 disease is directly attributable to elevated levels of PAI-1, which attenuate plasmin generation. These data highlight the important prognostic potential of PAI-1 and the possibility of using pre-existing drugs, such as tenecteplase, to treat COVID-19 disease and potentially other respiratory diseases.

Bringing Shame Out of the Shadows: Identifying Shame in Child Sexual Abuse Disclosure Processes and Implications for Psychotherapy.

Child sexual abuse (CSA) has been described as a highly stigmatizing experience. Despite the recognition of shame as a significant contributor to psychological distress following CSA, an inhibitor of CSA disclosure, and a challenging emotion to overcome in therapy, limited research has explored the experience of shame with young people who have been sexually abused. This study is unique in examining the transcripts of 47 young people aged 15-25 years from a large-scale study conducted in Ireland and Canada and exploring manifestations of shame in CSA disclosure narratives. Using a thematic analysis of both inductive and deductive coding, the data were examined for implicit, as distinct from explicit, manifestations of shame. Three key themes were identified in this study: languaging shame, avoiding shame, and reducing shame. The study supports previous authors in highlighting the need for nuanced measures of shame in research that takes account of the complexity of this emotion. Conceptualizations in the literature of the distinction between shame and guilt are challenged when these emotions are explored in the context of CSA. Finally, recommendations for working therapeutically with young people who have experienced CSA are offered with a view to addressing shame in therapeutic work.

"How many times did I not want to live a life because of him": the complex connections between child sexual abuse, disclosure, and self-injurious thoughts and behaviors.

BACKGROUND: Meta-analyses have confirmed an association between child sexual abuse (CSA) and non-suicidal and suicidal self-injurious thoughts and behaviors (SITB), yet the mechanisms linking these factors are, to date, poorly understood. The goal of the current study is to explore one potential influencing factor acting in the association between CSA and SITB, which is the disclosure experience. Disclosure has been identified as a prominent factor in the healing process of survivors, with a lack of support following disclosures heightening negative outcomes. Exploring the impact of CSA disclosure on SITB is necessary to build effective prevention and intervention strategies. METHODS: This qualitative study is part of a larger initiative spanning diverse research sites in Canada and in Ireland and aiming to lend voice to young people who were sexually abused in childhood/adolescence. Participants were recruited from community-based sexual abuse/assault agencies, hospital-based specialized clinics and child advocacy centres. The Long Interview Method, based on a branch of phenomenology, was used to guide research design and data collection. The current thematic analysis, informed by a stress-diathesis model, is based on a sample comprised of 21 ethnically diverse youth aged 15 to 25 who self-reported a sexual abuse experience in their childhood or teenage years and who, as part of the interview on their disclosure processes, revealed past or current SITB. RESULTS: The thematic analysis led to the identification of four main themes that both confirmed past research and conceptual models on SITB, and provided new insights. Participants perceived a clear link between their CSA experience and SITB and other mental health issues. They offered their views on the meanings of SITB for CSA victims: to cope with abuse; to end the abuse; to express self-hatred and loneliness; and to let people know about their suffering. They described how negative disclosure experiences led to more nonsuicidal and suicidal SITB. Yet, participants also revealed that receiving support for their SITB created opportunities for CSA disclosure and support. CONCLUSIONS: This study showed complex connections between CSA experiences, disclosure and nonsuicidal and suicidal SITB. Understanding the reciprocal influences between SITB, CSA disclosure and help-seeking could better equip mental health professionals and caregivers to provide support and foster healing and recovery in CSA victims.

Coronavirus Disease 2019 Infection in Children with Pre-Existing Heart Disease.

We present 7 children with congenital heart disease and coronavirus disease 2019. Of these, 5 were younger than 1 year of age and 3 had atrioventricular canal defect and trisomy 21. All 7 developed acute decompensation, with 1 death in an 18-year-old with hypertrophic cardiomyopathy and other comorbidities.

Synthesis, characterization, photophysical, and computational studies of rhenium(I) tricarbonyl complexes containing the derivatives of bipyrazine.

The chloro and pyridinate derivatives of rhenium(I) tricarbonyl complexes containing the diimine ligands 2,2'-bipyrazine (bpz) and 5,5'-dimethyl-2,2'-bipyrazine (Me2bpz) are reported. Absorption maxima occur in the visible and ultraviolet regions of the spectrum; emission is structureless at room temperature and at 77 K; the infrared spectrum consists of three carbonyl stretches; electrochemically, a reversible reduction, an irreversible reduction, and an irreversible oxidation take place. Some ring protons are shielded and others deshielded in the presence of the methyl substituents attached to the bpz ring. DFT and TDDFT calculations provide insight into interpreting electronic and vibrational properties of the complexes. When compared to similar rhenium(I) tricarbonyl complexes of 2,2'-bipyridine (bpy) and 2,2'-bipyrimidine (bpm), the Me2bpz complexes are comparable to bpm derivatives and their properties are intermediate between those of bpy and bpz complexes.