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In this case series, investigators report a very rare but life-threatening sequela of ChAdOx1 nCoV-19 vaccination. Beginning 5 to 16 days after a first injection, some patients had symptoms consistent with thrombocytopenia, disseminated intravascular coagulation, and thromboses, including cerebral venous sinus thrombosis with catastrophic outcome. An anti–PF4 antibody capable of platelet activation appears to be the cause. Intravenous immune globulin may be therapeutic.

Glioblastoma (GBM) is often complicated by venous thromboembolism (VTE), primarily driven by tissue factor (TF, F3 ) and podoplanin (PDPN). These factors promote local hypercoagulation and microthrombosis, thereby contributing to tumor progression by enhancing migration, invasion, and inflammation. Both TF and PDPN can be released via extracellular vesicles (EVs), which carry procoagulant and immunomodulatory cargo. We developed a translational workflow combining biobanked tumor samples, clinical data, ex vivo GBM cultures, and coagulation assays to investigate mechanisms of hypercoagulation. Intraoperative blood coagulation was profiled using ClotPro ® . Gene expression of coagulation-related markers was analyzed in tumor tissues and cell lines, complemented by RNAseq-based profiling of coagulation–inflammation links. Functional coagulation assays included clotting time, platelet aggregation, and EV-based analysis of prothrombotic and immunomodulatory activity. Peripheral coagulation in GBM patients was largely unaltered. However, tumor tissues consistently showed high F3 and PDPN expression and markedly low tissue factor pathway inhibitor ( TFPI ) levels ( p  < 0.001), indicating a shift toward a procoagulant phenotype. Patient-derived GBM cell lines showed variable TF and PDPN expression, which correlated with clotting potential. Distinct procoagulant mechanisms were observed, with some cells engaging both TF-mediated thrombin generation and PDPN-driven platelet activation. EVs isolated from GBM patient plasma and culture media showed similar procoagulant characteristics, with activity proportional to TF expression, and immune-modulating effects. Notably, GBM-derived EVs modulated microglial behavior, induced senescence, and triggered immune polarization in a cell line-dependent manner, likely contributing to tumor microenvironment remodeling. GBM-associated hypercoagulability is shaped by heterogeneous tumor-intrinsic pathways and EV-mediated mechanisms. The dual role of EVs in promoting coagulation and modulating immune responses provides a mechanistic framework for further studies investigating EVs as potential biomarkers and therapeutic targets relevant to future thromboprophylactic strategies in GBM patients.

Chronic pancreatitis (CP) is characterized by chronic inflammation and the progressive fibrotic replacement of exocrine and endocrine pancreatic tissue. We identify Treg cells as central regulators of the fibroinflammatory reaction by a selective depletion of FOXP3-positive cells in a transgenic mouse model (DEREG-mice) of experimental CP. In Treg-depleted DEREG-mice, the induction of CP results in a significantly increased stroma deposition, the development of exocrine insufficiency and significant weight loss starting from day 14 after disease onset. In CP, FOXP3 + CD25 + Treg cells suppress the type-2 immune response by a repression of GATA3 + T helper cells (Th2), GATA3 + innate lymphoid cells type 2 (ILC2) and CD206 + M2-macrophages. A suspected pathomechanism behind the fibrotic tissue replacement may involve an observed dysbalance of Activin A expression in macrophages and of its counter regulator follistatin. Our study identified Treg cells as key regulators of the type-2 immune response and of organ remodeling during CP. The Treg/Th2 axis could be a therapeutic target to prevent fibrosis and preserve functional pancreatic tissue. The function of T regulatory cells in the tissue fibrosis in chronic pancreatitis is not fully understood. Here the authors use a mouse model of chronic pancreatitis to show that Treg cells reduce IL-4 mediated chronic inflammation in the pancreas associated with M2-like macrophages in vivo.

This article focuses on the central role of antibodies against platelet factor 4 (PF4) in mediating immunothrombosis, from classical heparin-induced thrombocytopenia (HIT) to vaccine-induced immune thrombocytopenia and thrombosis (VITT). The latter condition gained international attention during the rollout of vaccines against SARS-CoV-2. Since then, an increased awareness for anti-PF4 mediated disorders arose and patients were recognized with anti-PF4 disorders occurring without prior heparin or adenoviral vector vaccine exposure. These disorders include various acute and chronic VITT-like conditions, i.e. post-viral VITT, diaplacentally transmitted anti-PF4 antibodies in neonatal stroke, monoclonal gammopathies of thrombotic significance (MGTS) and chronic autoimmune VITT of unknown origin. All anti-PF4 related disorders share key serological and immunopathological features with VITT, such as the formation of immune complexes and platelet activation via the Fcγ receptor IIA (FcγRIIA). Via their activation, platelets form procoagulant, aggregatory and secretory phenotypes shaping their interplay with neutrophils, monocytes, and coagulation factors to amplify thrombotic responses. Integrating recent mechanistic insights, clinical observations and diagnostic developments, this review proposes an updated conceptual framework for anti PF4-related immunothrombosis. We aim to raise awareness among clinicians and researchers, to promote early diagnosis and encourage further translational research towards improved therapeutic strategies in this clinically significant area.

BACKGROUNDResults of many randomized trials on COVID-19 convalescent plasma (CCP) have been reported, but information on long-term outcome after CCP treatment is limited. The objectives of this extended observation of the randomized CAPSID trial are to assess long-term outcome and disease burden in patients initially treated with or without CCP.METHODSOf 105 randomized patients, 50 participated in the extended observation. Quality of life (QoL) was assessed by questionnaires and a structured interview. CCP donors (n = 113) with asymptomatic to moderate COVID-19 were included as a reference group.RESULTSThe median follow-up of patients was 396 days, and the estimated 1-year survival was 78.7% in the CCP group and 60.2% in the control (P = 0.08). The subgroup treated with a higher cumulative amount of neutralizing antibodies showed a better 1-year survival compared with the control group (91.5% versus 60.2%, P = 0.01). Medical events and QoL assessments showed a consistent trend for better results in the CCP group without reaching statistical significance. There was no difference in the increase in neutralizing antibodies after vaccination between the CCP and control groups.CONCLUSIONThe trial demonstrated a trend toward better outcome in the CCP group without reaching statistical significance. A predefined subgroup analysis showed a significantly better outcome (long-term survival, time to discharge from ICU, and time to hospital discharge) among those who received a higher amount of neutralizing antibodies compared with the control group. A substantial long-term disease burden remains after severe COVID-19.Trial registrationEudraCT 2020-001310-38 and ClinicalTrials.gov NCT04433910.FundingBundesministerium für Gesundheit (German Federal Ministry of Health).

Platelet count is known to be associated with sex, age and mean platelet volume (MPV). Sex and age were proposed for adjustment of platelet count reference intervals, but MPV is currently not used for further adjustment. We investigated the association of MPV, age and sex with platelet counts and established individualized reference ranges respecting MPV. The association of platelet count with age, sex and MPV was assessed in healthy participants (n = 3,033 individuals; 1,542 women) in the cross-sectional population-based cohort Study of Health in Pomerania. Reference intervals respecting age, sex, and MPV were estimated using quantile regressions for the 2.5th and 97.5th percentile. Women had higher platelet counts than men (239 vs. 207 x109/L, p<0.001). Platelet counts correlated with age (p<0.001) and MPV (p<0.001). Quantile regression of lower and upper platelet count limits correlated less with age in female (p = 0.047 for 2.5th percentile; p = 0.906 for 97.5th percentile) and male subjects (p = 0.029 for 2.5th percentile; p = 0.195 for 97.5th percentile) compared to MPV (p<0.001 for upper and lower limit for both sexes). After adjustment for MPV, age did no longer correlate with the 2.5th (p = 0.165) or 97.5th percentile (p = 0.999) of platelet count. In contrast, after adjustment for age, MPV levels still significantly correlated with 2.5th, 50th and 97.5th percentile (p<0.001). MPV and sex have a stronger association with platelet count than age. MPV should be considered to adjust platelet count reference intervals and needs to be respected as confounder for platelet counts in epidemiological studies and clinical practice.

Background and Objectives: Vaccine induced thrombotic thrombocytopenia (VITT) may occur after COVID-19 vaccination with recombinant adenoviral vector-based vaccines. VITT can present as cerebral sinus and venous thrombosis (CSVT), often complicated by intracranial hemorrhage. Today it is unclear, how long symptomatic VITT can persist. Here, we report the complicated long-term course of a VITT patient with extremely high titers of pathogenic anti-platelet factor 4 (PF4)-IgG antibodies. Methods: Clinical and laboratory findings are presented, including the course of platelet counts, D-Dimer levels, clinical presentation, imaging, SARS-CoV-2-serological and immunological, platelet activating anti-PF4-IgG, as well as autopsy findings. Results: The patient presented with extended superior sagittal sinus thrombosis with accompanying bifrontal intracerebral hemorrhage. Repeated treatment with intravenous immune globuline (IVIG) resolved recurrent episodes of thrombocytopenia. Moreover, the patient’s serum remained strongly positive for platelet-activating anti-PF4-IgG over three months. After a period of clinical stabilization, the patient suffered a recurrent and fatal intracranial hemorrhage. Conclusions: Complicated VITT with extremely high anti-PF4-IgG titers over three months can induce recurrent thrombocytopenia despite treatment with IVIG and anticoagulation. Plasma exchange, immunoadsorption, and /or immunosuppressive treatment may be considered in complicated VITT to reduce extraordinarily high levels of anti-PF4-IgG. Long-term therapy in such cases must take the individual bleeding risk and CSVT risk into account.

Circulating platelets consist of subpopulations with different age, maturation state and size. In this review, we address the association between platelet size and platelet function and summarize the current knowledge on platelet subpopulations including reticulated platelets, procoagulant platelets and platelets exposing signals to mediate their clearance. Thereby, we emphasize the impact of platelet turnover as an important condition for platelet production . Understanding of the features that characterize platelet subpopulations is very relevant for the methods of platelet concentrate production, which may enrich or deplete particular platelet subpopulations. Moreover, the concept of platelet size being associated with platelet function may be attractive for transfusion medicine as it holds the perspective to separate platelet subpopulations with specific functional capabilities.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) and cerebral venous sinus thrombosis (CVST) have been recently described as rare complications following vaccination against SARS-CoV-2 with vector vaccines. We report a case of a young woman who presented with VITT and cerebral CVST 7 days following vaccination with ChAdOx1 nCov-19 (AstraZeneca). While the initial MRI was considered void of pathological findings, MRI 3 days later revealed extensive CVST of the transversal and sigmoidal sinus with intracerebral haemorrhage. Diagnostic tests including a platelet-factor-4-induced platelet activation assay confirmed the diagnosis of VITT. Treatment with intravenous immunoglobulins and argatroban resulted in a normalisation of platelet counts and remission of CVST.

Background The decision to maintain or halt antiplatelet medication in septic patients admitted to intensive care units presents a clinical dilemma. This is due to the necessity to balance the benefits of preventing thromboembolic incidents and leveraging anti-inflammatory properties against the increased risk of bleeding. Methods This study involves a secondary analysis of data from a prospective cohort study focusing on patients diagnosed with severe sepsis or septic shock. We evaluated the outcomes of 203 patients, examining mortality rates and the requirement for transfusion. The cohort was divided into two groups: those whose antiplatelet therapy was sustained ( n  = 114) and those in whom it was discontinued ( n  = 89). To account for potential biases such as indication for antiplatelet therapy, propensity score matching was employed. Results Therapy continuation did not significantly alter transfusion requirements (discontinued vs. continued in matched samples: red blood cell concentrates 51.7% vs. 68.3%, p  = 0.09; platelet concentrates 21.7% vs. 18.3%, p  = 0.82; fresh frozen plasma concentrates 38.3% vs. 33.3%, p  = 0.7). 90-day survival was higher within the continued group (30.0% vs. 70.0%; p  < 0.001) and the Log-rank test (7-day survivors; p  = 0.001) as well as Cox regression (both matched samples) suggested an association between continuation of antiplatelet therapy < 7 days and survival (HR: 0.24, 95%-CI 0.10 to 0.63, p  = 0.004). Sepsis severity expressed by the SOFA score did not differ significantly in matched and unmatched patients (both p  > 0.05). Conclusions The findings suggest that continuing antiplatelet therapy in septic patients admitted to intensive care units could be associated with a significant survival benefit without substantially increasing the need for transfusion. These results highlight the importance of a nuanced approach to managing antiplatelet medication in the context of severe sepsis and septic shock.