The COVID-19 pandemic has resulted in significant morbidity and mortality worldwide. To prevent severe infection, mass COVID-19 vaccination campaigns with several vaccine types are currently underway. We report pathological and immunological findings in 8 patients who developed vaccine-induced immune thrombotic thrombocytopenia (VITT) after administration of SARS-CoV-2 vaccine ChAdOx1 nCoV-19. We analyzed patient material using enzyme immune assays, flow cytometry and heparin-induced platelet aggregation assay and performed autopsies on two fatal cases. Eight patients (5 female, 3 male) with a median age of 41.5 years (range, 24 to 53) were referred to us with suspected thrombotic complications 6 to 20 days after ChAdOx1 nCoV-19 vaccination. All patients had thrombocytopenia at admission. Patients had a median platelet count of 46.5 x109/L (range, 8 to 92). Three had a fatal outcome and 5 were successfully treated. Autopsies showed arterial and venous thromboses in various organs and the occlusion of glomerular capillaries by hyaline thrombi. Sera from VITT patients contain high titer antibodies against platelet factor 4 (PF4) (OD 2.59±0.64). PF4 antibodies in VITT patients induced significant increase in procoagulant markers (P-selectin and phosphatidylserine externalization) compared to healthy volunteers and healthy vaccinated volunteers. The generation of procoagulant platelets was PF4 and heparin dependent. We demonstrate the contribution of antibody-mediated platelet activation in the pathogenesis of VITT.
COVID-19 may lead to severe acute respiratory distress syndrome (ARDS) resulting in increased morbidity and mortality. Heart failure and/or pre-existing cardiovascular disease may correlate with poor outcomes and thus require special attention from treating physicians. The present study sought to investigate a possible impact of impaired myocardial function as well as myocardial distress markers on mortality or ARDS with need for mechanical ventilation in 157 consecutive patients with confirmed SARS-CoV-2 infection. All patients were admitted and treated at the University Hospital of Tübingen, Germany, during the first wave of the pandemic. Electrocardiography, echocardiography, and routine blood sampling were performed at hospital admission. Impaired left-ventricular and right-ventricular function, tricuspid regurgitation > grade 1, and elevated RV-pressure as well as thrombotic and myocardial distress markers (D-dimers, NT-pro-BNP, and troponin-I) were associated with mechanical ventilation and/or all-cause mortality. Impaired cardiac function is more frequent amidst ARDS, leading to subsequent need for mechanical ventilation, and thus denotes a poor outcome in COVID-19. Since a causal treatment for SARS-CoV-2 infection is still lacking, guideline-compliant cardiovascular evaluation and treatment remains the best approach to improve outcomes in COVID-19 patients with cardiovascular comorbidities.
Objectives: Thin-slice prostate MRI might be beneficial for prostate cancer diagnostics. However, prolongation of acquisition time is a major drawback of thin-slice imaging. Therefore, the purpose of this study was to investigate the impact of a thin-slice deep learning accelerated T2-weighted (w) TSE imaging sequence (T2DLR) of the prostate as compared to conventional T2w TSE imaging (T2S). Materials and Methods: Thirty patients were included in this prospective study at one university center after obtaining written informed consent. T2S (3 mm slice thickness) was acquired first in three orthogonal planes followed by thin-slice T2DLR (2 mm slice thickness) in axial plane. Acquisition time of axial conventional T2S was 4:12 min compared to 4:37 min for T2DLR. Imaging datasets were evaluated by two radiologists using a Likert-scale ranging from 1–4, with 4 being the best regarding the following parameters: sharpness, lesion detectability, artifacts, overall image quality, and diagnostic confidence. Furthermore, preference of T2S versus T2DLR was evaluated. Results: The mean patient age was 68 ± 8 years. Sharpness of images and lesion detectability were rated better in T2DLR with a median of 4 versus a median of 3 in T2S (p < 0.001 for both readers). Image noise was evaluated to be significantly worse in T2DLR as compared to T2S (p < 0.001 and p = 0.021, respectively). Overall image quality was also evaluated to be superior in T2DLR versus T2S with a median of 4 versus 3 (p < 0.001 for both readers). Both readers chose T2DLR in 29 cases as their preference. Conclusions: Thin-slice T2DLR of the prostate provides a significant improvement of image quality without significant prolongation of acquisition time.
Objective: Retinoid X receptors (RXR) are a family of nuclear receptors that play critical roles in the regulation of numerous fundamental biological processes including cell proliferation, differentiation, and death. Earlier studies suggested that treatment with RXR agonists attenuates platelet activation in all adults (male and femal) and mice; however, the underlying molecular mechanisms have remained insufficiently understood. To elaborate further on this issue, we characterized megakaryocyte and platelet-specific RXR knockout mice to study platelet function in vitro and arterial thrombosis in vivo.Approach and results: First, we identified RXRβ as the dominant RXR receptor in mouse platelets, prompting us to generate a megakaryocyte and platelet-specific PF4 Cre ;RXRβ flox/flox mouse. Second, we studied activation, spreading, and aggregation of platelets from C57Bl/6 wild-type mice (WT), PF4 Cre+ ;RXRβ flox/flox mice, and PF4 Cre-;RXRβ flox/flox littermate controls in the presence or absence of RXR ligands, that is, 9-cis-retinoic acid (9cRA) and methoprene acid (MA). We found that in vitro treatment with RXR ligands attenuates spreading and aggregation of platelets and increases proplatelet particle formation from megakaryocytes (MK). However, these effects are also observed in RXRβ-deficient platelets and MKs and are thus independent of RXRβ. Third, we investigated arterial thrombus formation in an iron chloride (FeCl3)-induced vascular injury model in vivo, which is also not affected by the absence of RXRβ in platelets. Conclusions: Absence of the most abundant RXR receptor in mouse platelets, RXRβ, does not affect platelet function in vitro and thrombus formation in vivo. Furthermore, RXR agonists' mediated effects on platelet function are independent of RXRβ expression. Hence, our data do not support a significant contribution of RXRβ to arterial thrombosis in mice. K E Y W O R D S nuclear receptor, platelet function, retinoids, RXR, thrombosis S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Lüsebrink E, Warm V, Pircher J, et al. Role of RXRβ in platelet function and arterial thrombosis. J
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