Introduction: Auricular chondritis has been occasionally described in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Materials and methods: We report the case ...of a woman with a previous history of APS who presented with auricular chondritis with onset of SLE symptoms during the postpartum period. Conclusion: SLE and APS should be taken into consideration in the differential diagnosis of auricular chondritis.
Abstract
Background
Heparin-induced thrombocytopenia (HIT) is typically caused by platelet-activating immunoglobulin G (IgG) antibodies (Abs) against platelet factor 4 (PF4) complexed with heparin ...(H). Much less frequent “autoimmune” HIT is distinguished from typical HIT by platelet activation without heparin and the presence of both anti-PF4/H and anti-PF4 IgG. We developed three murine monoclonal anti-PF4 Abs with a human Fc-part, 1E12, 1C12, and 2E1, resembling autoimmune HIT Abs.
Objectives
To characterize 1E12, 1C12, and 2E1 in comparison to the heparin-dependent monoclonal anti-PF4/H Abs 5B9 and KKO, and polyclonal Abs from patients with typical HIT (group-2) and autoimmune HIT (group-3).
Methods
Interactions of Abs with PF4 and PF4/H were studied by enzyme-linked-immunosorbent assay, single-molecule force spectroscopy, isothermal titration calorimetry, and dynamic light scattering. Serotonin release assay and heparin-induced platelet activation assay were used to assess platelet activation. The binding sites of monoclonal Abs on PF4 were predicted in silico (MAbTope method).
Results
1C12, 1E12, and 2E1 displayed higher affinity for PF4/H complexes than 5B9 and KKO, comparable to human group-3 Abs. Only 1C12, 1E12, 2E1, and group-3 Abs formed large complexes with native PF4, and activated platelets without heparin. The predicted binding sites of 1C12, 1E12, and 2E1 on PF4 differed from those of KKO and 5B9, but were close to each other. 2E1 exhibited unique bivalent binding, involving its antigen recognition site to PF4 and charge-dependent interactions with heparin.
Conclusion
1C12, 1E12, and 2E1 are tools for studying the pathophysiology of autoimmune HIT. 2E1 provides evidence for a new binding mechanism of HIT Abs.
As of 4 April 2021, a total of 169 cases of cerebral venous sinus thrombosis (CVST) and 53 cases of splanchnic vein thrombosis were reported to EudraVigilance among around 34 million people ...vaccinated in the European Economic Area and United Kingdom with COVID-19 Vaccine AstraZeneca, a chimpanzee adenoviral vector (ChAdOx1) encoding the spike protein antigen of the SARS-CoV-2 virus. The first report of the European Medicines Agency gathering data on 20 million people vaccinated with Vaxzevria® in the UK and the EEA concluded that the number of post-vaccination cases with thromboembolic events as a whole reported to EudraVigilance in relation to the number of people vaccinated was lower than the estimated rate of such events in the general population. However, the EMA's Pharmacovigilance Risk Assessment Committee concluded that unusual thromboses with low blood platelets should be listed as very rare side effects of Vaxzevria®, pointing to a possible link. The same issue was identified with the COVID-19 Vaccine Janssen (Ad26.COV2.S).
Currently, there is still a sharp contrast between the clinical or experimental data reported in the literature on COVID-19 and the scarcity of data on the unusual thrombotic events observed after the vaccination with these vaccines. Different hypotheses might support these observations and should trigger further in vitro and ex vivo investigations. Specialized studies were needed to fully understand the potential relationship between vaccination and possible risk factors in order to implement risk minimization strategies.
•Vaxzevria® and COVID-19 Vaccine Janssen have been associated with rare case of thrombotic with thrombocytopenia syndrome.•Main mechanism explaining the risk involved antibodies directed against platelet factor 4.•Research of other physiopathological mechanisms has not been sufficiently investigated and should not be discarded.•There is a contrast between the clinical or experimental data on COVID-19 and the scarcity of data with these vaccines.•The benefits of these vaccines are well established and the risk-benefit balance remains largely positive.
Les thrombopénies et thromboses induites par les anticorps dirigés contre le facteur plaquettaire 4 (FP4) constituent un groupe hétérogène de syndromes clinico-biologiques rares mais sévères, ...comprenant les thrombopénies induites par l’héparine (TIH) classiques, et plus rarement auto-immunes, les thrombopénies et thromboses induites par les vaccins contre la Covid-19 (VITT pour vaccine-induced immune thrombotic thrombocytopenia), et, récemment, les syndromes VITT-like. Ces pathologies induisent toutes une hypercoagulabilité majeure, en lien avec une activation des cellules sanguines par les anticorps anti-FP4, conduisant à des thromboses potentiellement sévères, qu’il convient de traiter en urgence. La gravité de la thrombopénie et des thromboses, ainsi que leur localisation varient selon la pathologie, les TIH auto-immunes et les VITT étant associées à des formes particulièrement agressives, notamment des thromboses veineuses cérébrales. Le diagnostic des thrombopénies et thromboses induites par les anticorps anti-FP4 s’appuie sur un faisceau d’arguments, tout d’abord cliniques, puis biologiques, reposant sur la mise en évidence des anticorps anti-FP4 par des tests immunologiques et, le plus souvent, confirmation de leur pathogénicité à l’aide de tests d’activation plaquettaire. Les performances de ces différents outils étant très variables selon la pathologie, le biologiste possède un rôle majeur dans le choix des tests utilisés, et leur interprétation, pour assurer un diagnostic correct et une prise en charge adaptée du patient.
Thrombocytopenia and thromboses induced by antibodies to platelet factor 4 (PF4) constitute a heterogeneous group of rare but severe clinical and biological syndromes, including classical heparin-induced thrombocytopenia (HIT), and more rarely autoimmune HIT, vaccine-induced immune thrombotic thrombocy-topenia (VITT), and, recently, VITT-like syndromes. These pathologies all induce major hypercoagulability, related to blood cell activation by anti-PF4 antibodies, leading to potentially severe thromboses, which require urgent treatment. The severity of thrombocytopenia and thromboses, and their location, vary with the disease; autoimmune HIT and VITT are associated with particularly aggressive forms, including cerebral venous thrombosis. The diagnosis of thrombocytope-nia and thromboses induced by anti-PF4 antibodies relies on a combination of clinical and biological factors, including the detection of anti-PF4 antibodies by immunological assays and, in most cases, confirmation of their pathogenicity by platelet activation tests. As the performance of these tools varies greatly depending on the pathology, the biologist plays a major role in the choice of the assays, and their interpretation, to ensure correct diagnosis and appropriate management of the patient.
Thrombosis results in heparin-induced thrombocytopenia (HIT) from cellular activation involving Fc receptors. In this study, the FcγRIIA 131RR genotype was found to increase the risk of thrombosis in ...HIT patients (odds ratio: 5.9; 95% confidence interval: 1.7-20). When platelet aggregation tests (PATs) were performed with platelet-rich plasma (PRP), a shorter lag time was measured in 131RR donors compared to individuals with the HR and HH genotypes in response to HIT plasma or 5B9, a recently developed humanized monoclonal antibody to PF4/heparin. Importantly, this difference was no longer detectable when PATs were performed with washed platelets or immunoglobulin (Ig)G-depleted PRP. Moreover, polyclonal IgG or monoclonal IgG1 added to IgG-depleted PRP increased the lag time in response to 5B9. HH platelets were also sensitive to IgG2, which in contrast, failed to inhibit the response of 131RR platelets to 5B9. Finally, higher tissue factor messenger RNA levels were measured in the whole blood of 131RR donors after activation by HIT antibodies, with increased phospholipid procoagulant activity. These results demonstrate that HIT patients homozygous for the FcγRIIA 131R allele have a higher risk of thrombosis, probably due to increased cell activation by antibodies to PF4/heparin, with a lower inhibitory effect of endogenous IgG, especially from the IgG2 subclass.
•Normal IgG and IgG2 differentially inhibit HIT antibody-dependent platelet activation according to the FcγRIIA H131R polymorphism.•This variable effect of IgG and IgG2 probably explains the higher risk of thrombosis in patients homozygous for the FcγRIIA 131R allele.
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