Patients with severe COVID-19 often experience complications including coagulopathy and fatal thrombosis. COVID-19 pneumonia sometimes leads to acute respiratory distress syndrome, requiring ...extracorporeal membrane oxygenation (ECMO), during which thrombosis and bleeding are major causes of death. Anticoagulation such as heparin is essential for COVID-19 patients on ECMO; however, bleeding might be caused by not only heparin, but also acquired von Willebrand syndrome (AVWS). To date, no study has examined ECMO-related bleeding and AVWS in COVID-19 patients.We report a COVID-19 patient who experienced bleeding from AVWS in addition to disseminated intravascular coagulation (DIC) during ECMO. The level of high–molecular weight VWF multimers decreased during ECMO therapy, and these findings promptly improved after discontinuation of ECMO. Plasma levels of VWF antigen were extremely high, probably due to endothelial cell damage caused by COVID-19. On the other hand, plasma levels of ADAMTS13 activity were moderately reduced, to 20–30% of normal. The patient was successfully treated with cryoprecipitate in bleeding during ECMO without a reduction in heparin, which might have induced thromboembolism. Bleeding found in this patient might be caused by AVWS and DIC.Severe COVID-19 patients are in a thrombotic state and need to receive anticoagulant therapy. However, once they receive ECMO therapy, bleeding symptoms could be observed. In such cases, physicians should think of AVWS in addition to the side effect of heparin and DIC.
B cells can suppress autoimmunity by secreting interleukin-10 (IL-10). Although subpopulations of splenic B lineage cells are reported to express IL-10 in vitro, the identity of IL-10-producing B ...cells with regulatory function in vivo remains unknown. By using IL-10 reporter mice, we found that plasmablasts in the draining lymph nodes (dLNs), but not splenic B lineage cells, predominantly expressed IL-10 during experimental autoimmune encephalomyelitis (EAE). These plasmablasts were generated only during EAE inflammation. Mice lacking plasmablasts by genetic ablation of the transcription factors Blimp1 or IRF4 in B lineage cells developed an exacerbated EAE. Furthermore, IRF4 positively regulated IL-10 production that can inhibit dendritic cell functions to generate pathogenic T cells. Our data demonstrate that plasmablasts in the dLNs serve as IL-10 producers to limit autoimmune inflammation and emphasize the importance of plasmablasts as IL-10-producing regulatory B cells.
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•Plasmablasts predominantly express IL-10 in the dLNS during EAE induction•Plasmablasts prevent dendritic cells from generating pathogenic T cells•Deficiency of plasmablasts in mice develops an exacerbated EAE•Human plasmablasts derived from naive B cells selectively produce IL-10
Although B cells can suppress autoimmunity by secreting interleukin-10 (IL-10), their identification in vivo remains elusive. Baba and colleagues show that plasmablasts in the draining lymph nodes are predominant IL-10 producers that inhibit autoimmune inflammation.
Background
Despite an increase in our understandings of pathogenesis of thrombotic thrombocytopenic purpura (TTP), the approaches for initial diagnosis and management of TTP vary significantly.
...Objective
The evidence‐based guidelines of the International Society on Thrombosis and Haemostasis (ISTH) are intended to support patients, clinicians, and other health care professionals in their decisions about the initial diagnosis and management of acute TTP.
Methods
In June 2018, ISTH formed a multidisciplinary panel that included hematologists, an intensive care physician, nephrologist, clinical pathologist, biostatistician, and patient representatives, as well as a methodology team from McMaster University. The panel composition was designed to minimize the potential conflicts of interests. The panel used the Grading of Recommendations Assessment, Development, and Evaluation approach and the Population, Intervention, Comparison, Outcome framework to develop and grade their recommendations. Public comments were sought and incorporated in the final document.
Results
The panel agreed on three recommendations covering the initial diagnosis with emphasis on the importance of ADAMTS13 testing (eg, activity, anti‐ADAMTS13 IgG or inhibitor) and assessment of the pretest probability of TTP by clinical assessment and/or the risk assessment models like the PLASMIC or French score. The panel noted how availability and turnaround time of ADAMTS13 test results might affect early diagnosis and management, in particular the use of caplacizumab.
Conclusions
There is a lack of high‐quality evidence to support strong recommendations for the initial diagnosis and management of a suspected TTP. The panel emphasized the importance of obtaining ADAMTS13 testing in a proper clinical context. Future research should focus on how to monitor and act on ADAMTS13 levels during remission.
Background Thrombotic microangiopathies (TMAs) are pathological conditions characterized by generalized microvascular occlusion by platelet thrombi, thrombocytopenia, and microangiopathic hemolytic ...anemia. Two typical phenotypes of TMAs are hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Severe deficiency of plasma ADAMTS13 activity (ADAMTS13: AC) is more specific for TTP, but not for HUS. Since 1998, our laboratory has functioned as a nationwide referral center for TMAs by analyzing ADAMTS13. Methods Of 1,564 patients tested from 426 hospitals, 919 were positive for TMA. Levels of ADAMTS13: AC and the ADAMTS13 neutralizing autoantibody (ADAMTS13: INH) were determined by chromogenic act-ELISA and/or by classic von Willebrand factor multimer assay. Results TMA patients consisted of two groups: severe (less than 3% of normal control) and non-severe deficiency of ADAMTS13: AC. Both groups were divided into congenital (n=65) and acquired (n=854) TMA. Of the former, 41 had congenital deficiency of ADAMTS13: AC, while the remaining 24 had disease of unknown etiology. The 854 patients with acquired TMA could be largely grouped into three categories: idiopathic TTP (n=284), idiopathic HUS (n=106), and secondary TMAs (n=464). The secondary TMAs were observed in heterogeneous patient groups and were associated with drugs, connective tissue diseases, malignancies, transplantation, pregnancy, E. coli O157: H7 infection, and other factors. All of the patients with acquired severe ADAMTS13: AC deficiency were positive for ADAMTS13: INH. Conclusion Although TMAs are highly heterogeneous pathological conditions, one-third of TMA patients have severe deficiency of ADAMTS13: AC. Platelet transfusions to such patients are contraindicated. Rapid ADAMTS13: AC assays are therefore prerequisite to appropriately treat TMA patients.
Both disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) cause microvascular thrombosis associated with thrombocytopenia, bleeding tendency and organ failure.
The ...frequency of DIC is higher than that of thrombotic thrombocytopenic purpura (TTP). Many patients with TMA are diagnosed with DIC, but only about 15% of DIC patients are diagnosed with TMA. Hyperfibrinolysis is observed in most patients with DIC, and microangiopathic hemolytic anemia is observed in most patients with TMA. Markedly decreased ADAMTS13 activity, the presence of Shiga-toxin-producing
(STEC) and abnormality of the complement system are useful for the diagnosis of TTP, STEC-hemolytic uremic syndrome (HUS)and atypical HUS, respectively. However, there are no specific biomarkers for the diagnosis of DIC.
Although DIC and TMA are similar appearances, all coagulation, fibrinolysis and platelet systems are activated in DIC, and only platelets are markedly activated in TMA.
A chief Ca
2+ entry pathway in immune cells is store-operated Ca
2+ (SOC) influx, which is triggered by depletion of Ca
2+ from the endoplasmic reticulum (ER). However, its physiological role in B ...cells remains elusive. Here, we show that ER calcium sensors STIM1- and STIM2-induced SOC influx is critical for B cell regulatory function. B cell-specific deletion of STIM1 and STIM2 in mice caused a profound defect in B cell receptor (BCR)-induced SOC influx and proliferation. However, B cell development and antibody responses were unaffected. Remarkably, B cells lacking both STIM proteins failed to produce the anti-inflammatory cytokine IL-10 because of defective activation of nuclear factor of activated T cells (NFAT) after BCR stimulation. This resulted in exacerbation of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our data establish STIM-dependent SOC influx as a key signal for B cell regulatory function required to limit autoimmunity.
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► STIM proteins are required for BCR-mediated SOC influx and proliferation ► STIM proteins are dispensable for B cell development and antibody responses ► STIM-mediated NFAT activation induces IL-10 production by B cells ► STIM-dependent IL-10 production by B cells suppresses the development of autoimmunity
Thrombotic thrombocytopenic purpura (TTP) can rapidly progress into a life-threatening condition, thus the importance of appropriate diagnosis and treatment cannot be overstated. Until recently, TTP ...has mainly been diagnosed by clinical findings such as thrombocytopenia and non-immune hemolytic anemia. In addition to these clinical findings, however, reduced activity of a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) below 10% has been accepted internationally as a diagnostic criterion for TTP. In the present guidelines, we have taken all of these criteria into consideration. TTP is classified as acquired if the patient is positive for anti-ADAMTS13 autoantibodies, and as congenital if
ADAMTS13
gene abnormalities are detected. Fresh-frozen plasma (FFP) transfusion is performed in patients with congenital TTP to supplement ADAMTS13. Plasma exchange therapy using FFP is conducted in patients with acquired TTP to supplement ADAMTS13 and remove anti-ADAMTS13 autoantibodies. To suppress autoantibody production, corticosteroid therapy may be administered in conjunction with plasma exchange. Recent reports show that the monoclonal anti-CD-20 antibody rituximab is effective in patients with refractory or relapsed TTP.
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