The safety of plasma apheresis from donors recovering from COVID-19 infection in Japan.

PURPOSE: Since 2020, the novel coronavirus infection (COVID-19) has spread globally. A few studies have investigated the safety of COVID-19 convalescent plasma (CCP) apheresis from COVID-19. This study was the first retrospective observational study of CCP in Japan. METHODS: We recruit donors from April 2020 to November 2021 and plasmapheresis in our center (NCGM: national center for global health and medicine). We set the primary endpoint as the Donors Adverse Event (DAE) occurrence at the time of the CCP collection. Variable selection was used to explore the determinants of DAE. RESULTS: Mean and SD age was 50.5 (10.6) years old. Seventy-three (42.2 %) were female, and 87 (33.3 %) were multiple-times donors. Twelve (6.97 % by donors and 4.6 % in total collections) adverse events occurred. The DAEs were VVR (Vaso Vagal Reaction), paresthesia, hypotension, agitation, dizziness, malaise, and hearing impairment/paresthesia. Half of them were VVR during apheresis. DAE occurred only in first-time donors and more in severe illnesses such as using ventilation and ECMO. From the donor characteristics and variable selection, the risk factors are as follows: younger age, female, the severity of disease at the time of the disease, and lower SBP before initiation. Our DAE incidence did not differ from previous studies. DAEs were more likely to occur in CCP apheresis than in healthy donors. CONCLUSION: We confirm the safety of CCP apheresis in this study, although DAEs were more than healthy donors. More caution should be exercised in the plasma collection for future outbreaks of emerging infectious diseases.

[Fibrinolytic factors: novel molecular targets for cytokine storm-associated diseases].

The mortality rate due to coronavirus disease 2019 (COVID-19) reached 5.3 million. However, identifying the novel treatment targets that ultimately reduce or prevent disease aggravation will be possible by understanding the mechanism and pathophysiology underlying the COVID-19 aggravation. Authors of previous studies have identified the "cytokine storm" that constitutes the secretion of inflammatory cytokines driven by the coagulation/fibrinolytic system as an inflammatory cytodynamic control mechanism that contributes to the aggravated COVID-19 pathology and the pathophysiology of related diseases. Vasculature-lining endothelial cells are bioreactors that produce or contribute to the modulation status of cytokines and coagulation and fibrinolytic system factors. The key steps in the pathophysiology of organ damage include the destabilization of the angiocrine system triggered by vascular endothelial damage during severe COVID-19. Overproduced or imbalanced angiocrine factors and inflammatory cytokines contribute to major COVID-19 complications. Within its scope, this study outlines the significance of the fibrinolytic system in the pathophysiology of inflammatory diseases, focusing on the research results. The possibility of molecular that target these angiocrine and fibrinolytic factors for inflammatory diseases as novel treatment approaches for inflammatory diseases, such as COVID-19, was discussed.

The Role of Fibrinolytic Factors, a Subset of Angiocrine Factors in Cytokine Storm-Associated Diseases

Cytokine storm syndrome is a general term applied to maladaptive cytokine release in response to infection and other stimuli. It occurs during graft versus host disease after hematopoietic stem cell transplantation.Recent evidence suggested that, during the coronavirus disease 2019 (COVID-19) epidemic, the severe deterioration of some patient`s health with Coronavirus Disease 2019 (COVID-19) was compatible with symptoms as they are known for the cytokine storm syndrome. The cytokine storm syndrome in COVID-19 is associated with the development and progression of macrophage activation syndrome (MAS), vascular endotheliitis like Kawasaki disease, and acute respiratory distress syndrome. Abnormalities of coagulation and fibrinolysis are known clinical features of COVID-19 or MAS. We reported previously that plasmin inhibition reduced GVHD associated lethality and prevented increases in inflammatory cytokines in mice. But the role of the fibrinolytic system and its key player, plasmin, in the development of COVID-19 is not well defined. Toll-like receptors (TLRs) might contribute to the pathogenesis of the disease.We established a murine model of fulminant MAS by repeated injections of TLR-9 agonist and D-galactosamine in immunocompetent mice. We found increases in circulating urokinase and the angiocrine factor tissue-type plasminogen activator (tPA) levels during the progression of fulminant MAS in mice, which causes the enhanced conversion of the proenzyme plasminogen into plasmin. Genetic and pharmacological inhibition of plasmin counteracted MAS-associated lethality and other related symptoms. We show that plasmin regulates the influx of inflammatory cells and the production of inflammatory cytokines, chemokines, and proteases like soluble forms or membrane forms of matrix metalloproteases generating an amplification loop. Based on these data, we hypothesize that COVID-19-induced vascular endothelial dysfunction causes the aggravation of COVID-19 leading up to cytokine storm or MAS syndrome, endotheliitis, and hypercoagulability with the induction of disseminated intravascular coagulation syndrome(Fig.1.). In summary, we propose that plasmin and potentially MMPs inhibitors might offer a novel treatment to control the deadly cytokine storm syndrome in patients with MAS or COVID-19, thereby preventing multiple organ failure.Figure