Humoral immunity and thrombosis in COVID-19

Coronavirus disease 2019 (COVID-19) is due to the infection of the upper and lower airways by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is characterized by different clinical manifestations ranging from paucisymptomatic conditions to life-threatening acute respiratory distress syndrome and may present multisystem involvement. A hyperinflammatory response to the virus and the associated prothrombotic state (immunothrombosis) are the major causes of tissue/organ damage. Several humoral mediators have been described to mediate the immunothrombosis in COVID-19;among them, a lot of attention has been paid to the synthesis of nonorgan specific procoagulant autoantibodies, the hyperproduction of proinflammatory cytokines, and to the activation of the complement cascade. All the above-mentioned pathogenic pathways are affecting the endothelium as one of the main targets of the disease and contribute to the clinical manifestations. © 2023 Elsevier Inc. All rights reserved.

Involvement of the contact pathway in COVID-19 coagulopathy

Background: A novel acquired coagulopathy characterized by a severe procoagulant imbalance is common in COVID-19 patients and is associated with the clinical severity of the disease. Aim(s): Our study aims to elucidate the underlying mechanisms of coagulation activation in COVID-19 patients. Method(s): Symptomatic COVID-19 patients during Milan first wave were consecutively enrolled and stratified into 3 groups based on the intensity of care: Low, requiring only high-flow oxygen by nasal cannula;intermediate, requiring continuous positive airway pressure;high, requiring mechanical ventilation. Blood samples were tested for markers of activation of the intrinsic pathway (FXIa, FXIIa) together with its physiologic inhibitor (C1-inhibitor), of the extrinsic pathway (FVIIa), of global activation of the coagulation cascade (D-dimer, FDP, FM) and of fibrinolysis (plasminogen, t-PA, alpha2-antiplasmin, PAI-1). Result(s): 111 patients were included: 26 at low, 42 intermediate and 43 high care-intensity. Median age was 59 +/- 12 (34 patients >65 years);32 patients (29%) developed a venous thrombosis and 12 (11%) died (Table). Median D-dimer, FDP and FM plasma levels were higher in COVID-19 patients compared to controls, with a gradient of increase across the three care intensities, while all the fibrinolytic pathway parameters were in the normal range. Median plasma levels of FVIIa were lower in COVID-19 patients (27.5 mU/ml) than in controls (40.1 mU/ml) while median plasma levels of FXIIa and FXIa were higher in COVID-19 patients (11.2 and 11.3 mU/ml) than in controls (7.2 and 5.5 mU/ml), with a gradient of increase across the three care intensities. C1-inhibitor plasma levels were above the normal range in all the 3 COVID-19 patients' groups (Figure). Conclusion(s): Our study showed a prevalent activation of the contact pathway over the extrinsic pathway of the coagulation cascade in COVID-19 patients, which is proportional to the clinical severity of the infection, opening the possibility for targeted anticoagulant therapies. (Table Presented).

Industry 4.0 and production recovery in the covid era

This study aims to use a quantitative analysis to explore the effects of openness to Industry 4.0 on the perceived production recovery post the COVID-19 pandemic, mediated by digital and classical reorganization. Openness to Industry 4.0 is measured by the breadth of the number of technologies adopted. The production recovery is measured by the perception of firms that a return to pre-COVID-19 production levels will happen within either 2021, 2022, or 2023. The study takes a representative sample of 2622 manufacturing small and medium en-terprises across Italy (surveyed between October and November 2020) through a mediation analysis based on nonlinear probability models (KHB method). The results of the models show the following. First, openness to Industry 4.0 has a positive and significant direct effect on a perceived production recovery in the short term (within 2021) and medium term (within 2022 and 2023). Further, this effect is accelerated in the short term by digital reorganization and in the medium term by the addition of a classical reorganization. The research pro-vides relevant managerial implications based on a large sample of current empirical data, showing that Industry 4.0 technologies, when adopted in tandem with the digital reorganization of production activity, can accelerate production recovery to pre-COVID-19 levels.

Acute liver necrosis in a SARS-CoV-2 positive patient with triple positive antiphospholipid syndrome

Background : Several thrombotic manifestations have been reported with SARS-Cov-2 infection including liver vascular involvement. Aims : We present a dramatic case of acute liver necrosis in a 36-year-old SARS-Cov-2 positive Italian woman with no respiratory symptoms and triple positive antiphospholipid syndrome (APS). Methods : The patient was referred to our University Hospital for acute hypertransaminasemia and liver failure (Figure). She had systemic lupus erythematosus (positivity for: ANA, anti-dsDNA, complement activation, Coombs;thrombocytopenia, previous arthritis). Anti-phopspholipid antibodies (aPL) were detected for the first time in 2015 during routine pregnancy screening and chronically treated with aspirin. Apparently, no venous/arterial nor obstetric events were recorded up to the recent hospitalization. FIGURE 1 Results : At arrival, US-Doppler and CT-scan were consistent with signs of chronic liver disease and occlusion of the three hepatic veins defining a Budd-Chiari syndrome. We opted for a stepwise approach considering anticoagulation (clexane 100 UI/Kg b.i.d) the first line of therapy before any invasive intervention. Dexamethasone 6 mg/ day b.i.d., 6 sessions of plasma-exchange, i.v.-immunoglobulin were sequentially planned to revert the liver damage sustained by aPL. After 5-days, two hepatic-veins resulted recanalized in association with amelioration of liver-enzyme/function and aPL quantification. Then we performed hepatic vein catheterization and transjugular liver biopsy. The histology showed multiple areas of necrosis associated with liver cirrhosis. Unexpectedly, no signs of acute Budd-Chiari were observed (e.g. intraparenchymal hemorrhages, centrilobular congestion, sinusoidal dilation). Other etiologies were also excluded and we hypothesized the involvement of small arteries of the liver in a triple positive APS in a patients with SLE. We finally addressed the patient to a liver transplant program and a tight multispecialistic follow-up. Conclusions : Thrombosis of arterial/venous vessels or microcirculation causes liver damage in some patients with aPL. Our report suggests that SARS-Cov-2 can exacerbate this prothrombotic condition determining a life-threatening complication such as acute liver failure.