ABSTRACT
Background : The anticoagulant protein S (PS) circulates in two plasma pools: free (functional) or bound to complement factor 4-binding protein (c4bp). PS deficiency commonly occurs in Human Immunodeficiency Virus-1 (HIV-1)+ patients and is associated with thrombosis. We hypothesized a similar process contributes to thrombosis in COVID-19. Aims : To assess the regulation of PS in viral coagulopathies. Methods : This study was approved by the Institutional Review Board. Citrated plasma was collected from consenting HIV-1+ (19 naïve, 11 on antiretroviral therapy, ART) or SARS-CoV-2+ (28 inpatients, 49 outpatients) and healthy controls for both populations (10, 31, respectively). Results : HIV-1+ patients had lower total PS than controls (94.12 ± 8.71% vs 133.77 ± 10.45%, P = 0.008), in both naïve (42%) and ART-treated (27%) patients. Total PS negatively correlated with endogenous thrombin potential ( P = 0.01), suggesting PS deficiency contributes to increased thrombin generation in these patients. Total PS was not reduced in SARS-CoV-2+ patients, but free PS was (Table). To determine the cause of free PS deficiency, we measured known PS-binding proteins C4bp, protein C (PC), and Mer, and found no differences between patients and controls. By native gel, we identified PS bound to C4bp, Mer, PC, tissue factor pathway inhibitor (TFPI), and von Willebrand Factor (VWF). VWF was markedly elevated in inpatients. Purified VWF dose-dependently decreased free, but not total, PS when added to control plasma, and blocked the TFPI cofactor activity of PS. PS was also identified as a plasma binding partner of VWF by mass spectrometry, and this interaction increased 10-million-fold with shearing. Finally, despite anticoagulation, plasma thrombin generation in inpatient samples was comparable to controls, suggesting a profound hypercoagulability, possibly exacerbated by PS deficiency. Conclusions : In HIV-1, PS consumption leads to total PS deficiency. In SARS-CoV-2, VWF increases and binds PS, reducing the free pool. Thus, viruses can cause PS deficiency through multiple mechanisms, promoting thrombosis by shifting the procoagulant-anticoagulant balance.
ABSTRACT
Background The evolution of pulmonary 18F-FDG uptake is unknown in patients with pneumonia due to SARSCoV-2 (COVID-19 pneumonia) and in those with persistent respiratory symptoms post-COVID-19 termed Post-COVID-19 Lung-Disease (PCLD). The aim of this study was to assess the temporal evolution of pulmonary 18FFDG uptake and identify a potential role for the use of 18F-FDG-PET/CT imaging in the management of these patients. Methods Clinical data and CT imaging of all patients that underwent 18F-FDG-PET/CT imaging at UCLH, London over the 3-month peak of the UK pandemic were reviewed to identify SARS-CoV-2 infection. Patients were divided in to acute (early and late) COVID-19 pneumonia and PCLD. 18F-FDG uptake in the lungs was measured as a target-to-background ratio (SUVmax/SUVmin) TBRlung which was compared to temporal-stage and plasma CRP. Results There were 20 patients in total (median 61.5y, range 18-84y, 12-male): 11 incidental acute COVID-19 pneumonia cases identified retrospectively (5 Early, 6 Late), and 9 cases performed for PCLD. TBRlung was correlated with time since disease onset (rs=0.83, p=0.002). In the PCLD patients TBRlung correlated with CRP (rs=0.985, p<0.001) and was lower if steroid treatment had been administered (p=0.050). Conclusion Pulmonary 18F-FDG-uptake in COVID-19 pneumonia increases with time after infection. In patients with PCLD the pulmonary 18F-FDG-uptake rises further in the absence of infection, and correlates with CRP levels in serum, suggesting a role for inflammation. The lower pulmonary 18F-FDG-uptake in patients who had received steroid treatment for PCLD, may indicate a role for 18F-FDG-PET/CT in managing these millions of patients. Figure Lung FDG uptake (TBRlung) against the Estimated days since onset of disease (on a logarithmic scale) with superimposed linear-log regression using the 11 early & late patients.