Background: Studies have suggested that there is increased risk of thromboembolism (TE) associated with coronavirus disease 2019 (COVID-19). However, overall arterial and venous TE rates of COVID-19 and effect of TE on COVID-19 mortality is unknown. Methods: We did a systematic review and meta-analysis of studies evaluating TE in COVID-19. We searched PubMed, Cochrane, and Embase for studies published up to June 12, 2020. Random effects models were used to produce summary TE rates and odds ratios (OR) of mortality in COVID-19 patients with TE compared to those without TE. Heterogeneity was quantified with I 2. Findings: Of 425 studies identified, 42 studies enrolling 8271 patients were included in the meta-analysis. Overall venous TE rate was 21% (95% CI:17À26%): ICU, 31% (95% CI: 23À39%). Overall deep vein thrombosis rate was 20% (95% CI: 13À28%): ICU, 28% (95% CI: 16À41%); postmortem, 35% (95% CI:15À57%). Overall pulmonary embolism rate was 13% (95% CI: 11À16%): ICU, 19% (95% CI:14À25%); postmortem, 22% (95% CI:16À28%). Overall arterial TE rate was 2% (95% CI: 1À4%): ICU, 5% (95%CI: 3À7%). Pooled mortality rate among patients with TE was 23% (95%CI:14À32%) and 13% (95% CI:6À22%) among patients without TE. The pooled odds of mortality were 74% higher among patients who developed TE compared to those who did not (OR, 1.74; 95%CI, 1.01À2.98; P = 0.04). Interpretation: TE rates of COVID-19 are high and associated with higher risk of death. Robust evidence from ongoing clinical trials is needed to determine the impact of thromboprophylaxis on TE and mortality risk of COVID-19. Funding: None.

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The reactions of metmyoglobin (metMb) and methemoglobin (metHb), oxidized to their respective oxoferryl free radical species (.Mb-FeIV = O/.Hb-4FeIV = O) by tert-butyl hydroperoxide (t-BuOOH), with nitric oxide (NO.) were studied by a combination of optical, electron spin resonance (ESR), ionspray mass (MS), fluorescence, and chemiluminescence spectrometries to gain insight into the mechanism by which NO. protects against oxidative injury produced by .Mb-FeIV = O/.Hb-4FeIV = O. Oxidation of metMb/metHb by t-BuOOH in a nitrogen atmosphere proceeded via the formation of two protein electrophilic centers, which were heme oxoferryl and the apoprotein radical centered at tyrosine (for the .Mb-FeIV = O form, the g value was calculated to be 2.0057), and was accompanied by the formation of t-BuOOH-derived tert-butyl(per)oxyl radicals. We hypothesized that NO. may reduce both oxoferryl and apoprotein free radical electrophilic centers of .Mb-FeIV = O/.Hb-4FeIV = O and eliminate tert-butyl(per)oxyl radicals, thus protecting against oxidative damage. We found that NO. reduced .Mb-FeIV = O/.Hb-4FeIV = O to their respective ferric (met) forms and prevented the following: (i) oxidation of cis-parinaric acid (PnA) in liposomes, (ii) oxidation of luminol, and (iii) formation of the tert-butyl(per)oxyl adduct with the spin trap DMPO. NO. eliminated the signals of tyrosyl radical detected by ESR and oxoferryl detected by MS in the reaction of t-BuOOH with metMb. As evidenced by MS of apomyoglobin, this effect was due to the two-electron reduction of .Mb-FeIV = O by NO. at the oxoferryl center rather than to nitrosylation of the tyrosine residues. Results of our in vitro experiments suggest that NO. exhibits a potent, targetable antioxidant effect against oxidative damage produced by oxoferryl Mb/Hb.

We studied protective effects of NO against tert-butylhydroperoxide (t- BuOOH Nitric oxide (NO)1 is an important physiological regulator of biological responses such as vasodilation, blood coagulation, neurotransmission, renal function, inflammation, and antitumor immune surveillance (1-6). Paradoxically, it can simultaneously exert adverse effects on cells. Cytotoxic effects of NO are believed to be produced through three major pathways as follows: (i) direct modification of proteins by NO via nitrosylation of sulfhydryl groups, heme and non-heme sites, and possibly tyrosyl residues (e.g. modification of poly(ADP-ribose) synthetase, ribonucleotide reductase, and enzymes of mitochondrial electron transport) (4 -10); (ii) NO-induced activation of enzymes involved in posttranscriptional regulation of protein expression (e.g. transferrin/ferritin pathway for iron mobilization) (11, 12); and (iii) oxidative damage to critical biomolecules such as nucleic acids, proteins, and lipids. The latter is mainly associated with the production of peroxynitrite (13-17). It has been demonstrated recently that NO can also act as an antioxidant, thus protecting cells against oxidative damage (17)(18)(19). In Chinese hamster V79 lung fibroblasts and human umbilical vein endothelial cells, this antioxidant effect of NO was associated with its ability to scavenge lipid alkoxyl and peroxyl radicals (18 -20). The balance between intracellular antioxidant and pro-oxidant effects of NO in vivo remains to be elucidated.It has been suggested that the interaction of NO with hemoglobin and myoglobin may prevent hydroperoxide-induced formation of oxoferryl hemoproteins, thus blocking subsequent generation of oxygen-derived reactive species and oxidative damage (18,19,(21)(22)(23)(24)(25). In line with this, our previous studies demonstrated that NO was capable of inhibiting oxoferrylinduced oxidation in simple model systems such as tert-butylhydroperoxide (t-BuOOH)/hemoglobin or t-BuOOH/myoglobin (24). The proposed antioxidant mechanism of NO involves reduction of oxoferryl-derived radicals (24). Whether this mechanism operates in cells remained unclear.In the present work, we attempted to elucidate the antioxidant role of NO against intracellular oxoferryl hemoglobininduced oxidative stress. We studied the effects of NO on tBuOOH-induced, heme and non-heme iron-dependent oxidation of membrane phospholipids and cytotoxicity in a sub-

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