Mesenchymal Stem Cells in the Treatment of COVID-19, a Promising Future.

Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have a potent self-renewal capacity and can differentiate into multiple cell types. They also affect the ambient tissue by the paracrine secretion of numerous factors in vivo, including the induction of other stem cells' differentiation. In vitro, the culture media supernatant is named secretome and contains soluble molecules and extracellular vesicles that retain potent biological function in tissue regeneration. MSCs are considered safe for human treatment; their use does not involve ethical issues, as embryonic stem cells do not require genetic manipulation as induced pluripotent stem cells, and after intravenous injection, they are mainly found in the lugs. Therefore, these cells are currently being tested in various preclinical and clinical trials for several diseases, including COVID-19. Several affected COVID-19 patients develop induced acute respiratory distress syndrome (ARDS) associated with an uncontrolled inflammatory response. This condition causes extensive damage to the lungs and may leave serious post-COVID-19 sequelae. As the disease may cause systemic alterations, such as thromboembolism and compromised renal and cardiac function, the intravenous injection of MSCs may be a therapeutic alternative against multiple pathological manifestations. In this work, we reviewed the literature about MSCs biology, focusing on their function in pulmonary regeneration and their use in COVID-19 treatment.

Association between warfarin and COVID-19-related outcomes compared with direct oral anticoagulants: population-based cohort study.

BACKGROUND: Thromboembolism has been reported as a consequence of severe COVID-19. Although warfarin is a commonly used anticoagulant, it acts by antagonising vitamin K, which is low in patients with severe COVID-19. To date, the clinical evidence on the impact of regular use of warfarin on COVID-19-related thromboembolism is lacking. METHODS: On behalf of NHS England, we conducted a population-based cohort study investigating the association between warfarin and COVID-19 outcomes compared with direct oral anticoagulants (DOACs). We used the OpenSAFELY platform to analyse primary care data and pseudonymously linked SARS-CoV-2 antigen testing data, hospital admissions and death records from England. We used Cox regression to estimate hazard ratios (HRs) for COVID-19-related outcomes comparing warfarin with DOACs in people with non-valvular atrial fibrillation. We also conducted negative control outcome analyses (being tested for SARS-CoV-2 and non-COVID-19 death) to assess the potential impact of confounding. RESULTS: A total of 92,339 warfarin users and 280,407 DOAC users were included. We observed a lower risk of all outcomes associated with warfarin versus DOACs [testing positive for SARS-CoV-2, HR 0.73 (95% CI 0.68-0.79); COVID-19-related hospital admission, HR 0.75 (95% CI 0.68-0.83); COVID-19-related deaths, HR 0.74 (95% CI 0.66-0.83)]. A lower risk of negative control outcomes associated with warfarin versus DOACs was also observed [being tested for SARS-CoV-2, HR 0.80 (95% CI 0.79-0.81); non-COVID-19 deaths, HR 0.79 (95% CI 0.76-0.83)]. CONCLUSIONS: Overall, this study shows no evidence of harmful effects of warfarin on severe COVID-19 disease.

Accelerated fibrin clot degradation is associated with arterial thromboembolism in patients following venous thrombosis: a cohort study.

Several lines of evidence have suggested that patients following venous thromboembolism (VTE) are at higher risk of arterial thromboembolism (ATE). Prothrombotic fibrin clot characteristics were reported in individuals with cardiovascular risk factors. We investigated whether specific fibrin clot properties measured after 3-4 months of anticoagulation characterize VTE patients with subsequent ATE. We enrolled 320 patients following VTE aged below 70 years (median age, 46). Ten patients were lost to follow-up. ATE occurred in 21 individuals after a median 54 (31-68) months during a follow-up of 87.5 months (incidence 0.94%; 95% confidence interval [CI], 0.59-1.4 per patient-year). Patients with ATE had faster fibrin clot degradation, reflected by maximum rate of D-dimer increase during plasma clot lysis induced by tissue-type plasminogen activator (D-Drate) at baseline. Clot permeability, turbidimetric variables, clot lysis time, and thrombin generation were unrelated to ATE. Univariable Cox proportional hazards analysis showed that age, diabetes, and D-Drate were risk factors for subsequent ATE. Increased D-Drate (by 0.001 mg/L/min; hazard ratio, 1.08; 95% CI 1.02-1.14) was an independent predictor of ATE after adjustment for potential confounders. Faster fibrin clot degradation at 3 months since VTE may increase the risk of ATE among VTE patients during follow-up.

Low Incidence of Symptomatic Thrombotic Events in Adult Patients Hospitalized with Coronavirus 19: A Retrospective Cohort Study.

BACKGROUND: Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pandemic, there have been many reports of increased incidence of venous thromboembolism and arterial events as a complication. OBJECTIVE: To determine the incidence of symptomatic thrombotic events (TEs) in patients hospitalized for SARS-CoV2 disease (coronavirus 19 [Covid-19]). METHODS: A retrospective single-center cohort study with adult patients with a positive reverse transcriptase-polymerase chain reaction (rt-PCR) for SARS-CoV2, included from the date of diagnosis of Covid-19 and followed for 90 days or until death. RESULTS: A total of 1621 patients were included in this study. The median age was 73 years (interquartile range25th-75th [IQR] 53-87 years) and 57% (913) were female. Overall mortality was 21.6% (348). The overall incidence of symptomatic TEs within 90 days of diagnosis was 1.8% (30 of 1621) occurring in 28 patients, including an incidence of pulmonary embolism of 0.9% (15, 95% confidence interval [CI] 0.60%-1.6%), deep venous thrombosis of 0.61% (10, 95% CI 0.2%-1%), ischemic stroke of 0.25% (4, 95% CI 0.09%-0.65%), and ischemic arterial events of 0.06% (1, 95% CI 0.008%-0.43%). No acute coronary syndrome events were recorded. The incidence of symptomatic TEs was significantly lower in the general ward than in intensive care units (1.2% vs 5.7%; p < .001). The median time since positive rt-PCR for SARS-CoV2 to symptomatic TE was 22.5 days (IQR 19-43 days). There was no significant difference in the proportion of patients receiving (53.6%) and not receiving thromboprophylaxis (66.5%) and the development of TEs. CONCLUSION: The overall incidence of symptomatic TEs among these patients was lower than the incidence previously reported.

Correlation of Neuroimaging Findings with Clinical Presentation and Laboratory Data in Patients with COVID-19: A Single-Center Study.

BACKGROUND: This study was aimed at revealing neuroimaging findings in COVID-19 patients and at discussing their relationship with epidemiological data and some laboratory parameters. Materials and Method. This study included 436 cases of COVID-19 and 40 cases of non-COVID-19 acute/subacute thromboembolism who underwent at least one neuroimaging procedure due to neurological symptoms between April 2020 and December 2020. The group of COVID-19-positive acute/subacute thromboembolism cases was compared with both the group of normal brain imaging cases and the non-COVID-19 acute/subacute thromboembolism group in terms of demographic data and laboratory parameters. RESULTS: When the acute/subacute thromboembolism group and neuroimaging findings were compared in terms of negative group, presence of comorbid disease, D-dimer level, and lymphocyte count in COVID-19 patients, a statistically significant difference was found (p = 0.047, 0.014, and <0.001, respectively). COVID-19-positive and COVID-19-negative acute/subacute thromboembolism cases that were compared in terms of gender, neuroimaging reason, C-reactive protein, D-dimer level and lymphocyte count, a statistically significant difference was found (p = 0.003, <0.001, 0.005, 0.02, and <0.001, respectively). CONCLUSION: Acute thromboembolic events are common in patients with COVID-19 due to a potentially increased procoagulant process. Neurological evaluation and, if necessary, detailed neuroimaging should be performed, especially in cases with high D-dimer levels.

Mesenchymal stem cell transfusion: Possible beneficial effects in COVID-19 patients.

SARS-CoV-2 attaches to the angiotensin-converting enzyme 2 (ACE-2) receptor on human cells. The virus causes hypercytokinemia, capillary leak, pulmonary edema, acute respiratory distress syndrome, acute cardiac injury, and leads to death. Mesenchymal stem cells (MSCs) are ACE-2 negative cells; therefore, can escape from SARS-CoV-2. MSCs prevent hypercytokinemia and help the resolution of the pulmonary edema and other damages occurred during the course of COVID-19. In addition, MSCs enhance the regeneration of the lung and other tissues affected by SARS-CoV-2. The case series reported beneficial effect of MSCs in COVID-19 treatment. However, there are some concerns about the safety of MSCs, particularly referring to the increased risk of disseminated intravascular coagulation, and thromboembolism due to the expression of TF/CD142. Prospective, randomized, large scale studies are needed to reveal the optimum dose, administration way, time, efficacy, and safety of MSCs in the COVID-19 treatment.

Fibrinogen-Albumin-Ratio is an independent predictor of thromboembolic complications in patients undergoing VA-ECMO.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) supports patients suffering from refractory cardiogenic shock. Thromboembolic complications (TeC) are common in VA-ECMO patients and are associated with increased morbidity and mortality. Valid markers to predict TeC in VA-ECMO patients are lacking. The present study investigated the predictive value of baseline Fibrinogen-Albumin-Ratio (FAR) for in-hospital TeC in patients undergoing VA-ECMO. This retrospective cohort study included patients who underwent VA-ECMO therapy due to cardiogenic shock at the University Hospital Duesseldorf, Germany between 2011 and 2018. Main exposure was baseline FAR measured at initiation of VA-ECMO therapy. The primary endpoint was the in-hospital incidence of TeC. In total, 344 patients were included into analysis (74.7% male, mean age 59 ± 14 years). The in-hospital incidence of TeC was 34%. Receiver operating characteristics (ROC) curve of FAR for in-hospital TeC revealed an area under the curve of 0.67 [95% confidence interval (CI) 0.61-0.74]. Youden index determined a cutoff of 130 for baseline FAR. Multivariate logistic regression revealed an adjusted odds-ratio of 3.72 [95% CI 2.26-6.14] for the association between FAR and TeC. Baseline FAR is independently associated with in-hospital TeC in patients undergoing VA-ECMO. Thus, FAR might contribute to the prediction of TeC in this cohort.

Tissue factor and its procoagulant activity on cancer-associated thromboembolism in pancreatic cancer.

Pancreatic cancer frequently involves cancer-associated thromboembolism, which is strongly associated with poor prognosis. Tissue factor, a blood coagulation factor largely produced in cancer patients as a component of extracellular vesicles, plays a key role in the incidence of cancer-associated thromboembolism in patients with pancreatic cancer. However, no prospective studies have been published on the relationship between tissue factor and cancer-associated thromboembolism or patient clinical characteristics, including recent chemotherapy regimens. Thus, we aimed to address this in a Japanese cohort of 197 patients and 41 healthy volunteers. Plasma tissue factor levels were measured by ELISAs preevaluated by tissue factor specificity. Multivariable analysis was used to identify independent predictors of cancer-associated thromboembolism. We found that the cancer-associated thromboembolism rate in the patient cohort was 6.6% (4.6%, venous thromboembolism; 2.0%, arterial thromboembolism). Tissue factor levels of 100 pg/mL or higher at patient registration were predictive of cancer-associated thromboembolism, with positive and negative predictive values of 23.1% and 94.6%, respectively. Multivariable analysis showed that plasma tissue factor levels were an independent predictive factor for cancer-associated thromboembolism, with a risk ratio of 5.54 (95% confidence interval, 1.02-30.09). Unlike in healthy volunteers and patients without cancer-associated thromboembolism, tissue factor levels were highly correlated with extracellular vesicles' procoagulant activity in patients developing cancer-associated thromboembolism. Taken together, our data show that the tissue factor levels at patient registration were a predictive factor for cancer-associated thromboembolism in this cohort of patients with pancreatic cancer.

Thromboembolic events in younger women exposed to Pfizer-BioNTech or Moderna COVID-19 vaccines.

Introduction: Concerns about the increased risk of blood clots associated with the VAXZEVRIA (previously named Oxford-AstraZeneca COVID-19 vaccine) and Johnson & Johnson (Janssen) COVID-19 vaccines raises the question of the thrombotic safety of other COVID-19 vaccines such as Pfizer-BioNTech or Moderna, especially in younger women, who at the early stage of the pandemic was a priority group for vaccination. Methods: Using the US-based Vaccine Adverse Event Reporting System (VAERS) and the FDA Event Reporting System (FAERS), we retrieved cases of thrombosis following vaccinations or hormonal contraceptive use in women aged ≤ 50 years. We used the reporting odds ratio (ROR) as a disproportionality measure. Results: On 19 March 2021, out of 13.6 million women aged ≤ 50 exposed to at least one dose of Pfizer-BioNTech or Moderna COVID-19 vaccines in the US, only 61 cases were reported with a total of 68 thromboembolic events (1 case per 222,951 vaccinated). None of the thromboembolic events included in our analysis were disproportionally reported for the two COVID-19 vaccines. Conclusion: Our results do support that, when compared to hormonal contraceptive use, the mRNA vaccines do not show disproportional reporting of thromboembolic events in younger women.

Extra cellular vesicles in blood circulation as biomarkers and messengers of patho-hysiological activity and alterations.

There is an increasing interest in Extracellular Vesicles released by many cells through membrane shedding. In addition to cell signaling, these particles are true messenger cargos, which can carry cell surface proteins, miRNAs and non-coding RNAs to other and distant cells. They are part of the inter-cellular crosstalk and they contribute to transferring biological messages far away from the triggering event. EVs are biomarkers of many diseases, including thrombo-embolic pathology, infections, neurological or metabolic disorders, and malignancy. Their role and significance are presented and discussed in this short review, as consequences of disease and causes of its progression. But they can also be beneficial for tissue healing or repair, and they can be prepared in vitro to be used for cell- targeted treatments. Many identification and measurement methods for EV's are sophisticated, which restricts their use to research studies, but they have, nevertheless, a high laboratory potential for diagnosis, prognosis and evolution as follow-up of many pathologies. New emerging laboratory tools offer more friendly and easy applications for characterizing EVs and testing their associated activity, especially for the procoagulant ones.

More Effective Anticoagulation During Non-Cardiac Arterial Procedures Using Activated Clotting Time Guided Heparin Administration.

OBJECTIVES: Arterial thrombo-embolic complications (ATEC) are still common during and after non-cardiac arterial procedures (NCAP) despite the administration of (a fixed bolus of) heparin. These ATEC could be due to existing individual differences in heparin sensitivity. The purpose of this study was to evaluate the feasibility and safety of an ACT guided heparin dose protocol and to evaluate if a more effective target ACT can be achieved during NCAP. METHODS: In this multi-center prospective study, 194 patients undergoing elective and non-elective NCAP were enrolled and received heparin according to a heparin dose protocol which aimed to obtain a target ACT of 250 seconds (s.), measured by the Medtronic HMS Plus. Patients received a standardized bolus of 5 000 IU followed by additional boluses depending on the actual ACT. Primary outcome was the ACT value reached. Secondary outcomes were incidence of all ATEC and haemorrhagic complications. RESULTS: The mean baseline ACT was 138 ± 17 s. The mean ACT five minutes after the initial heparin bolus of 5 000 IU was 197 ± 31 s. 48% of patients reached an ACT of 200 s. and six per cent of patients reached an ACT of 250 s. Additional dosages of heparin were administered in 72% of patients. With this ACT guided heparin protocol 86% of patients reached an ACT of 200 s. and 26% of patients reached an ACT of 250 s. A negative correlation was found between body weight and the ACT at T1 (P ˂ 0.001). ATEC and haemorrhagic complications occurred in 11.3% and 16.5% of patients. The lowest incidence of ATEC was found in patients with peak ACT between 200 and 250 s, namely 6.3%. CONCLUSION: This ACT guided heparin protocol proved to be feasible, safe and more patients reached an ACT > of 200 s. compared to a standardized heparin bolus of 5 000 IU. Further research is needed to investigate if ACT guided heparin administration could be preferable over not monitoring the anticoagulant effect of peri-procedural heparin and results in a lower incidence of ATEC, without an increase in haemorrhagic complications.

Expression of miR-93-5p as a Potential Predictor of the Severity of Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: MicroRNAs (miRNAs) play an important role in the pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH). However, the potential correlation between miRNA expression and the severity of CTEPH remains unclear. Our previous study indicated that miRNAs hsa-let-7b-3p, hsa-miR-17-5p, hsa-miR-106b-5p, hsa-miR-3202, hsa-miR-665, and hsa-miR-93-5p are closely involved in CTEPH. This study assessed the associations between the expression levels of these miRNAs and clinical parameters in CTEPH patients. METHODS: A total of eight CTEPH patients and eight healthy adults as a reference group were included, and clinical data including total protein (TP), albumin (Alb), lactate dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), uric acid (UA), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were collected. Right heart catheterization was conducted to obtain hemodynamic data including cardiac index (CI). The expression levels of let-7b-3p, miR-17-5p, miR-106b-5p, miR-3202, miR-665, and miR-93-5p were measured by quantitative real-time PCR (qPCR). Correlation analysis was applied to estimate the associations between miRNA expression levels and clinical parameters in CTEPH patients. RESULTS: Serum TP and Alb levels were decreased, while LDH, HBDH, and UA levels were increased in CTEPH patients compared with the reference group (P < 0.05). miR-3202 and miR-665 were upregulated, whereas let-7b-3p, miR-17-5p, miR-106b-5p, and miR-93-5p were downregulated in CTEPH patients relative to the reference group (P < 0.05). miR-93-5p expression was positively correlated with NT-proBNP level and negatively correlated with CI (P < 0.05). Moreover, let-7b-3p tended to be positively correlated with mean pulmonary arterial pressure. CONCLUSIONS: miR-93-5p expression was associated with the severity of CTEPH and could act as a potential predictor of high-risk CTEPH.

Antiphospholipid antibodies in critically ill COVID-19 patients with thromboembolism: cause of disease or epiphenomenon?

Coronavirus 2019 disease (COVID-19) is associated with coagulation dysfunction that predisposes patients to an increased risk for both arterial (ATE) and venous thromboembolism (VTE) and consequent poor prognosis; in particular, the incidence of ATE and VTE in critically ill COVID-19 patients can reach 5% and 31%, respectively. The mechanism of thrombosis in COVID-19 patients is complex and still not completely clear. Recent literature suggests a link between the presence of antiphospholipid antibodies (aPLs) and thromboembolism in COVID-19 patients. However, it remains uncertain whether aPLs are an epiphenomenon or are involved in the pathogenesis of the disease.

Thrombolome and Its Emerging Role in Chronic Kidney Diseases.

Patients with chronic kidney disease (CKD) are at an increased risk of thromboembolic complications, including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. These complications lead to increased mortality. Evidence points to the key role of CKD-associated dysbiosis and its effect via the generation of gut microbial metabolites in inducing the prothrombotic phenotype. This phenomenon is known as thrombolome, a panel of intestinal bacteria-derived uremic toxins that enhance thrombosis via increased tissue factor expression, platelet hyperactivity, microparticles release, and endothelial dysfunction. This review discusses the role of uremic toxins derived from gut-microbiota metabolism of dietary tryptophan (indoxyl sulfate (IS), indole-3-acetic acid (IAA), kynurenine (KYN)), phenylalanine/tyrosine (p-cresol sulfate (PCS), p-cresol glucuronide (PCG), phenylacetylglutamine (PAGln)) and choline/phosphatidylcholine (trimethylamine N-oxide (TMAO)) in spontaneously induced thrombosis. The increase in the generation of gut microbial uremic toxins, the activation of aryl hydrocarbon (AhRs) and platelet adrenergic (ARs) receptors, and the nuclear factor kappa B (NF-κB) signaling pathway can serve as potential targets during the prevention of thromboembolic events. They can also help create a new therapeutic approach in the CKD population.

Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation.

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p < 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann-Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13-0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Platelet Protein-Related Abnormalities in Response to Acute Hypoglycemia in Type 2 Diabetes.

Introduction: Patients with severe COVID-19 infections have coagulation abnormalities indicative of a hypercoagulable state, with thromboembolic complications and increased mortality. Platelets are recognized as mediators of inflammation, releasing proinflammatory and prothrombotic factors, and are hyperactivated in COVID-19 infected patients. Activated platelets have also been reported in type 2 diabetes (T2D) patients, putting these patients at higher risk for thromboembolic complications of COVID-19 infection. Methods: A case-control study of T2D (n=33) and control subjects (n=30) who underwent a hyperinsulinemic clamp to induce normoglycemia in T2D subjects: T2D: baseline glucose 7.5 ± 0.3mmol/l (135.1 ± 5.4mg/dl), reduced to 4.5 ± 0.07mmol/l (81 ± 1.2mg/dl) with 1-hour clamp; Controls: maintained at 5.1 ± 0.1mmol/l (91.9 ± 1.8mg/dl). Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was used to determine a panel of platelet proteins. Results: Prothrombotic platelet proteins were elevated in T2D versus controls: platelet factor 4 (PF4, p<0.05); platelet glycoprotein VI (PGVI p<0.05); P-selectin (p<0.01) and plasminogen activator inhibitor I (PAI-1, p<0.01). In addition, the antithrombotic platelet-related proteins, plasmin (p<0.05) and heparin cofactor II (HCFII, p<0.05), were increased in T2D. Normalization of glucose in the T2D cohort had no effect on platelet protein levels. Conclusion: T2D patients have platelet hyperactivation, placing them at higher risk for thromboembolic events. When infected with COVID-19, this risk may be compounded, and their propensity for a more severe COVID-19 disease course increased. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03102801, identifier NCT03102801.

Diagnostic Value of D-Dimer in COVID-19: A Meta-Analysis and Meta-Regression.

The prognostic role of hypercoagulability in COVID-19 patients is ambiguous. D-dimer, may be regarded as a global marker of hemostasis activation in COVID-19. Our study was to assess the predictive value of D-dimer for the severity, mortality and incidence of venous thromboembolism (VTE) events in COVID-19 patients. PubMed, EMBASE, Cochrane Library and Web of Science databases were searched. The pooled diagnostic value (95% confidence interval [CI]) of D-dimer was evaluated with a bivariate mixed-effects binary regression modeling framework. Sensitivity analysis and meta regression were used to determine heterogeneity and test robustness. A Spearman rank correlation tested threshold effect caused by different cut offs and units in D-dimer reports. The pooled sensitivity of the prognostic performance of D-dimer for the severity, mortality and VTE in COVID-19 were 77% (95% CI: 73%-80%), 75% (95% CI: 65%-82%) and 90% (95% CI: 90%-90%) respectively, and the specificity were 71% (95% CI: 64%-77%), 83% (95% CI: 77%-87%) and 60% (95% CI: 60%-60%). D-dimer can predict severe and fatal cases of COVID-19 with moderate accuracy. It also shows high sensitivity but relatively low specificity for detecting COVID-19-related VTE events, indicating that it can be used to screen for patients with VTE.