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Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID Pneumonitis: Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics (preprint)

07 Oct 2021-medRxiv (Cold Spring Harbor Laboratory Press)-

AbstractBackground: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is Nafamostat Mesylate. Methods: We present the findings of a phase Ib/II open label, platform randomised controlled trial of intravenous Nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2mg/kg/hour for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. Results: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. 78% of Nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The Nafamostat group developed significantly higher plasma creatinine levels and had a lower number of oxygen free days (posterior mean difference 10.57 micromol/L, 95% HPD interval 2.43 - 18.92, rate ratio 0.55- 95% HPD interval 0.31- 0.99 respectively). There were no other statistically significant differences in endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D-Dimers. Interpretation: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Further evaluation of Nafamostat delivered via a different route may be warranted. Clinical Trial Registration Details: This trial has been registered on ISRCTN (https://www.isrctn.com/) ISRCTN14212905, and Clinicaltrials.gov (https://www.clinicaltrials.gov/) NCT04473053. Funding Information: DEFINE was funded by LifeArc (an independent medical research charity under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230). Declaration of Interests: The authors report no conflict of interests. Ethics Approval Statement: The DEFINE trial has received full ethical approval from Scotland A REC (20/SS/0066), the MHRA (EudraCT 2020-002230-32) and NHS Lothian. Written informed consent was taken by trial clinicians prior to any trial procedures being performed. If a patient lacked capacity, consent could be provided by their next of kin.

Topics: Nafamostat (71%), Clinical trial (51%), Population (51%), Randomized controlled trial (51%)

Summary (4 min read)

INTRODUCTION

  • COVID-19, caused by the coronavirus SARS-CoV-2, was declared a global pandemic on the 11th of March 2020 [1] and an ongoing global health, social and economic crisis has ensued.
  • At the time of writing, dexamethasone and interleukin-6 receptor antagonists [2] are the only effective treatments available for COVID-19 [3] [4], however, the mortality rate of unvaccinated COVID-19 in hospitalised patients remains high at 22.9% [2].
  • In addition to the potential antiviral effects, Nafamostat inhibits platelet aggregation, inhibits thrombin, kallikrein, plasmin and other complement factors and reduces endothelial activation [9].
  • The authors report the first detailed assessment of safety, PK/PD; immunology and coagulation effects of the drug at the recommended dose and route, using a platform RCT.

Trial design and participants

  • The DEFINE trial is a platform, multicentre, randomised controlled open label trial.
  • Here the authors report the finding for the Nafamostat arm compared to SoC.
  • The trial protocol has been reported previously. [10].
  • A current or recent history of severe uncontrolled cardiac disease, diabetes mellitus, renal impairment or hepatic impairment, anaemia, thrombocytopaenia, hyponatraemia or hyperkalaemia, were also exclusion criteria (see pre-print protocol with full inclusion/exclusion criteria [10]).
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

Endpoints

  • The primary endpoint was to evaluate the safety and tolerability of intravenous Nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis.
  • Secondary endpoints were to explore the Pharmacokinetics/Pharmacodynamics (PK/PD) of Nafamostat; assess the response of key biomarkers during the treatment period; evaluate SARS-CoV-2 viral load over time.
  • Clinical secondary endpoints included oxygen free days; the change in the oxygen saturations and fraction of inspired oxygen concentration (SpO2/FiO2 ratio); time to discharge; the use of kidney replacement therapy.

Interventions

  • Participants randomised to intravenous Nafamostat were administered the drug as a continuous infusion at a dose of 0.2 mg/kg/hr through a dedicated intravenous cannula.
  • The infusion was prepared as per local guidelines and changed every 24 hours for a total of 7 days, or until discharge or withdrawal.
  • In the event of biochemical side effects, namely clinically significant hyperkalaemia or hyponatraemia, treatment was ceased.
  • Treatment was also terminated if there was a clotting event requiring anticoagulation or antiplatelet therapy, but trial participants continued to provide daily bloods, ECG and clinical assessments despite no longer receiving a trial medication.
  • SoC included all appropriate supportive measures for SARS-CoV-2 and approved therapies as per national guidance at the time including dexamethasone, remdesivir and tocilizumab as per NHS guidelines.

Clinical and laboratory monitoring

  • Nursing and medical staff visited patients daily until discharge, withdrawal, or day 16 of participation.
  • A list of daily observations and blood parameters recorded are listed in Table 3 (supplementary material).
  • Symptoms were elicited from patients and recorded as adverse events (AE) if indicated.
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
  • The copyright holder for this preprint this version posted October 7, 2021.

Pharmacokinetics

  • Blood samples for the analysis of plasma Nafamostat levels and its breakdown metabolite (4-GBA) were obtained.
  • To determine Nafamostat breakdown products, levels of 4-GBA were measured pre-infusion .
  • 4-GBA was undetectable in the pre-infusion samples confirming no intrinsic 4-GBA.
  • Following Nafamostat administration, 4-GBA was detected at elevated levels in plasma .
  • Taken together, this suggests in hospitalised patients with COVID19 pneumonitis, there is rapid breakdown of intravenous Nafamostat to its inactive metabolite, 4- GBA, resulting in very low levels of circulating Nafamostat, and intravenous Nafamostat therefore had unfavourable PK characteristics in this cohort of patients.

Viral Load

  • Qualitative and quantitative polymerase chain reaction (PCR) of oropharyngeal/nasal measurements for SARS-CoV-2 were taken from the final 37 participants in the trial.
  • A volume of 110μL of eluate containing purified RNA was obtained following automated extraction carried out on the NucliSENS® easyMag® using an ‘off-board’ extraction where 200μL of the sample was added to 2ml of easyMAG lysis buffer.
  • Nasopharygeal and saliva samples were then tested using the Altona RealTime PCR kit (Hamburg, Germany).
  • Ct values were converted to copies per mL by relating values to a standard linearity panel with values in copies/mL derived by digital droplet PCR (Quality Control for Molecular Diagnostics, Glasgow).
  • Measurements of anticoagulation effect, clot strength and antifibrinolytic effect were executed.

Cytokine analysis

  • Samples were frozen on dry-ice in aliquots and stored at -80°C and assayed at the end of the trial using the ELLA platform (Simple protein, Bio-Techne, R&D, USA).
  • Results beyond the limit of detection and .
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
  • The copyright holder for this preprint this version posted October 7, 2021.

Flow cytometry

  • All staining and processing were performed in an MSCII biosafety cabinet with centrifugation steps using capped tubes in the biosafety bucket which were loaded and unloaded within the MSCII Peripheral blood was taken for detailed immunophenotyping.
  • Red blood cells were lysed using BD FACS lyse.
  • 5 minutes later, 50 µl of antibody staining cocktail (prepared in FACS staining buffer (PBS 2% FCS (Gibco)) containing 10% Brilliant violet plus buffer (BD 566385)) was added to each tube and then incubated in the dark, at room temperature for 20 minutes and washed twice in staining buffer before fixation (Biolegend Fixation buffer).
  • After 20 minutes, fixed samples were moved from the MSCII to cold storage.
  • Freshly prepared 8 peak calibration beads were run daily prior to sample collection.

Statistics

  • The analysis population consisted of (i) all patients randomised to Nafamostat who received any dose of the trial drug and (ii) all patients randomised to the control arm (SoC) who would also have been eligible to receive Nafamostat.
  • Therefore, any patients who were randomised to Nafamostat but did not receive the trial drug were excluded.
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
  • The authors also separately analysed the outcome of “at least one AE during follow-up” using a Bayesian logistic regression model, with trial arm as the only explanatory variable.
  • The cytokine data were presented as means and 95% confidence intervals with best-fit line by linear regression and comparing intercepts and slopes.

Participants

  • Amongst 299 individuals screened, 66 met eligibility criteria and were randomised.
  • 44 participants were enrolled to the Nafamostat vs SoC comparison reported here.
  • There were no baseline differences between Nafamostat and SoC groups .

Adverse events

  • Patients’ clinical course, in-hospital AE occurrence and time in the trial are summarised for each arm in Figure 2A and Table 6.
  • The Nafamostat group experienced more AEs compared to SoC (n=50 vs n=35), with 78% of Nafamostat-treated patients experiencing at least one AE compared to 57% of the SoC group.
  • There were no serious adverse events (SAEs) in either group.
  • Other than clinical deterioration, hyperkalaemia was the most common reason for early cessation (6/21), although there were no related complications.
  • One patient developed a pulmonary embolism, and one patient suffered an ischaemic CVA whilst on Nafamostat .

Clinical endpoints

  • A Kaplan-Meier plot of duration of hospital stay is shown in Figure 2B, with an average longer hospital stay in Nafamostat patients (Table 2).
  • Nafamostat-treated patients were on oxygen for a median of 2 days more than SoC patients (Table 2) and there were a significantly lower number of oxygen free days for those on Nafamostat (rate ratio 0.55- 95% HPD interval 0.31- 0.99).
  • There were no other statistically significant differences regarding primary endpoints.
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

Viral data

  • Nasopharyngeal and saliva samples were taken at baseline, day 3 and day 5 for RT PCR analysis.
  • Viral load decreased over time in both groups, with no difference observed between the Nafamostat and SoC groups .

Thromboelastometry

  • In most patients receiving intravenous Nafamostat, little or no anticoagulant effect was evident .
  • An antifibrinolytic effect was seen in patients receiving Nafamostat .
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
  • A similar trend was seen with Protein C .

Peripheral blood immunophenotyping

  • To assess immune perturbations associated with COVID-19 infection, and whether kinetic changes in the immune response correlated with treatment, flow cytometry was used to characterise peripheral blood leukocytes on entry to the trial (pre-treatment), and on day four and day seven whilst hospitalised.
  • Evidence of activation of the adaptive immune response during COVID-19 infection was seen as the presence of HLA-DR+CD38+ activated T cells and CD19+CD27+CD38+ antibody secreting cells (ASC) .
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
  • In summary, Nafamostat did not influence the rate of change in any immune parameters . .
  • The copyright holder for this preprint this version posted October 7, 2021.

DISCUSSION

  • Nafamostat was delivered at its recommended dose for its licenced indication.
  • CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
  • The copyright holder for this preprint this version posted October 7, 2021.
  • This experimental medicine trial with extensive phenotyping of PK and PD, does not support the use of intravenous Nafamostat in hospitalised COVID-19 patients.
  • The authors thank Nichi-Iko for kindly supplying Futhan (intravenous Nafamostat) for the trial;.

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TITLE: Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis:
Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics
Tom M. Quinn
#1,2
, Erin E. Gaughan
#1,2
, Annya Bruce
1
, Jean Antonelli
1
, Richard O’Connor
1
, Feng Li
1
,
Sarah McNamara
1
, Oliver Koch
3
, Claire MacIntosh
3
, David Dockrell
1,3
, Timothy Walsh
1,2
, Kevin G.
Blyth
4
, Colin Church
5
, Jürgen Schwarze
1
, Cecilia Boz
1
, Asta Valanciute
1
, Matthew Burgess
1
, Philip
Emanuel
1
, Bethany Mills
1
, Giulia Rinaldi
1
, Gareth Hardisty
1
, Ross Mills
1
, Emily Findlay
1
, Sunny
Jabbal
2
, Andrew Duncan
3
, Sinéad Plant
3
, Adam D. L. Marshall
1,2
, Irene Young
1
, Kay Russell
1
, Emma
Scholefield
1
, Alastair F. Nimmo
2
, Islom B. Nazarov
6,7
, Grant C. Churchill
7
, James S.O. McCullagh
9
,
Kourosh H. Ebrahimi
13
, Colin Ferrett
8
, Kate Templeton
2
, Steve Rannard
10
, Andrew Owen
10
, Anne
Moore
1
, Keith Finlayson
1
, Manu Shankar-Hari
1
, John Norrie
11
, Richard A. Parker
11
, Ahsan R.
Akram
1,2
, Daniel C. Anthony
7
, James W. Dear
2,12
, Nik Hirani
1,2
, Kevin Dhaliwal*
1,2
#
contributed equally
*Correspondence to Kev.Dhaliwal@ed.ac.uk
1
Centre for Inflammation Research, Queens Medical Research Institute, BioQuarter, University of Edinburgh, Edinburgh,
UK
2
Royal Infirmary of Edinburgh, BioQuarter, Little France, Edinburgh
3
Regional Infectious Disease Unit, NHS Lothian
4
Institute of Cancer Sciences, University of Glasgow
5
Department of Respiratory Medicine, Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde Health
Board, Glasgow, UK
6
Latus Therapeutics, Oxford, UK
7
Department of Pharmacology, University of Oxford, Oxford, UK
8
Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
9
Department of Chemistry, University of Oxford, Oxford, UK
10
Centre of Excellence for Long-acting Therapeutics, Materials Innovation Factory & Department of Pharmacology and
Therapeutics, University of Liverpool
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

11
Edinburgh Clinical Trials Unit (ECTU), Usher Institute, University of Edinburgh, Edinburgh, UK
12
Centre for Cardiovascular Science, Queen’s Medical Research Institute, Bioquarter, University of Edinburgh, Edinburgh,
UK
13
Institute of Pharmaceutical Science, King's College London, UK
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint

TITLE: Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis:
Phase 2A Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics
ABSTRACT
Despite the success of vaccines and selected repurposed treatments, COVID-19 is likely to remain a
global health problem and further chemotherapeutics are required. Many repurposed drugs have
progressed rapidly to Phase 2 and 3 trials without characterisation of Pharmacokinetics
(PK)/Pharmacodynamics (PD) including safety in COVID-19. One such drug is Nafamostat Mesylate
(Nafamostat), a synthetic serine protease inhibitor with anticoagulant and anti-inflammatory
properties. Preclinical data has demonstrated that it is has potent antiviral activity against SARS-CoV-
2 by directly inhibiting the transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell
entry.
Methods:
We present the findings of a phase Ib/II open label, platform randomised controlled trial (RCT),
exploring the safety of intravenous Nafamostat in hospitalised patients with confirmed COVID-19
pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative
therapy. Secondary endpoints included clinical endpoints such as number of oxygen free days and
clinical improvement/ deterioration, PK/PD, thromboelastometry, D Dimers, cytokines, immune cell
flow cytometry and viral load.
Results:
Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous
Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more
adverse events and a lower number of oxygen free days. There were no other statistically significant
differences in the primary or secondary endpoints between Nafamostat and SoC. PK data
demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We
observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry.
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint

Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no
differences in cytokine profile and immune cell phenotype and viral loads between the groups.
Conclusion
In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory,
anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials
with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to
selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat
delivered via a different route may be warranted. This trial demonstrates the importance of
experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint

INTRODUCTION
COVID-19, caused by the coronavirus SARS-CoV-2, was declared a global pandemic on the 11
th
of
March 2020 [1] and an ongoing global health, social and economic crisis has ensued. Vaccination
programmes are at varying stages globally, with concerns in vaccinated populations regarding
resistant strains ever-present. Identifying effective treatments for preventing clinical deterioration is
therefore of paramount importance. At the time of writing, dexamethasone and interleukin-6 receptor
antagonists [2] are the only effective treatments available for COVID-19 [3] [4], however, the
mortality rate of unvaccinated COVID-19 in hospitalised patients remains high at 22.9% [2].
Further chemotherapeutics are therefore required, with the repurposing of pre-existing drugs, quicker
and more cost-effective than the development of new medications.
Nafamostat Mesylate (Nafamostat) is a synthetic protease inhibitor and directly inhibits the
transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell entry of MERS-CoV,
therefore, blocking human cell entry [5]. This method of cell entry is shared by other coronaviruses
including SARS-CoV-2, and in-vitro studies have confirmed activity against SARS-CoV-2 [6, 7].
Nafamostat has shown to significantly reduce weight loss and lung tissue SARS-CoV-2 titres in
murine models [8]. Nafamostat has a short half-life and poor oral bioavailability, which necessitates
intravenous administration, limiting the potential use of the current formulation outside of a hospital
setting. It has been used to treat disseminated intravascular coagulation (DIC), acute pancreatitis, and
as an anticoagulant in extracorporeal hemofiltration and dialysis since the 1980s. In addition to the
potential antiviral effects, Nafamostat inhibits platelet aggregation, inhibits thrombin, kallikrein,
plasmin and other complement factors and reduces endothelial activation [9]. Given the prominent
activation of thrombotic pathways and endothelial inflammation in COVID-19 immunopathogenesis,
these are potentially beneficial attributes.
In this context Nafamostat is a drug highlighted as a potential target due to its antiviral,
immunomodulatory and anticoagulant effects. Nine trials are ongoing without testing whether at the
current recommended dose and route of administration, it has the expected PK/PD and safety profile.
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted October 7, 2021. ; https://doi.org/10.1101/2021.10.06.21264648doi: medRxiv preprint

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TL;DR: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Abstract: BackgroundCoronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.MethodsIn this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment.ResultsA total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55).ConclusionsIn patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936. opens in new tab; ISRCTN number, 50189673. opens in new tab.)

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TL;DR: In the recent outbreak of novel coronavirus infection in Wuhan, China, significantly abnormal coagulation parameters in severe novel coronvirus pneumonia (NCP) cases were a concern.
Abstract: Background: In the recent outbreak of novel coronavirus infection in Wuhan, China, significantly abnormal coagulation parameters in severe novel coronavirus pneumonia (NCP) cases were a concern. Objectives: To describe the coagulation feature of patients with NCP. Methods: Conventional coagulation results and outcomes of 183 consecutive patients with confirmed NCP in Tongji hospital were retrospectively analyzed. Results: The overall mortality was 11.5%, the non-survivors revealed significantly higher D-dimer and fibrin degradation product (FDP) levels, longer prothrombin time and activated partial thromboplastin time compared to survivors on admission (P < .05); 71.4% of non-survivors and 0.6% survivors met the criteria of disseminated intravascular coagulation during their hospital stay. Conclusions: The present study shows that abnormal coagulation results, especially markedly elevated D-dimer and FDP are common in deaths with NCP.

3,232 citations


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TL;DR: Three months ago, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) broke out in Wuhan, China, and spread rapidly around the world.
Abstract: Background Three months ago, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) broke out in Wuhan, China, and spread rapidly around the world. Severe novel coronavirus pneumonia (NCP) patients have abnormal blood coagulation function, but their venous thromboembolism (VTE) prevalence is still rarely mentioned. Objectives To determine the incidence of VTE in patients with severe NCP. Methods In this study, 81 severe NCP patients in the intensive care unit (ICU) of Union Hospital (Wuhan, China) were enrolled. The results of conventional coagulation parameters and lower limb vein ultrasonography of these patients were retrospectively collected and analyzed. Results The incidence of VTE in these patients was 25% (20/81), of which 8 patients with VTE events died. The VTE group was different from the non-VTE group in age, lymphocyte counts, activated partial thromboplastin time (APTT), D-dimer, etc. If 1.5 µg/mL was used as the D-dimer cut-off value to predicting VTE, the sensitivity was 85.0%, the specificity was 88.5%, and the negative predictive value (NPV) was 94.7%. Conclusions The incidence of VTE in patients with severe NCP is 25% (20/81), which may be related to poor prognosis. The significant increase of D-dimer in severe NCP patients is a good index for identifying high-risk groups of VTE.

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04 Sep 2020-Science
TL;DR: High-dimensional flow cytometry of hospitalized COVID-19 patients found three prominent and distinct immunotypes that are related to disease severity and clinical parameters, and a compendium of immune cell information and roadmaps for potential therapeutic interventions is provided.
Abstract: Coronavirus disease 2019 (COVID-19) is currently a global pandemic, but human immune responses to the virus remain poorly understood. We used high-dimensional cytometry to analyze 125 COVID-19 patients and compare them with recovered and healthy individuals. Integrated analysis of ~200 immune and ~50 clinical features revealed activation of T cell and B cell subsets in a proportion of patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses reaching >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable with that in uninfected individuals. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. Our analyses identified three immunotypes associated with poor clinical trajectories versus improving health. These immunotypes may have implications for the design of therapeutics and vaccines for COVID-19.

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Nafamostat Mesylate ( NafAmostat ) is a synthetic protease inhibitor and directly inhibits the transmembrane protease serine 2 ( TMPRSS2 ) dependent stage of host cell entry this paper.