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A decision-tree approach to treat platelet hyperactivity and anomalous blood clotting in acute COVID-19 patients

TL;DR: In this article, the authors present two treatment protocols that may be used to treat thrombotic and bleeding or thromboelastrography-based pathologies in COVID-19 patients.
Abstract: The coronavirus disease 2019 (COVID-19) (SARS-Cov-2) has caused a worldwide, sudden and substantial increase in hospitalizations for pneumonia with multiorgan problems. An important issue is also that there is still no unified standard for the diagnosis and treatment of COVID-19. Substantial vascular events are significant accompaniments to lung complications in COVID-19 patients. Various papers have now also shown the significance of thromboelastrography (TEG®) as point-of-care technology to determine the levels of coagulopathy (both clotting and bleeding) in COVID-19, in managing COVID-19 patients. Here we present two treatment protocols that may used to treat thrombotic and bleeding or thrombocytopenia pathologies. Both the protocols use clinical parameters like D-dimer and CRP, as well as the TEG®, to closely follow the daily clotting propensity of COVID-19 patients. We conclude by suggesting that the treatment of COVID-19 patients, should be based on a combination of blood biomarkers, and results from point-of-care analyses like the TEG®. Such a combination approach closely follow the physiological responses of the immune system, the haematological, as well as the coagulation system, in real-time.

Summary (2 min read)

INTRODUCTION

  • The coronavirus disease 2019 (COVID-19) (SARS-Cov-2) has caused a worldwide, sudden and substantial increase in hospitalizations for pneumonia with multiorgan problems (Docherty, et al 2020, Wiersinga, et al 2020, Wynants, et al 2020).
  • Approximately 5% of patients with significant COVID-19 symptoms, experience severe symptoms necessitating intensive care (Wiersinga, et al 2020), where as many individuals are probably never diagnosed because of a very mild version of the disease.
  • This can also be the case for relatively young patients who were previously healthy, or who had only minor underlying conditions (Ottestad, et al 2020).
  • An important issue is also that there is still no unified standard for the diagnosis and treatment of COVID-19 (Oldenburg and Doan 2020).
  • Various antiviral agents, some antibiotics and anti-inflammatory agents have been explored and their efficacy debated (see Table 1 for such a list of medications).

Protease inhibitors

  • Presently, it is suggested that best practices for supportive management of acute hypoxic respiratory failure and acute respiratory distress syndrome (ARDS) should be followed (Alhazzani, et al 2020, Wiersinga, et al 2020).
  • The new guidance - "COVID-19: Interim Guidance on Management Pending Empirical Evidence"- is published as an open access document on the American Thoracic Society's website (https://www.thoracic.org/covid/covid-19-guidance.pdf).
  • It should be noted that the timeline of the rollercoaster disease progression can be hours and it is a continuum rather than a clear event or “flip” between hypercoagulation and bleeding.
  • The authors also suggest that COVID-19 patients with acute respiratory failure represent the consequence of severe hypercoagulability, that when left untreated results in consumptive coagulopathy (end-stage DIC) and that excessive fibrin formation and polymerization may predispose to thrombosis and correlate with a worse outcome (Spiezia, et al 2020).
  • An important consideration is that TEG® can be used to study the clotting parameters of both whole blood (WB) and platelet poor plasma (PPP).

MATERIALS AND METHODS:

  • The decision-tree treatment protocol was developed by qualified clinicians, working in private practice, based on standard clinical treatment practices.
  • All pharmaceutical intervention suggested is within therapeutic levels and used within prescribed standard clinical protocols.
  • All drugs suggested in the decision-tree protocol must be used as originally indicated/designed and no “off-label” treatment should done.
  • Co-authors (EP, LMG, DBK, CV) are not medically qualified did not participate in either the development or use of the protocol.
  • Two clinical protocols are suggested, based on clinical features of the patient: A prognostic indicator scoring system was developed, based on a points system, to predict which patient is most likely to develop severe disease.

The prognostic indicator

  • A prognostic indicator score system was developed to determine risk of developing severe disease (see Table 4).
  • This score indicator system allows the clinician to allocate points for various parameters, including age, effort intolerance, Hypoxemia, O2 saturation, chest Z-ray and/or CT scan carotid intima-media thickness, and other co-morbidities.
  • In addition, a scoring based on parameters from the point-of-care TEG is also suggested.

Prognostic indicator

  • Proposed treatment decision-tree protocol Protocol 1: If clinical features point to hypercoagulation [early phase on the ‘rollercoaster’ diagram Figure 1A]: Figure 4A shows the decision-tree protocol that was developed by the clinical team, when a patient is admitted to the hospital with one or more possible clinical features after a positive COVID-19 nasal swab diagnosis.
  • The British Thoracic Society Severity Score (https://www.brit-thoracic.org.uk/about-us/covid-19-information-for-the-respiratory- community/) is another such lung CT scan scoring system used in COVID-19 grading.
  • If symptoms persist, CRP and TEG are done as needed.
  • The protocol also discussed the use of the potent platelet inhibitor, glycoprotein (GP) IIβ/IIIα inhibitor.
  • If clinical features point to bleeding [late phase on the rollercoaster diagram ], also known as Protocol 2.

CONCLUSION

  • Here the authors suggest that when hypercoagulation is present in the early stages of the condition, coagulation parameters can be tracked very successfully with the TEG®.
  • A close monitoring of clinical parameters of clotting, including D-dimer and TEG® parameters were crucial in managing patients.
  • A major challenge in early response in a rapidly evolving epidemic caused by a novel pathogen is the lack of traditional randomized placebo-controlled trials (RCTs) on which to make treatment and prevention decisions (Oldenburg and Doan 2020).
  • With this statement the authors most certainly do not imply that clinicians and researchers should lower the bar for standards of evidence.
  • The authors therefore suggest that COVID- 19 is indeed (also) a true vascular disease.

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1
A decision-tree approach to treat platelet hyperactivity and
anomalous blood clotting in acute COVID-19 patients
Gert Jacobus Laubscher
1
, Petrus Johannes Lourens
1
,
Chantelle Venter
2
, Lize Mireille
Grobbelaar
2
, Douglas B Kell
2,3,4*
, Etheresia Pretorius
2*
1
Stellenbosch Mediclinic, Elsie du Toit street, Stellenbosch 7600, South Africa
2
Department of Physiological Sciences, Faculty of Science, Stellenbosch University,
Stellenbosch, Private Bag X1 Matieland, 7602, South Africa
3
Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and
Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, L69 7ZB, UK.
4
The Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark,
Kemitorvet 200, 2800 Kgs Lyngby, Denmark.
*Corresponding authors:
*Etheresia Pretorius
Department of Physiological Sciences, Stellenbosch University, Private Bag X1 Matieland,
7602, SOUTH AFRICA
resiap@sun.ac.za
http://www.resiapretorius.net/
ORCID: 0000-0002-9108-2384
*Douglas B. Kell
Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and
Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, L69 7ZB, UK.
dbk@liv.ac.uk
ORCID: 0000-0001-5838-7963
Email addresses of authors:
GJ Laubscher: laubscher911@gmail.com
PJ Lourens: wodie@iafrica.com
E Pretorius: resiap@sun.ac.za
C Venter: chantellev@sun.ac.za
LM Grobbelaar: 21074682@sun.ac.za
DB Kell: dbk@liv.ac.uk
. CC-BY-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 July 25, 2021. ; https://doi.org/10.1101/2021.07.05.21260012doi: 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.

2
ABSTRACT
The coronavirus disease 2019 (COVID-19) (SARS-Cov-2) has caused a worldwide, sudden
and substantial increase in hospitalizations for pneumonia with multiorgan problems. An
important issue is also that there is still no unified standard for the diagnosis and treatment of
COVID-19. Substantial vascular events are significant accompaniments to lung complications
in COVID-19 patients. Various papers have now also shown the significance of
thromboelastrography (TEG
®
) as point-of-care technology to determine the
levels of
coagulopathy (both clotting and bleeding) in COVID-19, in managing COVID-19 patients.
Here we present two treatment protocols that may used to treat thrombotic and bleeding or
thrombocytopenia pathologies. Both the protocols use clinical parameters like D-dimer and
CRP, as well as the TEG
®
, to closely follow the daily clotting propensity of COVID-19 patients.
We conclude by suggesting that the treatment of COVID-19 patients, should be based on a
combination of blood biomarkers, and results from point-of-care analyses like the TEG
®
. Such
a combination approach closely follow the physiological responses of the immune system, the
haematological, as well as the coagulation system, in real-time.
Keywords: COVID-19; Platelets; Blood clotting; Treatment regime
. CC-BY-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 July 25, 2021. ; https://doi.org/10.1101/2021.07.05.21260012doi: medRxiv preprint

3
INTRODUCTION
The coronavirus disease 2019 (COVID-19) (SARS-Cov-2) has caused a worldwide, sudden
and substantial increase in hospitalizations for pneumonia with multiorgan problems
(Docherty, et al 2020, Wiersinga, et al 2020, Wynants, et al 2020). Severe cases of COVID-
19 are almost inevitably accompanied by respiratory failure and hypoxia, and treatment
includes best practices for supportive management of acute hypoxic respiratory failure
(Wiersinga, et al 2020). Approximately 5% of patients with significant COVID-19 symptoms,
experience severe symptoms necessitating intensive care (Wiersinga, et al 2020), where as
many individuals are probably never diagnosed because of a very mild version of the disease.
Depending on the clinical protocol followed by the specific hospital, among patients in the
intensive care unit (ICU) with COVID-19, between 29% to 91% require invasive mechanical
ventilation (Docherty, et al 2020, Grasselli, et al 2020). Some COVID-19 patients deteriorate
rapidly and seemingly without warning (Ottestad, et al 2020). This can also be the case for
relatively young patients who were previously healthy, or who had only minor underlying
conditions (Ottestad, et al 2020). We have recently shown that in COVID-19, the clotting
protein, fibrin(ogen), change to an amyloid form, that platelets are hyperactivated and that
they form complexes with erythrocytes (Pretorius, et al 2020, Venter, et al 2020). In addition
iron and p-selectin levels are also significantly dysregulated. It is also now accepted that
coagulation pathology is central in the disease (Giannis, et al 2020, Kollias, et al 2020, Levi,
et al 2020, Liu, et al 2020, Middeldorp, et al 2020, Miesbach and Makris 2020).
Despite the worsening trends of COVID-19 deaths, currently no drugs have been validated to
have significant efficacy in large-scale studies (Jean, et al 2020). An important issue is also
that there is still no unified standard for the diagnosis and treatment of COVID-19 (Oldenburg
and Doan 2020). However, various antiviral agents, some antibiotics and anti-inflammatory
agents have been explored and their efficacy debated (see Table 1 for such a list of
medications).
. CC-BY-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 July 25, 2021. ; https://doi.org/10.1101/2021.07.05.21260012doi: medRxiv preprint

4
Table 1: Various antiviral agents, antibiotics and anti-inflammatory agents suggested to be useful in
the treatment of COVID-19.
Agent
Use and comments
References
(general references and those
investigating use in COVID-19)
Inhibition of the RNA-dependent RNA polymerase (antivirals)
Remdesivir
Anti-viral therapeutic.
Results vary: No statistically significant clinical
benefits for severe COVID-19; or
improvement time to recovery (hospital discharge
or no supplemental oxygen requirement) from 15
to 11 days.
(Holshue, et al 2020, Jean, et al 2020,
Wang, et al 2020, Wiersinga, et al 2020)
Favipiravir
Known to be active in vitro against oseltamivir-
resistant influenza A, B, and C viruses.
Favipiravir was approved for treatment of novel
influenza on February 15, 2020 in China.
A 2020 study showed significantly better
treatment outcomes is COVID-19
(Cai, et al 2020, Dong, et al 2020, Wang,
et al 2019)
Protease inhibitors
Lopinavir/ritonavir
Inhibition of papain-like protease and 3C-like
protease, but in hospitalized adult patients with
severe Covid-19, no benefit was observed with
lopinavirritonavir treatment
(Cao, et al 2020, Dong, et al 2020)
Inhibition of cathepsin L and cathepsin B in host cells
Other therapies of interest
Monoclonal or
polyclonal antibodies
Prophylactic and therapeutic tools against some
viral infections, such as influenza.
Large gaps exist in our understanding of the risk
of immunopathology in COVID-19, the
epidemiological risk factors, the mechanism and
immune mediators of pathology during CoV
infections.
Monoclonal antibodies and hyperimmune globulin
may provide additional preventive strategies.
(Beigel, et al 2019, de Alwis, et al 2020,
Wiersinga, et al 2020)
Convalescent plasma
A rapid method to derive antiviral treatment for
Covid-19 is the use of convalescent plasma
derived hyperimmune globulin. No clear evidence
of benefit yet and a randomized trial found that it
did not shorten time to recovery.
(Bloch, et al 2020, Brown and
McCullough 2020, de Alwis, et al 2020,
Wiersinga, et al 2020)
Dexamethazone
Emerging data indicate that dexamethasone
therapy reduces 28-day mortality in patients
requiring supplemental oxygen compared with
usual care.
(Wiersinga, et al 2020)
L-ergothioneine
Potent antioxidant
(Borodina, et al 2020, Cheah and
Halliwell 2020)
Lactoferrin
Iron chelator and interferes with viral attachment
to membrane receptors
(Kell, et al 2020)
Niclosamide
Niclosamide has been identified as a potent
inhibitor of SARS-Cov-2 by Institut Pasteur
Korea, with potency >40 x higher than remdesivir
https://news.cision.com/union-
therapeutics/r/union-receives-approval-
from-danish-medicines-agency-to-
initiate-clinical-study-with-niclosamide-
for,c3145312
. CC-BY-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 July 25, 2021. ; https://doi.org/10.1101/2021.07.05.21260012doi: medRxiv preprint

5
Presently, it is suggested that best practices for supportive management of acute hypoxic
respiratory failure and acute respiratory distress syndrome (ARDS) should be followed
(Alhazzani, et al 2020, Wiersinga, et al 2020). The American Thoracic Society-led international
task force has also released a guidance document to help clinicians manage COVID-19. The
new guidance - "COVID-19: Interim Guidance on Management Pending Empirical Evidence"-
is published as an open access document on the American Thoracic Society's website
(https://www.thoracic.org/covid/covid-19-guidance.pdf). These guidelines in broad terms
suggest the use of ventilation in patients who have refractory hypoxemia and ARDS, to
consider extracorporeal membrane oxygenation in patients who have refractory hypoxemia,
COVID-19 pneumonia (i.e. ARDS), and have failed prone ventilation. Most significant is that
the guidelines recognise and state that: "We believe that in urgent situations like a pandemic,
we can learn while treating by collecting real-world data."
Evidence-based guideline initiatives have also been established by many countries and
professional societies, e.g. in South Africa, the South African Society of Anaesthesiologists
(SASA) has detailed guidelines on their website (https://sasacovid19.com/#guidance-
documents). In addition, guidelines are updated regularly by the National Institutes of Health
(https://www.covid19treatmentguidelines.nih.gov/).
Although current practice in the treatment of patients with severe COVID-19 suggests
mechanical ventilation, many patients might have normal lung compliance, yet they remain
hypoxic in spite of high inspiratory fractions. An important question to ask is therefore why is
the survival rate for patients in ICUs still so low? We note that most COVID-19 deaths are
because of ARDS. Recently it was reported that the mortality rate of patients on ventilators in
China is 80% (Yang, et al 2020). In general, the mortality rate of patients with ARDS is
proportionate to the severity of the disease, with 27%, 32%, and 45% for mild, moderate, and
severe disease, respectively (Diamond 2020). It was also noted that the pooled mortality rate
for all ARDS from 1994 to 2006 in the studies that were evaluated was 43% (Diamond 2020).
The question that now comes to mind is whether there might there be a pathophysiology link
that is not considered in the current best-practice protocols.
Significant evidence for hypercoagulation during the early stages of COVID-19 disease
We have presented evidence that COVID-19 can be seen as a two-phase rollercoaster of
events, characterized by (i) thrombotic and (ii) bleeding or thrombocytopenia pathologies
(Grobler, et al 2020). These substantial vascular events are significant accompaniments to
ARDS and lung complications and both vascular events are seen in COVID-19 patients. (Al-
Samkari, et al 2020, Bikdeli, et al 2020, Boccia, et al 2020, Connors and Levy 2020, Li, et al
. CC-BY-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 July 25, 2021. ; https://doi.org/10.1101/2021.07.05.21260012doi: medRxiv preprint

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Abstract: Niclosamide (NCL) is an anthelminthic drug, which is widely used to treat various diseases due to its pleiotropic anti-inflammatory and antiviral activities. NCL modulates of uncoupling oxidative phosphorylation and different signaling pathways in human biological processes. The wide-spectrum antiviral effect of NCL makes it a possible candidate for recent pandemic SARS-CoV-2 infection and may reduce Covid-19 severity. Therefore, the aim of the present study was to review and clarify the potential role of NCL in Covid-19. This study reviewed and highlighted the protective role of NCL therapy in Covid-19. A related literature search in PubMed, Scopus, Web of Science, Google Scholar, and Science Direct was done. NCL has noteworthy anti-inflammatory and antiviral effects. The primary antiviral mechanism of NCL is through neutralization of endosomal PH and inhibition of viral protein maturation. NCL acts as a proton carrier, inhibits homeostasis of endosomal PH, which limiting of viral proliferation and release. The anti-inflammatory effects of NCL are mediated by suppression of inflammatory signaling pathways and release of pro-inflammatory cytokines. However, the major limitation in using NCL is low aqueous solubility, which reduces oral bioavailability and therapeutic serum concentration that reducing the in vivo effect of NCL against SARS-CoV-2. NCL has anti-inflammatory and immune regulatory effects by modulating the release of pro-inflammatory cytokines, inhibition of NF-κB /NLRP3 inflammasome and mTOR signaling pathway. NCL has an anti-SARS-CoV-2 effect via interruption of viral life-cycle and/or induction of cytopathic effect. Prospective clinical studies and clinical trials are mandatory to confirm the potential role of NCL in patients with Covid-19 concerning the severity and clinical outcomes.

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TL;DR: This case highlights the importance of close coordination between clinicians and public health authorities at the local, state, and federal levels, as well as the need for rapid dissemination of clinical information related to the care of patients with this emerging infection.
Abstract: An outbreak of novel coronavirus (2019-nCoV) that began in Wuhan, China, has spread rapidly, with cases now confirmed in multiple countries. We report the first case of 2019-nCoV infection confirmed in the United States and describe the identification, diagnosis, clinical course, and management of the case, including the patient's initial mild symptoms at presentation with progression to pneumonia on day 9 of illness. This case highlights the importance of close coordination between clinicians and public health authorities at the local, state, and federal levels, as well as the need for rapid dissemination of clinical information related to the care of patients with this emerging infection.

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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.

4,510 citations

Journal ArticleDOI
28 Apr 2020-JAMA
TL;DR: Patients with coronavirus disease 2019 (COVID-19) requiring treatment in an intensive care unit (ICU) in the Lombardy region of Italy were characterized, including data on clinical management, respiratory failure, and patient mortality.
Abstract: Importance In December 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) emerged in China and has spread globally, creating a pandemic. Information about the clinical characteristics of infected patients who require intensive care is limited. Objective To characterize patients with coronavirus disease 2019 (COVID-19) requiring treatment in an intensive care unit (ICU) in the Lombardy region of Italy. Design, Setting, and Participants Retrospective case series of 1591 consecutive patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinator center (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network and treated at one of the ICUs of the 72 hospitals in this network between February 20 and March 18, 2020. Date of final follow-up was March 25, 2020. Exposures SARS-CoV-2 infection confirmed by real-time reverse transcriptase–polymerase chain reaction (RT-PCR) assay of nasal and pharyngeal swabs. Main Outcomes and Measures Demographic and clinical data were collected, including data on clinical management, respiratory failure, and patient mortality. Data were recorded by the coordinator center on an electronic worksheet during telephone calls by the staff of the COVID-19 Lombardy ICU Network. Results Of the 1591 patients included in the study, the median (IQR) age was 63 (56-70) years and 1304 (82%) were male. Of the 1043 patients with available data, 709 (68%) had at least 1 comorbidity and 509 (49%) had hypertension. Among 1300 patients with available respiratory support data, 1287 (99% [95% CI, 98%-99%]) needed respiratory support, including 1150 (88% [95% CI, 87%-90%]) who received mechanical ventilation and 137 (11% [95% CI, 9%-12%]) who received noninvasive ventilation. The median positive end-expiratory pressure (PEEP) was 14 (IQR, 12-16) cm H2O, and Fio2was greater than 50% in 89% of patients. The median Pao2/Fio2was 160 (IQR, 114-220). The median PEEP level was not different between younger patients (n = 503 aged ≤63 years) and older patients (n = 514 aged ≥64 years) (14 [IQR, 12-15] vs 14 [IQR, 12-16] cm H2O, respectively; median difference, 0 [95% CI, 0-0];P = .94). Median Fio2was lower in younger patients: 60% (IQR, 50%-80%) vs 70% (IQR, 50%-80%) (median difference, −10% [95% CI, −14% to 6%];P = .006), and median Pao2/Fio2was higher in younger patients: 163.5 (IQR, 120-230) vs 156 (IQR, 110-205) (median difference, 7 [95% CI, −8 to 22];P = .02). Patients with hypertension (n = 509) were older than those without hypertension (n = 526) (median [IQR] age, 66 years [60-72] vs 62 years [54-68];P Conclusions and Relevance In this case series of critically ill patients with laboratory-confirmed COVID-19 admitted to ICUs in Lombardy, Italy, the majority were older men, a large proportion required mechanical ventilation and high levels of PEEP, and ICU mortality was 26%.

4,331 citations

Journal ArticleDOI
TL;DR: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care, and future trials in patients withsevere illness may help to confirm or exclude the possibility of a treatment benefit.
Abstract: Background No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods We conducted a randomized, controlled, open-label trial involvin...

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