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COVID-19 & thrombotic disorders - Selected papers of interest - Research Publications

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Stago has listed articles and publications related to the current COVID-19 infection and focusing on thrombosis and haemostasis issues.

In this section, guidance and recommendations published by national and international societies are addressed.

This page is updated regularly once new information is published.

 

In a separate section, Opens external link in current window“Guidances & Recommendations”, all published scientific content of interest is collected.

 


RESEARCH PUBLICATIONS 

June 22, 2020. Systemic Inflammatory Response Syndrome is a Major Contributor to COVID-19-Associated Coagulopathy: Insights from a Prospective SingleCenter Cohort Study

Source : Paul Masi, Guillaume Hékimian, Manon Lejeune et al. Circulation. 2020,
https://doi.org/10.1161/CIRCULATIONAHA.120.048925

This recent paper, published in Circulation, helps better understand the Covid-19 infection pathophysiology from a haemostasis perspective in patients with acute respiratory distress syndrome (ARDS), in comparison with non-Covid-19 ARDS patients. The test panel comprises core lab parameters along with data generated with the Quantra® point of care viscoelastic analyser. This study confirms the ability of Quantra® to show Covid-19-associated coagulopathy, as previously described by Ranucci et al. (please see article below), and to differentiate Covid-19 from non-Covid-19 ARDS coagulopathy.

 

May 29, 2020. Understanding pathophysiology of hemostasis disorders in critically ill patients with COVID‑19

Source: Joly BS, Siguret V, Veyradier A. Intensive Care Med. 2020 May 15;1-4. doi: 10.1007/s00134-020-06088-1
https://link.springer.com/article/10.1007/s00134-020-06088-1

This short review uses easy-to-understand illustrations to summarize the complex mechanisms behind the haemostasis disorders observed in critically ill COVID-19 patients.

 

May 29, 2020. Involvement of ADAMTS13 and von Willebrand factor in thromboembolic events in patients infected with SARS-CoV-2

Source: Huisman A et al, Int J Lab Hematol. 2020;00:1–2.  DOI: 10.1111/ijlh.13244
https://onlinelibrary.wiley.com/doi/full/10.1111/ijlh.13244

As thrombotic microangiopathy (TMA) is one of the consequences of sepsis, authors measured ADAMTS13 and vWF levels in 12 patients with SARSCoV-2 infection with a clinical suspicion of TMA. The combination of low ADAMTS13 activity and high vWF levels might contribute to the microangiopathic state observed in these patients.
Authors therefore suggest including ADAMTS13 and vWF in the diagnostic workup of patients infected with SARS-CoV-2 when a microangiopathic state is suspected.

 

May 29, 2020. COVID-19 and hypercoagulability in the outpatient setting

Source: Emert R, Shah P, Zampella JG. Thromb Res. 2020 Aug; 192: 122–123. Doi: 10.1016/j.thromres.2020.05.031
https://www.thrombosisresearch.com/article/S0049-3848(20)30203-6/fulltext

This article raises the issue of hypercoagulability in outpatients with COVID-19 infection. Caution should be taken not to omit exploring the development of VTE in COVID-19 outpatients.
Some of the issues raised in T. Akel’s article (https://doi.org/10.1016/j.thromres.2020.05.033), which reported on outpatients who developed PE, are raised again here.
The authors suggest that risk stratification and anticoagulation could also be requested for outpatients.

 

May 29, 2020. Fibrinolysis Shutdown Correlates to Thromboembolic Events in Severe COVID-19 Infection

Source: Wright FL, Vogler TO, Moore EE et al, J Am Coll Surgeons:
https://linkinghub.elsevier.com/retrieve/pii/S1072751520304002

In this paper, the authors highlight that the reduction of fibrinolysis, evidenced by an increased D-dimer level (proposed threshold 2600 ng/mL) and a complete failure in TEG® clot lysis after 30minutes, is correlated with thromboembolic events and renal failure requiring hemodialysis. These results would therefore suggest the need for early therapeutic anticoagulation or fibrinolytic therapy to address this state of fibrinolysis shutdown.

May 20, 2020. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis

Source: Klok FA, Kruip MJHA, van der Meer NJM, et al. Thromb Res. 2020 Apr 10. doi: 10.1016/j.thromres.2020.04.013.
https://www.thrombosisresearch.com/article/S0049-3848(20)30120-1/pdf

 

May 20, 2020. Incidence of venous thromboembolism in hospitalized patients wiath COVID‐19

Source: Middeldorp S, Coppens M, van Haaps TF, et al. J Thromb Haemost. 2020 May 5. doi: 10.1111/jth.14888.
https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14888

These two articles confirm the elevated incidence of thromboembolic events in ICU COVID-19 patients: 49% (95% CI: 41–57) at 14 days in Klok’s study and 59% (95% CI: 42-72) at 21 days in Middeldorp’s study. Chronic anticoagulation therapy at admission is recommended in both articles to improve survival.

 

May 20, 2020. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19

Source: Wichmann D, Sperhake JP, Lütgehetmann M et al. Ann Intern Med. 2020 May 6. doi: 10.7326/M20-2003.
https://www.acpjournals.org/doi/10.7326/M20-2003

Complete autopsy was performed on 12 patients with confirmed COVID-19 infection. Autopsy revealed deep venous thrombosis in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death; pulmonary embolism was the direct cause of death in 4 patients.
These findings underline the significant role of COVID-19–induced coagulopathy.

 

May 20, 2020. A Proposal for Staging COVID-19 Coagulopathy

Source: Thachil J, Cushman M, Srivastava A. Res Pract Thromb Haemost. 2020 May . Doi: 10.1002/rth2.12372
https://onlinelibrary.wiley.com/doi/abs/10.1002/rth2.12372

COVID-19 is associated with thrombotic complications. This forum discusses the lungs as the epicenter for the haemostatic issues, puts forward a proposal for staging COVID-19 coagulopathy based on available diagnostic markers, and suggests current and future treatment options be considered based on these different stages.

 

High risk of thrombosis in patients with severe SARS‑CoV‑2 infection: a multicenter prospective cohort study

Source: Helms J, Tacquard C, Severac F et al. Intensive Care Med. 2020 May 4. doi: 10.1007/s00134-020-06062-x.
https://link.springer.com/article/10.1007/s00134-020-06062-x

This study aims at evaluating the thrombotic risk in ARDS COVID-19 patients. Over 150 patients, 64 clinically relevant thrombotic complications were diagnosed (mainly pulmonary embolism, 17%). Most patients (> 95%) had elevated D-dimer and fibrinogen. No patient developed disseminated intravascular coagulation. 50/57 tested patients (87.7%) had positive lupus anticoagulant.
These results show that life-threatening thrombotic complications are frequent and that higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.


COVID-19 and its implications for thrombosis and anticoagulation

Source: Connors JM, Levy JH. Blood. 2020 Apr 27. doi: 10.1182/blood.2020006000.
https://ashpublications.org/blood/article/doi/10.1182/blood.2020006000/454646/COVID-19-and-its-implications-for-thrombosis-and

This paper reviews the coagulation abnormalities that occur in association with COVID-19, and clinical management questions likely to arise. Authors thus suggest to perform coagulation test screening, including the measurement of D-dimer and fibrinogen levels, and to manage coagulopathy as it would be for any critically ill patient. However, they do not suggest the use of full intensity anticoagulation doses unless otherwise clinically indicated.


Lupus Anticoaulant and Abnormal Coagulation Tests in Patients with Covid-19

Source: Bowles L, Platton S, Yartey N et al. N Engl J Med. 2020 May 5. doi: 10.1056/NEJMc2013656.
https://www.nejm.org/doi/full/10.1056/NEJMc2013656


In this study, aPTT prolongation has been investigated in 35 patients and 31 of them were positive lupus anticoagulant (91%) and often had an associated factor XII deficiency.
In general cases, a prolonged aPTT could be seen as a reason to avoid the use of anticoagulation at both therapeutic and prophylactic doses. However no factor deficiency, nor bleeding tendency were reported. Authors suggest that a prolonged aPTT should not be a barrier to the use of anticoagulation therapies in the prevention and treatment of venous thrombosis in patients with Covid-19.


Soluble urokinase plasminogen activator receptor (suPAR) as an early predictor of severe respiratory failure in patients with COVID-19 pneumonia

Source: Rovina N, Akinosoglou K, Eugen-Olsen J et al. Crit Care. 2020 Apr 30;24(1):187. doi: 10.1186/s13054-020-02897-4.
https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-02897-4

In this letter, authors suggest that the soluble urokinase plasminogen activator receptor (suPAR) may reflect the endothelial activation in patients with COVID-19 infection, and may thus be an early predictor of severe respiratory failure (SRF). Receiver operator characteristics curve analysis identified levels ≥ 6 ng/ml as the best predictor for SRF. At that cutoff point, the sensitivity, specificity, positive predictive value, and negative predictive value for the prediction of SRF was 85.7%, 91.7%, 85.7%, and 91.7%, respectively.

COVID-19 cytokine storm: the interplay between inflammation and coagulation

Source: Jose RJ, Manuel A. Lancet Respir Med. 2020 Apr 27. doi: 10.1016/S2213-2600(20)30216-2.
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30216-2/fulltext

This letter reviews the interaction between coagulation and inflammatory systems in COVID-19 patients. The cytokine storm observed in patients enhances thrombin generation, and the thrombin generated may further augment inflammation via proteinase activated receptors (PARs). Authors thus suggest that targeting thrombin, coagulation factor Xa or PAR-1, might therefore be an attractive approach to reduce SARS-CoV-2 microthrombosis, lung injury, and associated poor outcomes.

Direct oral anticoagulant plasma levels striking increase in severe COVID-19 respiratory
Syndrome patients treated with antiviral agents. The Cremona experience

Source: Testa S, Prandoni P, Paoletti O et al. J Thromb Haemost. 2020 Apr 23. doi: 10.1111/jth.14871.
https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14871

The authors showed in this paper that DOAC patients treated with antiviral drugs show an alarming increase in DOAC plasma levels, with C‐trough levels 6.14 times higher during hospitalization than in pre‐hospitalization period. They recommend to replace DOAC with alternative parenteral antithrombotic strategies for as long as antiviral agents are deemed necessary and until discharge.


COVID‐19 Coagulopathy in Caucasian patients

Source: Fogarty H, Townsend L, Ni Cheallaigh C. Br J Haematol 2020 Apr 24. doi: 10.1111/bjh.16749.
https://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.16749

This paper shows haemostasis parameters depicting the coagulopathy in Caucasian patients (until now, most of reports reports were from Chinese patients).
Authors conclude that the marked increase in D-dimer levels is consistent with progressive coagulation activation, along with concurrent activation of fibrinolysis within the lungs. They also suggest that the pulmonary inflammation observed in COVID-19 is associated with a novel pulmonary-specific vasculopathy which they termed pulmonary intravascular coagulopathy (PIC) as distinct to DIC.


Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19

Source: Whyte CS, Morrow GB, Mitchell JL et al. J Thromb Haemost. 2020 Apr 23. doi: 10.1111/jth.14872.
https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14872

It appears that in addition to high-dose anticoagulation, fibrinolytic therapy may be necessary to degrade microthrombi present in the pulmonary alveoli of COVID-19 patients with ARDS. This review presents the repurposing of fibrinolytic drugs, namely tissue-type plasminogen activator (tPA), to treat COVID-19 associated with ARDS. Nebulizer plasminogen activators, currently in Phase II clinical trial, may provide a targeted approach in COVID-19 patients to degrade fibrin and improving oxygenation in critically ill patients.


Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2

Source: Beun R, Kusadasi N,Sikma M, et al. Int J Lab Hematol. 20 April 2020. Doi: 10.1111/ijlh.13230
https://onlinelibrary.wiley.com/doi/abs/10.1111/ijlh.13230

The high risk for arterial or venous thrombosis lead clinician to set up anticoagulant therapy in COVID-19 patients. As they observed heparin resistance in some patients, the authors suggest to monitor the heparin activity of UFH treatment based on anti-Xa levels with a target value of 0.3 - 0.7 U/L in all patients with SARS-CoV-2 instead of treatment based on aPTT levels.


Changes in Blood Coagulation in Patients with Severe Coronavirus Disease 2019 (COVID-19): a Meta-Analysis

Source: Xiong M, Liang X, Wei YD. Br J Haematol. 2020 Apr 18. doi: 10.1111/bjh.16725.
https://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.16725

In this article, authors pooled data from 9 studies performed in China evaluating coagulation abnormalities in COVID-19 patients, between severe and mild patients.
Pooled results revealed that prothrombin time and D-dimer levels were significantly higher in patients with severe COVID-19. However, no significant difference in PLT and APTT values between severe and mild patients were observed


The procoagulant pattern of patients with COVID‐19 acute respiratory distress syndrome

Source: Ranucci  M, Ballotta A,  Di Dedda U, et al. J THromb Haemost, 17 April 2020. Doi: 10.1111/jth.14854

Sixteen patients with COVID-19 ARDS were followed with haemostasis assays (aPTT, PT, platelet count, fibrinogen,D-dimer and antithrombin activity) and the Quantra® analyzer (Haemosonics, Charlottesville), a viscoelastic POC testing. The authors confirmed the pro‐coagulant pattern of these patients that may justify the thromboembolic complications (pulmonary embolism) during the course of the disease. Further studies are needed to assess the best prophylaxis and treatment of this condition.

View more at : https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14854

 

Tissue Plasminogen Activator (tPA) Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series

Source: Wang J, Hajizadeh N, Moore EE et al. J Thromb Haemost. 2020 Apr 8. doi: 10.1111/jth.14828.
https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14828

As thrombosis and DIC are frequently observed in patients who die from COVID-19, an American team has reported the off-label use of tPA (Alteplase®) in 3 critically-ill patients. They report clinical improvement in these patients with a decrease in hypoxemia as long as the tPA infusion lasted. These preliminary data, subject to confirmation in independent study, provide insights for improving the anticoagulant and fibrinolytic strategy in critically ill COVID-19 patients. The risk of catastrophic bleeding from use of tPA must be considered in the context of patient treatment.

 

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.

Source: Tang N, Li D, Wang X, Sun Z. J Thromb Haemost. 2020 Apr;18(4):844–7.
Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/jth.14768

In this paper, the coagulation features of patients with COVID-19 infection is described, by use of datacomparing survivors (n=162) and non-survivors (n=21). The non-survivors revealed significantly higher D-dimer and FDP levels, longer PT results (expressed in seconds) and significantly lower antithrombin levels compared with survivors on admission. A decrease in fibrinogen levels in non-survivors was found on days 10 and 14. DIC, mostly due to virus sepsis, appeared in most of the non-survivors.


Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.

Source: Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. J Thromb Haemost [Internet]. 2020 Mar 27
http://doi.wiley.com/10.1111/jth.14817

A paper retrospectively investigating the effect of anticoagulation on COVID-19 outcomes included 449 patients, 22% received treatment with UFH or LMWH. Use of anticoagulant treatment was associated with better prognosis in severe COVID‐19 patients meeting sepsis-induced coagulopathy criteria (SIC score) >4 or with markedly elevated D‐dimer (> 3 μg/L).

 

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