Anticoagulants as panacea in COVID-19 infection

Marcone Lima Sobreira Marcos Arêas Marques About the authors

The association between viral infections, such as human immunodeficiency virus (HIV), hepatitis C, and influenza, and venous thromboembolism (VTE) is well-established in the medical literature and the scientific community demonstrated this link again during the Chikungunya and Zika epidemics of 2017.11 Marques MA, Adami de Sá FP, Lupi O, Brasil P, von Ristow A. Deep venous thrombosis and chikungunya virus. J Vasc Bras. 2017;16(1):60-2. http://dx.doi.org/10.1590/1677-5449.009616. PMid:29930626.
http://dx.doi.org/10.1590/1677-5449.0096...
,22 Ramacciotti E, Agati LB, Aguiar VCR, et al. Zika and chikungunya virus and risk for venous thromboembolism. Clin Appl Thromb Hemost. 2019;25:1-5. http://dx.doi.org/10.1177/1076029618821184. PMid:30808213.
http://dx.doi.org/10.1177/10760296188211...
The ongoing global COVID-19 pandemic that started in Wuhan (China) and is caused by the SARS-CoV-2 coronavirus strain has already infected around 310,000 Brazilians and caused more than 20,000 deaths, according to data from the Ministry of Health.33 Brasil. Ministério da Saúde. Coronavírus: Brasil registra 49.492 casos e 3.313 mortes. Brasília: Ministério da Saúde; 2020. [citado 2020 maio 20]. https://www.saude.gov.br/noticias/agencia-saude/46771-coronavirus-brasil-registra-49-492-casos-e-3-313-mortes
https://www.saude.gov.br/noticias/agenci...

Although it has a wide clinical spectrum, ranging from an asymptomatic form to a severe acute respiratory syndrome (SARS),44 Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. http://dx.doi.org/10.1016/S0140-6736(20)30183-5. PMid:31986264.
http://dx.doi.org/10.1016/S0140-6736(20)...
what has attracted the attention of angiologists and vascular surgeons are the symptoms related to inflammation of the vascular system and the hypercoagulability, which cause manifestations such as vasculitis of small vessels and micro and macrovascular thrombosis of arteries and/or veins. Another observation that has attracted attention since the outset is the relationship between elevation of D-dimer (DD) and poor disease prognosis,55 Han H, Yang L, Liu R, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. 2020. Clin Chem Lab Med. 2020. 2020. Epub ahead of print. http://dx.doi.org/10.1515/cclm-2020-0188. PMid:32172226.
http://dx.doi.org/10.1515/cclm-2020-0188...
demonstrating a clear association between exacerbation of the systemic inflammatory response and the resulting prothrombotic state.66 Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Research. 2020;191:145-7. https://doi.org/10.1016/j.thromres.2020.04.013.
https://doi.org/10.1016/j.thromres.2020....

As the number of severe COVID-19 cases progressively increased, it was observed worldwide that there were elevated rates of deep venous thrombosis and pulmonary embolism in this subset of patients, even with pharmacoprophylaxis or full anticoagulation that would theoretically be sufficient for hospitalized clinical patients.77 Llitjos JF, Leclerc M, Chochois C, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost. 2020;1-4. http://dx.doi.org/10.1111/jth.14869. PMid:32320517.
http://dx.doi.org/10.1111/jth.14869...
In view of the above context, it is to be expected that there will be a progressive increase in publications relating VTE with infection by COVID-19 in the medical literature, aiming to share the as-yet scant knowledge that has been accumulated on this new infection.

However, despite the growing research networks that have formed to investigate COVID-19, it is noteworthy that the majority of studies present weak evidence, because, in general, what has been published to date are guidelines from specialty societies, expert opinions, in vitro studies, case reports, and some cases series (with small sample sizes). Moreover, hand-in-hand with this explosion of publications, we are confronted with a range of theories and normative statements on prophylaxis and treatment for VTE, serial measurement of DD, and administration of anticoagulants at the most varied posologies to these patients, without adequate scientific evidence, albeit because there has not been sufficient time to produce it.

What can be stated with confidence, so far, is that SARS-CoV-2 infection appears to have an elevated thrombogenic potential, with repercussions for pulmonary microcirculation, and so there may be some benefit, which remains to be proved, from systemic anticoagulation.88 Negri EM, Piloto BM, Morinaga LK, et al. Heparin therapy improving hypoxia in COVID-19 patients - a case series. medRxiv – The Preprint Server for Health Sciences. 2020. Epub ahead of print. https://doi.org/10.1101/2020.04.15.20067017.
https://doi.org/10.1101/2020.04.15.20067...
It is important to remember that, when dealing with anticoagulants, it is always necessary to consider the risk/benefit balance, weighing the potential efficacy: prevention of thrombosis pulmonary microcirculation and also at the arteriole-capillary level,99 Gauna MEG, Bernava JL. Recomendaciones diagnósticas y terapéuticas ante la Respuesta Inmune Trombótica Asociada a COVID-19 (RITAC). Argentina: Bonamí Estudio Creativo; 2020. [citado 2020 abr 26]. https://fundacionio.com/wp-content/uploads/2020/04/Si%CC%81ndrome-RITAC.pdf.pdf.pdf.pdf.pdf.pdf.pdf
https://fundacionio.com/wp-content/uploa...
against the risk of complications, such as bleeding.

Some reports by Chinese authors suggest that clinical improvement of patients infected by SARS-CoV-2 was associated with parenteral anticoagulation, notably low molecular weight heparin (LMWH); however, it is worth mentioning that the lack of criteria for indicating anticoagulant treatment and consequent indiscriminate use of anticoagulation may not be of benefit to patients,1010 Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Throm Haemost. 2020(18)5:1094-99. http://dx.doi.org/10.1111/jth.14817.
http://dx.doi.org/10.1111/jth.14817...
and it is too early to recommend this as the routine conduct in general. The beneficial effects of heparin in these patients (unfractionated heparin [UFH] or LMWH) appear to be multifaceted. In addition to their known anticoagulant and anti-inflammatory effects, heparins appear to play a protective role in endothelium, by antagonizing histones that cause endothelial injury and, as a result, microcirculation damage, and also appear to have an antiviral activity by competing with the virus for the binding site on the cell surface.1111 Thachil J. The versatile heparin in COVID-19. J Thromb Haemost. 2020;18(5):1020-2. http://dx.doi.org/10.1111/jth.14821. PMid:32239799.
http://dx.doi.org/10.1111/jth.14821...

We must be very careful not to fall into the panacea of using anticoagulants unchecked, for prophylaxis and treatment of the obvious hypercoagulability and its clinical manifestations that occur in these patients, especially based on serial DD assays, without a foundation in randomized, double-blind, controlled, multicenter clinical trials that can reliably demonstrate the scientific evidence necessary to guide management of this disease and, primarily, of patients. In the absence of such studies, we can and should rely on the existing guidelines for VTE treatment and prophylaxis in clinical patients, since they are evidence-based and valid.

More recently, a panel of experts published a document in which they discuss rationalization of use of anticoagulants in COVID-19 positive patients. They suggest that hospitalized patients should be categorized for risk of VTE in order to then be given the best prophylaxis for each specific case. With regard to continuing prophylaxis (especially chemical prophylaxis) for patients after discharge, there is no evidence on which to base systematic prescription; so it is suggested that patients are once more categorized at discharge for thrombotic and hemorrhagic risk and that the best treatment be chosen on this basis, in addition to instructing all to remain active when confined at home. There are still controversies and arguments with regard to use of intermediate or therapeutic heparin doses in these patients: the majority recommend use of prophylactic doses, whereas a minority consider that it is reasonable to use full or intermediate doses in this subset of patients.1212 Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol. 2020. Epub ahead of print. http://dx.doi.org/10.1016/j.jacc.2020.04.031.
http://dx.doi.org/10.1016/j.jacc.2020.04...

Knowledge with respect to this disease’s response to any type of suggested treatment is extremely fluid and concepts are constantly being renewed constantly, so great judgment and care are needed to manage it, attempting to always keep in mind a palpable and solid scientific basis, to avoid harming the patient.

  • How to cite: Sobreira ML, Marques MA. Anticoagulants as panacea in COVID-19 infection. J Vasc Bras. 2020;19:e20200063. https://doi.org/10.1590/1677-5449.200063
  • Financial support: None.
  • The study was carried out at Universidade Estadual Paulista (UNESP), Botucatu, SP, Brazil.

References

  • 1
    Marques MA, Adami de Sá FP, Lupi O, Brasil P, von Ristow A. Deep venous thrombosis and chikungunya virus. J Vasc Bras. 2017;16(1):60-2. http://dx.doi.org/10.1590/1677-5449.009616 PMid:29930626.
    » http://dx.doi.org/10.1590/1677-5449.009616
  • 2
    Ramacciotti E, Agati LB, Aguiar VCR, et al. Zika and chikungunya virus and risk for venous thromboembolism. Clin Appl Thromb Hemost. 2019;25:1-5. http://dx.doi.org/10.1177/1076029618821184 PMid:30808213.
    » http://dx.doi.org/10.1177/1076029618821184
  • 3
    Brasil. Ministério da Saúde. Coronavírus: Brasil registra 49.492 casos e 3.313 mortes. Brasília: Ministério da Saúde; 2020. [citado 2020 maio 20]. https://www.saude.gov.br/noticias/agencia-saude/46771-coronavirus-brasil-registra-49-492-casos-e-3-313-mortes
    » https://www.saude.gov.br/noticias/agencia-saude/46771-coronavirus-brasil-registra-49-492-casos-e-3-313-mortes
  • 4
    Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. http://dx.doi.org/10.1016/S0140-6736(20)30183-5 PMid:31986264.
    » http://dx.doi.org/10.1016/S0140-6736(20)30183-5
  • 5
    Han H, Yang L, Liu R, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. 2020. Clin Chem Lab Med. 2020. 2020. Epub ahead of print. http://dx.doi.org/10.1515/cclm-2020-0188 PMid:32172226.
    » http://dx.doi.org/10.1515/cclm-2020-0188
  • 6
    Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Research. 2020;191:145-7. https://doi.org/10.1016/j.thromres.2020.04.013
    » https://doi.org/10.1016/j.thromres.2020.04.013
  • 7
    Llitjos JF, Leclerc M, Chochois C, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost. 2020;1-4. http://dx.doi.org/10.1111/jth.14869 PMid:32320517.
    » http://dx.doi.org/10.1111/jth.14869
  • 8
    Negri EM, Piloto BM, Morinaga LK, et al. Heparin therapy improving hypoxia in COVID-19 patients - a case series. medRxiv – The Preprint Server for Health Sciences. 2020. Epub ahead of print. https://doi.org/10.1101/2020.04.15.20067017
    » https://doi.org/10.1101/2020.04.15.20067017
  • 9
    Gauna MEG, Bernava JL. Recomendaciones diagnósticas y terapéuticas ante la Respuesta Inmune Trombótica Asociada a COVID-19 (RITAC). Argentina: Bonamí Estudio Creativo; 2020. [citado 2020 abr 26]. https://fundacionio.com/wp-content/uploads/2020/04/Si%CC%81ndrome-RITAC.pdf.pdf.pdf.pdf.pdf.pdf.pdf
    » https://fundacionio.com/wp-content/uploads/2020/04/Si%CC%81ndrome-RITAC.pdf.pdf.pdf.pdf.pdf.pdf.pdf
  • 10
    Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Throm Haemost. 2020(18)5:1094-99. http://dx.doi.org/10.1111/jth.14817
    » http://dx.doi.org/10.1111/jth.14817
  • 11
    Thachil J. The versatile heparin in COVID-19. J Thromb Haemost. 2020;18(5):1020-2. http://dx.doi.org/10.1111/jth.14821 PMid:32239799.
    » http://dx.doi.org/10.1111/jth.14821
  • 12
    Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol. 2020. Epub ahead of print. http://dx.doi.org/10.1016/j.jacc.2020.04.031
    » http://dx.doi.org/10.1016/j.jacc.2020.04.031

Publication Dates

  • Publication in this collection
    12 June 2020
  • Date of issue
    2020

History

  • Received
    06 May 2020
  • Accepted
    25 May 2020
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