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COVID-19 and Hypercoagulable State: A New Therapeutic Perspective

COVID-2019; Betacoronavirus; Catastrophic Illness; Viral, Pneumonia; Pandemics; Coronavirus Infections; Complications, Cardiovasculares; Thrombophilia; Anticoagulants/therapeutic use

The novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the outbreak of the viral pneumonia identified for the first time in the Chinese city of Wuhan at the end of 2019. The outbreak has expanded rapidly, affecting 184 countries. The experience acquired in past months identified different clinical presentations with varied severity, ranging from asymptomatic infection to death due to multiple organic dysfunction. The World Health Organization (WHO) has recently defined the complex process of the SARS-CoV-2 infection as novel coronavirus disease 2019 (COVID-19).

COVID-19, whose notification grows fast in different countries, currently affects more than one million people worldwide according to the WHO, which has characterized the infection as a pandemic.11. Organização Mundial da Saúde. Relatórios de situação da doença coronavírus 2019 (COVID-2019).[Acesso em 29 de abril 2020] Disponível em: <https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports>
https://www.who.int/emergencies/diseases...
As of April 29, 2020, Brazil had registered 73,235 confirmed cases of COVID-19 and 5,083 deaths, with a case-fatality rate of 6,9%.22. Brasil.Ministério da Saúde. Boletim Epidemiológico Especial 08 – COE Coronavírus – 09 de abril de 2020. [Acesso em 29 de abril de 2020] Disponível em: < https://www.saude.gov.br/images/pdf/2020/April/09/be-covid-08-final-2.pdf >.
https://www.saude.gov.br/images/pdf/2020...
Hospitalization is necessary in up to 20% of the patients infected by SARS-CoV-2, and 5% to 10% of them require admission to the intensive care unit because of the need for hemodynamic and/or ventilatory support.33. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.

4. Liu K, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl). 2020 Feb 07, (online ahead of print)10.1097/CM9.0000000000000744.

5. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Feb 28; NEJM 0a2002032

6. Livingston E, Bucher K. Coronavirus Disease 2019 (COVID-19) in Italy. JAMA. 2020 Mar 17(online ahead of print).
-77. Grasselli G, Pesenti A, Cecconi M. Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response. JAMA. 2020 Mar 13 (online ahead of print). The mortality rate ranges from 0.8% to 12% depending on the country, and this difference might result from multiple factors, of which the healthcare system structure stands out.88. Wu Z, McGoogan JM. Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24 (online ahead of print).

9. Organização Mundial da Saúde (OMS). Relatório da Missão Conjunta OMS-China sobre a Doença de Coronavírus 2019 (COVID-2019). [Acesso em 04 abr 2020] Disponível em: http://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf>.
http://www.who.int/docs/default-source/c...

10. Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy. JAMA. 2020 May 23 (online ahead of print).
-1111. Korea Centers for Disease Control and Preservation. (KCDC)Atualizações sobre o COVID-19 na Coréia. [Acesso em 04 abr 2020] Disponível em: <https://www.cdc.go.kr/board/board.es?mid=a30402000000&bid=0030>
https://www.cdc.go.kr/board/board.es?mid...
Patients with the moderate and severe forms of the disease had manifestations mainly of the respiratory system involvement, with clinical findings ranging from mild pneumonia to acute respiratory distress syndrome (ARDS).77. Grasselli G, Pesenti A, Cecconi M. Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response. JAMA. 2020 Mar 13 (online ahead of print).,1111. Korea Centers for Disease Control and Preservation. (KCDC)Atualizações sobre o COVID-19 na Coréia. [Acesso em 04 abr 2020] Disponível em: <https://www.cdc.go.kr/board/board.es?mid=a30402000000&bid=0030>
https://www.cdc.go.kr/board/board.es?mid...

12. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020. https://doi.org/10.10116/S2213-2600(20)30079-5
https://doi.org/10.10116/S2213-2600(20)3...
-1313. Estimativas preliminares da prevalência de doenças subjacentes selecionadas em pacientes com doença de coronavírus 2019. E.U.A. [Acesso em 04 abr 2020] Disponível em: <https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e2.htm>.
https://www.cdc.gov/mmwr/volumes/69/wr/m...

Complications usually occur between the 7th and 12th day of disease.33. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.,1414. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Feb 07 (online ahead of print]. The most severe clinical manifestation, ARDS, is characterized by hypoxemia, bilateral pulmonary infiltrate, and variable phenotypic presentations, such as ‘normal lung compliance and low potential for lung recruitment’ and ‘low lung compliance and high potential for lung recruitment’. From 20% to 30% of the patients have cardiovascular complications, such as myocardial ischemia, acute coronary syndrome, myocarditis, arrhythmias, heart failure and shock. Kidney failure occurs in 30-50% of critically ill patients infected by SARS-CoV-2, 30% of whom require renal replacement therapy.1414. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Feb 07 (online ahead of print].

15. Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1295. Epub 2020 Mar 26.

16. Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, et al. Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State. JAMA. 2020 Mar 19;2204326.
-1717. Zhang T, Sun LX, Feng RE. Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Apr 3;43(0):E040.

The SARS-CoV-2 enters the cell via the angiotensin-converting enzyme 2 (ACE2) receptor present in the alveoli. The severe form of the infection is characterized by an intense immune-inflammatory response, evidenced by the presence of neutrophils, lymphocytes, monocytes and macrophages.18 Minimally invasive autopsies have revealed diffuse alveolar damage, hyaline membrane formation and interstitial mononuclear inflammatory infiltrate, with microcirculatory thrombosis.1717. Zhang T, Sun LX, Feng RE. Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Apr 3;43(0):E040. High serum levels of pro-inflammatory cytokines (interleukins 1 and 6, tumor necrosis factor and interferon-g), known as “cytokine storm”, have been reported in those patients.

Thrombosis and damage to extrapulmonary organs have been observed without the confirmed presence of the virus in those sites, which led to the assumption that SARS-CoV-2 infection involves intense inflammatory response with a hypercoagulable state and ischemia, aggravated by hypoxemia.1717. Zhang T, Sun LX, Feng RE. Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Apr 3;43(0):E040.,1919. Yao Xiaohong, Li Tingyuan, He Zhicheng, Coronavirus disease pneumonia 2019 (COVID-19): 3 cases of puncture histopathology in several locations. Chin J Pathol. 2020,49.,2020. Luo W, Yu H, Gou J, Li X, Sun Y, Li J, et al. Clinical Pathology of Critical Patient with Novel Coronavirus Pneumonia (COVID-19). Preprints. 2020, 2020020407. In Brazil, preliminary findings of minimally invasive autopsies performed at the São Paulo Medical School have shown similar results to those from China.2121. Agência Fapesp. Autópsia em mortos por COVID-19 ajuda no tratamento de casos graves da doença. [Acesso em 04 abr 2020] Disponível em: <http://agencia.fapesp.br/autopsia-em-mortos-por-covid-19-ajuda-no-tratamento-de-casos-graves-da-doenca/32882/>
http://agencia.fapesp.br/autopsia-em-mor...

When elevated, D-dimer, a product of fibrin degradation, has been associated with a higher mortality rate.2222. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507. Epub 2020 Jan 30. Expert opinion, based on clinical experience and analysis of a few descriptive studies, highlights the role of the hypercoagulable state on the pathophysiology of COVID-19, supported by the progressive increase in D-dimer levels as the disease worsens. The phase in which ARDS develops and the radiographic pattern worsens is marked by the significant elevation of D-dimer. The most severe cases develop myocardial injury and disseminated intravascular coagulation (DIC).2323. Zhang Y, Cao W, Xiao M, Li YJ, Yang Y, Zhao J, Zhou X, Jiang W, Zhao YQ, Zhang SY, Li TS. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za Zhi. 2020 Mar 28;41(0):E006.,2424. Taisheng Li, Hongzhou Lu, Wenhong Zhang. Clinical observation and management of COVID-19 patients. Emerg Microbes Infect. 2020 Dec;9(1):687-90.

Systemic inflammatory response in patients with infection can result in endothelial damage, with a consequent increase in thrombin generation and a reduction in endogenous fibrinolysis.2525. Levi M, van der Poll T. Coagulation and sepsis. Thromb Res. 2017; 149:38–44.,2626. Schmitt FCF, Manolov V, Morgenstern J, Fleming T, Heitmeier S, Ubile F, et al.Acute fibrinolysis shutdown occurs early in septic shock and is associated with increased morbidity and mortality: results of an observational pilot study. Ann Intensive Care. 2019; 9(1):19. This prothrombotic state is called sepsis-induced coagulopathy (SIC) and precedes DIC.2727. Iba T, Levy JH, Warkentin TE, Tachill J, van der Poll T. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost. 2019; 17(11):1989–94.,2828. Iba T, Nisio MD, Levy JH, Kitamura N, Thachil J. New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey. BMJ Open. 2017; 7(9):e017046. The several mechanisms involved in SIC act simultaneously towards a pro-hemostatic state. Apparently, inflammatory cytokines are the most important factors mediating that coagulation system disorder during sepsis.

Evidence has shown a bidirectional relationship between inflammation and coagulation, in which inflammation activates coagulation, and coagulation heightens inflammatory activity (Figure 1).2929. Levi AM, van der Poll HR.. Buller, The bidirectional relationship between coagulation and inflammation, Circulation.2004;109(22):2698-704.

30. Zimmerman BGA, McIntyre TM, Prescott SM, Stafforini S. The platelet-activating factor signaling system and its regulators in syndromes of inflammation and thrombosis. Crit Care Med. 2002; 30(Suppl):S294-S301.

31. Shebuski CRJ, Kilgore KS. Role of inflammatory mediators in thrombogenesis. J Pharmacol Exp Ther. 2002;300(3):729-35.
-3232. Levi DM, van der Poll T. Coagulation in patients with severe sepsis. Semin. Thromb. Hemost.2015;41(1):9-15. Platelets play a central role in the development of coagulation abnormalities in sepsis and they can be activated directly by pro-inflammatory mediators, such as platelet activating factors, as well as by the thrombin generated. Platelet activation can also stimulate the formation of fibrin via an alternative mechanism. The expression of P-selectin in platelet membrane not only mediates the adhesion of platelets to leukocytes and endothelial cells, but also increases the tissue factor expression in monocytes. Under normal circumstances, the activation of coagulation is controlled by three important physiological anticoagulant pathways: the antithrombin system, the activated C-protein system, and the tissue-factor pathway inhibitor. In sepsis, all three pathways are dysfunctional. Amidst all this coagulation system imbalance, endogenous fibrinolysis is largely reduced.

Figure 1
The novel coronavirus, SARS-CoV-2, activates the inflammatory and thrombotic process. The disease it causes is associated with an increase in inflammatory cytokines (cytokine storm) and coagulation disorders, with predisposition to thrombus formation. Mononuclear cells interact with activated platelets and the coagulation cascade, which activate inflammatory cells by binding thrombin and tissue factor with specific protease activated receptors and by binding fibrin to Toll-like receptor 4. The activation of inflammatory cells results in the release of pro-inflammatory cytokines, leading to impairment of the natural coagulation pathways and shut down of fibrinolysis. PAR: protease-activated receptor; TLR4: Toll-like receptor 4; aPTT: activated partial thromboplastin time; PT: prothrombin time; IL: interleukin; TNFα: tumor necrosis factor-α. Figure adapted from Levi M, van der Poll T.25

According to the criteria established by the International Society on Thrombosis and Hemostasis (ISTH), better clinical outcomes can be identified in patients with SIC on anticoagulant therapy.2727. Iba T, Levy JH, Warkentin TE, Tachill J, van der Poll T. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost. 2019; 17(11):1989–94.,2828. Iba T, Nisio MD, Levy JH, Kitamura N, Thachil J. New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey. BMJ Open. 2017; 7(9):e017046. The use of anticoagulants, mainly in critically ill patients, is not free from risk and might be related to severe hemorrhagic complications. Thus, the indication of anticoagulants should be personalized, respecting thrombotic and hemorrhagic risk profiles.

Hemophagocytic syndrome (HPS) is characterized by a systemic inflammatory response triggered by the inappropriate activation and proliferation of lymphocytes, which activate macrophages and histiocytes, resulting in phagocytosis of hematological cells. The disease is associated with a large production of inflammatory cytokines. The initial clinical findings of HPS are marked by those of the systemic inflammatory response syndrome. As HPS develops, the following might be observed: neurological findings, liver function changes, DIC, hepatosplenomegaly, pancytopenia, and high ferritin levels. Those findings can be triggered by infections, such as COVID-19, which shows, in some cases, a large release of cytokines, mainly interleukin 6, in association with systemic inflammatory response and DIC. Such conditions should be considered based on clinical and laboratory findings, and an early therapeutic approach should be defined to reverse them.2828. Iba T, Nisio MD, Levy JH, Kitamura N, Thachil J. New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey. BMJ Open. 2017; 7(9):e017046.

SARS-CoV-2 infection, in its most severe presentation, marked by organic dysfunction, such as acute respiratory failure, meets the diagnostic criteria for sepsis.3333. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-10. Recent observational studies have correlated the hypercoagulable state with the severe form of COVID-19, in which SIC and/or DIC seem to be present in most fatal cases.33. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.,2121. Agência Fapesp. Autópsia em mortos por COVID-19 ajuda no tratamento de casos graves da doença. [Acesso em 04 abr 2020] Disponível em: <http://agencia.fapesp.br/autopsia-em-mortos-por-covid-19-ajuda-no-tratamento-de-casos-graves-da-doenca/32882/>
http://agencia.fapesp.br/autopsia-em-mor...

22. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507. Epub 2020 Jan 30.
-2323. Zhang Y, Cao W, Xiao M, Li YJ, Yang Y, Zhao J, Zhou X, Jiang W, Zhao YQ, Zhang SY, Li TS. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za Zhi. 2020 Mar 28;41(0):E006.,3434. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020.18(4):844-7. The reduction in oxygen arterial pressure found in critical patients contributes directly and indirectly to the development of ischemic syndrome.3535. Gupta N, Zhao YY, Evans CE. The stimulation of thrombosis by hypoxia. Thromb Res.2019;181:77–83. In line of this, results suggest that the prothrombotic pathophysiology already described in sepsis might be related to intrinsic aspects of the novel coronavirus, and, thus, the beneficial potential of the use of anticoagulants in selected groups of patients should be analyzed individually. A retrospective study conducted in the hospital of Tongji (Wuhan, China) has reported lower mortality in patients with severe COVID-19 who had used anticoagulants, unfractionated heparin or low-molecular weight heparin (LMWH), with a SIC score of ≥ 4 and/or very high D-dimer (> 6 times the upper limit of reference range).3636. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.J Thromb Haemost. 2020 Mar 27 (online ahead of print). Accepted Author Manuscript. doi:10.1111/jth.14817.

Anticoagulant therapy in patients with severe COVID-19 and signs of SIC and/or very high D-dimer in association with other biomarkers of severity, in the absence of contraindication to anticoagulation, can be considered a therapeutic strategy for SARS-CoV-2 infection, based on expert consensus and a few retrospective studies. Moreover, that strategy requires the use of strict institutional protocols that enable surveillance and rapid intervention if complications occur. Figure 2 shows the algorithm to assess thrombogenesis in patients with COVID-19, as well as a suggestion of treatment. However, data are still insufficient to determine important aspects for the elaboration of a therapeutic plan, such as the best drug choice, its dosage and administration time schedule, as well as the duration of treatment.

Figure 2
The diagnosis of COVID-19 should be confirmed according to the World Health Organization recommendations.37 Patients with the severe form of that disease8,38 in addition to a sepsis-induced coagulopathy score ≥ 4 or disseminated intravascular coagulation and/or D-dimer levels > 6 times the upper limit of reference range might benefit from anticoagulant therapy. INR, international normalized ratio; SIC, sepsis-induced coagulopathy; ISTH, International Society on Thrombosis and Hemostasis; SOFA, sequential organ failure assessment; DIVC, disseminated intravascular coagulation; ULRR, upper limit of reference range.

Further studies, mainly prospective, are required to better support the indication of anticoagulation for critical patients infected by the novel coronavirus. The possible benefit from attenuating the hypercoagulable state should be balanced against the risk of bleeding. Anticoagulant therapy might be more beneficial when initiated in the pre-thrombotic stage and not in advanced phases, when the risk of bleeding is higher. If deciding to use anticoagulation, LMWH should be chosen for stable patients with normal creatinine clearance (dose of 1 mg/kg, 12/12h, subcutaneous). In case of shock or creatinine clearance below 50 mL/min/m2, intravenous heparin (18 IU/kg/h) should be used, aiming at an activated partial thromboplastin time between 1.5 and 1.8. However, there is no evidence to support the wide use of the therapeutic dose of heparin in COVID-19.

In conclusion, the pathophysiology of COVID-19 involves activation of the inflammatory response and induction of the thrombotic system. Currently, the expert consensus suggests anticoagulant treatment for patients with the pro-coagulant phenotype (high D-dimer, prolongation of prothrombin time and increased plasma levels of fibrin fragments). Further studies are required to confirm the real role of anticoagulation to prevent COVID-19 complications.

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  • Study Association
    This article is part of the thesis of master submitted by Jorge Henrique Paiter Nascimento, from Universidade Federal do Rio de Janeiro.
  • Ethics approval and consent to participate
    This article does not contain any studies with human participants or animals performed by any of the authors.
  • Sources of Funding
    There were no external funding sources for this study.

Publication Dates

  • Publication in this collection
    01 June 2020
  • Date of issue
    May 2020

History

  • Received
    10 Apr 2020
  • Reviewed
    15 Apr 2020
  • Accepted
    15 Apr 2020
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