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COVID-19 and Dysfunctional Endothelium: The Mexican Scenario

Authors:
Jose Antonio Alvarado-Moreno at Mexican Institute of Social Security
Jose Antonio Alvarado-Moreno
Abraham Majluf-Cruz at Mexican Institute of Social Security
Abraham Majluf-Cruz
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OPINION
COVID-19 and Dysfunctional Endothelium: The Mexican Scenario
Jose Antonio Alvarado-Moreno and Abraham Majluf-Cruz
Unidad de Investigaci
on M
edica en Trombosis, Hemostasia y Aterogenesis, Hospital General Regional No.1, Dr. Carlos MacGregor S
anchez Navarro,
Instituto Mexicano del Seguro Social, Ciudad de M
exico, M
exico
Received for publication May 7, 2020; accepted May 12, 2020 (ARCMED_2020_643).
The pandemic of a new coronavirus started in December
2019 in Wuhan China and is the cause of a high percentage
of the world population infected with symptoms of the Se-
vere Acute Respiratory Syndrome (SARS), now SARS-
CoV-2. The World Health Organization (WHO) named it
COVID19 disease and alerted countries with vulnerable
health systems to establish an urgent response (1). The
clinical conditions detected in infected patients are quite
similar to those observed during previous pandemics,
SARS-CoV in 2003 and MERS-CoVA in 2012. Age of
people infected with COVID-19 ranges from
20e80 years old although most deaths occur in patients
older than 60 yearold. Moreover, death is associated with
chronic diseases such as hypertension, diabetes and
vascular diseases (2). However, after the pandemic spreads
in America, it has been observed, particularly in Mexico,
that deaths occur in patients at a mean of 40e59 years
old (3). According to the WHO, Mexico is between the
world leading ranks in terms of chronic diseases and the
consequent endothelial dysfunction. Is there an explanation
for this apparent earlier age for death in Mexican patients?
It has been reported that patients with COVID-19 may pre-
sent venous thromboembolic disease or disseminated intra-
vascular coagulopathy, events involving hemostatic
elements as wells as the innate immune response (4). Endo-
thelial dysfunction leads to platelet and leukocyte activa-
tion, abnormalities in the anticoagulant and fibrinolytic
mechanisms and the resulting abnormalities of the blood
coagulation tests and increased plasma D-dimer, circu-
lating thrombin and activated protein C, closely associated
to endothelial dysfunction, there is also increased inflam-
matory cytokines in which tumor necrosis factor a(TNF-
a) has a predominant role. Patients with recurrent unpro-
voked venous thromboembolic disease also have both,
endothelial dysfunction recognized from the early endothe-
lial colony-forming cells (a subpopulation of circulating
endothelial progenitor cells), and increased TNF-asynthe-
sis which induces a chronic inflammatory state that may
resemble the cytokine storm identified in patients with
COVID-19 (5). It seems quite apparent that SARS-CoV-2
may induce endothelial dysfunction as suggested by the
increased expression of the human angiotensin-converting
enzyme type 2 (ACE2), a receptor necessary for the entry
of the virus (6). Perhaps, deaths occurring in Mexico at
younger age as compared with other countries may be
related to the high frequency of vascular risk factors and
the consequent endothelial dysfunction (Figure 1). Such
chronic conditions may worsen as soon as the virus infects
a young patient with chronic endothelial dysfunction. An
old epidemic with a new face?
Conflict of Interest
We declare no competing interests.
Acknowledgments
Supported by Instituto Mexicano del Seguro Social (IMSS,
Mexico), by the grant FIS/IMSS/PROT/PRIO/18/077.
Address reprint requests to: Jose Antonio Alvarado-Moreno, Calle Es-
peranza No. 1021, C-403 Narvarte, 03020, Benito Ju
arez, Ciudad de
M
exico, M
exico; Phone: (þ52) (55) 5519-4785 FAX: (þ52) (55) 5510-
7580; E-mail: alvarado_m01@yahoo.com.mx
0188-4409/$ - see front matter. Copyright Ó2020 IMSS. Published by Elsevier Inc.
https://doi.org/10.1016/j.arcmed.2020.05.004
Archives of Medical Research -(2020) -
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Figure 1. As the epidemics of obesity and related comorbidities (risk factors), appears earlier in the Mexican population, endothelial cell dysfunction also
appears in youngest patients. When a severe trigger event affects a patient with increased vascular risk factors, namely COVID-19 infection, the critical level
of endothelial cell dysfunction also appears earlier in that individual. The relationship between high frequency of vascular factors, COVID-19, and endothe-
lial cell dysfunction may explain the deaths at a younger age in Mexico as compared with other populations.
2Alvarado-Moreno and Majluf-Cruz / Archives of Medical Research -(2020) -
... Este virus se propagó rápidamente alrededor del mundo y le tomó tres meses llegar a convertirse en una Pandemia. Desde un inicio se lo consideró como agente causal de la neumonía, hoy se sabe que está relacionado con una disfunción endotelial (1)(2)(3). ...
... En un estudio se habló ya de la posibilidad de que el COVID-19 produce un aumento de la expresión de la enzima convertidora de angiotensina 2 (ACE2) como un receptor necesario para que el virus pueda ingresar (3,18). ...
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Introducción: El primer estudio retrospectivo realizado en el lugar donde inició la pandemia COVID-19 no reporta manifestaciones cutáneas en los pacientes. Posterior hubo un reporte de 0,2% luego 4,9% y 20,4% de afecciones dermatológicas presentes en contagiados por la enfermedad, sin embargo, siempre se consideraban inespecíficas e inusuales, por lo que es notorio que no se estudió la dermatología en pacientes contagiados. Objetivo: analizar las manifestaciones cutáneas que se presentan en pacientes infectados por COVID-19 mediante una revisión sistemática Métodos: esta investigación detalla las manifestaciones cutáneas de los primeros estudios realizados desde el año 2020 mediante la selección por criterios de inclusión y exclusión. Resultados: dependen de varios factores y es posible encontrar lesiones tipo pseudo-sabañones, lesiones vasculo-purpúricas, urticaria, rash, maculopapular, lesiones acrales con eritema, livedo y necrosis, no obstante, existe un factor clave y es que muchas veces se podía confundir las manifestaciones cutáneas con las reacciones adversas provocados por medicamentos utilizados para combatir la enfermedad. Pese a los resultados obtenidos en esta revisión, en los niños no se puede definir los mismos determinantes ya que en ellos no se reportan dichas manifestaciones que ofrezcan datos de importancia, solo existen reportes de eccemas maculopapular eritematosos, no pruriginosos en cuello y tronco, urticaria. Conclusiones: al tener un primer contacto con un paciente contagiado por COVID-19 se debe realizar un abordaje completo e integral del paciente ya que existen numerosas manifestaciones que orientan al diagnóstico y no se debe pasar inadvertido la dermatología en un paciente infectado.
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... Отсутствие истории течения этого заболевания, данных рандомизированных исследований часто затрудняет правильный выбор тактики лечения и назначения адекватной профилактики у больных, перенесших COVID-19. Имеется большое количество публикаций, указывающих на выраженное влияние дисфункции эндотелия на развитие и прогрессирование этого малоизученного заболевания [1][2][3][4][5]. Прогрессирование дисфункции эндотелия неизбежно связано с развитием коагулопатии и другими нарушениями в системе гемостаза, что чаще всего клинически проявляется микротромбо образованием [6][7][8][9][10]. ...
The potential of high-frequency ultrasound Dopplerography in the assessment of microcirculatory disorders in post-COVID-19 patients with a cardiovascular profile
Article
  • Jan 2022
Introduction. Patients with cardiovascular diseases have endothelial dysfunction and a higher risk of severe course of COVID-19, and thrombotic complications. Associated endotheliitis caused by virus penetration and cytokines storm leads to the release of tissue factor, the formation of excess thrombin and fibrin and thrombosis. The aim . To identify the potential of high-frequency ultrasound Dopplerography (HFUDG) for the assessment of microcirculatory disorders in post-COVID-19 patients with cardiovascular profile and to assess the microcirculatory bed condition before and after treatment with sulodexide. Materials and methods. 49 patients recovered from moderate-severe COVID-19 one month ago, aged 20–80, were examined. 24 patients, received prophylaxis with POACs for 1 month, formed group I, group II – 25 patients without prophylaxis. The nail bed of the upper limb 1st finger was examined using HFUDG and a 25 MHz sensor. Shape and spectrum of curves taken from dopplerograms were analyzed. The control examination was performed 4 weeks after therapy. Results. In patients after COVID19, depletion of spectral characteristics was revealed in comparison with dopplerograms of healthy individuals. The predominantly red part of the spectrum corresponding to the fastest particles was recorded. Slow-moving particles corresponding to the lighter part of the spectrum were nearly non-existent. In patients administrated POAC prophylaxis, amplitude indices were higher. Significant increase in D-dimer, antithrombin III, and soluble fibrin monomer complexes (SFMC) was also detected. The remaining parameters of the coagulogram were within the norm before and after treatment. After a course of sulodexide therapy, the spectral characteristics and coagulogram parameters returned to normal. Conclusion. HFUDG allows to detect stasis of capillary blood flow, the appearance of shunt blood flow corresponding to microtrombosis. Microcirculation indicators in post-COVID-19 patients improved after a course of preventive therapy with sulodexide.
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... Our results strongly suggest an abnormal functional endothelial status determined by an absence or reduction of endothelial regeneration in subacute, moderate COVID-19 patients. We may speculate that all disturbances found in ECFCs from COVID-19 patients are worse during the acute phase of a severe disease, a fact that may help to explain the highly significant increase of thrombotic episodes observed in these patients [9]. ...
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... What have emerged as key components in the pathogenesis and lethality of this syndrome are the cardiac and vascular complications. [2][3][4] Infection by SARS-CoV-2 can lead to acute respiratory distress syndrome (ARDS), which is associated with a robust cytokine storm, coagulation disturbances, and multi-organ failure (MOF). 5 It can be hypothesized that systemic vascular injury and inflammation caused by the virus are major drivers behind the disease pathology of SARS-CoV-2 infection, where patients develop ARDS and subsequent MOF, reminiscent of what has been observed in bacterial sepsis or massive hemorrhage. ...
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... Furthermore, it has been shown that, within the pathophysiology of PAH due to OSA, pulmonary microcirculation presents hypoxic vasoconstriction and endothelial dysfunction that promotes a pro-inflammatory and local procoagulant state [45]. These factors may be important in the progression of COVID-19 by promoting viral-induced damage of the endothelium of pulmonary capillaries, causing local inflammation and thrombotic events [46,47]. Therefore, the combination of these factors could favour severe pulmonary inflammation in patients with obesity, which could explain the greater requirements of IMV, ICU admission and mortality. ...
Obesity is a strong risk factor for short-term mortality and adverse outcomes in Mexican patients with COVID-19: A national observational study
Article
Full-text available
  • Apr 2021
Conflicting results have been obtained through meta-analyses for the role of obesity as a risk factor for adverse outcomes in patients with COVID-19, possibly due to the inclusion of predominantly multimorbid patients with severe COVID-19. Here, we aimed to study obesity alone or in combination with other comorbidities as a risk factor for short-term all-cause mortality and other adverse outcomes in Mexican patients evaluated for suspected COVID-19 in ambulatory units and hospitals in Mexico. We performed a retrospective observational analysis in a national cohort of 71,103 patients from all 32 states of Mexico from the National COVID-19 Epidemiological Surveillance Study. Two statistical models were applied through Cox regression to create survival models and logistic regression models to determine risk of death, hospitalization, invasive mechanical ventilation, pneumonia, and admission to an intensive care unit, conferred by obesity and other comorbidities (diabetes mellitus [DM], chronic obstructive pulmonary disease [COPD], asthma, immunosuppression, hypertension, cardiovascular disease [CVD], and chronic kidney disease [CKD]). Models were adjusted for other risk factors. From February 24 to April 26, 2020, 71,103 patients were evaluated for suspected COVID-19; 15,529 (21.8%) had a positive test for SARS-CoV-2; 46,960 (66.1%), negative, and 8,614 (12.1%), pending results. Obesity alone increased adjusted mortality risk in positive patients (HR=2.7, 95%CI:2.04-2.98), but not in negative and pending-result patients. Obesity combined with other comorbidities further increased risk of death (DM: HR=2.79, 95%CI:2.04-3.80; immunosuppression: HR=5.06, 95%CI:2.26-11.41; hypertension: HR=2.30, 95%CI:1.77-3.01) and other adverse outcomes. In conclusion, obesity is a strong risk factor for short-term mortality and critical illness in Mexican patients with COVID-19; risk increases when obesity is present with other comorbidities.
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... This is quite apparent in Mexico, since the prevalence of vascular risk factors is very high and, therefore, the occurrence of serious infections is observed in younger patients in comparison with that which occurs in Europe, for example. 5,6 An explanation for this phenomenon is that endothelial dysfunction affects the Mexican population earlier. In addition to this, we know that COVID-19-associated coagulopathy initiation and maintenance are largely determined by the entry of the virus into the endothelium, an early phenomenon in the course of infection that translates into higher endothelial dysfunction. ...
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... Esto es muy aparente en México ya que la prevalencia de factores de riesgo vascular es muy alta y, por lo tanto, se observa la aparición de infecciones graves en enfermos más jóvenes en comparación con lo que ocurre en Europa, por ejemplo. 5,6 Una explicación para este fenómeno es que la disfunción endotelial afecta más tempranamente a la población mexicana. Aunado a esto, sabemos que el inicio y mantenimiento de la coagulopatía asociada con COVID-19 están determinados en gran medida por la entrada del virus al endotelio, fenómeno temprano en la infección que se traduce en mayor disfunción endotelial. ...
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... Both the inflammatory response and the infection can activate the endothelium, leading finally to its dysfunction associated with greater platelet and leucocyte activation, along with altered anticoagulant and fibrinolytic mechanisms detected through some serum markers such as increased levels of d-dimer, c-reactive protein or TNF-α (117). In fact, elevated serum levels of some of these compounds have been linked to a poorer prognosis and a greater severity commencing early on (118). ...
View
... Both the inflammatory response and the infection can activate the endothelium, leading finally to its dysfunction associated with greater platelet and leucocyte activation, along with altered anticoagulant and fibrinolytic mechanisms detected through some serum markers such as increased levels of d-dimer, c-reactive protein or TNF-α (117). In fact, elevated serum levels of some of these compounds have been linked to a poorer prognosis and a greater severity commencing early on (118). ...
An integrative look at SARS‑CoV‑2 (Review)
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Full-text available
  • Dec 2020
SARS‑CoV‑2 is a newly discovered member of the betacoronaviruses and the etiological agent of the disease COVID‑19. SARS‑CoV‑2 is responsible for the worldwide pandemic which has been taking place in 2020, and is causing a markedly higher number of infections and deaths compared to previous coronaviruses, such as SARS‑CoV or MERS‑CoV. Based on updated scientific literature, the present review compiles the most relevant knowledge of SARS‑CoV‑2, COVID‑19 and the clinical and typical responses that patients have exhibited against this virus, discussing current and future therapies, and proposing strategies with which to combat the disease and prevent a further global threat. The aggressiveness of SARS‑CoV‑2 arises from its capacity to infect, and spread easily and rapidly through its tight interaction with the human angiotensin‑converting enzyme 2 (ACE‑2) receptor. While not all patients respond in a similar manner and may even be asymptomatic, a wide range of manifestations associated with COVID‑19 have been described, particularly in vulnerable population groups, such as the elderly or individuals with other underlying conditions. The proper function of the immune system plays a key role in an individual's favorable response to SARS‑CoV‑2 infection. A hyperactivated response, on the contrary, could account for the more severe cases of COVID‑19, and this may finally lead to respiratory insufficiency and other complications, such as thrombotic or thromboembolic events. The development of novel therapies and vaccines designed to control and regulate a proper immune system response will be key to clinical management, prevention measures and effective population screening to attenuate the transmission of this novel RNA virus.
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Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis
Article
Full-text available
  • Mar 2020
  • INT J INFECT DIS
Background: An outbreak of coronavirus disease 2019 (COVID-19) occurred in Wuhan, China; the epidemic is more widespread than initially estimated, with cases now confirmed in multiple countries. Aims: The aim of this meta-analysis was to assess the prevalence of comorbidities in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)infected patients and the risk of underlying diseases in severe patients compared to non-severe patients. Methods: A literature search was conducted using the databases PubMed, EMBASE, and Web of Science through February 25, 2020. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using random-effects models. Results: Seven studies were included in the meta-analysis, including 1 576 infected patients. The results showed the most prevalent clinical symptom was fever (91.3%, 95% CI: 86–97%), followed by cough (67.7%, 95% CI: 59–76%), fatigue (51.0%, 95% CI: 34–68%) and dyspnea (30.4%, 95% CI: 21–40%). The most prevalent comorbidities were hypertension (21.1%, 95% CI: 13.0–27.2%) and diabetes (9.7%, 95% CI: 7.2– 12.2%), followed by cardiovascular disease (8.4%, 95% CI: 3.8–13.8%) and respiratory system disease (1.5%, 95% CI: 0.9–2.1%). When compared between severe and non-severe patients, the pooled OR of hypertension, respiratory system disease, and cardiovascular disease were 2.36 (95% CI: 1.46–3.83), 2.46 (95% CI: 1.76–3.44) and 3.42 (95% CI: 1.88–6.22) respectively. Conclusion: We assessed the prevalence of comorbidities in the COVID-19 patients and found that underlying disease, including hypertension, respiratory system disease and cardiovascular disease, may be risk factors for severe patients compared with non-severe patients.
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Abnormal Coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia
Article
Full-text available
  • Feb 2020
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 consecutive 183 patients with confirmed NCP in Tongji hospital were retrospectively analysed. 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<0.05). 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.
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World Health Organization declares Global Emergency: A review of the 2019 Novel Coronavirus (COVID-19)
Article
  • Feb 2020
  • Int J Surg
An unprecedented outbreak of pneumonia of unknown aetiology in Wuhan City, Hubei province in China emerged in December of 2019. A novel coronavirus was identified as the causative agent and was subsequently termed COVID-19 by the World Health Organization (WHO). Considered a relative of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), COVID-19 is a betacoronavirus that affects the lower respiratory tract and manifests as pneumonia in humans. Despite rigorous global containment and quarantine efforts, the incidence of COVID-19 continues to rise, with 50,580 laboratory-confirmed cases and 1,526 deaths worldwide. In response to this global outbreak, we summarise the current state of knowledge surrounding COVID-19.
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Endothelial colonyforming cells: biological and functional abnormalities in patients with a history of recurrent, unprovoked venous thromboembolic disease
  • Jan 2016
  • THROMB RES
  • 157-168
  • J A Alvarado-Moreno
  • J R Hern Andez-L Opez
  • Ch Avez-Gonz Alez
Alvarado-Moreno JA, Hern andez-L opez JR, Ch avez-Gonz alez A, et al. Endothelial colonyforming cells: biological and functional abnormalities in patients with a history of recurrent, unprovoked venous thromboembolic disease. Thromb Res 2016;137:157e168.