CC BY
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УДК 616.9:578.834.1
DOI 10.34014/2227-1848-2020-3-21-27
COVID-19 PNEUMONIA: THE POINT OF VIEW OF VASCULAR SPECIALIST
Luca Costanzo1, Simona Antonina Grasso2, Francesco Paolo Palumbo3, Giorgio Ardita1, Luigi Di Pino4, Pier Luigi Antignani5, Leonardo Aluigi6, Enrico Arosio7, Giacomo Failla1
1 Angiology Unit, San Marco Hospital, Department of cardiovascular disease, AOU Policlinico "G. Rodolico-San Marco", University of Catania, Catania, Italy; 2 Department of Anesthesia and Intensive Care, San Marco Hospital, AOU Policlinico "G. Rodolico-San Marco", Catania, Italy; 3 Surgery Unit, Villa Fiorita Clinic, Prato, Italy; 4 Cardiology and Angiology, Department of cardiovascular disease, C.A.S.T., A.O.U. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy; 5 Vascular center, Nuova Villa Claudia - Rome, Italy; 6 Angiology, Care Unit Villalba, Bologna, Italy; 7 University of Verona, Verona, Italy
The development of coagulopathy is emerging as one of the most significant poor prognostic features in COVID-19 pneumopathy. Thromboembolic manifestations such as pulmonary embolism and disseminated intravascular coagulation (DIC) have been reported and resulted in poor prognosis for the patient. Starting from the evidence in the literature, the purpose of this paper is to analyze potential mechanism involved in coagulation impairment following COVID-19 infection and identify possible vascular therapeutic strategies.
D-dimer, a protein product of fibrin degradation, has been found elevated in the most severe cases and correlated to mortality. Potentially involved factors in the impairment of coagulation caused by viral infection include the dysregulated inflammatory response, platelet and endothelial dysfunction with impaired fibrinolysis. Heparin is an anticoagulant molecule that also showed anti-inflammatory properties and a potential antiviral effect. A favorable outcome was highlighted with the use of LMWH in severe patients with COVID-19 who meet the SIC criteria (sepsis-induced coagulopathy) or with markedly high D-dimer. The use of low molecular weight heparin could prevent thromboembolic complications in COVID-19 pneumopathy. However, the correct timing of prophylaxis according to the stage of COVID-19 disease and the appropriate therapeutic dosage to use in severe cases need further researches.
Keywords: COVID-19, pneumonia, thrombosis, coagulopathy, D-dimer, low molecular weight heparin.
Introduction. Recent studies have shown that coagulopathy can occur during COVID-19 disease. Thromboembolic manifestations such as pulmonary embolism [1] and disseminated intravascular coagulation (DIC) [2] have been reported and resulted in poor prognosis for the patient.
Starting from the evidence in the literature, the purpose of this paper is to analyze potential mechanism involved in coagulation impairment following COVID-19 infection and identify possible vascular therapeutic strategies.
The interactions between inflammation and coagulation
A correlation between inflammation and coagulation has been widely demonstrated: inflame-
mation can lead to an altered coagulation, with a consequent imbalance between the pro- and anticoagulant state [3]. Several inflammatory cytokines such as IL-6, IL-8, and tumor necrosis factor-alpha (TNF-a) promote a procoagulant state through the expression of the tissue factor with a mechanism that includes the activation of endo-thelial cells, platelets and leukocytes [4]. Furthermore, an increased release of histones and nucle-osomes (DNA + histones), elements toxic to the endothelium, has been shown in sepsis and other inflammatory conditions. In contrast, activated protein C inactivates histones protecting the en-dothelium [5]. In response to the infection, extracellular DNA fibers extruded by neutrophils
(Neutrophil Extracellular Traps, NETs) are produced to allow neutrophils to trap and destroy invading microorganisms. NETs stimulate the formation and deposition of fibrin in order to trap microorganisms and control infection [6]. NETs also cause platelet adhesion and the link with deep vein thrombosis occurrence has been shown in some experimental models [7].
D-dimer is an epitope resulting from the plasmin degradation of cross-linked fibrin. D-dimer elevates in several conditions such as thrombosis, DIC and inflammation [8]. Notably, D-Dimer can promote the inflammatory cascade by activating neutrophils and monocytes, inducing the secretion of some inflammatory cytokines such as IL-6 [9].
Coagulation and viral infection
In several viral infections, a reduced platelet function as well as reduced platelets production or destruction has been documented phenomenon. Thrombocytopenia often occurs in both hemorrhagic and non-hemorrhagic viral infections. In most cases, thrombocytopenia is caused by autoimmune antibodies against platelets. Other mechanisms include increased platelet adhesion and activation resulting in platelet consumption and bone marrow infection that directly affects megakaryocytes and thus platelet production [3]. In SARS-CoV infection, thrombocytopenia caused by autoantibodies, presence of high levels of von Willebrand factor in the blood [10] and activation of the coagulation cascade with final generation of fibrin have been described [11]. Fibrin clots in the alveoli are an important feature of SARS-CoV infection in humans and mice. The goal of this coagulation response is probably to protect the host by sealing the alveoli, preventing edema and alveolar hemorrhages, but limiting the exchange of oxygen [12].
Markers of impaired coagulation in viral infection
A procoagulative state can be evidenced through an increase in the levels of coagulation proteins. Increased levels of fibrinogen, D-dimer, thrombin-antithrombin complexes and / or plas-min-alpha-2-antiplasmin complexes and thrombo-modulin have been found in respiratory tract infections, influenza and SARS-CoV infection. Furthermore, an increase in the levels of the plasminogen-1 activator inhibitor, suggestive of impaired fibrinolysis, was also reported [3]. Recently, Tang and
collaborators reported in 15 (71.4 %) deaths for COVID-19 alterations in laboratory parameters that fulfil the diagnostic criteria of the International Society on Thrombosis and Haemostasis for DIC [2]. In particular, in the final stage of disease, the authors found high levels of D-dimer and products of the degradation of fibrinogen.
Viral infection and coagulopathy
Either bleeding or thrombosis phenomena have been described as complication in several viral infections. An exaggerated response to the infection may even lead to intravascular coagulation disseminated with the formation of microvascular thrombi in various organs [13]. Respiratory tract infections increase the risk of deep vein thrombosis and pulmonary embolism. In the H1N1 flu epidemic (swine flu), both thrombotic and hemorrhagic complications such as deep vein thrombosis, pulmonary embolism and pulmonary hemorrhage with hemoptysis, hematemesis, pete-chial rash, and a case of diffuse petechial cerebral hemorrhage have been reported [3]. The occurrence of disseminated intravascular coagulation, pulmonary hemorrhage and thrombocytopenia has been reported in avian influenza (H5N1) in several patients [14]. In the SARS infection induced by a coronavirus, the clinical picture related to coagulation consisted of vascular endo-thelial damage in small and medium-sized pulmonary vessels, disseminated intravascular coagulation, deep vein thrombosis and pulmonary throm-boembolism [11].
Recently, Tang and collaborator reported a consumption coagulopathy in advanced stage of Covid-19 pneumopathy. Development of DIC results when monocytes and endothelial cells are activated to the point of cytokine release following injury, with expression of tissue factor and secretion of von Willebrand factor. Final result is circulation of free thrombin that can activate platelets and stimulate fibrinolysis [2].
Rationale for the use of heparins in Covid-19 infection
Heparins are anticoagulant drugs currently used for the prophylaxis and therapy of venous thromboembolism and are classified according to their molecular weight [15]. Heparin indirectly exerts its anticoagulant properties by binding re-versibly antithrombin III (AT) amplifying its subsequent inhibitory effect on activated factor X and
thrombin (factor Xa) [16, 17]. Only UFH containing at least 18 saccharide sequences can influence the action of AT on thrombin; however, UFH fragments of any length containing a unique pen-tasaccharide sequence can inhibit the action of factor Xa. This feature has been exploited by pharmacological research for realization of low molecular weight heparins (LMWH) [18].
Fondaparinux, a synthetic analogue of the pentasaccharide sequence, has longer half-life than LMWH and does not interact with platelets [19]. Fondaparinux binds reversibly to AT to produce an irreversible conformational change that enhances its reactivity with factor Xa. This results in inhibion and depletion of factor Xa which in turn inhibits thrombin generation in the coagulating signal transduction pathway. Notably, this molecule is characterized by therapeutic coverage in the 24-h and non-interference with platelets. Currently, is indicated for the prophylaxis and treatment of venous thromboembolism [20].
Heparin also exhibits anti-inflammatory properties [21]. Although still to be fully clarified, some of the proposed mechanisms include binding with inflammatory cytokines, inhibition of neutrophil chemotaxis and leukocyte migration, neutralization of complement factor C5a and sequestration of acute phase proteins such as P-se-lectin and L-selectin and induction to cell apopto-sis through TNF-a and NF-kB pathways [22, 23]. The ubiquitous endothelial cell is often affected by pathogenic invasion with consequent dysfunction. In addition, histones released from damaged cells may also be responsible for endothelial injury [5]. Heparin can antagonize histones and thus "protect" the endothelium [24, 25]. Another mechanism is through its effects on histone meth-ylation and on the MAPK and NF-kB signal pathways [26]. Therefore, heparin can protect from microcirculatory dysfunction and possibly decrease organ damage.
Another interesting concept is the potential antiviral role of heparin, which has been studied in experimental models. The polyanionic nature of heparin allows it to bind to different proteins and therefore act as an effective inhibitor of viral adhesion [27]. For example, in the case of herpes simplex virus infections, heparin competes with the host cell surface glycoprotein virus to limit infection and in Zika virus infection prevents cell vi-
rus-induced cell death human neural progenitors [27, 28]. Furthermore, the use of heparin at a concentration of 100 mcg/mL halved the infection in experimental cells contaminated with sputum from a patient with SARS-CoV pneumonia [29].
In a recent work, surface plasmon resonance and circular dichroism have been used and it has been shown that the binding domain of the Spike S1 SARS-CoV-2 protein receptor interacts with the heparin [30].
Finally, in the recent report by Tang and collaborators, a favorable outcome was highlighted with the use of LMWH in severe patients with COVID-19 who meet the SIC criteria (sepsis-induced coagulopathy) or with markedly high D-di-mer [31, 32]. Of 99 patients treated with heparin for at least 7 days, in almost all patients (n=94) a dosage of 40/60 mg die of enoxaparin subcutane-ously was used while in 5 patients unfractionated heparin was administered (10000-15000 U/day).
Considerations and possible therapeutic implications
The growing evidence puts the emphasis on an involvement of the coagulation system due to inflammation in COVID-19 pneumopathy. Although the data are still numerically insufficient to establish what the appropriate therapeutic regimen may be, the addition of heparin can have a favorable impact in COVID-19 infection disease progression. The reported data show that in most cases the infection has an asymptomatic course. The use of heparin is probably unnecessary in this population. However, in case of the onset and persistence of respiratory symptoms, even in patients in isolation at home, it is considered useful to start a prophylaxis with low molecular weight heparin (LMWH) or with Fondaparinux if renal function is preserved (creatinine clearance >50 ml/min). Should the patient develop a progressive worsening of respiratory symptoms in association with the increase in coagulation markers, therapy with LMWH should be carried out at therapeutic / sub-therapeutic doses taking into account clinical characteristics and hemorrhagic risk of patient. In advanced states, as powerful intravascular generation of thrombin occurs, unfractionated heparin could have a role. Furthermore, in these patients, careful monitoring of the coagulation parameters is necessary due to the possible evolution in DIC in the end stage of the disease [2].
Conflict of interest. The authors declare no conflict of interest.
Authors' contributions: all authors contributed to the conception and design of manuscript. LC wrote the manuscript, SAG, FPP, GA, LDP, PLA, LA, EA, GF contributed by reading and improving the manuscript.
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Received 25 June 2020; accepted 03 August 2020.
Information about the authors
Luca Costanzo, MD, San Marco Hospital, Department of cardiovascular disease, A.O.U. "Policlinico-Vit-torio Emanuele", University of Catania, Catania, Italy. Via Antonello da Messina 75 - 95021 Acicastello, Catania - Italy; e-mail: [email protected], ORCID ID: https://orcid.org/0000-0003-3595-3461.
Simona Antonina Grasso, MD, Department of Anesthesia and Intensive Care, San Marco Hospital, AOU Policlinico "G. Rodolico-San Marco", Catania, Italy. Via Rosso di San Secondo 17 - 95128 Catania - Italy; e-mail: [email protected], ORCID ID: https://orcid.org/0000-0001-8930-9714.
Francesco Paolo Palumbo, MD, Surgery Unit, Villa Fiorita Clinic, Prato, Italy. Viale Del Ciclope 14 - 90149 Palermo - Italy; e-mail: [email protected], ORCID ID: https://orcid.org/0000-0003-3121-6579.
Giorgio Ardita, MD, San Marco Hospital, Department of cardiovascular disease, A.O.U. "Policlinico-Vit-torio Emanuele", University of Catania, Catania, Italy. Via Pavia 7 - 95123 Catania - Italy; e-mail: [email protected], ORCID ID: https://orcid.org/0000-0002-2535-3967.
Luigi Di Pino, PhD, MD, professor, Cardiology and Angiology, Department of cardiovascular disease, C.A.S.T., A.O.U. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy. Via Ungaretti 1/R, 95014 Giarre, Catania - Italy; e-mail: [email protected], ORCID ID: https://orcid.org/0000-0003-4442-7199.
Pier Luigi Antignani, PhD, MD, professor, Vascular center, Nuova Villa Claudia - Rome, Italy. Via Germanico 211 - 00192 - Rome - Italy; e-mail: [email protected], ORCID ID: https://orcid.org/0000-0002-3982-5275.
Leonardo Aluigi, PhD, MD, professor, Angiology, Care Unit Villalba, Bologna, Italy. Via Giulietta Masina 5 40016 San Giorgio di Piano (BO) - Italy; e-mail: [email protected], ORCID ID: https://orcid.org/0000-0001-8507-1585.
Enrico Arosio, PhD, MD, professor, University of Verona, Verona, Italy. Via Porto San Pancrazio 111 -37133 - Verona - Italy; e-mail: [email protected], ORCID ID: https://orcid.org/0000-0002-6702-9727.
Giacomo Failla, MD, San Marco Hospital, Department of cardiovascular disease, A.O.U. "Policlinico-Vit-torio Emanuele", University of Catania, Catania, Italy. Via A Di Sangiuliano 50, Sant'Agata Li Battiati 95030 Catania, Italy; e-mail: [email protected], ORCID ID: https://orcid.org/0000-0003-1327-3908.
For citation
Luca Costanzo, Simona Antonina Grasso, Francesco Paolo Palumbo, Giorgio Ardita, Luigi Di Pino, Pier Luigi Antignani, Leonardo Aluigi, Enrico Arosio, Giacomo Failla.- COVID-19 Pneumonia: the Point of View of Vascular Specialist. Ul'yanovskiy mediko-biologicheskiy zhurnal. 2020; 3: 21-27. DOI: 10.34014/22271848-2020-3-21-27.
ПНЕВМОНИЯ ПРИ COVID-19: ВЗГЛЯД СОСУДИСТОГО ХИРУРГА
Лука Костанцо1, Симона Антонина Грассо2, Франческо Паоло Палумбо3, Джорджио Ардита1, Луиджи Ди Пино4, Пьер Луиджи Антиньяни5, Леонардо Алуиджи6, Энрико Арозио7, Джакомо Файлла1
1 Отделение ангиологии больницы Сан-Марко, отделение сердечно-сосудистых заболеваний, поликлиника Родолико-Сан-Марко, Катанийский университет, г. Катания, Италия;
2 Отделение анестезии и интенсивной терапии больницы Сан-Марко,
поликлиника Родолико-Сан-Марко, г. Катания, Италия;
3 Операционное отделение клиники Вилла Фиорита, г. Прато, Италия;
4 Кардиология и ангиология, отделение сердечно-сосудистых заболеваний, поликлиника Витторио Эмануэле, Катанийский университет, г. Катания, Италия; 5 Сосудистый центр, Нуова Вилла Клаудиа, г. Рим, Италия; 6 Ангиология, Медицинское отделение Виллалба, г. Болонья, Италия; 7 Университет Вероны, г. Верона, Италия
Одним из наиболее неблагоприятных прогностических признаков пневмопатии при COVID-19 является развитие коагулопатии. У пациентов с COVID-19 наблюдались признаки тромбоэмболии, например тромбоэмболия легочной артерии и ДВС-синдром, что негативно сказывалось на здоровье пациента.
Целью исследования является анализ потенциального механизма нарушения свертывания крови у пациентов, перенесших COVID-19, и определение возможных терапевтических стратегий. Было обнаружено, что у пациентов с тяжелой формой заболевания уровень D-димера, белкового продукта распада фибрина, повышен и напрямую взаимосвязан со смертностью. К факторам, влияющим на нарушение коагуляции, вызванной вирусной инфекцией, относятся неуправляемый воспалительный процесс, тромбоцитарная и эндотелиальная дисфункция с нарушением фибрино-лиза.
Гепарин, являясь прямым антикоагулянтом, также обладает противовоспалительными свойствами и выраженным противовирусным эффектом. Благоприятный исход наблюдался при использовании низкомолекулярного гепарина у тяжелых пациентов с COVID-19 с коагулопатией, вызванной сепсисом, или высоким уровнем D-димера.
Использование низкомолекулярного гепарина может предотвратить тромбоэмболические осложнения пневмопатии у пациентов с COVID-19. Тем не менее точное время профилактики в зависимости от стадии заболевания COVID-19 и соответствующая терапевтическая дозировка, которая может быть использована в тяжелых случаях, требуют дальнейших исследований.
Ключевые слова: COVID-19, пневмония, тромбоз, коагулопатия, D-димер, низкомолекулярный гепарин.
Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов.
Поступила в редакцию 25.06.2020; принята 3.08.2020.
Авторский коллектив
Лука Костанцо - доктор медицины, больница Сан-Марко, отделение сердечно-сосудистых заболеваний поликлиники Витторио Эмануэле, Катанийский университет, г. Катания, Италия. Via Antonello da Messina 75 - 95021 Acicastello, Catania - Italy; e-mail: [email protected], ORCID ID: https://or-cid.org/0000-0003-3595-3461.
Симона Антонина Грассо - доктор медицины, отделение анестезии и интенсивной терапии больницы Сан-Марко, поликлиника Родолико-Сан-Марко, г. Катания, Италия. Via Rosso di San Secondo i7 -95i2S Catania - Italy. Viale Del Ciclope i4 - 90i49 Palermo - Italy; e-mail: [email protected], GRCID ID: https://orcid.org/0000-000i-S930-97i4.
Франческо Паоло Палумбо - доктор медицины, хирургическое отделение клиники Вилла Фиорита, г. Прато, Италия. Viale Del Ciclope i4 - 90i49 Palermo - Italy; e-mail: [email protected], GRCID ID: https://orcid.org/0000-0003-3121-6579.
Джорджио Ардита - доктор медицины, больница Сан-Марко, отделение сердечно-сосудистых заболеваний поликлиники Витторио Эмануэле, Катанийский университет, г. Катания, Италия. Via Pavia 7 -95i23 Catania - Italy; e-mail: [email protected], GRCID ID: https://orcid.org/0000-0002-2535-39б7.
Луиджи Ди Пино - доктор медицины, профессор, кардиология и ангиология, отделение сердечнососудистых заболеваний поликлиники Витторио Эмануэле, Катанийский университет, г. Катания, Италия. Via Ungaretti i/R, 950i4 Giarre, Catania - Italy; e-mail: [email protected], GRCID ID: https://orcid.org/0000-0003-4442-7i99.
Пьер Луиджи Антиньяни - доктор медицины, профессор, Сосудистый центр, Нуова Вилла Клаудиа, г. Рим, Италия. Via Germanico 2ii - 00i92 - Rome - Italy; e-mail: [email protected], GRCID ID: https://orcid.org/0000-0002-39S2-5275.
Леонардо Алуиджи - доктор медицины, профессор, ангиология, отделение медицинской помощи Виллалба, г. Болонья, Италия. Via Giulietta Masina 5 400^ San Giorgio di Piano (BG) - Italy; e-mail: [email protected], GRCID ID: https://orcid.org/0000-000i-S507-i5S5
Энрико Аросио - доктор медицины, профессор, Веронский университет, г. Верона, Италия. Via Porto San Pancrazio iii - 37i33 - Verona - Italy; e-mail: [email protected], GRCID ID: https://or-cid.org/0000-0002^702-9727.
Джакомо Фаилла - доктор медицины, больница Сан-Марко, отделение сердечно-сосудистых заболеваний поликлиники Витторио Эмануэле, Катанийский университет, г. Катания, Италия. Via A Di Sangiuliano 50, Sant'Agata Li Battiati 95030 Catania, Italy; e-mail: [email protected], GRCID ID: https://orcid.org/0000-0003-i327-390S.
Образец цитирования
Luca Costanzo, Simona Antonina Grasso, Francesco Paolo Palumbo, Giorgio Ardita, Luigi Di Pino, Pier Luigi Antignani, Leonardo Aluigi, Enrico Arosio, Giacomo Failla. CGVID-i9 Pneumonia: the Point of View of Vascular Specialist. Ульяновский медико-биологический журнал. 2020; 3: 2i-27. DGI: i0.340i4/2227-iS4S-2020-3-2i-27.
