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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 54-57

Coronavirus disease-2019 and its macro- and microvascular implications: The Italian Microcirculation Society's analyses

1 Department of Microcirculation, J.F. Merlen Research Centre for Vascular Disease, Frosinone, Italy
2 Department of Clinical Microcirculation, Società Italiana di Microcircolazione, Rome, Italy
3 Department of Vascular Surgery, Presidio Ospedaliero di Tortona ASL Alessandria, Tortona, Italy
4 Department of Angiology, Azienda Ospedaliera Universitaria Policlinico Vittorio Emanuele Unità Operativa Angiologia Ospedale San Marco, Catania, Sicily, Italy
5 Department of Vascular Surgery, Aurelia Hospital, Rome, Italy
6 Department of Angiology, Azienda Ospedaliera dei Colli, Naples, Italy
7 Department of Angiology, Casa di Cura Privata Accreditata I.N.I. – Div. Città Bianca Veroli, La Vittoria, Rome, Italy
8 Department of Angiology, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
9 Department of Dermatology, Università di Trieste, Trieste, Italy

Date of Submission08-May-2020
Date of Decision10-May-2020
Date of Acceptance11-May-2020
Date of Web Publication09-Jul-2020

Correspondence Address:
Dr. Salvino Bilancini
Via Mola Vecchia, 4, 03100 Frosinone
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/VIT.VIT_12_20

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Coronavirus disease-2019 (COVID-19) is characterized by a violent multiorgan inflammation which activates coagulation, thereby inducing arterial and venous thrombosis. In particular, it leads to thrombi of the microcirculation in a variety of organs and apparatus. Compelling data have confirmed this hypothesis and studies that demonstrate how coagulation parameters, such as D-dimer and fibrinogen, might provide important prognostic evidence. On reviewing the relevant literature available to date, the authors have set out to express their opinion as to the need not to underestimate the thrombotic component of COVID-19 at all levels (arterial, venous, and microcirculatory).

Keywords: Coronavirus disease-2019, microcirculation, thrombosis

How to cite this article:
Bilancini S, Allegra C, Bonadeo P, Failla G, Guarnera G, Leonardo G, Lucchi M, Mollo PE, Nicosia PM, Trevisan G. Coronavirus disease-2019 and its macro- and microvascular implications: The Italian Microcirculation Society's analyses. Vasc Invest Ther 2020;3:54-7

How to cite this URL:
Bilancini S, Allegra C, Bonadeo P, Failla G, Guarnera G, Leonardo G, Lucchi M, Mollo PE, Nicosia PM, Trevisan G. Coronavirus disease-2019 and its macro- and microvascular implications: The Italian Microcirculation Society's analyses. Vasc Invest Ther [serial online] 2020 [cited 2021 Jan 26];3:54-7. Available from: https://www.vitonline.org/text.asp?2020/3/2/54/289240

  Introduction Top

Coronavirus disease (COVID), known by the acronym COVID-19, presents peculiar physiopathological aspects that involve the vascular system as a whole, related in particular to microcirculatory flow in the internal organs and organ systems, as well as in the skin. Vascular involvement seems to be the result of severe and generalized activation of secondary coagulation associated with elevated inflammation triggered by the COVID-19 infection. This activation is manifested not only by venous thrombosis and pulmonary embolisms but also by various arterial thrombosis, such as coronary and cerebral thrombosis, and microcirculatory thrombosis of various internal organs, which can lead to multiple organ failure (MOF) or disseminated intravascular coagulation (DIC).

  Physiopathology Top

It is well known that inflammatory processes are strictly linked to and associated with coagulation.[1] Indeed, cytokines (especially interleukin [IL] 6, IL8, and tumor necrosis factor) determine the activation of platelets and leukocytes, with subsequent endothelial dysfunction and production of tissue factor.

Bearing in mind that COVID-19 exploits angiotensin converting enzyme 2 receptors expressed on the endothelial cell, it can be presumed that this too may contribute to damaging the endothelium, lowering its antithrombotic defense.[2] Furthermore, the inflammatory processes determine an increase in blood viscosity due to a rise in fibrinogen. COVID-19 itself triggers a platelet activation and an elevated production of the von Willebrand factor, thus further heightening coagulation activity.[3] An increase in the plasminogen activator inhibitor, in the thrombin-antithrombin and plasmin-antiplasmin complexes, has been registered in severe acute respiratory syndrome (SARS) CoV. Both SARS and COVID-19 show a marked rise in D-dimer levels that correlate with patient prognosis.[4]

  Clinical Data and Anatomopathological Patterns Top

In severe cases of COVID-19, pulmonary embolism is very frequent and may exceed 10% (SFA Guidelines) in the intensive care unit patients; risk of venous thromboembolism (VTE) is very high as well.[5] Madjid et al.[6] demonstrate an increment in the risk of Myocardial infarction (MI) and ischemic stroke. A recent in-depth article by Laroche[7] considers COVID-19 a risk factor for worsening of obstructive arterial disease in the lower limbs. From an anatomopathological point of view, a study by Yao et al.[8] has illustrated thrombosis in pulmonary microcirculation, at times associated with focal hemorrhage, and has highlighted the presence of virus particles. Massive thromboses have been observed with necrotic tissue in the microcirculation of other internal organs, where no virus particles were detected. Zang et al.[9] have compared these data with that of SARS and have claimed that the microthrombosis dysfunction of extrapulmonary organs was much less frequent in the latter disease. This fact leads to the hypothesis that a coagulation cascade, once the virus has set in, progresses autonomously and independently from it. In another paper, Zhang et al.[10] describe seven hospitalized patients who were affected by acute acral ischemia along with a progressive increase in the D-dimer of fibrinogen and fibrinogen degradation products (FDPs). Four patients presented a fully developed DIC. Mortality was very high: five of the seven deceased. In addition, cases were described in which the first clinical sign of COVID-19 was the appearance of perniosis-like acral nevi on the foot, probably linked to microvasculitis induced by the virus. To this purpose, a Register edited by Claire Le Hello del CHU di Saint-Etienne[7] has been set up in France to assess the possibility. These data clearly reveal to what extent the complex pathogenesis of this disease involves the microcirculatory system. Zhou et al.[11] have confirmed that an elevated level of D-dimer (above 1000 ng/ml), a high value of sequential organ failure assessment (SOFA), and advanced age were the main risk factors for a fatal prognosis. Tang et al.[12] have pointed out that a value of 4 or higher for sepsis-induced coagulopathy (SIC) and a D-dimer above 3000 ng/ml correlate positively with 28-day mortality. Terpos et al.[5] concur with the importance of D-dimer as a prognostic factor, but they state that the inflammation indices, such as C Reactive Protein, lactate dehydrogenase, and IL6, need to be monitored to avoid worsening. DIC may be suspected and prevented by keeping a regular check on the trend for D-dimer (rising), TP and partial thromboplastin time (lengthening), FDP (rising), and platelet count (thrombocytopenia).[5],[11] The data presented thus far, despite the limited number of clinical cases, lead to a consideration: COVID-19 follows a pattern that starts as a viral infection and develops progressively into a more complicated condition with a devastating macro- and microcirculatory coagulopathy.

  Heparin and Coronavirus Disease-2019 Top

Heparin is a potent anticoagulant that also possesses intrinsic anti-inflammatory properties, which are implemented through the effects exerted on cytokines, on the complement system, and on leukocyte chemotaxis. Moreover, it provides protective action for the endothelium, neutralizing attacks from histones released from the damaged cells.[13],[14] This action takes place mainly at the microvascular level. It would appear logical, therefore, that this drug be administered to block the hemocoagulation cascade induced by inflammation. Tang et al.[15] have demonstrated that the use of heparin in COVID-19 patients (in most cases, enoxaparin) for at least 7 days has reduced 28-day mortality by over 20% in patients with an SIC score above or equal to 4 and by approximately 20% in patients with a D-dimer over 3000 ng/ml. In view of the fact that a study conducted by Wang et al.,[16] which reported the use of tissue plasminogen activator for more critical patients, had revealed results that did not prove to be convincing, the study by Tang et al. opens up a compelling therapeutic scenario that takes into consideration the thrombotic condition, which is far from being a secondary aspect of the disease. La Societè Francaise de Anestesiologie through the Groupe d'Interet en Hémostase Perioperatoire and the Groupe Francaise d'études sur l'Hémostase et la Thrombose have published a document[17] in which it recommends using low molecular weight heparin (LMWH) with COVID-19 patients.

The document is an outline with four points in which it sets out to:

  1. Define the risk of thrombosis in COVID-19 patients and take into account other risk factors for each patient (cancer, previous texturized vegetable protein, etc.) as well as the primary illness itself. Four levels of risk are determined by this assessment: low risk, intermediate risk, high risk, and very high risk
  2. Monitor hemostasis in hospitalized COVID-19 patients
  3. Prescribe anticoagulant therapy by following separate indications for each group: in intermediate-risk patients, prophylaxis with LMWH or fondaparinux is to be administered; in high-risk patients, intermediate doses of LMWH are to be given; based on patient's body weight, in patients with a very high risk of thrombosis, therapeutic doses of LMWH are recommended; in obese patients, dosage should be adjusted to body weight (e.g. in a high- or very high-risk patient who weighs over 120 kg, prophylactic doses of enoxaparin will range from 4000 to 6000 U aXa × 2); the therapeutic dose suggested for obese patients is 100 U aXa/kg every 12 h but should not exceed 10,000 U aXa × 2/die or, where unfractionated heparin is administered, 500 UI/Kg over a 24-h period (via pump infusion). In the event of a D-dimer above 3000 ng/ml (or rapidly increasing) or fibrinogen above 800 mg/dl, therapeutic doses are recommended even if there is no clinical evidence of thrombosis, bearing in mind, however, the risk of hemorrhage. In case of DIC or MOF, dosage must be re-assessed according to the considerable increase of risk of the patient bleeding or, in our opinion, an alternative therapy (antithrombin, thrombomodulin, or others)[18] should be taken into consideration
  4. Treat through non pharmacological interventions as an alternative method of VTE prophylaxis. There are many validated scores to calculate risk of thrombosis, such as the Padua score and the Caprini RAM, which validated over 1000 clinical trials.[19]

  Discussion Top

Although the data contained in the literature are still limited and are awaiting implementation, a scenario emerges in which macro- and microcirculatory thrombosis is a key element in the prognosis of COVID-19 patients. Heparin seems to be a viable therapeutic option. However, due to the limits of a reduced number of clinical cases to date and insufficient knowledge in the physiopathological sphere, there are still many uncertainties, in particular those related to dosage and duration of the treatment. Many questions arise which continue to call for an answer. For example, how should symptomatic patients with a low risk of thrombosis be managed according to the SFA parameters? Unfortunately, these months have taught us that the clinical situation for COVID patients might plummet suddenly, so why wait for the patients to become a high risk before protecting them with a prophylactic dose of heparin? How can laboratory testing be used to manage patients clinically to identify an imminent danger of DIC and prevent it? In fact, treatment of fully developed DIC is to date difficult and controversial. A recent revised study[20] on the topic has cast doubt on the effectiveness of any anticoagulant therapy to lower DIC mortality. To this purpose, there is a valid tool, i.e. the SIC score[21] on which Tang et al. based their work. The SIC score [Table 1] is based both on simple laboratory parameters (international normalized ratio [INR], platelet count) and on the SOFA score,[22] which highlights organ dysfunction. A score of 4 or higher indicates the presence of coagulopathy, provided that the score of the platelet count and of INR together is above 2 and that the SOFA score higher than 2. This makes it possible to administer suitable anticoagulant therapy as Tang et al. did, with a good chance of obtaining a positive outcome, limiting the risk of bleeding to an acceptable level. Indeed, once a full-blown DIC is underway, it becomes very difficult to manage the situation due to a general organ dysfunction and high risk of hemorrhage. The Agenzia Italiana del Farmaco (Italian Medicines Agency) [AIFA] has just authorized the INHIXA COVID-19 Study, in which COVID-19 patients at different stages of the disease will be enrolled and treated with various doses of biosimilar enoxaparin. This study should, therefore, provide thorough information as to how to treat such patients and what doses should be used. Of course, when faced with a disease which significantly involves and attacks macrocirculation, and in particular, microcirculation (MOF and DIC are manifestations correlated with microcirculatory function and dysfunction), the inevitable need to use every weapon at our disposal, appropriately and rationally, arises: heparin appears to be an important option in the set of available therapeutic resources for the professional figures involved in treating COVID-19 patients.
Table 1: The values which provide a diagnosis of sepsis-induced coagulopathy

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Conflicts of interest

There are no conflicts of interest.

  References Top

Dolmatova EV, Wang K, Mandavilli R, Griendling KK. The effects of sepsis on endothelium and clinical implications. Cardiovasc Res 2020;Mar 26 pii:cvaa070.  Back to cited text no. 1
Atri D, Siddiqi HK, Lang J, Nauffal V, Morrow DA, Bohula EA. COVID-19 for the cardiologist: A current review of the virology, clinical epidemiology, cardiac and other clinical manifestations and potential therapeutic strategies. JACC Basic Transl Sci 2020; 04.002;1-62.  Back to cited text no. 2
Durbin RP. Letter: Acid secretion by gastric mucous membrane. Am J Physiol 1975;229:1726.  Back to cited text no. 3
Yin S, Huang M, Li D, Tang N. Ditterence of coagulation features between severe pneumonia induced by SARS Co V 2 and non SARS Co V 2. J Tromb Thrombolysis 2020; April 3, doi 10.1007/s11239-020-02105-8:1-4.  Back to cited text no. 4
Terpos E, Ntanasis- Stathopoulos I., Elalamy J, Kastritis E., Sergenatis TN, Politou M, et al. Hematological findings and complications of COVID-19. Am J Hematol 2020; Apr 13.doi: 10.1002/ajh.25829.  Back to cited text no. 5
Madjid M, Safavi -Naeini P, Solomon SD, Vaedeny O. Potential effects of coronaviruses on the cardiovascular system: A review. JAMA Cardiol 2020; Mar 27.doi 10.1001.  Back to cited text no. 6
Laroche JP. COVID-19 et Medecine Vasculaire. Montrouge; France: John Libbey Eurotext; April 6 ; 2020.  Back to cited text no. 7
Yao XH, Li TY, He ZC, Ping YF, Liu HW, Yc SC, et al. A pathological report of three COVID 19 cases by minimally invasive autopsies. Zohonghua Bing Li Xue Za Zhi 2020;49:E009.  Back to cited text no. 8
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Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020;395:1054-62.  Back to cited text no. 11
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;18:844-7.  Back to cited text no. 12
Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. Anti-inflammatory effects of Heparin and its derivatives. A systematic review. Adv Farmacol Sci 2015;2015:507151.  Back to cited text no. 13
Zhu C, Liang Y, Li X, Chen N, Ma X. Unfractionated heparin attenuates histone-mediated cytotoxicityin vitro and prevents intestinal microcirculatory dysfunction in histone-infused rats. J Trauma Acute Care Surg 2019;87:614-22.  Back to cited text no. 14
Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreseated mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Harmost 2020;18:1094-9.  Back to cited text no. 15
Wang J, Hajizadeh N, Moore EE, McIntyre RC, Moore PK, Veress LA, et al. Tissue Plasminogen activator (tPA) treatment for COVID 19, associate acute respiratory distress syndrome (ARDS): A case series. J Thromb Haemost 2020; doi : 10.1111/JTH. 14828.  Back to cited text no. 16
Susen S, Tacquard CA, Godon A, Mansour A., Garrigue D., Nguyen P, et al. Traitement Anticoagulant Pour la Prevention du Risque Thrombotique Chez Un Patient Hospitalise Avec COVID-19 et Surveillance del'Hemostase. Proposition du GIHP et du GFHT. Version Courte; 2020.  Back to cited text no. 17
Umegaki T, Kunisawa S, Nishimoto K, Kamibayashi T, Imanaka Y. Effectiveness of combined antithrombin and thrombomodulin therapy on in-hospital mortality in mechanically ventilated septic patients with disseminated intravascular coagulation. Nat Res Sci Rep 2020; 10:4874/https//doi.org/101038/s41598-020-61809-2.  Back to cited text no. 18
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Inata Y. Should we treat sepsis-induced DIC with anticoagulants? J Intensive Care 2020;8:18.  Back to cited text no. 20
Iba T, Di Nisio M, 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:e017048.  Back to cited text no. 21
Vincent JL, de Mendonça A, Cantraine F, Moreno R, Takala J, Suter PM, et al. Use of the SOFS score to assess the incidence of organ dysfunction/failure in intensive care units: Results of a multicenter, prospective study. Crit Care Med 1998;26:1793-800.  Back to cited text no. 22


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