The primary role of the endothelium is to maintain vascular permeability, blood rheology and homeostasis. Furthermore, the endothelium has several additional crucial physiological functions that play a role in setting up the innate immune response as well as exhibiting intrinsic properties involved in the activation of the adaptive immune response.1 Recent evidence has shown that endothelial dysfunction may actively play a role in the thrombo-inflammatory process that ultimately results in Coronavirus Disease-2019 (COVID-19)-associated coagulopathy as measured by an increase in endothelial markers (i.e., von Willebrand factor (vWF), soluble P-selectin, and soluble thrombomodulin).2
Endothelial dysfunction has been associated with the pathogenesis and progression of various diseased states – including but not limited to – cardiovascular, renal, and metabolic complications, along with sepsis and the acute respiratory distress syndrome, or ARDS.
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the virus responsible for COVID-19, utilizes the angiotensin-converting enzyme 2 (ACE2) receptor on the cell membrane of the host cell to facilitate its entry. ACE2 receptors have been found in arterial and venous endothelial cells in various human tissues, including the oral and nasal mucosa, lung, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, heart, kidney, and brain.1
However, cell invasion depends on both the expression of ACE2 and the availability of the protease transmembrane protease serine 2 (TMPRSS-2), or other serine proteases, to cleave the viral spike protein.1 The resulting infection may lead to a hyperinflammatory response, also known as cytokine storm or cytokine release syndrome (CRS), resulting in the release of pro-inflammatory cytokines such as interleukin-6 (IL-6), soluble interleukin 2 receptor (IL-2R), and tumor necrosis factor-α (TNF-α).3 The progression to cytokine storm is manifested clinically by severe disease and the development of life-threatening multi-organ system failure.
IL-6 plays a major role in the activation of the endothelium, especially during the early phases of inflammation. Thus, IL-6 induces an increased vascular permeability, in addition to the secretion of more pro-inflammatory cytokine/chemokines by endothelial cells (IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1)), and the activation of the complement system via C5a.4 This significant increase in pro-inflammatory cytokines, in particular, IL-6, TNF-α, and IL-1β, which are elevated in patients with COVID-19, as well as increased vascular permeability results in the loss of the normal antithrombotic and anti-inflammatory functions of the endothelium.5 The endothelial dysfunction as a result of the hyperinflammatory response contributes to hemostatic dysregulation, complement and platelet activation, and leukocyte recruitment in the microvasculature.
The increase in vascular permeability leads to an inflammation-mediated endothelial activated procoagulant state, as measured by vWF activity/antigen as well as considerable elevation in factor VIII (FVIII) activity.6 The inflamed endothelium contributes to hypercoagulability by upregulating procoagulant proteins like tissue factor (TF), P-selectin, FVIII, fibrinogen, and vWF, while simultaneously downregulating natural anticoagulants such as thrombomodulin (TM) and endothelial protein C receptor (EPCR).
Further evidence of this enhanced procoagulant state is the increase in the main fibrinolytic inhibitor plasminogen-activator inhibitor-1 (PAI-1), which is known to be elevated in Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and SARS-CoV-2, resulting in a hypofibrinolytic state.6 Venous thrombosis (VTE) and pulmonary thromboembolism (PE) have emerged as a leading cause of death in patients with COVID-19.7 In addition to the macrovascular thrombotic events (i.e., VTE and PE), microvascular thrombotic complications also contribute to many of the COVID-19-related morbidities (i.e., multi-organ failure).8
The clinical laboratory plays a critical role in the care of COVID-19 patients. The International Society of Thrombosis and Haemostasis (ISTH) has recommended monitoring certain laboratory markers in COVID-19 patients including elevated D-dimer together with PT/INR, platelet count, and fibrinogen to guide and monitor treatment in COVID-19 patients.9 In addition, elevated D-dimer levels have been found to be the best laboratory marker to indicate thrombotic risk in COVID-19 patients. Anticoagulant therapy for thromboprophylaxis has been recommended by all major societies (i.e., ISTH, American Society of Hematology). Several randomized clinical trials are currently underway to help define optimal treatment protocols for patients with COVID-19. (A list of these studies can be found on https://www.clinicaltrials.gov/.) In addition, several other studies have begun enrollment (NCT04359277, NCT04362085, NCT04345848, and NCT04366960).
Conclusion
In summary, the hypoxia, immobility of hospitalized patients, and the sequalae associated with SARS-CoV-2 infection are potent triggers of thrombosis.
References:
- Pons S, Fodil S, Azoulay E, Zafrani L. The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection. Crit Care. 2020 Jun 16;24(1):353. doi: 10.1186/s13054-020-03062-7.
- Goshua G, Pine AB, Meizlish ML, et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol. 2020 Aug;7(8):e575-e582. doi: 10.1016/S2352-3026(20)30216-7.
- Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620–2699.
- Laudes IJ, Chu JC, Huber-Lang M, Guo R-F, Riedemann NC, Sarma JV, et al. Expression and function of C5a receptor in mouse microvascular endothelial cells. J Immunol. 2002;169:5962–5970.
- Pons S, Arnaud M, Loiselle M, Arrii E, Azoulay E, Zafrani L. Immune consequences of endothelial cells’ activation and dysfunction during sepsis. Crit Care Clin. 2020;36:401–413.
- Al-Samkari H, Karp Leaf RS, Dzik WH, Carlson JCT, Fogerty AE, Waheed A, Goodarzi K, Bendapudi PK, Bornikova L, Gupta S, Leaf DE, Kuter DJ, Rosovsky RP. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood 2020;136:489-500.
- Bikdeli B, Madhavan MV, Jimenez D et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75:2950-2973.
- Iba T, Levy JH, Levi M, Connor JM. Coagulopathy of Coronavirus Disease 2019. Crit Care Med. 2020 May 27;10.1097/CCM.0000000000004458. doi: 10.1097/CCM.0000000000004458.
- Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, Clark C, Iba T. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18:1023-1026.