Dysregulated immune response

The viral infection induces an inflammatory state through the activation of endothelial cells, platelets, and leukocytes⁵. A "cytokines storm" with overexpression of interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha has been described during viral infection⁶. The severe inflammatory response induces a procoagulant state through the expression of tissue factor and von Willebrand factor. Result is the activation of the coagulation cascade with final generation of fibrin. In SARS-CoV infection, evidence of fibrin clots in the alveoli has been found⁷. Fibrin accumulation in the lung is a hallmark of acute lung injury and ARDS, and a reduced capacity to cleave and remove fibrin deposits corresponded to a poor clinical patient outcome⁸. Similar findings have been described in patients who died from COVID-19 disease. Histopathological examination revealed fibrin exudation in alveoli and, notably, formation of hyaline thrombus in small vessels in other organs and tissues⁹.

Thrombocytopenia and platelet dysfunction

In viral infections, platelet dysfunction, destruction, or a reduced platelets production have been reported⁵. A recent meta-analysis of nine studies including nearly 400 patients with severe COVID-19 disease identified that the platelet count was significantly lower in severe cases¹⁰. Although pathogenesis of thrombocytopenia in COVID-19 disease has not been fully clarified, thrombocytopenia caused by autoantibodies and a reduced platelets production has been described in other respiratory infections such as SARS-CoV and influenza⁵,¹¹. Another described mechanism is the binding of the virus to platelets followed by their activation, exposure of P- selectin on the platelet surface that triggers the formation of platelet-leukocyte aggregates. Subsequently, endothelial cells are activated and an increase in von Willebrand factor can be found⁵.

Endothelial dysfunction and impaired fibrinolysis

Endothelial cells play a crucial role in the regulation of coagulation, both producing and presenting anticoagulant markers and procoagulant factors.

The direct endothelial cells involvement in COVID-19 could be hypothesized because the virus accesses host cells through the protein angiotensin-converting enzyme 2¹² that is also expressed by endothelial cells¹³. Viral infection activates endothelial cells causing the activation of coagulation that is mainly marked by an increase in von Willebrand factor secretion, which can bind platelets after vessel wall damage¹⁴.

In COVID-19 infection, fibrinolysis can be impaired and the pathogenesis could be the same as SARS. In this infection, increased levels of plasminogen activator inhibitor-1 and increased plasma concentrations of tissue plasminogen activator and soluble thrombomodulin were found¹⁵,¹⁶.

Role of anticoagulation as a therapy for COVID-19

As discussed before, COVID-19 infection could cause a coagulopathy through severe inflammatory state, endothelial dysfunction, and impaired fibrinolytic activity. Therefore, anticoagulant therapy is emerging as one potential adjunctive treatment for COVID-19 disease.

Heparins are anticoagulant drugs used for the prophylaxis and therapy of venous thromboembolism. In a retrospective analysis conducted by Tang et al. on 449 Chinese patients affected by severe COVID- 19, a favorable outcome was reported thanks to the use of heparin. In particular, 94 patients received low-molecular-weight heparin (LMWH, 40-60 mg enoxaparin/day) and 5 received unfractionated heparin (UFH, 10,000-15,000 U/day). Heparin therapy significantly reduced mortality in patients with sepsis-induced coagulopathy (SIC) score ≥ 4 but not in those with SIC score < 4¹⁷. Apart from the well-known anticoagulant action, anti-inflammatory properties have also postulated: binding with inflammatory cytokines, inhibition of neutrophil chemotaxis and leukocyte migration, and antagonization of histones released from damaged cells¹⁸-²⁰. A potential antiviral role has been questioned and an interaction with the binding domain of the spike S1 SARS-CoV-2 protein receptor has been recently investigated²¹. In summary, heparin could protect from thrombotic complications, microcirculatory dysfunction and possibly decrease multiorgan damage. However, large-size studies and higher-quality data are lacking to provide definitive indications for anticoagulant use. Future researches should focus on how COVID-19 infection triggers thrombotic diseases in some patients while in most of cases, infection remains asymptomatic, what are the patient’s clinical characteristics that raise thrombotic risk, who benefits from early thrombotic prophylaxis, who needs to continue the treatment after hospital discharge, what is the appropriate dose of heparin, and how to monitor efficacy of anticoagulant treatment.