4. Anticoagulant and antiplatelet drugs
As shown in figure 1, among the most serious clinical complications of COVID-19, there is the onset of a coagulopathy that accompanied by an hyperinflammatory state (representing the so-called cytokine storm) and progression to multiple-organ dysfunction is a cause of death in COVID-19 patients along with respiratory failure (Asakura and Ogawa, 2020). Firstly, the state of hyperinflammation and hypercoagulability was identified as disseminated intravascular coagulation (DIC) (Marietta et al., 2020). However, it was then noticed that the pathophysiology of COVID-19-associated DIC is different from that of classic DIC (septic or traumatic DIC) (Asakura and Ogawa, 2020). In fact, in COVID-19 patients, the most common pattern of coagulopathy is characterized by increased levels of fibrinogen and D-dimer, a mild prolongation of PT/aPTT, and a mild thrombocytopenia, which can also be absent in some patient (American Society of Hematology, 2020a; Atallah et al., 2020). On the contrary, the classic DIC is characterized by severe thrombocytopenia, extend prolongation of PT and aPTT, high levels of D-dimer, and reduced levels of fibrinogen (American Society of Hematology, 2020a; Atallah et al., 2020).
The exact mechanisms contributing to coagulopathy in COVID-19 patients are not completely understood. In general, inflammation and coagulation are known to be linked by different molecular signals (Li and Ma, 2017; Levi et al., 2020). Pro-inflammatory mediators can stimulate the expression of intravascular tissue factor, leukocyte adhesion molecules, and plasminogen activator inhibitor-1 (PAI-1) (Gozzo et al., 2020). Moreover, inflammation can activate the coagulation cascade by overexpressing thrombin both systemically and locally in the lungs, leading to fibrin deposition and subsequent tissue damage (Li et al., 2020c). SARS-CoV-2 could also directly damage vascular endothelial cells through its bond to ACE2, which could represent the first injury triggering the abnormal coagulation (Li et al., 2020a). However, some studies showed that ACE2 is expressed mainly on type II pneumocytes, and almost absent in endothelial cells (McGonagle et al., 2020). In this context, the generalized hypercoagulable state of COVID-19 patients could be due to the involvement of type II pneumocytes, the extensive pulmonary microvascular network, and the extensive hyperinflammatory state that is similar to the macrophage activation syndrome (Gozzo et al., 2020; McGonagle et al., 2020). Finally, the development of hypoxemia, secondary to the COVID-19-induced ARDS, might also activate the coagulation cascade and could contribute to endothelial dysfunction (McGonagle et al., 2020).
A better understanding of the thromboembolic risk in patients suffering from COVID-19 could help to optimize both diagnostic strategies and pharmacological management (Capuano et al., 2020a; Lodigiani et al., 2020). To date, the anticoagulation therapy is part of the therapeutic management of COVID-19 patients and some authors have suggested of using this strategy in patients with elevated D-dimer levels (American Association for Clinical Chemistry, 2020). In this regards, an observational study found that the in-hospital mortality in patients who required mechanical ventilation was lower for those treated with anticoagulation than those not receiving the anticoagulant treatment (Paranjpe et al., 2020). Undoubtedly heparins , either unfractionated or at low molecular weight (LMWH), for their ability of blocking or limiting the state of hypercoagulability, represent a good therapeutic option for anticoagulation in patients with COVID-19. Heparins other than having anticoagulant properties appear to mitigate the inflammatory state exercising non-anticoagulant mechanisms such as: inhibition of heparanase activity, (responsible for endothelial leakage); chemokines, and cytokines neutralisation; interference with leukocyte trafficking; neutralisation of extracellular cytotoxic histones, and reduction of viral cellular entry (Buijsers et al., 2020). Therefore, the benefit of using heparins could be related to the ability of blocking both coagulation and inflammation. Accordingly, a retrospective observational study, evaluating the effect of LMWH treatment on disease progression, demonstrated that this treatment improved the coagulation dysfunction of COVID-19 patients and exerted anti-inflammatory effects by reducing IL-6 and increasing lymphocyte percentage (SHI et al., 2020). Another observational study found that the treatment with heparin was associated with a lower mortality in hospitalized patients with COVID-19 (Ayerbe et al., 2020). The WHO has recommended the use of LMWH, such as enoxaparin, in patients (adults and adolescents) hospitalized with COVID-19 to prevent venous thromboembolism, unless contraindicated (World Health Organization, 2020a). However, an argument debated is the optimal anticoagulant dosage that must be used in patients with COVID-19. A study suggested to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to ICU, and to use high-prophylactic doses (Klok et al., 2020). To date, guidelines recommend to use prophylactic doses of LMWH in hospitalized COVID-19 patients unless contraindicated, but not in non-hospitalized patients (Gozzo et al., 2020; NIH, 2020; World Health Organization, 2020a). As reported by the American Society of Haematology, many protocols have adopted an intermediate-intensity dose (administering the usual daily LMWH dose twice daily) or even a therapeutic-intensity dose strategy for thromboprophylaxis based on local experience (American Society of Hematology, 2020b). Another guideline suggests to use in acutely/critically ill patients with COVID-19 a standard dose of anticoagulant over intermediate (LMWH twice-daily or increased weight-based dosing) or full treatment dosing (Moores et al., 2020). This recommendation is based on the lack of evidence regarding the risk of venous thromboembolism in hospitalized COVID-19 patients and the risk of bleeding in critically ill COVID-19 patients, who might also be at high risk of bleedings considering the severity of illness (Moores et al., 2020). Moreover, this guideline also suggests to prefer unfractionated heparins over LMWH in patients at high risk of bleeding (including those with severe renal failure) (Moores et al., 2020). A recent retrospective observational study, evaluating the impact of different doses of LMWH on the incidence of bleedings in COVID-19 patients admitted to ICUs, showed that the use of therapeutic doses of heparin did not increase the risk of bleeding in their patient population. Moreover, the study suggested the importance of applying a risk stratification based on D-dimer values for critically ill patients with COVID-19 (Pavoni et al., 2020). Based on these considerations, a close clinical monitoring and an individual patient evaluation for the risk of thrombosis and bleedings should be applied (Gozzo et al., 2020). Clinical trials are strongly needed to assess the optimal dose of heparin for COVID-19 and to assess their benefit/risk profile. Currently, different clinical trials are ongoing to evaluate the treatment with heparin in hospitalized patients with COVID-19 (www.clinicaltrials.gov). In Italy, for example, there are 5 ongoing clinical trials of patients with COVID-19 evaluating the efficacy of heparins (at different doses and regimen), alone or in combination with corticosteroids.
Among other pharmacological strategies that are being investigated for the prevention of thrombosis in COVID-19 patients, there isaspirin (acetylsalicylic acid ), an irreversible platelet inhibitor used for conditions such as myocardial infarction, strokes and pre-eclampsia in pregnant women. Aspirin, in addition to its anti-inflammatory and antithrombotic effects, has shown a significant antiviral activity against DNA and RNA viruses, including different human coronaviruses (Bianconi et al., 2020). Moreover, the use of aspirin has been associated with reduced thrombo-inflammation and lower rates of clinical complications and in-hospital mortality in different types of infections (Bianconi et al., 2020). Conflicting data have instead been reported on the use of aspirin in ARDS (Erlich et al., 2011; Kor et al., 2011, 2016; Boyle et al., 2015; Chen et al., 2015). Observational studies demonstrated some benefit in reducing the risk of ICU mortality, acute lung injury (ALI), and ARDS (Erlich et al., 2011; Boyle et al., 2015; Chen et al., 2015), while a larger observational study did not demonstrate any difference between aspirin use and ALI (Kor et al., 2011). Moreover, a randomized, double-blind, placebo-controlled, randomized clinical trial, conducted on 390 patients, showed that the use of aspirin compared with placebo did not reduce the risk of ARDS (Kor et al., 2016). First data from a retrospective, observational cohort study of adult patients hospitalized with COVID-19 have showed, after adjustment, that aspirin was associated with a decreased risk of mechanical ventilation, ICU admission, and in-hospital mortality, with no difference for major bleedings between aspirin and non-aspirin users (Chow et al., 2020). The drug will be tested for its effect of reducing blood clots in the world’s largest clinical trial of treatments for patients hospitalised with COVID-19 (RECOVERY trial) (University of Oxford, 2020a). If effective, aspirin may be beneficial because it is safe, accessible and inexpensive.
Other than the aforementioned drugs, oral anticoagulants or other antiplatelet agents (P2Y12 receptor antagonists) are available in the market. However, concerns were raised about their interactions with multiple medications that are being used and tested for the treatment of COVID-19 (Gozzo et al., 2020). For instance, sarilumab and tocilizumab can reduce plasma concentrations of apixaban, rivaroxaban, and warfarin, while atazanavir and lopinavir/ritonavir can increase drug concentrations of apixaban and rivaroxaban and reduce the active metabolite of clopidogrel and prasugrel (American Society of Hematology, 2020b). Another question is about patients who are already in treatment with oral anticoagulants or antiplatelet agents for underlying conditions, for which guidelines suggest to continue their treatment even after the diagnosis of COVID-19 (NIH, 2020). In conclusion, the use of heparins in hospitalized critically ill patients is preferred over other anticoagulants because of the shorter half-life and fewer drug-drug interactions, being also the first choice for pregnant women.