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.