Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
1.
Trials ; 21(1): 1005, 2020 Dec 09.
Article in English | MEDLINE | ID: covidwho-969799

ABSTRACT

BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.


Subject(s)
COVID-19/complications , Inflammation/etiology , SARS-CoV-2/genetics , Venous Thromboembolism/etiology , Antirheumatic Agents/administration & dosage , Antirheumatic Agents/therapeutic use , Aprotinin/administration & dosage , Aprotinin/therapeutic use , Belgium/epidemiology , Bradykinin/drug effects , Bradykinin/metabolism , COVID-19/epidemiology , COVID-19/virology , Critical Care/statistics & numerical data , Drug Therapy, Combination , Female , Heparin, Low-Molecular-Weight/administration & dosage , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Incidence , Inflammation/epidemiology , Inflammation/metabolism , Inflammation/prevention & control , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Kallikreins/drug effects , Kallikreins/metabolism , Male , Outcome Assessment, Health Care , SARS-CoV-2/drug effects , Severity of Illness Index , Venous Thromboembolism/epidemiology , Venous Thromboembolism/metabolism , Venous Thromboembolism/prevention & control
2.
Int Angiol ; 39(6): 445-451, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-745642

ABSTRACT

The SARS-CoV-2 infection (COVID-19) is causing an ongoing pandemic and potentially fatal disease. Development of coagulopathy with thrombotic complications such as deep vein thrombosis and pulmonary embolism are emerging as factors for progression to severe disease and death. Also, a markedly increased level of D-dimer, a protein product of fibrin degradation, has been associated to mortality. Furthermore, activation of immune response due to virus infection may led to uncontrolled severe inflammation with damage to host cells and induction of endotheliitis and cellular apoptosis and pyroptosis. The use of low molecular weight heparin in early stage of the disease could prevent vascular complications and reduce the progression to severe stage of the disease. Aim of this paper was to summarize current evidence about vascular involvement in COVID-19 disease and potential antithrombotic therapy.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/epidemiology , Cardiology , Consensus , Pandemics , Societies, Medical , Thrombosis/etiology , COVID-19/complications , COVID-19/drug therapy , Humans , SARS-CoV-2 , Thrombosis/blood , Thrombosis/prevention & control
3.
Acta Obstet Gynecol Scand ; 99(9): 1110-1120, 2020 09.
Article in English | MEDLINE | ID: covidwho-651627

ABSTRACT

Those who are infected with Severe Acute Respiratory Syndrome-related CoronaVirus-2 are theoretically at increased risk of venous thromboembolism during self-isolation if they have reduced mobility or are dehydrated. Should patients develop coronavirus disease (COVID-19) pneumonia requiring hospital admission for treatment of hypoxia, the risk for thromboembolic complications increases greatly. These thromboembolic events are the result of at least two distinct mechanisms - microvascular thrombosis in the pulmonary system (immunothrombosis) and hospital-associated venous thromboembolism. Since pregnancy is a prothrombotic state, there is concern regarding the potentially increased risk of thrombotic complications among pregnant women with COVID-19. To date, however, pregnant women do not appear to have a substantially increased risk of thrombotic complications related to COVID-19. Nevertheless, several organizations have vigilantly issued pregnancy-specific guidelines for thromboprophylaxis in COVID-19. Discrepancies between these guidelines reflect the altruistic wish to protect patients and lack of high-quality evidence available to inform clinical practice. Low molecular weight heparin (LMWH) is the drug of choice for thromboprophylaxis in pregnant women with COVID-19. However, its utility in non-pregnant patients is only established against venous thromboembolism, as LMWH may have little or no effect on immunothrombosis. Decisions about initiation and duration of prophylactic anticoagulation in the context of pregnancy and COVID-19 must take into consideration disease severity, outpatient vs inpatient status, temporal relation between disease occurrence and timing of childbirth, and the underlying prothrombotic risk conferred by additional comorbidities. There is currently no evidence to recommend the use of intermediate or therapeutic doses of LMWH in thromboprophylaxis, which may increase bleeding risk without reducing thrombotic risk in pregnant patients with COVID-19. Likewise, there is no evidence to comment on the role of low-dose aspirin in thromboprophylaxis or of anti-cytokine and antiviral agents in preventing immunothrombosis. These unanswered questions are being studied within the context of clinical trials.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Fibrinolytic Agents/therapeutic use , Pneumonia, Viral/complications , Pregnancy Complications, Cardiovascular/prevention & control , Pregnancy Complications, Infectious/prevention & control , Thrombosis/prevention & control , COVID-19 , Coronavirus Infections/prevention & control , Female , Humans , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pregnancy , Pregnancy Complications, Cardiovascular/virology , SARS-CoV-2 , Thrombosis/virology
4.
J Popul Ther Clin Pharmacol ; 27(S Pt 1): e14-e25, 2020 06 27.
Article in English | MEDLINE | ID: covidwho-638400

ABSTRACT

COVID-19 disease is the most recent pandemic, since it has affected more than four and a half million people and caused more than 300,000 deaths. It is a very complex systemic disease in terms of pathogenesis, treatment, and prognosis. Pharmacological treatment may include antiviral and antimalarial drugs, antibiotics, monoclonal antibodies, corticosteroids as well as low-molecular-weight heparins to prevent the evolution of the disease from reaching the severe inflammatory phase that can lead to respiratory complications, multiple organ failure, disseminated intravascular coagulation (DIC), and finally death. Therefore, pending the development of the much sought-after vaccine, there needs to be a multidisciplinary approach to tackling this disease, and it is essential to use different medical treatments at the correct pathogenic moment. The aim of this article is to evaluate the rationale and reason behind the use of antirheumatic drugs, by expert point of view, in the various phases of the disease. Another important aspect in the management of the disease is to identify patients at high risk, both to change their lifestyle and to correct the state of their health through non-pharmacological measures for improving their immuno-balance. Our literature review reveals the important role and the therapeutic potential of antirheumatic agents in preventing the progression of the disease and aiding recovery from the disease. However, there is a lack of clinical evidence to support the use of these agents, indicating that further randomized controlled studies are required.


Subject(s)
Antirheumatic Agents/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Antibodies, Monoclonal/therapeutic use , Antimalarials/therapeutic use , COVID-19 , Coronavirus Infections/pathology , Humans , Pandemics , Pneumonia, Viral/pathology
5.
Med Hypotheses ; 142: 109743, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-88380

ABSTRACT

Currently, our world is facing the 2019 Novel Coronavirus (COVID-19) outbreak and tremendous efforts are made for developing drugs to treat and vaccines to prevent the disease. At present, there is no specific antiviral drug or vaccine for COVID-19. The pathogenic infectivity of the virus requires the S1 subunit of the spike (S) protein to bind the host cell receptor, angiontensin converting enzyme (ACE2). While the binding to host cell receptor is the first step of infection, the entrance of the virus into the cell needs the cleavage of S1-S2 subunits to expose S2 for fusion to cell membrane via host proteases including cathepsins, cell surface transmembrane protease/serine (TMPRSS) proteases, furin, trypsin and factor Xa. Previous in vitro studies have shown that factor Xa inhibition can decrease viral infectivity. We suppose that host cell proteases including furin (as expressed highly in lungs), factor Xa and cathepsin are possible targets to decrease viral burden, therefore unfractioned heparin and low molecular weight heparin-LMWH (specifically dalteparin and tinzaparin for their anti inflammatory action) can be potential inhibitors of multiple endoproteases involved in virus infectivity. Our hypothesis needs to be tested in in vitro and clinical studies, however as we are in an urgent situation as the burden of SARS-CoV2 is increasing all around the world, we recommend the usage of unfractioned heparin or LMWH in intensive care unit (ICU) and non-ICU hospitalized patients with the risk-benefit judgement of the clinician. Whether our hypothesis is clinically applicable and successful in decreasing viral infection will be evaluated for further studies.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Heparin, Low-Molecular-Weight/pharmacology , Heparin/pharmacology , Pneumonia, Viral/drug therapy , Protease Inhibitors/pharmacology , COVID-19 , Coronavirus Infections/blood , Drug Administration Schedule , Factor Xa/metabolism , Humans , Models, Theoretical , Pandemics , Pneumonia, Viral/blood , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL