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 & controlABSTRACT
We report a case of haemolytic due to the use of piperacillin-tazobactam in a 50-year-old woman. Since 2002 4 other cases were reported. Either the presence of piperacillin as tazobactam can induce haemolysis. In all cases discontinuating the drugs resolves the haemolysis. Although drug-induced haemolytic anaemia due to piperacillin-tazobactam is rare, the common use of this antibioticum in the critical care setting should alert the physician as a possible culprit in cases of haemolytic anaemia.