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1.
Hematology ; 27(1): 318-321, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1713441

ABSTRACT

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction associated with thrombosis. Clinical scoring systems and the presence of anti-platelet factor 4 (anti-PF4)/heparin antibodies determine the diagnosis. CASE PRESENTATION: A 57-year-old man who was treated with acenocoumarol due to a chronic left ventricular thrombus was admitted to the hospital for severe SARS-CoV-2 pneumonia and pulmonary embolism. The patient was started on bemiparin and discharged. Left lower limb acute arterial ischemia and thrombocytopenia were diagnosed 18 days later. Computed tomography angiography revealed a large left ventricular thrombus and multiple arterial thrombi. Left femoral-popliteal thromboembolectomy was performed. Anti-PF4/heparin antibodies confirmed an HIT diagnosis. Fondaparinux (7.5 mg/24 h) was initiated, but cardiac surgery was necessary. Bivalirudin was used during surgery, with an initial load (1.25 mg/kg) and maintenance infusion (2.5 mg/kg/h). The cardiac thrombus was extracted, but the patient experienced a postsurgical myocardial infarction. Percutaneous cardiovascular intervention (PCI) required a bivalirudin load (0.75 mg/kg) and maintenance infusion (1.75 mg/kg/h). No coronary lesions were detected, and argatroban was started afterwards (0.5 µg/kg/min). When the platelet count exceeded 100 × 109/L, acenocoumarol was initiated. Thereupon, acetylsalicylic acid (100 mg/24 h) was added. No other complications have been reported to date. CONCLUSION: The clinical presentation of intraventricular and multiple arterial thrombi is remarkable. SARS-CoV-2 infection likely contributed to a hypercoagulable state. The management of patients with HIT undergoing cardiac surgery is challenging. If surgery cannot be delayed, then treatment with bivalirudin is recommended. Additionally, this drug is recommended for PCI. Bivalirudin is safe and well-tolerated in both procedures.


Subject(s)
Acenocoumarol/administration & dosage , Anticoagulants/administration & dosage , Arginine/analogs & derivatives , COVID-19/drug therapy , Heparin , Hirudins/administration & dosage , Peptide Fragments/administration & dosage , Percutaneous Coronary Intervention , Pipecolic Acids/administration & dosage , SARS-CoV-2 , Sulfonamides/administration & dosage , Thrombocytopenia , Thrombosis , Arginine/administration & dosage , COVID-19/complications , Heparin/administration & dosage , Heparin/adverse effects , Humans , Male , Middle Aged , Recombinant Proteins/administration & dosage , Thrombocytopenia/chemically induced , Thrombocytopenia/therapy , Thrombosis/chemically induced , Thrombosis/therapy
2.
Drug Dev Res ; 82(1): 38-48, 2021 02.
Article in English | MEDLINE | ID: covidwho-1279360

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-COV-2), a novel coronavirus responsible for the recent infectious pandemic, is known to downregulate angiotensin-converting enzyme-2 (ACE2). Most current investigations focused on SARS-COV-2-related effects on the renin-angiotensin system and especially the resultant increase in angiotensin II, neglecting its effects on the kinin-kallikrein system. SARS-COV-2-induced ACE2 inhibition leads to the augmentation of bradykinin 1-receptor effects, as ACE2 inactivates des-Arg9-bradykinin, a bradykinin metabolite. SARS-COV-2 also decreases bradykinin 2-receptor effects as it affects bradykinin synthesis by inhibiting cathepsin L, a kininogenase present at the site of infection and involved in bradykinin production. The physiologies of both the renin-angiotensin and kinin-kallikrein system are functionally related suggesting that any intervention aiming to treat SARS-COV-2-infected patients by triggering one system but ignoring the other may not be adequately effective. Interestingly, the snake-derived bradykinin-potentiating peptide (BPP-10c) acts on both systems. BPP-10c strongly decreases angiotensin II by inhibiting ACE, increasing bradykinin-related effects on the bradykinin 2-receptor and increasing nitric oxide-mediated effects. Based on a narrative review of the literature, we suggest that BPP-10c could be an optimally effective option to consider when aiming at developing an anti-SARS-COV-2 drug.


Subject(s)
Bradykinin/administration & dosage , COVID-19/drug therapy , Peptide Fragments/administration & dosage , Snake Venoms/administration & dosage , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Animals , Bradykinin/metabolism , COVID-19/metabolism , Humans , Peptide Fragments/metabolism , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Snake Venoms/metabolism
3.
Front Immunol ; 12: 641447, 2021.
Article in English | MEDLINE | ID: covidwho-1264330

ABSTRACT

The newly emerged novel coronavirus, SARS-CoV-2, the causative agent of COVID-19 has proven to be a threat to the human race globally, thus, vaccine development against SARS-CoV-2 is an unmet need driving mass vaccination efforts. The receptor binding domain of the spike protein of this coronavirus has multiple neutralizing epitopes and is associated with viral entry. Here we have designed and characterized the SARS-CoV-2 spike protein fragment 330-526 as receptor binding domain 330-526 (RBD330-526) with two native glycosylation sites (N331 and N343); as a potential subunit vaccine candidate. We initially characterized RBD330-526 biochemically and investigated its thermal stability, humoral and T cell immune response of various RBD protein formulations (with or without adjuvant) to evaluate the inherent immunogenicity and immunomodulatory effect. Our result showed that the purified RBD immunogen is stable up to 72 h, without any apparent loss in affinity or specificity of interaction with the ACE2 receptor. Upon immunization in mice, RBD generates a high titer humoral response, elevated IFN-γ producing CD4+ cells, cytotoxic T cells, and robust neutralizing antibodies against live SARS-CoV-2 virus. Our results collectively support the potential of RBD330-526 as a promising vaccine candidate against SARS-CoV-2.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , Immunity, Humoral/drug effects , Immunogenicity, Vaccine , Peptide Fragments/administration & dosage , Spike Glycoprotein, Coronavirus/administration & dosage , Th1 Cells/drug effects , Adjuvants, Immunologic/administration & dosage , Animals , Biomarkers/blood , COVID-19 Vaccines/immunology , Chlorocebus aethiops , Drug Stability , Glycosylation , HEK293 Cells , Humans , Immunization , Interferon-gamma/blood , Male , Mice, Inbred C57BL , Peptide Fragments/immunology , Protein Interaction Domains and Motifs , Protein Stability , Spike Glycoprotein, Coronavirus/immunology , Th1 Cells/immunology , Th1 Cells/metabolism , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/immunology , Vero Cells
4.
Viruses ; 12(12)2020 11 30.
Article in English | MEDLINE | ID: covidwho-948866

ABSTRACT

SARS-CoV-2 infection is mediated by the binding of its spike protein to the angiotensin-converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The study of RAS dysregulation due to SARS-CoV-2 infection is fundamentally important for a better understanding of the pathogenic mechanisms and risk factors associated with COVID-19 coronavirus disease and to design effective therapeutic strategies. In this context, we developed a mathematical model of RAS based on data regarding protein and peptide concentrations; the model was tested on clinical data from healthy normotensive and hypertensive individuals. We used our model to analyze the impact of SARS-CoV-2 infection on RAS, which we modeled through a downregulation of ACE2 as a function of viral load. We also used it to predict the effect of RAS-targeting drugs, such as RAS-blockers, human recombinant ACE2, and angiotensin 1-7 peptide, on COVID-19 patients; the model predicted an improvement of the clinical outcome for some drugs and a worsening for others. Our model and its predictions constitute a valuable framework for in silico testing of hypotheses about the COVID-19 pathogenic mechanisms and the effect of drugs aiming to restore RAS functionality.


Subject(s)
COVID-19/pathology , Models, Theoretical , Renin-Angiotensin System/physiology , Angiotensin I/administration & dosage , Angiotensin I/pharmacology , Angiotensin Receptor Antagonists/administration & dosage , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme 2/administration & dosage , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/pharmacology , COVID-19/virology , Computer Simulation , Humans , Peptide Fragments/administration & dosage , Peptide Fragments/pharmacology , Renin/antagonists & inhibitors , Renin-Angiotensin System/drug effects , SARS-CoV-2 , Viral Load
5.
Adv Drug Deliv Rev ; 167: 47-65, 2020 12.
Article in English | MEDLINE | ID: covidwho-921794

ABSTRACT

To date, no effective vaccines or therapies are available against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pandemic agent of the coronavirus disease 2019 (COVID-19). Due to their safety, efficacy and specificity, peptide inhibitors hold great promise for the treatment of newly emerging viral pathogens. Based on the known structures of viral proteins and their cellular targets, antiviral peptides can be rationally designed and optimized. The resulting peptides may be highly specific for their respective targets and particular viral pathogens or exert broad antiviral activity. Here, we summarize the current status of peptides inhibiting SARS-CoV-2 entry and outline the strategies used to design peptides targeting the ACE2 receptor or the viral spike protein and its activating proteases furin, transmembrane serine protease 2 (TMPRSS2), or cathepsin L. In addition, we present approaches used against related viruses such as SARS-CoV-1 that might be implemented for inhibition of SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/metabolism , Peptide Fragments/administration & dosage , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Drug Delivery Systems/methods , Humans , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Protein Binding/drug effects , Protein Binding/physiology , Protein Structure, Secondary , Protein Structure, Tertiary , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/metabolism
7.
J Cardiothorac Vasc Anesth ; 35(4): 1149-1153, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-650635

ABSTRACT

In its severe manifestation, coronavirus disease 2019 (COVID-19) compromises oxygenation in a manner that is refractory to maximal conventional support and requires escalation to extracorporeal membrane oxygenation (ECMO). Maintaining ECMO support for extended durations requires a delicately balanced anticoagulation strategy to maintain circuit viability by preventing thrombus deposition while avoiding excessive anticoagulation yielding hemorrhage-a task that is complicated in COVID-19 secondary to an inherent hypercoagulable state. Bivalirudin, a member of the direct thrombin inhibitor drug class, offers potential advantages during ECMO, including to its ability to exert its effect by directly attaching to and inhibiting freely circulating and fibrin-bound thrombin. Herein, the successful use of an anticoagulation strategy using the off-label use of a continuous infusion of bivalirudin in a case of severe hypoxemic and hypercarbic respiratory failure caused by COVID-19 requiring venovenous ECMO is reported. Importantly, therapeutic anticoagulation intensity was achieved rapidly with stable pharmacokinetics, and there was no need for any circuit interventions throughout the patient's 27-day ECMO course. In COVID-19, bivalirudin offers a potential option for maintaining systemic anticoagulation during ECMO in a manner that may mitigate the prothrombotic nature of the underlying pathophysiologic state.


Subject(s)
Anticoagulants/administration & dosage , Antithrombins/administration & dosage , COVID-19/diagnosis , COVID-19/therapy , Extracorporeal Membrane Oxygenation/adverse effects , Hirudins/administration & dosage , Peptide Fragments/administration & dosage , Thrombosis/prevention & control , Aged , Anticoagulants/therapeutic use , Antithrombins/therapeutic use , COVID-19/complications , COVID-19 Nucleic Acid Testing , Female , Humans , Peptide Fragments/therapeutic use , Polymerase Chain Reaction , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , Respiratory Insufficiency/etiology , Respiratory Insufficiency/therapy , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Treatment Outcome
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