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1.
The Lancet ; 399(10319):50-59, 2022.
Article in English | GIM | ID: covidwho-1815305

ABSTRACT

Background: Patients hospitalised with COVID-19 are at risk for thrombotic events after discharge;the role of extended thromboprophylaxis in this population is unknown.

2.
Clin Appl Thromb Hemost ; 28: 10760296221091770, 2022.
Article in English | MEDLINE | ID: covidwho-1775237

ABSTRACT

INTRODUCTION: Previous studies have shown that inflammation may contribute to the interplay of endogenous glycosaminoglycans (GAGs) and anti-PF4 antibodies. In this study, we quantified the levels of anti-PF4 antibody isotypes and endogenous GAGs together with inflammatory biomarkers in pulmonary embolism (PE) patients to determine whether there is a relationship in between. Identification of this relationship may provide insight to the complex pathophysiology of PE and HIT and may also be useful for development of potential prognostic, diagnostic and therapeutic interventions. MATERIALS AND METHODS: Plasma samples from PE patients (n: 210) were analyzed for anti-PF4 antibody isotypes and various thrombo-inflammatory cytokines utilizing commercially available biochip array and ELISA methods. The endogenous GAG levels in PE patients' plasma were quantified using a fluorescence quenching method. The collected data analyzed to demonstrate the relationship between various parameters. RESULTS: The endogenous GAG levels were increased in the PE group (P < .05). The levels of anti-PF4 antibody isotypes were higher in varying levels in comparison to the normal group (P < .05). Inflammatory cytokines have shown varying levels of increase with IL-6, IL-8 and IL-10 showing the most pronounced values. Mortality outcome was related to increased GAGs and some of the cytokines. CONCLUSION: In this study, we demonstrated increased levels of anti-PF4 antibody isotypes, endogenous GAGs, and inflammatory biomarkers in a large patient cohort in PE. The levels of the endogenous GAGs and inflammatory biomarkers were associated with PE severity and mortality. More studies are needed to understand this complex pathophysiology.


Subject(s)
Pulmonary Embolism , Thrombocytopenia , Biomarkers , Glycosaminoglycans , Heparin , Humans , Platelet Factor 4 , Thrombocytopenia/diagnosis
3.
Hemato ; 3(1):204-219, 2022.
Article in English | MDPI | ID: covidwho-1732001

ABSTRACT

In some patients, SARS-CoV-2 infection induces cytokine storm, hypercoagulability and endothelial cell activation leading to worsening of COVID-19, intubation and death. Prompt identification of patients at risk of intubation is an urgent need. Objectives. To derive a prognostic score for the risk of intubation or death in patients with COVID-19 admitted in intensive care unit (ICU), by assessing biomarkers of hypercoagulability, endothelial cell activation and inflammation and a large panel of clinical analytes. Design, Setting and Participants. A prospective, observational study enrolled 118 patients with COVID-19 admitted in the ICU. On the first day of ICU admission, all patients were assessed for biomarkers (protein C, protein S, antithrombin, D-Dimer, fibrin monomers, FVIIa, FV, FXII, FXII, FVIII, FvW antigen, fibrinogen, procoagulant phospholipid dependent clotting time, TFPI, thrombomodulin, P-selectin, heparinase, microparticles exposing TF, IL-6, complement C3a, C5a, thrombin generation, PT, aPTT, hemogram, platelet count) and clinical predictors. Main Outcomes and Measures. The clinical outcomes were intubation and mortality during hospitalization in ICU. Results: The intubation and mortality rates were 70% and 18%, respectively. The COMPASS-COVID-19-ICU score composed of P-Selectin, D-Dimer, free TFPI, TF activity, IL-6 and FXII, age and duration of hospitalization predicted the risk of intubation or death with high sensitivity and specificity (0.90 and 0.92, respectively). Conclusions and Relevance. COVID-19 is related to severe endothelial cell activation and hypercoagulability orchestrated in the context of inflammation. The COMPASS-COVID-19-ICU risk assessment model is accurate for the evaluation of the risk of mechanical ventilation and death in patients with critical COVID-19. The COMPASS-COVID-19-ICU score is feasible in tertiary hospitals and could be placed in the diagnostic procedure of personalized medical management and prompt therapeutic intervention.

4.
Pharmaceuticals (Basel) ; 15(2)2022 Feb 21.
Article in English | MEDLINE | ID: covidwho-1699238

ABSTRACT

With the increased prevalence of new SARS-CoV-2 variants of concern, such as Delta and Omicron, the COVID-19 pandemic has become an ongoing human health disaster, killing millions worldwide. SARS-CoV-2 invades its host through the interaction of its spike (S) protein with a host cell receptor, angiotensin-converting enzyme 2 (ACE2). In addition, heparan sulfate (HS) on the surface of host cells plays an important role as a co-receptor for this viral pathogen-host cell interaction. Our previous studies demonstrated that many sulfated glycans, such as heparin, fucoidans, and rhamnan sulfate have anti-SARS-CoV-2 activities. In the current study, a small library of sulfated glycans and highly negatively charged compounds, including pentosan polysulfate (PPS), mucopolysaccharide polysulfate (MPS), sulfated lactobionic acid, sulodexide, and defibrotide, was assembled and evaluated for binding to the S-proteins and inhibition of viral infectivity in vitro. These compounds inhibited the interaction of the S-protein receptor-binding domain (RBD) (wild type and different variants) with immobilized heparin, a highly sulfated HS, as determined using surface plasmon resonance (SPR). PPS and MPS showed the strongest inhibition of interaction of heparin and S-protein RBD. The competitive binding studies showed that the IC50 of PPS and MPS against the S-protein RBD binding to immobilized heparin was ~35 nM and ~9 nM, respectively, much lower than the IC50 for soluble heparin (IC50 = 56 nM). Both PPS and MPS showed stronger inhibition than heparin on the S-protein RBD or spike pseudotyped lentiviral particles binding to immobilized heparin. Finally, in an in vitro cell-based assay, PPS and MPS exhibited strong antiviral activities against pseudotyped viral particles of SARS-CoV-2 containing wild-type or Delta S-proteins.

5.
Clin Appl Thromb Hemost ; 28: 10760296211056648, 2022.
Article in English | MEDLINE | ID: covidwho-1685920

ABSTRACT

The progress in the development of various vaccine platforms against SARS-CoV-2 have been rather remarkable owing to advancement in molecular and biologic sciences. Most of the current vaccines and those in development focus on targeting the viral spike proteins by generating antibodies of varying spectrum. These vaccines represent a variety of platforms including whole virus vaccines, viral vector vaccines, nucleic acid vaccines representing RNA, DNA, and their hybrid forms.The therapeutic efficacy of these vaccines varies owing to their pharmacodynamic individualities. COVID-19 variants are capable of inducing different pathologic responses and some of which may be resistant to antibodies generated by current vaccines. The current clinical use of these vaccines has been through emergency use authorization until recently. Moreover, the efficacy and safety of these vaccines have been tested in substantial numbers of individuals but studies in special populations that better reflect the global population are pending results. These specialized populations include young children, immunocompromised patients, pregnant individuals, and other specialized groups. Combination approaches, molecularly modified vaccination approaches, and vaccines conferring longer periods of immunity are being currently being investigated, as well as pharmacovigilance studies.The continual transformation of SARS-CoV-2 and its variants are of concern along with the breakthrough infections. These considerations pose new challenges for the development of vaccination platforms. For this purpose, booster doses, combination vaccine approaches, and other modalities are being discussed. This review provides an updated account of currently available vaccines and those in advanced development with reference to their composition and mechanisms of action.A discussion on the use of vaccines in special populations including immunocompromised patients, pregnant women and other specialized populations are also included.


Subject(s)
COVID-19 Vaccines/pharmacology , COVID-19/prevention & control , SARS-CoV-2/immunology , /methods , Adolescent , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/therapeutic use , Child , Female , Humans , Immunocompromised Host , Pregnancy , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/prevention & control , Pregnancy Complications, Infectious/virology
6.
Clin Appl Thromb Hemost ; 27: 10760296211066942, 2021.
Article in English | MEDLINE | ID: covidwho-1574701

ABSTRACT

INTRODUCTION: We conducted a cross-sectional survey as a part of an educational program in collaboration with the Global Thrombosis Forum (GTF), an affiliate of North American Thrombosis Forum (NATF), and Loyola University about public perceptions of COVID-19 and COVID-19 vaccinations in the US. In this study, we are reporting the results of this survey. MATERIALS AND METHODS: The survey, in the form of a questionnaire, has been developed by GTF and faculty members. A prepared questionnaire was sent to the members of the Georgia and Illinois communities. RESULTS: In our current study, the COVID-19 vaccine willingness rate was 94.5% and vaccination rate was 90.9%. In multivariate analysis believing to have enough information about the safety and efficacy of COVID-19 vaccines (OR: 3.730, 95% CI: 1.199-11.603, p: 0.023) and gender (OR: 0.123, 95% CI: 0.016-0.967, p: 0.046) were significant predictors for vaccine willingness. Previous COVID-19 infection (OR: 0.215, 95% CI: 0.061-0.758, p: 0.017), moderate and severe effects of COVID-19 pandemic on participant's life (OR: 4.631, 95% CI 1.681-12.760, p: 0.003) and believing to have enough information about the safety and efficacy of COVID-19 vaccines (OR: 4.119, 95% CI: 1.508-11.253, p: 0.006) were significant predictors for final vaccination status. CONCLUSION: In conclusion, currently vaccination remains one of the most effective tools in the fight against the COVID-19 pandemic. The vaccine hesitancy is a complex phenomenon that is driven by individuals' perceptions of safety, and efficiency of the vaccines. We must continue to educate the public and communities that vaccines are safe, that they are effective and that they are still required even after a COVID-19 infection.


Subject(s)
COVID-19 Vaccines/therapeutic use , SARS-CoV-2/metabolism , Vaccination/methods , Adolescent , Adult , COVID-19 Vaccines/pharmacology , Cross-Sectional Studies , Female , Humans , Male , Perception , Pilot Projects , Surveys and Questionnaires , Young Adult
7.
Lancet ; 399(10319): 50-59, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1569147

ABSTRACT

BACKGROUND: Patients hospitalised with COVID-19 are at risk for thrombotic events after discharge; the role of extended thromboprophylaxis in this population is unknown. METHODS: In this open-label, multicentre, randomised trial conducted at 14 centres in Brazil, patients hospitalised with COVID-19 at increased risk for venous thromboembolism (International Medical Prevention Registry on Venous Thromboembolism [IMPROVE] venous thromboembolism [VTE] score of ≥4 or 2-3 with a D-dimer >500 ng/mL) were randomly assigned (1:1) to receive, at hospital discharge, rivaroxaban 10 mg/day or no anticoagulation for 35 days. The primary efficacy outcome in an intention-to-treat analysis was a composite of symptomatic or fatal venous thromboembolism, asymptomatic venous thromboembolism on bilateral lower-limb venous ultrasound and CT pulmonary angiogram, symptomatic arterial thromboembolism, and cardiovascular death at day 35. Adjudication was blinded. The primary safety outcome was major bleeding. The primary and safety analyses were carried out in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04662684. FINDINGS: From Oct 8, 2020, to June 29, 2021, 997 patients were screened. Of these patients, 677 did not meet eligibility criteria; the remaining 320 patients were enrolled and randomly assigned to receive rivaroxaban (n=160 [50%]) or no anticoagulation (n=160 [50%]). All patients received thromboprophylaxis with standard doses of heparin during hospitalisation. 165 (52%) patients were in the intensive care unit while hospitalised. 197 (62%) patients had an IMPROVE score of 2-3 and elevated D-dimer levels and 121 (38%) had a score of 4 or more. Two patients (one in each group) were lost to follow-up due to withdrawal of consent and not included in the intention-to-treat primary analysis. The primary efficacy outcome occurred in five (3%) of 159 patients assigned to rivaroxaban and 15 (9%) of 159 patients assigned to no anticoagulation (relative risk 0·33, 95% CI 0·12-0·90; p=0·0293). No major bleeding occurred in either study group. Allergic reactions occurred in two (1%) patients in the rivaroxaban group. INTERPRETATION: In patients at high risk discharged after hospitalisation due to COVID-19, thromboprophylaxis with rivaroxaban 10 mg/day for 35 days improved clinical outcomes compared with no extended thromboprophylaxis. FUNDING: Bayer.


Subject(s)
Aftercare , Blood Coagulation/drug effects , COVID-19/complications , Factor Xa Inhibitors/pharmacology , Factor Xa Inhibitors/therapeutic use , Rivaroxaban/pharmacology , Rivaroxaban/therapeutic use , Venous Thromboembolism/prevention & control , Adult , Aged , COVID-19/drug therapy , Female , Heparin/administration & dosage , Heparin/therapeutic use , Hospitalization , Humans , Male , Middle Aged , Patient Discharge , Treatment Outcome
10.
Blood ; 136(Supplement 1):6-8, 2020.
Article in English | PMC | ID: covidwho-1339051

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a heterogeneous clinical condition caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The initial stage of infection occurs at the time of respiratory viral invasion through angiotensin-converting enzyme 2 (ACE2) receptors in alveolar pneumocytes and macrophages. In the second stage of established pulmonary disease without and with hypoxia, viral multiplication and localized inflammation occurs. The third stage COVID-19 is the most severe, characterized by systemic hyperinflammation, acute respiratory distress syndrome (ARDS) and generalized microangiopathy, with significantly elevated biomarkers including IL-2, IL-6, IL-7, granulocyte-colony stimulating factor, macrophage inflammatory protein 1α, tumor necrosis factor-α, C-reactive protein, ferritin, D-dimer, von Willebrand factor (vWF) and thrombomodulin (TM). Evidence suggests that endothelial damage and activation play a key role in the pathobiology of the disease, and thus protecting endothelium and reversing endotheliitis may be a key therapeutic goal (Teuwen et al,Nat Rev Immunol2020).Defibrotide (DF), a complex mixture of poly-deoxyribonucleotides extracted from porcine mucosa, modulates expression of thrombogenic and inflammatory mediators produced in response to endothelial cell injury and/or leukocyte activation. DF increases tissue plasminogen activator (t-PA) and TM expression, thereby enhancing the enzymatic activity of plasmin to hydrolyze fibrin clot, while also decreasing vWF and plasminogen activator inhibitor-1 (PAI-1). Platelet adhesion is inhibited via increases in nitric oxide (NO), prostaglandin I2 (PGI2), and prostaglandin E2 (PGE2) (Falanga A et al,Leukemia 2003). Anti-inflammatory properties via inhibition of p38 MAPK pathway have been demonstrated with DF, attenuating the release of inflammatory mediators including IL-6, thromboxane A2, leukotriene B4, tumor necrosis factor-alpha, and reactive oxygen species (Mitsiades et al,Clin Cancer Res2009). Additionally, DF inhibits both the expression and activity of heparanase, which in turn modulates heparan sulfate, a vital moiety for viral infection (Richardson et al,Blood Adv2018;Koganti et al,Cell Mol Life Sci2020).DF also modulates endothelial cell injury in murine models by down-regulating the expression of endothelial cell adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), that are critical to leukocyte adhesion and migration, and by increasing the endothelial cell release of anti-inflammatory cytokines, conferring survival benefit (Garcia-Bernal et al,J Cell Mol Med2020). DF is approved for the treatment of severe veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) complicating stem cell transplantation and has demonstrated efficacy and safety in critically ill patients with multi-organ failure, underpinned by vasculopathy, endotheliitis, immune activation and hemorrhagic risk (Richardson et al,Blood2016). This multi-target and pleiotropic approach makes DF an attractive candidate for the treatment of advanced stage COVID 19 and the systemic endothelial complications underpinning both its pathobiology and ensuing mortality (Figure 1).Various clinical studies in Spain, Italy, Ireland, the UK and USA are underway, with the larger randomized placebo-controlled prospective phase 2 study in Spain (clinicaltrials.gov: NCT04348383) leading in accrual with promising early results, demonstrating safety to date with potential efficacy, as reflected by favorable outcome in a subset of intubated patients as part of an ongoing multi-center trial. Other studies within the group have focused on safety and particularly the therapeutic role of DF in advanced disease, including those patients requiring extracorporeal membrane oxygenation (ECMO) and full dose systemic anticoagulation. These trials include common in-depth biological correlatives, assessing biomarkers including heparanase, inflammatory cytokines, immune cell sub-populations, vWF a d soluble TM, as well as other novel markers and pharmacokinetics. In aggregate, these studies will hopefully help demonstrate the effects of DF on the proposed targets in COVID-19 and successfully correlate these effects with improved clinical outcome.

11.
Thromb Haemost ; 121(8): 992-1007, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1320246

ABSTRACT

BACKGROUND: One year after the declaration of the coronavirus disease 2019 (COVID-19) pandemic by the World Health Organization (WHO) and despite the implementation of mandatory physical barriers and social distancing, humanity remains challenged by a long-lasting and devastating public health crisis. MANAGEMENT: Non-pharmacological interventions (NPIs) are efficient mitigation strategies. The success of these NPIs is dependent on the approval and commitment of the population. The launch of a mass vaccination program in many countries in late December 2020 with mRNA vaccines, adenovirus-based vaccines, and inactivated virus vaccines has generated hope for the end of the pandemic. CURRENT ISSUES: The continuous appearance of new pathogenic viral strains and the ability of vaccines to prevent infection and transmission raise important concerns as we try to achieve community immunity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and its variants. The need of a second and even third generation of vaccines has already been acknowledged by the WHO and governments. PERSPECTIVES: There is a critical and urgent need for a balanced and integrated strategy for the management of the COVID-19 outbreaks organized on three axes: (1) Prevention of the SARS-CoV-2 infection, (2) Detection and early diagnosis of patients at risk of disease worsening, and (3) Anticipation of medical care (PDA). CONCLUSION: The "PDA strategy" integrated into state policy for the support and expansion of health systems and introduction of digital organizations (i.e., telemedicine, e-Health, artificial intelligence, and machine-learning technology) is of major importance for the preservation of citizens' health and life world-wide.


Subject(s)
COVID-19/epidemiology , COVID-19/prevention & control , Public Health , COVID-19/diagnosis , COVID-19 Testing/methods , COVID-19 Vaccines/therapeutic use , Disease Management , Humans , Immunization Programs/methods , Pandemics/prevention & control , Public Health/methods , Risk Assessment , SARS-CoV-2/isolation & purification
12.
Expert Opin Ther Targets ; 25(6): 423-433, 2021 06.
Article in English | MEDLINE | ID: covidwho-1281815

ABSTRACT

INTRODUCTION: Defibrotide (DF) is a polyribonucleotide with antithrombotic, pro-fibrinolytic, and anti-inflammatory effects on endothelium. These effects and the established safety of DF present DF as a strong candidate to treat viral and post-infectious syndromes involving endothelial dysfunction. AREAS COVERED: We discuss DF and other therapeutic agents that have the potential to target endothelial components of pathogenesis in viral and post-infectious syndromes. We introduce defibrotide (DF), describe its mechanisms of action, and explore its established pleiotropic effects on the endothelium. We describe the established pathophysiology of Coronavirus Disease 2019 (COVID-19) and highlight the processes specific to COVID-19 potentially modulated by DF. We also present influenza A and viral hemorrhagic fevers, especially those caused by hantavirus, Ebola virus, and dengue virus, as viral syndromes in which DF might serve therapeutic benefit. Finally, we offer our opinion on novel treatment strategies targeting endothelial dysfunction in viral infections and their severe manifestations. EXPERT OPINION: Given the critical role of endothelial dysfunction in numerous infectious syndromes, in particular COVID-19, therapeutic pharmacology for these conditions should increasingly prioritize endothelial stabilization. Several agents with endothelial protective properties should be further studied as treatments for severe viral infections and vasculitides, especially where other therapeutic modalities have failed.


Subject(s)
COVID-19/complications , Endothelium, Vascular/drug effects , Polydeoxyribonucleotides/pharmacology , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/etiology , COVID-19/physiopathology , COVID-19/virology , Endothelium, Vascular/physiopathology , Humans , Polydeoxyribonucleotides/therapeutic use , SARS-CoV-2/isolation & purification
13.
Clin Appl Thromb Hemost ; 27: 10760296211021498, 2021.
Article in English | MEDLINE | ID: covidwho-1249538

ABSTRACT

Today the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a global health problem. After more than a year with the pandemic, although our knowledge has progressed on COVID-19, there are still many unknowns in virological, pathophysiological and immunological aspects. It is obvious that the most efficient solution to end this pandemic are safe and efficient vaccines. This manuscript summarizes the pathophysiological and thrombotic features of COVID-19 and the safety and efficacy of currently approved COVID-19 vaccines with an aim to clarify the recent concerns of thromboembolic events after COVID-19 vaccination. The influx of newer information is rapid, requiring periodic updates and objective assessment of the data on the pathogenesis of COVID-19 variants and the safety and efficacy of currently available vaccines.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , SARS-CoV-2 , Thrombosis/etiology , Autoantibodies/biosynthesis , COVID-19/epidemiology , COVID-19/physiopathology , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Clinical Trials as Topic , Disseminated Intravascular Coagulation/epidemiology , Disseminated Intravascular Coagulation/etiology , Drug Approval , Female , Genetic Vectors , Glycosaminoglycans/immunology , Humans , Male , Models, Cardiovascular , Pandemics/prevention & control , Platelet Factor 4/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Safety , Sinus Thrombosis, Intracranial/epidemiology , Sinus Thrombosis, Intracranial/etiology , Thrombosis/epidemiology , Thrombosis/physiopathology , Vaccines, Inactivated/adverse effects , Vaccines, Inactivated/genetics , Vaccines, Inactivated/immunology , Vaccines, Synthetic/adverse effects , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology
14.
Int J Biol Macromol ; 183: 203-212, 2021 Jul 31.
Article in English | MEDLINE | ID: covidwho-1201630

ABSTRACT

The world is currently facing a novel coronavirus (SARS-CoV-2) pandemic. The greatest threat that is disrupting the normal functioning of society is the exceptionally high species independent transmission. Drug repurposing is understood to be the best strategy to immediately deploy well-characterized agents against new pathogens. Several repurposable drugs are already in evaluation for determining suitability to treat COVID-19. One such promising compound includes heparin, which is widely used in reducing thrombotic events associated with COVID-19 induced pathology. As part of identifying target-specific antiviral compounds among FDA and world-approved libraries using high-throughput virtual screening (HTVS), we previously evaluated top hits for anti-SARS-CoV-2 activity. Here, we report results of highly efficacious viral entry blocking properties of heparin (IC50 = 12.3 nM) in the complete virus assay, and further, propose ways to use it as a potential transmission blocker. Exploring further, our in-silico analysis indicated that the heparin interacts with post-translational glycoconjugates present on spike proteins. The patterns of accessible spike-glycoconjugates in open and closed states are completely contrasted by one another. Heparin-binding to the open conformation of spike structurally supports the state and may aid ACE2 binding as reported with cell surface-bound heparan sulfate. We also studied spike protein mutant variants' heparin interactions for possible resistance. Based on available data and optimal absorption properties by the skin, heparin could potentially be used to block SARS-CoV-2 transmission. Studies should be designed to exploit its nanomolar antiviral activity to formulate heparin as topical or inhalation-based formulations, particularly on exposed areas and sites of primary viremia e.g. ACE2 rich epithelia of the eye (conjunctiva/lids), nasal cavity, and mouth.


Subject(s)
Drug Repositioning , Heparin/chemistry , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , COVID-19/drug therapy , COVID-19/prevention & control , COVID-19/transmission , Heparin/therapeutic use , Humans , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
15.
Br J Haematol ; 193(1): 43-51, 2021 04.
Article in English | MEDLINE | ID: covidwho-1066629
16.
Clin Appl Thromb Hemost ; 26: 1076029620954913, 2020.
Article in English | MEDLINE | ID: covidwho-841480

ABSTRACT

INTRODUCTION: Sulodexide represents a mixture of fast-moving heparin (FMH) and dermatan sulfate (DS) and has been used for the management of venous diseases such as DVT and related disorders. The purpose of this study is to compare sulodexide and its components with unfractionated heparin (UFH) to determine its suitability for the indications in which UFH is used. MATERIALS AND METHOD: Active pharmaceutical ingredients (API) versions of sulodexide, FMH and DS were obtained from Alfasigma. API versions of UFH were obtained from Medefil Inc. Normal human citrated plasma was obtained from blood bank of the Loyola University Medical Center. Each of the individual agents were supplemented in plasma at a graded concentration of 0.0-10 µg/mL. Clotting assays (PiCT, aPTT, PT and TT), anti-Xa and anti-IIa and thrombin generation studies were carried out. Results were compiled as mean ± SD of 3 individual determination. RESULT: In the clot based (PiCT, aPTT and TT), anti-Xa and IIa assays, both the UFH and FMH produced stronger activities in these assays followed by sulodexide. DS did not show any anticoagulant activity. In the thrombin generation assay, FMH and UFH produced comparable inhibition of thrombin generation as measured by various parameters. Sulodexide was slightly weaker in this assay, whereas DS produced relatively weaker effects. CONCLUSION: In comparison to sulodexide, both UFH and FMH exhibit comparable anticoagulant activity despite differences in their molecular weight. These results suggest that sulodexide can be developed as a parenteral anticoagulant for indications in which UFH is used.


Subject(s)
Anticoagulants/pharmacology , Blood Coagulation/drug effects , Glycosaminoglycans/pharmacology , Thrombin/pharmacology , Anticoagulants/administration & dosage , Antithrombins/administration & dosage , Antithrombins/pharmacology , Glycosaminoglycans/administration & dosage , Heparin/administration & dosage , Heparin/pharmacology , Humans , Italy , Sensitivity and Specificity , Thrombin/administration & dosage
17.
Clin Appl Thromb Hemost ; 26: 1076029620954911, 2020.
Article in English | MEDLINE | ID: covidwho-772058

ABSTRACT

Definitive pharmacological therapies for COVID-19 have yet to be identified. Several hundred trials are ongoing globally in the hope of a solution. However, nearly all treatments rely on systemic delivery but COVID-19 damages the lungs preferentially. The use of a targeted delivery approach is reviewed where engineered products are able to reach damaged lung tissue directly, which includes catheter-based and aerosol-based approaches. In this review we have outlined various target directed approaches which include microbubbles, extracellular vesicles including exosomes, adenosine nanoparticles, novel bio-objects, direct aerosol targeted pulmonary delivery and catheter-based drug delivery with reference to their relative effectiveness for the specific lesions. Currently several trials are ongoing to determine the effectiveness of such delivery systems alone and in conjunction with systemic therapies. Such approaches may prove to be very effective in the controlled and localized COVID-19 viral lesions in the lungs and potential sites. Moreover, localized delivery offered a safer delivery mode for such drugs which may have systemic adverse effects.


Subject(s)
Antiviral Agents/administration & dosage , Betacoronavirus , Coronavirus Infections/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , COVID-19 , Coronavirus Infections/epidemiology , Humans , Lung , Microtubules , Pneumonia, Viral/epidemiology , SARS-CoV-2
18.
Thromb Haemost ; 120(12): 1597-1628, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-759630

ABSTRACT

COVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH.


Subject(s)
COVID-19/diagnosis , Cardiology , Cardiovascular Diseases/diagnosis , SARS-CoV-2/physiology , Anticoagulants/therapeutic use , COVID-19/drug therapy , COVID-19/epidemiology , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/epidemiology , Europe , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Inflammation , Practice Guidelines as Topic , Risk Factors , Rivaroxaban/therapeutic use , Societies, Medical , Thrombophilia , Thrombosis
20.
Clin Appl Thromb Hemost ; 26: 1076029620936776, 2020.
Article in English | MEDLINE | ID: covidwho-657787

ABSTRACT

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/complications , Pandemics , Pneumonia, Viral/complications , Thrombophilia/etiology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Anticoagulants/therapeutic use , Arterial Occlusive Diseases/etiology , Arterial Occlusive Diseases/physiopathology , Arterial Occlusive Diseases/virology , COVID-19 , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Catheterization, Swan-Ganz , Combined Modality Therapy , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Endothelium, Vascular/physiopathology , Endothelium, Vascular/virology , Fibrinolytic Agents/therapeutic use , Humans , Hyperbaric Oxygenation , Platelet Aggregation Inhibitors/therapeutic use , Pneumonia, Viral/blood , Pneumonia, Viral/drug therapy , Pulmonary Embolism/etiology , Pulmonary Embolism/therapy , Pulmonary Embolism/virology , Respiratory Distress Syndrome/etiology , SARS-CoV-2 , Thrombolytic Therapy/instrumentation , Thrombolytic Therapy/methods , Thrombophilia/physiopathology , Thrombophilia/therapy , Venous Thrombosis/etiology , Venous Thrombosis/physiopathology , Venous Thrombosis/virology , Virus Internalization/drug effects
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