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2.
EBioMedicine ; 73: 103672, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1568646

ABSTRACT

BACKGROUND: Phospho-Akt1 (pAkt1) undergoes prolyl hydroxylation at Pro125 and Pro313 by the prolyl hydroxylase-2 (PHD2) in a reaction decarboxylating α-ketoglutarate (αKG). We investigated whether the αKG supplementation could inhibit Akt-mediated activation of platelets and monocytes, in vitro as well as in vivo, by augmenting PHD2 activity. METHODS: We treated platelets or monocytes isolated from healthy individuals with αKG in presence of agonists in vitro and assessed the signalling molecules including pAkt1. We supplemented mice with dietary αKG and estimated the functional responses of platelets and monocytes ex vivo. Further, we investigated the impact of dietary αKG on inflammation and thrombosis in lungs of mice either treated with thrombosis-inducing agent carrageenan or infected with SARS-CoV-2. FINDINGS: Octyl αKG supplementation to platelets promoted PHD2 activity through elevated intracellular αKG to succinate ratio, and reduced aggregation in vitro by suppressing pAkt1(Thr308). Augmented PHD2 activity was confirmed by increased hydroxylated-proline and enhanced binding of PHD2 to pAkt in αKG-treated platelets. Contrastingly, inhibitors of PHD2 significantly increased pAkt1 in platelets. Octyl-αKG followed similar mechanism in monocytes to inhibit cytokine secretion in vitro. Our data also describe a suppressed pAkt1 and reduced activation of platelets and leukocytes ex vivo from mice supplemented with dietary αKG, unaccompanied by alteration in their number. Dietary αKG significantly reduced clot formation and leukocyte accumulation in various organs including lungs of mice treated with thrombosis-inducing agent carrageenan. Importantly, in SARS-CoV-2 infected hamsters, we observed a significant rescue effect of dietary αKG on inflamed lungs with significantly reduced leukocyte accumulation, clot formation and viral load alongside down-modulation of pAkt in the lung of the infected animals. INTERPRETATION: Our study suggests that dietary αKG supplementation prevents Akt-driven maladies such as thrombosis and inflammation and rescues pathology of COVID19-infected lungs. FUNDING: Study was funded by the Department of Biotechnology (DBT), Govt. of India (grants: BT/PR22881 and BT/PR22985); and the Science and Engineering Research Board, Govt. of India (CRG/000092).


Subject(s)
Ketoglutaric Acids/therapeutic use , Prolyl Hydroxylases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Thrombosis/prevention & control , Animals , Blood Platelets/cytology , Blood Platelets/drug effects , Blood Platelets/metabolism , COVID-19/pathology , COVID-19/prevention & control , COVID-19/veterinary , COVID-19/virology , Cricetinae , Dietary Supplements , Down-Regulation/drug effects , Humans , Ketoglutaric Acids/pharmacology , Lung/metabolism , Lung/pathology , Mesocricetus , Mice , Mice, Inbred BALB C , Monocytes/cytology , Monocytes/drug effects , Monocytes/metabolism , Phosphorylation , Platelet Aggregation/drug effects , Protein Isoforms/genetics , Protein Isoforms/metabolism , Proto-Oncogene Proteins c-akt/genetics , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Thrombosis/chemically induced , Thrombosis/pathology , Thrombosis/veterinary
3.
Platelets ; 33(1): 48-53, 2022 Jan 02.
Article in English | MEDLINE | ID: covidwho-1541393

ABSTRACT

Coagulopathy is an evident complication of COVID-19 with predominance of a prothrombotic state. Platelet activation plays a key role. The terms "hyper-reactivity" and "hyperactivity" used in recent literature may not be clear or sufficient to explain the pathological events involved in COVID-related thrombosis (CRT). Inflammation may play a bigger role compared to thrombosis in COVID-related mortality because a smaller percentage of patients with COVID-19 die due to direct effects of thrombosis. Not all COVID-19 patients have thrombocytopenia and a few show thrombocytosis. We believe the platelet pathology is more complex than just activation or hyper-activation, particularly due to the platelets' role in inflammation. Understanding the pathology and consequences of platelets' role may help optimize management strategies and diminish CRT-associated morbidity and mortality. In this viewpoint report, we examine the published evidence of platelet hyper-reactivity in COVID-19 with a focused analysis of the key pathologies, diverse alterations, disease outcomes, and therapeutic targets. We believe that COVID-19 is a disease of inflammation and pathologic platelets, and based on the complexity and diverse pathologies, we propose the term "thrombocytopathy" as a more reflective term of the platelets' involvement in COVID-19. In our opinion, thrombocytopathy is the unpredictable pathologic alterations of platelets in function, morphology and number, caused by different factors with a variety of presentations.


Subject(s)
Blood Platelets/pathology , COVID-19/complications , Cytokine Release Syndrome/complications , Disseminated Intravascular Coagulation/complications , Pulmonary Embolism/complications , SARS-CoV-2/pathogenicity , Abciximab/therapeutic use , Acute Disease , Anticoagulants/therapeutic use , Aspirin/therapeutic use , Blood Platelets/drug effects , Blood Platelets/virology , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/virology , Clopidogrel/therapeutic use , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Disseminated Intravascular Coagulation/diagnosis , Disseminated Intravascular Coagulation/drug therapy , Disseminated Intravascular Coagulation/virology , Fibrinolytic Agents/therapeutic use , Humans , Lung/blood supply , Lung/drug effects , Lung/pathology , Lung/virology , Platelet Activation/drug effects , Pulmonary Embolism/diagnosis , Pulmonary Embolism/drug therapy , Pulmonary Embolism/virology , Treatment Outcome
4.
Clin Appl Thromb Hemost ; 27: 10760296211048808, 2021.
Article in English | MEDLINE | ID: covidwho-1495924

ABSTRACT

We aimed to investigate association between mean platelet volume (MVP), platelet distribution width (PDW) and red cell distribution width (RDW) and mortality in patients with COVID-19 and find out in which patients the use of acetylsalicylic acid (ASA) affects the prognosis due to the effect of MPV on thromboxan A2. A total of 5142 patients were divided into those followed in the intensive care unit (ICU) and those followed in the ward. Patient medical records were examined retrospectively. ROC analysis showed that the area under curve (AUC) values were 0.714, 0.750, 0.843 for MPV, RDW and D-Dimer, the cutoff value was 10.45fl, 43.65fl, 500.2 ng/mL respectively. (all P < .001). Survival analysis showed that patients with MPV >10.45 f/l and D-Dimer >500.2 ng/mL, treatment with ASA had lower in-hospital and 180-day mortality than patients without ASA in ICU patients (HR = 0.773; 95% CI = 0.595-0.992; P = .048, HR = 0.763; 95% CI = 0.590-0.987; P = .036). Administration of low-dose ASA in addition to anti-coagulant according to MPV and D-dimer levels reduces mortality.


Subject(s)
Blood Platelets , COVID-19/blood , Erythrocyte Indices , Erythrocytes , Mean Platelet Volume , Aged , Aged, 80 and over , Anticoagulants/therapeutic use , Aspirin/therapeutic use , Blood Platelets/drug effects , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/mortality , Female , Hospital Mortality , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/therapeutic use , Predictive Value of Tests , Retrospective Studies , Severity of Illness Index , Time Factors , Treatment Outcome
7.
Nat Commun ; 12(1): 5552, 2021 09 21.
Article in English | MEDLINE | ID: covidwho-1434105

ABSTRACT

Sepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection (e.g., bacterial infection, COVID-19), resulting in the dysfunction of multiple organs. Currently, there is no direct treatment for sepsis. Here we report an abiotic hydrogel nanoparticle (HNP) as a potential therapeutic agent for late-stage sepsis. The HNP captures and neutralizes all variants of histones, a major inflammatory mediator released during sepsis. The highly optimized HNP has high capacity and long-term circulation capability for the selective sequestration and neutralization of histones. Intravenous injection of the HNP protects mice against a lethal dose of histones through the inhibition of platelet aggregation and migration into the lungs. In vivo administration in murine sepsis model mice results in near complete survival. These results establish the potential for synthetic, nonbiological polymer hydrogel sequestrants as a new intervention strategy for sepsis therapy and adds to our understanding of the importance of histones to this condition.


Subject(s)
Hydrogels/therapeutic use , Nanoparticles/therapeutic use , Sepsis/drug therapy , Animals , Blood Platelets/drug effects , Cell Adhesion , Cell Survival/drug effects , Disease Models, Animal , Histones/antagonists & inhibitors , Histones/metabolism , Histones/toxicity , Hydrogels/chemistry , Hydrogels/metabolism , Hydrogels/pharmacology , Lung/drug effects , Lung/metabolism , Lung/pathology , Mice , Nanoparticles/chemistry , Nanoparticles/metabolism , Platelet Aggregation/drug effects , Polyethylene Glycols/chemistry , Polyethylene Glycols/metabolism , Polyethylene Glycols/pharmacology , Polyethylene Glycols/therapeutic use , Protein Binding , Sepsis/mortality , Survival Rate
8.
Pediatr Blood Cancer ; 68(12): e29355, 2021 12.
Article in English | MEDLINE | ID: covidwho-1414402

ABSTRACT

OBJECTIVE: To characterize viscoelastic testing profiles of children with multisystem inflammatory syndrome in children (MIS-C). METHODS: This single-center retrospective review included 30 patients diagnosed with MIS-C from March 1 to September 1, 2020. Thromboelastography (TEG) with platelet mapping was performed in 19 (63%) patients and compared to age- and sex-matched controls prior to cardiac surgery. Relationships between TEG parameters and inflammatory markers were assessed using correlation. RESULTS: Patients with MIS-C had abnormal TEG results compared to controls, including decreased kinetic (K) time (1.1 vs. 1.7 minutes, p < .01), increased alpha angle (75.0° vs. 65.7°, p < .01), increased maximum amplitude (70.8 vs. 58.3 mm, p < .01), and decreased lysis in 30 minutes (Ly30) (1.1% vs. 3.7%, p = .03); consistent with increased clot formation rate and strength, and reduced fibrinolysis. TEG maximum amplitude was moderately correlated with erythrocyte sedimentation rate (ESR) (r = 0.60, p = .02), initial platelet count (r = 0.67, p < .01), and peak platelet count (r = 0.51, p = .03). TEG alpha angle was moderately correlated with peak platelet count (r = 0.54, p = .02). Seventeen (57%) patients received aspirin (ASA) and anticoagulation, five (17%) received only ASA, and three (10%) received only anticoagulation. No patients had a symptomatic thrombotic event. Six (20%) patients had a bleeding event, none of which was major. CONCLUSIONS: Patients with MIS-C had evidence of hypercoagulability on TEG. Increased ESR and platelets were associated with higher clot strength. Patients were prophylactically treated with ASA or anticoagulation with no symptomatic thrombosis or major bleeding. Further multicenter study is required to characterize the rate of thrombosis and optimal thromboprophylaxis algorithm in this patient population.


Subject(s)
Blood Coagulation , COVID-19/complications , Systemic Inflammatory Response Syndrome/blood , Thrombophilia/blood , Adolescent , Anticoagulants/therapeutic use , Aspirin/therapeutic use , Blood Coagulation/drug effects , Blood Platelets/drug effects , COVID-19/blood , COVID-19/drug therapy , Child , Child, Preschool , Female , Humans , Male , Retrospective Studies , Systemic Inflammatory Response Syndrome/drug therapy , Thrombelastography , Thrombophilia/drug therapy
9.
J Med Virol ; 93(9): 5390-5395, 2021 09.
Article in English | MEDLINE | ID: covidwho-1363677

ABSTRACT

Hypercoagulability and thrombosis caused by coronavirus disease 2019 (COVID-19) are related to the higher mortality rate. Because of limited data on the antiplatelet effect, we aimed to evaluate the impact of aspirin add-on therapy on the outcome of the patients hospitalized due to severe COVID-19. In this cohort study, patients with a confirmed diagnosis of severe COVID-19 admitted to Imam Hossein Medical Center, Tehran, Iran from March 2019 to July 2020 were included. Demographics and related clinical data during their hospitalization were recorded. The mortality rate of the patients was considered as the primary outcome and its association with aspirin use was assessed. Nine hundred and ninety-one patients were included, of that 336 patients (34%) received aspirin during their hospitalization and 655 ones (66%) did not. Comorbidities were more prevalent in the patients who were receiving aspirin. Results from the multivariate COX proportional model demonstrated a significant independent association between aspirin use and reduction in the risk of in-hospital mortality (0.746 [0.560-0.994], p = 0.046). Aspirin use in hospitalized patients with COVID-19 is associated with a significant decrease in mortality rate. Further prospective randomized controlled trials are needed to assess the efficacy and adverse effects of aspirin administration in this population.


Subject(s)
Aspirin/therapeutic use , COVID-19/drug therapy , Disseminated Intravascular Coagulation/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Pulmonary Embolism/drug therapy , SARS-CoV-2/pathogenicity , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adult , Aged , Alanine/analogs & derivatives , Alanine/therapeutic use , Antiviral Agents/therapeutic use , Blood Platelets/drug effects , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/complications , COVID-19/mortality , COVID-19/virology , Coronary Artery Disease/complications , Coronary Artery Disease/drug therapy , Coronary Artery Disease/mortality , Coronary Artery Disease/virology , Diabetes Mellitus/drug therapy , Diabetes Mellitus/mortality , Diabetes Mellitus/virology , Disseminated Intravascular Coagulation/complications , Disseminated Intravascular Coagulation/mortality , Disseminated Intravascular Coagulation/virology , Drug Combinations , Female , Hospital Mortality , Humans , Hypertension/complications , Hypertension/drug therapy , Hypertension/mortality , Hypertension/virology , Iran , Lopinavir/therapeutic use , Lung/blood supply , Lung/drug effects , Lung/pathology , Lung/virology , Male , Middle Aged , Pulmonary Embolism/complications , Pulmonary Embolism/mortality , Pulmonary Embolism/virology , Respiration, Artificial/mortality , Respiration, Artificial/statistics & numerical data , Retrospective Studies , Ritonavir/therapeutic use , SARS-CoV-2/drug effects , Severity of Illness Index , Survival Analysis , Treatment Outcome
11.
Carbohydr Res ; 505: 108326, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1213065

ABSTRACT

The viral infection caused by SARS-CoV-2 has increased the mortality rate and engaged several adverse effects on the affected individuals. Currently available antiviral drugs have found to be unsuccessful in the treatment of COVID-19 patients. The demand for efficient antiviral drugs has created a huge burden on physicians and health workers. Plasma therapy seems to be less accomplishable due to insufficient donors to donate plasma and low recovery rate from viral infection. Repurposing of antivirals has been evolved as a suitable strategy in the current treatment and preventive measures. The concept of drug repurposing represents new experimental approaches for effective therapeutic benefits. Besides, SARS-CoV-2 exhibits several complications such as lung damage, blood clot formation, respiratory illness and organ failures in most of the patients. Based on the accumulation of data, sulfated marine polysaccharides have exerted successful inhibition of virus entry, attachment and replication with known or unknown possible mechanisms against deadly animal and human viruses so far. Since the virus entry into the host cells is the key process, the prevention of such entry mechanism makes any antiviral strategy effective. Enveloped viruses are more sensitive to polyanions than non-enveloped viruses. Besides, the viral infection caused by RNA virus types embarks severe oxidative stress in the human body that leads to malfunction of tissues and organs. In this context, polysaccharides play a very significant role in providing shielding effect against the virus due to their polyanionic rich features and a molecular weight that hinders their reactive surface glycoproteins. Significantly the functional groups especially sulfate, sulfate pattern and addition, uronic acids, monosaccharides, glycosidic linkage and high molecular weight have greater influence in the antiviral activity. Moreover, they are very good antioxidants that can reduce the free radical generation and provokes intracellular antioxidant enzymes. Additionally, polysaccharides enable a host-virus immune response, activate phagocytosis and stimulate interferon systems. Therefore, polysaccharides can be used as candidate drugs, adjuvants in vaccines or combination with other antivirals, antioxidants and immune-activating nutritional supplements and antiviral materials in healthcare products to prevent SARS-CoV-2 infection.


Subject(s)
Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Immunologic Factors/therapeutic use , Polysaccharides/therapeutic use , Pulmonary Embolism/drug therapy , Respiratory Insufficiency/drug therapy , Anticoagulants/chemistry , Anticoagulants/isolation & purification , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Blood Platelets/drug effects , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/complications , COVID-19/diagnosis , COVID-19/virology , Humans , Immunologic Factors/chemistry , Immunologic Factors/isolation & purification , Lung/blood supply , Lung/drug effects , Lung/pathology , Lung/virology , Phaeophyta/chemistry , Polysaccharides/chemistry , Polysaccharides/isolation & purification , Pulmonary Embolism/complications , Pulmonary Embolism/diagnosis , Pulmonary Embolism/virology , Respiratory Insufficiency/complications , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/virology , Rhodophyta/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Sulfuric Acid Esters/chemistry , Virus Attachment/drug effects , Virus Internalization/drug effects
12.
J Med Virol ; 93(9): 5390-5395, 2021 09.
Article in English | MEDLINE | ID: covidwho-1206845

ABSTRACT

Hypercoagulability and thrombosis caused by coronavirus disease 2019 (COVID-19) are related to the higher mortality rate. Because of limited data on the antiplatelet effect, we aimed to evaluate the impact of aspirin add-on therapy on the outcome of the patients hospitalized due to severe COVID-19. In this cohort study, patients with a confirmed diagnosis of severe COVID-19 admitted to Imam Hossein Medical Center, Tehran, Iran from March 2019 to July 2020 were included. Demographics and related clinical data during their hospitalization were recorded. The mortality rate of the patients was considered as the primary outcome and its association with aspirin use was assessed. Nine hundred and ninety-one patients were included, of that 336 patients (34%) received aspirin during their hospitalization and 655 ones (66%) did not. Comorbidities were more prevalent in the patients who were receiving aspirin. Results from the multivariate COX proportional model demonstrated a significant independent association between aspirin use and reduction in the risk of in-hospital mortality (0.746 [0.560-0.994], p = 0.046). Aspirin use in hospitalized patients with COVID-19 is associated with a significant decrease in mortality rate. Further prospective randomized controlled trials are needed to assess the efficacy and adverse effects of aspirin administration in this population.


Subject(s)
Aspirin/therapeutic use , COVID-19/drug therapy , Disseminated Intravascular Coagulation/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Pulmonary Embolism/drug therapy , SARS-CoV-2/pathogenicity , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adult , Aged , Alanine/analogs & derivatives , Alanine/therapeutic use , Antiviral Agents/therapeutic use , Blood Platelets/drug effects , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/complications , COVID-19/mortality , COVID-19/virology , Coronary Artery Disease/complications , Coronary Artery Disease/drug therapy , Coronary Artery Disease/mortality , Coronary Artery Disease/virology , Diabetes Mellitus/drug therapy , Diabetes Mellitus/mortality , Diabetes Mellitus/virology , Disseminated Intravascular Coagulation/complications , Disseminated Intravascular Coagulation/mortality , Disseminated Intravascular Coagulation/virology , Drug Combinations , Female , Hospital Mortality , Humans , Hypertension/complications , Hypertension/drug therapy , Hypertension/mortality , Hypertension/virology , Iran , Lopinavir/therapeutic use , Lung/blood supply , Lung/drug effects , Lung/pathology , Lung/virology , Male , Middle Aged , Pulmonary Embolism/complications , Pulmonary Embolism/mortality , Pulmonary Embolism/virology , Respiration, Artificial/mortality , Respiration, Artificial/statistics & numerical data , Retrospective Studies , Ritonavir/therapeutic use , SARS-CoV-2/drug effects , Severity of Illness Index , Survival Analysis , Treatment Outcome
13.
Thromb Haemost ; 121(11): 1395-1399, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1182893

ABSTRACT

A series of cases with rare thromboembolic incidents including cerebral sinus vein thrombosis (some of them fatal) and concomitant thrombocytopenia occurring shortly after vaccination with the coronavirus disease 2019 (COVID-19) vaccine AZD1222 (Vaxzevria) have caused significant concern and led to its temporary suspension in many countries. Immediate laboratory efforts in four of these patients have identified a tentative pathomechanism underlying this syndrome termed initially vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) and renamed recently vaccine-induced immune thrombotic thrombocytopenia (VITT). It encompasses the presence of platelet-activating antibodies to platelet factor-4/heparin complexes, possibly emulated by polyanionic constituents of AZD1222, and thus resembles heparin-induced thrombocytopenia (HIT). Because these immune complexes bind and activate platelets via Fcγ receptor IIA (FcγRIIA), high-dose intravenous immunoglobulin G has been suggested for treatment of VITT in addition to non-heparin anticoagulants. Here we propose inhibitors of Bruton tyrosine kinase (Btk) approved for B cell malignancies (e.g., ibrutinib) as another therapeutic option in VITT, as they are expected to pleiotropically target multiple pathways downstream of FcγRIIA-mediated Btk activation, for example, as demonstrated for the effective inhibition of platelet aggregation, dense granule secretion, P-selectin expression and platelet-neutrophil aggregate formation stimulated by FcγRIIA cross-linking. Moreover, C-type lectin-like receptor CLEC-2- and GPIb-mediated platelet activation, the interactions and activation of monocytes and the release of neutrophil extracellular traps, as encountered in HIT, could be attenuated by Btk inhibitors. As a paradigm for emergency repurposing of approved drugs in COVID-19, off-label use of Btk inhibitors in a low-dose range not affecting haemostatic functions could thus be considered a sufficiently safe option to treat VITT.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Blood Platelets/drug effects , COVID-19 Vaccines/adverse effects , Platelet Activation/drug effects , Protein Kinase Inhibitors/therapeutic use , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Vaccination/adverse effects , Agammaglobulinaemia Tyrosine Kinase/metabolism , Animals , Autoantibodies/blood , Blood Platelets/enzymology , Blood Platelets/immunology , COVID-19 Vaccines/administration & dosage , Humans , Molecular Targeted Therapy , Platelet Factor 4/immunology , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/enzymology , Purpura, Thrombocytopenic, Idiopathic/immunology , Receptors, IgG/metabolism , Signal Transduction
14.
Thromb Haemost ; 121(12): 1610-1621, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1172583

ABSTRACT

BACKGROUND: High levels of D-dimer and low platelet counts are associated with poor outcome in coronavirus disease 2019 (COVID-19). As anticoagulation appeared to improve survival, hospital-wide recommendations regarding higher doses of anticoagulation were implemented on April 9, 2020. OBJECTIVES: To investigate if trends in D-dimer levels and platelet counts were associated with death, thrombosis, and the shift in anticoagulation. METHODS: Retrospective cohort study of 429 patients with COVID-19 at Karolinska University Hospital. Information on D-dimer levels and platelet counts was obtained from laboratory databases and clinical data from medical records. RESULTS: Thirty-day mortality and thrombosis rates were 19% and 18%, respectively. Pulmonary embolism was common, 65/83 (78%). Increased D-dimer levels in the first week in hospital were significantly associated with death and thrombosis (odds ratio [OR]: 6.06; 95% confidence interval [CL]: 2.10-17.5 and 3.11; 95% CI: 1.20-8.10, respectively). If platelet count increased more than 35 × 109/L per day, the mortality and thrombotic risk decreased (OR: 0.16; 95% CI: 0.06-0.41, and OR: 0.36; 95% CI: 0.17-0.80). After implementation of updated hospital-wide recommendations, the daily mean significantly decreased regarding D-dimer levels while platelet counts rose; -1.93; 95% CI: -1.00-2.87 mg/L FEU (fibrinogen-equivalent unit) and 65; 95% CI: 54-76 ×109/L, and significant risk reductions for death and thrombosis were observed; OR: 0.48; 95% CI: 0.25-0.92 and 0.35; 95% CI: 0.17-0.72. CONCLUSION: In contrast to D-dimer levels, increase of platelet count over the first week in hospital was associated with improved survival and reduced thrombotic risk. The daily mean levels of D-dimer dropped while the platelet counts rose, coinciding with increased anticoagulation and a decline in thrombotic burden and mortality.


Subject(s)
Anticoagulants/administration & dosage , Blood Platelets/drug effects , COVID-19/drug therapy , Fibrin Fibrinogen Degradation Products/metabolism , Thrombosis/drug therapy , Administration, Oral , Aged , Anticoagulants/adverse effects , Biomarkers/blood , Blood Platelets/metabolism , COVID-19/blood , COVID-19/diagnosis , COVID-19/mortality , Female , Hospital Mortality , Humans , Male , Middle Aged , Retrospective Studies , Sweden/epidemiology , Thrombosis/blood , Thrombosis/diagnosis , Thrombosis/mortality , Time Factors , Treatment Outcome
15.
Blood Coagul Fibrinolysis ; 32(3): 167-171, 2021 Apr 01.
Article in English | MEDLINE | ID: covidwho-1171412

ABSTRACT

Coronavirus disease 2019 infection produce a prothrombotic state. This is initiated through multiple pathways and is finally aggravated by cross talks with cytokine storm and neutrophil, platelet, complement activation. All these combine towards the second week of illness to produce thrombosis in the lung capillaries surrounding the alveolus producing characteristic pulmonary dysfunction (PaO2/FiO2 > 300, normal or minimally increased lung compliance and very high d-dimer levels) and a high rate of peripheral venous thrombosis. International and many national guidelines have approached this state in different ways but all emphasized the need for management and prevention of widespread thrombosis. It is felt more aggressive and graded thrombosis prevention and management should be initiated early in the treatment. d-Dimer, neutrophil count, SaO2, fibrinogen levels should be used to control the hypercoagulability. Drugs like statins which have anti-inflammatory action as well as ability to reduce fibrinogen and other clotting factors should be used in the beginning along with antiplatelet drugs and progressively complement activation and neutrophil extracellular traps inhibitors, oral mucopolysaccharides, full-scale anticoagulation along with judicial use of fibrinolysis supporting drugs should be added. In the present review, we have evaluated the various studies and argued the rationality that the anticoagulation in this condition should be initiated early during the infection and should be increased in a graded manner depending on clinical and laboratory progression of the condition until a strong specific antiviral drug for coronavirus disease 2019 infection is available.


Subject(s)
Blood Coagulation/drug effects , COVID-19/drug therapy , COVID-19/physiopathology , Thrombophilia/drug therapy , Thrombosis/drug therapy , Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , Blood Platelets/drug effects , Extracellular Traps/drug effects , Fibrinolytic Agents/therapeutic use , Glycosaminoglycans/pharmacology , Glycosaminoglycans/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Inflammation/drug therapy , Lung/drug effects , Lung/physiopathology , Lung/virology , Platelet Aggregation Inhibitors/therapeutic use
16.
Int J Mol Sci ; 22(5)2021 Feb 27.
Article in English | MEDLINE | ID: covidwho-1120857

ABSTRACT

The beneficial effects of long-chain polyunsaturated omega-3 fatty acids (omega-3 PUFAs) in cardioprotection are widely known and generally accepted. In this literature review, we have focused on the known and postulated mechanisms of action of omega-3 PUFAs and their metabolites on various components of the haemostatic system, in particular on blood platelets and endothelium. We have also made an attempt to provide a comprehensive review of epidemiological studies with particular regard to clinical trials. Notably, the results of these studies are contradictory, and some of them failed to report the beneficial effects of taking or supplementing omega-3 PUFAs in the diet. A potential explanation, in our opinion, could be the need to use higher doses of omega-3 PUFAs and a proper ratio of omega-3 and omega-6 PUFAs. An additional problem which is difficult to solve is the use of a proper neutral placebo for interventional studies. Despite some controversies regarding the beneficial effects of supplementation of omega-3 PUFAs in cardiovascular disease, our review suggests that a promising aspect of future studies and applications is to focus on the anti-thrombotic properties of these compounds. An argument supporting this assumption is the recent use of omega-3 PUFAs as a supporting tool for the treatment of COVID-19 complications.


Subject(s)
COVID-19/complications , Cardiovascular Diseases/drug therapy , Fatty Acids, Omega-3/administration & dosage , Blood Platelets/drug effects , Blood Platelets/metabolism , COVID-19/blood , COVID-19/drug therapy , Cardiovascular Diseases/blood , Cardiovascular Diseases/metabolism , Diet , Fatty Acids, Omega-3/metabolism , Fatty Acids, Omega-6/administration & dosage , Fibrinolytic Agents/administration & dosage , Hemostasis/drug effects , Humans , Randomized Controlled Trials as Topic , SARS-CoV-2/isolation & purification , Thrombosis/drug therapy
17.
Mar Drugs ; 19(1)2021 Jan 10.
Article in English | MEDLINE | ID: covidwho-1033055

ABSTRACT

Microalgae are at the start of the food chain, and many are known producers of a significant amount of lipids with essential fatty acids. However, the bioactivity of microalgal lipids for anti-inflammatory and antithrombotic activities have rarely been investigated. Therefore, for a sustainable source of the above bioactive lipids, the present study was undertaken. The total lipids of microalga Chlorococcum sp., isolated from the Irish coast, were fractionated into neutral-, glyco-, and phospho-lipids, and were tested in vitro for their anti-inflammatory and antithrombotic activities. All tested lipid fractions showed strong anti-platelet-activating factor (PAF) and antithrombin activities in human platelets (half maximal inhibitory concentration (IC50) values ranging ~25-200 µg of lipid) with the highest activities in glyco- and phospho-lipid fractions. The structural analysis of the bioactive lipid fraction-2 revealed the presence of specific sulfoquinovosyl diacylglycerols (SQDG) bioactive molecules and the HexCer-t36:2 (t18:1/18:1 and 18:2/18:0) cerebrosides with a phytosphingosine (4-hydrosphinganine) base, while fraction-3 contained bioactive phosphatidylcholine (PC) and phosphatidylethanolamine (PE) molecules. These novel bioactive lipids of Chlorococcum sp. with putative health benefits may indicate that marine microalgae can be a sustainable alternative source for bioactive lipids production for food supplements and nutraceutical applications. However, further studies are required towards the commercial technology pathways development and biosafety analysis for the use of the microalga.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Lipids/chemistry , Lipids/pharmacology , Microalgae/chemistry , Antithrombins/pharmacology , Blood Platelets/drug effects , Fatty Acids/chemistry , Fatty Acids/pharmacology , Humans , Platelet Activating Factor/antagonists & inhibitors , Platelet Aggregation/drug effects , Water Microbiology
18.
Biofactors ; 46(6): 927-933, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-966303

ABSTRACT

Recent articles report elevated markers of coagulation, endothelial injury, and microthromboses in lungs from deceased COVID-19 patients. However, there has been no discussion of what may induce intravascular coagulation. Platelets are critical in the formation of thrombi and their most potent trigger is platelet activating factor (PAF), first characterized by Demopoulos and colleagues in 1979. PAF is produced by cells involved in host defense and its biological actions bear similarities with COVID-19 disease manifestations. PAF can also stimulate perivascular mast cell activation, leading to inflammation implicated in severe acute respiratory syndrome (SARS). Mast cells are plentiful in the lungs and are a rich source of PAF and of inflammatory cytokines, such as IL-1ß and IL-6, which may contribute to COVID-19 and especially SARS. The histamine-1 receptor antagonist rupatadine was developed to have anti-PAF activity, and also inhibits activation of human mast cells in response to PAF. Rupatadine could be repurposed for COVID-19 prophylaxis alone or together with other PAF-inhibitors of natural origin such as the flavonoids quercetin and luteolin, which have antiviral, anti-inflammatory, and anti-PAF actions.


Subject(s)
COVID-19/prevention & control , Cyproheptadine/analogs & derivatives , Disseminated Intravascular Coagulation/prevention & control , Platelet Activating Factor/antagonists & inhibitors , Pulmonary Embolism/prevention & control , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/prevention & control , Antiviral Agents/therapeutic use , Blood Platelets/drug effects , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/blood , COVID-19/pathology , COVID-19/virology , Cyproheptadine/therapeutic use , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/pathology , Disseminated Intravascular Coagulation/virology , Gene Expression Regulation , Humans , Inflammation , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Lung/drug effects , Lung/pathology , Lung/virology , Luteolin/therapeutic use , Mast Cells/drug effects , Mast Cells/pathology , Mast Cells/virology , Platelet Activating Factor/genetics , Platelet Activating Factor/metabolism , Pulmonary Embolism/blood , Pulmonary Embolism/pathology , Pulmonary Embolism/virology , Quercetin/therapeutic use , SARS-CoV-2/drug effects , Severe Acute Respiratory Syndrome/blood , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/virology
19.
Nitric Oxide ; 107: 11-18, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-949808

ABSTRACT

Nitric oxide, NO, has been explored as a therapeutic agent to treat thrombosis. In particular, NO has potential in treating mechanical device-associated thrombosis due to its ability to reduce platelet activation and due to the central role of platelet activation and adhesion in device thrombosis. Nitrite is a unique NO donor that reduces platelet activation in that it's activity requires the presence of red blood cells whereas NO activity of other NO donors is blunted by red blood cells. Interestingly, we have previously shown that red blood cell mediated inhibition of platelet activation by adenosine diphosophate (ADP) is dramatically enhanced by illumination with far-red light that is likely due to photolysis of red cell surface bound NO congeners. We now report the effects of nitrite, far-red light, and their combination on several measure of blood coagulation using a variety of agonists. We employed turbidity assays in platelet rich plasma, platelet activation using flow cytometry analysis of a fluorescently labeled antibody to the activated platelet fibrinogen binding site, multiplate impedance-based platelet aggregometry, and assessment of platelet adhesion to collagen coated flow-through microslides. In all cases, the combination of far-red light and nitrite treatment decreased measures of coagulation, but in some cases mono-treatment with nitrite or light alone had no effect. Perhaps most relevant to device thrombosis, we observed that platelet adhesions was inhibited by the combination of nitrite and light treatment while nitrite alone and far-red light alone trended to decrease adhesion, but the results were mixed. These results support the potential of combined far-red light and nitrite treatment for preventing thrombosis in extra-corporeal or shallow-tissue depth devices where the far-red light can penetrate. Such a combined treatment could be advantageous due to the localized treatment afforded by far-red light illumination with minimal systemic effects. Given the role of thrombosis in COVID 19, application to treatment of patients infected with SARS Cov-2 might also be considered.


Subject(s)
Blood Coagulation/drug effects , Blood Coagulation/radiation effects , Nitric Oxide Donors/pharmacology , Nitrites/pharmacology , Blood Platelets/drug effects , Blood Platelets/radiation effects , COVID-19/drug therapy , COVID-19/radiotherapy , Humans , Light , Nitric Oxide/metabolism , Platelet Activation/drug effects , Platelet Activation/radiation effects , Platelet Adhesiveness/drug effects , Platelet Adhesiveness/radiation effects , Platelet Aggregation/drug effects , Platelet Aggregation/radiation effects , SARS-CoV-2/drug effects
20.
J Med Virol ; 92(10): 2205-2208, 2020 10.
Article in English | MEDLINE | ID: covidwho-935121

ABSTRACT

Acute respiratory distress syndrome and coagulopathy played an important role in morbidity and mortality of severe COVID-19 patients. A higher frequency of pulmonary embolism (PE) than expected in COVID-19 patients was recently reported. The presenting symptoms for PE were untypical including dyspnea, which is one of the major symptoms in severe COVID-19, especially in those patients with acute respiratory distress syndrome (ARDS). We reported two COVID-19 cases with coexisting complications of PE and ARDS, aiming to consolidate the emerging knowledge of this global health emergency and raise the awareness that the hypoxemia or severe dyspnea in COVID-19 may be related to PE and not necessarily always due to the parenchymal disease.


Subject(s)
COVID-19/complications , Pulmonary Embolism/complications , Respiratory Distress Syndrome/complications , SARS-CoV-2/pathogenicity , Acute Disease , Aged , Biomarkers/blood , Blood Platelets/drug effects , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/diagnostic imaging , COVID-19/drug therapy , COVID-19/virology , Ceftazidime/therapeutic use , Dyspnea/physiopathology , Fibrin Fibrinogen Degradation Products/metabolism , Heparin/therapeutic use , Humans , Hypoxia/physiopathology , Lung/blood supply , Lung/drug effects , Lung/pathology , Lung/virology , Male , Methylprednisolone/therapeutic use , Middle Aged , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/drug therapy , Pulmonary Embolism/virology , Respiratory Distress Syndrome/diagnostic imaging , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/virology , Ribavirin/therapeutic use , Tomography, X-Ray Computed , Treatment Outcome
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