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1.
Vaccine ; 40(13): 1996-2002, 2022 03 18.
Article in English | MEDLINE | ID: covidwho-1692819

ABSTRACT

ChAdOx1 nCoV-19 adenoviral vector vaccine (ChAd) against coronavirus disease 2019 has been associated with vaccine-induced thrombosis and thrombocytopenia (VITT), especially in young women who have presented with unusual localized thrombosis after receiving the vaccine. The pathogenesis of VITT remains incompletely understood. We tried to provide new insights into mechanisms underlying this phenomenon in the model of arterial thrombosis electrically induced in the carotid artery of female rats. At 28 days post-vaccination, ChAd induced SARS-CoV-2-specific neutralizing antibody responses in all animals. The analysis of the blood vessel/thrombus area showed slight luminal narrowing of the carotid artery with extravasation of blood in vaccinated rats. These small changes were not accompanied by differences in thrombus weight and composition. The vaccinated animals presented a slight increase (by around 14-24%) in platelet aggregation. ChAd did not significantly affect blood coagulation, platelet counts, and their activation markers. Unaffected thrombus formation, the lack of thrombocytopenia and all the measured blood and hemostasis parameters that predominantly stayed unchanged, indicate that the ChAd does not increase the risk of arterial thrombosis development in female rats.


Subject(s)
COVID-19 , Thrombosis , Vaccines , Animals , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Female , Humans , Platelet Aggregation , Rats , SARS-CoV-2 , Thrombosis/etiology , Thrombosis/prevention & control
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.
Nat Commun ; 12(1): 7135, 2021 12 09.
Article in English | MEDLINE | ID: covidwho-1565715

ABSTRACT

A characteristic clinical feature of COVID-19 is the frequent incidence of microvascular thrombosis. In fact, COVID-19 autopsy reports have shown widespread thrombotic microangiopathy characterized by extensive diffuse microthrombi within peripheral capillaries and arterioles in lungs, hearts, and other organs, resulting in multiorgan failure. However, the underlying process of COVID-19-associated microvascular thrombosis remains elusive due to the lack of tools to statistically examine platelet aggregation (i.e., the initiation of microthrombus formation) in detail. Here we report the landscape of circulating platelet aggregates in COVID-19 obtained by massive single-cell image-based profiling and temporal monitoring of the blood of COVID-19 patients (n = 110). Surprisingly, our analysis of the big image data shows the anomalous presence of excessive platelet aggregates in nearly 90% of all COVID-19 patients. Furthermore, results indicate strong links between the concentration of platelet aggregates and the severity, mortality, respiratory condition, and vascular endothelial dysfunction level of COVID-19 patients.


Subject(s)
COVID-19/diagnosis , Platelet Aggregation , Single-Cell Analysis , Thrombosis/virology , COVID-19/blood , Female , Humans , Male , Microscopy , Sex Factors
4.
Blood Adv ; 6(3): 866-881, 2022 01 08.
Article in English | MEDLINE | ID: covidwho-1546752

ABSTRACT

Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposed to C5b-9 in inducing endothelial dysfunction and loss of antithrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS), a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation, and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player in endothelial thromboresistance loss. C5a added to normal human serum fully recapitulated the prothrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of von Willebrand factor (vWF) and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 who suffered from acute activation of complement triggered by severe acute respiratory syndrome coronavirus 2 infection, we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common prothrombogenic effector spanning from genetic rare diseases to viral infections, and it may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition because the former preserves the formation of C5b-9, which is critical for controlling bacterial infections that often develop as comorbidities in severely ill patients. The ACCESS trial registered at www.clinicaltrials.gov as #NCT02464891 accounts for the results related to aHUS patients treated with CCX168.


Subject(s)
Atypical Hemolytic Uremic Syndrome , COVID-19 , Endothelial Cells , Humans , Platelet Aggregation , SARS-CoV-2
5.
J Thromb Haemost ; 20(2): 387-398, 2022 02.
Article in English | MEDLINE | ID: covidwho-1506601

ABSTRACT

BACKGROUND: Thromboembolic events are frequently reported in patients infected with the SARS-CoV-2. Recently, we observed that platelets from patients with severe COVID-19 infection express procoagulant phenotype. The molecular mechanisms that induce the generation of procoagulant platelets in COVID-19 patients are not completely understood. OBJECTIVES: In this study, we investigated the role of AKT (also known as Protein Kinase B), which is the major downstream effector of PI3K (phosphoinositid-3-kinase) (PI3K/AKT) signaling pathway in platelets from patients with COVID-19. PATIENTS AND METHODS: Platelets, Sera and IgG from COVID-19 patients who were admitted to the intensive care unit (ICU) were analyzed by flow cytometry as well as western blot and adhesion assays. RESULTS: Platelets from COVID-19 patients showed significantly higher levels of phosphorylated AKT, which was correlated with CD62p expression and phosphatidylserine (PS) externalization. In addition, healthy platelets incubated with sera or IgGs from ICU COVID-19 patients induced phosphorylation of PI3K and AKT and were dependent on Fc-gamma-RIIA (FcγRIIA). In contrast, ICU COVID-19 sera mediated generation of procoagulant platelets was not dependent on GPIIb/IIIa. Interestingly, the inhibition of phosphorylation of both proteins AKT and PI3K prevented the generation of procoagulant platelets. CONCLUSIONS: Our study shows that pAKT/AKT signaling pathway is associated with the formation of procoagulant platelets in severe COVID-19 patients without integrin GPIIb/IIIa engagement. The inhibition of PI3K/AKT phosphorylation might represent a promising strategy to reduce the risk for thrombosis in patients with severe COVID-19.


Subject(s)
COVID-19 , Proto-Oncogene Proteins c-akt , Blood Platelets , Humans , Phosphatidylinositol 3-Kinases , Platelet Activation , Platelet Aggregation , Platelet Glycoprotein GPIIb-IIIa Complex , SARS-CoV-2
6.
Am J Pathol ; 192(1): 112-120, 2022 01.
Article in English | MEDLINE | ID: covidwho-1506166

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) increases the risk of myocardial injury that contributes to mortality. This study used multiparameter immunofluorescence to extensively examine heart autopsy tissue of 7 patients who died of COVID-19 compared to 12 control specimens, with or without cardiovascular disease. Consistent with prior reports, no evidence of viral infection or lymphocytic infiltration indicative of myocarditis was found. However, frequent and extensive thrombosis was observed in large and small vessels in the hearts of the COVID-19 cohort, findings that were infrequent in controls. The endothelial lining of thrombosed vessels typically lacked evidence of cytokine-mediated endothelial activation, assessed as nuclear expression of transcription factors p65 (RelA), pSTAT1, or pSTAT3, or evidence of inflammatory activation assessed by expression of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), tissue factor, or von Willebrand factor (VWF). Intimal EC lining was also generally preserved with little evidence of cell death or desquamation. In contrast, there were frequent markers of neutrophil activation within myocardial thrombi in patients with COVID-19, including neutrophil-platelet aggregates, neutrophil-rich clusters within macrothrombi, and evidence of neutrophil extracellular trap (NET) formation. These findings point to alterations in circulating neutrophils rather than in the endothelium as contributors to the increased thrombotic diathesis in the hearts of COVID-19 patients.


Subject(s)
COVID-19 , Coronary Vessels , Myocarditis , Myocardium , SARS-CoV-2/metabolism , Thrombosis , Aged , Aged, 80 and over , Blood Platelets/metabolism , Blood Platelets/pathology , COVID-19/metabolism , COVID-19/pathology , Coronary Vessels/metabolism , Coronary Vessels/pathology , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Female , Gene Expression Regulation , Humans , Male , Middle Aged , Myocarditis/metabolism , Myocarditis/pathology , Myocardium/metabolism , Myocardium/pathology , Neutrophil Activation , Neutrophils/metabolism , Neutrophils/pathology , Platelet Aggregation , Thrombosis/metabolism , Thrombosis/pathology
8.
Adv Sci (Weinh) ; 8(23): e2103266, 2021 12.
Article in English | MEDLINE | ID: covidwho-1479368

ABSTRACT

Activation of endothelial cells following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be the primary driver for the increasingly recognized thrombotic complications in coronavirus disease 2019 patients, potentially due to the SARS-CoV-2 Spike protein binding to the human angiotensin-converting enzyme 2 (hACE2). Vaccination therapies use the same Spike sequence or protein to boost host immune response as a protective mechanism against SARS-CoV-2 infection. As a result, cases of thrombotic events are reported following vaccination. Although vaccines are generally considered safe, due to genetic heterogeneity, age, or the presence of comorbidities in the population worldwide, the prediction of severe adverse outcome in patients remains a challenge. To elucidate Spike proteins underlying patient-specific-vascular thrombosis, the human microcirculation environment is recapitulated using a novel microfluidic platform coated with human endothelial cells and exposed to patient specific whole blood. Here, the blood coagulation effect is tested after exposure to Spike protein in nanoparticles and Spike variant D614G in viral vectors and the results are corroborated using live SARS-CoV-2. Of note, two potential strategies are also examined to reduce blood clot formation, by using nanoliposome-hACE2 and anti-Interleukin (IL) 6 antibodies.


Subject(s)
Blood Coagulation/physiology , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antibodies/chemistry , Antibodies/immunology , Antibodies/metabolism , COVID-19/diagnosis , COVID-19/virology , Endothelial Cells/chemistry , Endothelial Cells/cytology , Endothelial Cells/metabolism , Fibrin/chemistry , Fibrin/metabolism , Genetic Vectors/genetics , Genetic Vectors/metabolism , Humans , Interleukin-6/immunology , Liposomes/chemistry , Microfluidics/methods , Mutation , Nanoparticles/chemistry , Platelet Aggregation , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/analysis , Spike Glycoprotein, Coronavirus/genetics
9.
Sci Rep ; 11(1): 19752, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1454813

ABSTRACT

Although metabolic syndrome (MetS) is linked to an elevated risk of cardiovascular disease (CVD), the cardiac-specific risk mechanism is unknown. Obesity, hypertension, and diabetes (all MetS components) are the most common form of CVD and represent risk factors for worse COVID-19 outcomes compared to their non MetS peers. Here, we use obese Yorkshire pigs as a highly relevant animal model of human MetS, where pigs develop the hallmarks of human MetS and reproducibly mimics the myocardial pathophysiology in patients. Myocardium-specific mass spectroscopy-derived metabolomics, proteomics, and transcriptomics enabled the identity and quality of proteins and metabolites to be investigated in the myocardium to greater depth. Myocardium-specific deregulation of pro-inflammatory markers, propensity for arterial thrombosis, and platelet aggregation was revealed by computational analysis of differentially enriched pathways between MetS and control animals. While key components of the complement pathway and the immune response to viruses are under expressed, key N6-methyladenosin RNA methylation enzymes are largely overexpressed in MetS. Blood tests do not capture the entirety of metabolic changes that the myocardium undergoes, making this analysis of greater value than blood component analysis alone. Our findings create data associations to further characterize the MetS myocardium and disease vulnerability, emphasize the need for a multimodal therapeutic approach, and suggests a mechanism for observed worse outcomes in MetS patients with COVID-19 comorbidity.


Subject(s)
COVID-19/pathology , Disease Susceptibility , Metabolic Syndrome/pathology , Animals , Blood Coagulation Factors/genetics , Blood Coagulation Factors/metabolism , COVID-19/complications , COVID-19/virology , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Diet, High-Fat/veterinary , Disease Models, Animal , Humans , Immunity, Innate/genetics , Metabolic Syndrome/complications , Metabolic Syndrome/metabolism , Methyltransferases/genetics , Methyltransferases/metabolism , Myocardium/metabolism , Oxidative Stress/genetics , Platelet Aggregation , Receptors, Purinergic P2Y1/genetics , Receptors, Purinergic P2Y1/metabolism , Renin-Angiotensin System , Risk Factors , SARS-CoV-2/isolation & purification , Swine , Urokinase-Type Plasminogen Activator/genetics , Urokinase-Type Plasminogen Activator/metabolism
10.
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
11.
Adv Ther ; 38(7): 3911-3923, 2021 07.
Article in English | MEDLINE | ID: covidwho-1258274

ABSTRACT

INTRODUTION: COVID-19 is associated with an increased risk of thrombotic events. However, the contribution of platelet reactivity (PR) to the aetiology of the increased thrombotic risk associated with COVID-19 remains unclear. Our aim was to evaluate PR in stable patients diagnosed with COVID-19 and hospitalized with respiratory symptoms (mainly dyspnoea and dry cough), in comparison with a control group comprised of non-hospitalized healthy controls. METHODS: Observational, case control study that included patients with confirmed COVID-19 (COVID-19 group, n = 60) and healthy individuals matched by age and sex (control group, n = 60). Multiplate electrode aggregometry (MEA) tests were used to assess PR with adenosine diphosphate (MEA-ADP, low PR defined as < 53 AUC), arachidonic acid (MEA-ASPI, low PR < 86 AUC) and thrombin receptor-activating peptide 6 (MEA-TRAP, low PR < 97 AUC) in both groups. RESULTS: The rates of low PR with MEA-ADP were 27.5% in the COVID-19 group and 21.7% in the control group (OR = 1.60, p = 0.20); with MEA-ASPI, the rates were, respectively, 37.5% and 22.5% (OR = 3.67, p < 0.001); and with MEA-TRAP, the incidences were 48.5% and 18.8%, respectively (OR = 9.58, p < 0.001). Levels of D-dimer, fibrinogen, and plasminogen activator inhibitor 1 (PAI-1) were higher in the COVID-19 group in comparison with the control group (all p < 0.05). Thromboelastometry was utilized in a subgroup of patients and showed a hypercoagulable state in the COVID-19 group. CONCLUSION: Patients hospitalized with non-severe COVID-19 had lower PR compared to healthy controls, despite having higher levels of D-dimer, fibrinogen, and PAI-1, and hypercoagulability by thromboelastometry. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04447131.


Subject(s)
COVID-19 , Blood Platelets , Case-Control Studies , Humans , Platelet Aggregation , Platelet Aggregation Inhibitors/pharmacology , SARS-CoV-2
13.
J Cutan Pathol ; 48(9): 1166-1172, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1208906

ABSTRACT

Retiform purpura has been described as a relatively frequent cutaneous finding in patients with coronavirus disease 2019 (COVID-19). The etiology is hypothesized to be related to thrombotic vasculopathy based on lesional biopsy specimen findings, but the pathogenesis of the vasculopathy is not completely understood. Here, we present a case of a retiform purpuric patch on the sacrum/buttocks in a hospitalized patient prior to subsequent diagnosis of COVID-19 and an eventual fatal disease course. Two lesional biopsy specimens at different time points in the disease course revealed thrombotic vasculopathy, despite therapeutic anticoagulation. Detailed histopathologic evaluation using immunohistochemical markers suggest the etiology of the vasculopathy involves both persistent complement activation and platelet aggregation, which possibly promote ongoing thrombus formation. This case highlights that sacral/buttock retiform purpuric patches may be a presenting sign of infection with SARS-CoV-2 virus and may represent an ominous sign supporting a future severe disease course. In addition, biopsy specimen findings at separate time points demonstrate that cutaneous vasculopathy may persist despite adequate systemic anticoagulation, possibly due to the combination of persistent complement and platelet activation. Finally, occlusive thrombi in sacral/buttock retiform purpuric patches may contribute to future ulceration and significant cutaneous morbidity in patients who survive COVID-19.


Subject(s)
Buttocks/pathology , COVID-19/complications , COVID-19/pathology , Purpura/diagnosis , Sacrum/pathology , Aged , Anticoagulants/therapeutic use , Biopsy/methods , Buttocks/virology , COVID-19/diagnosis , COVID-19/immunology , Calciphylaxis/diagnosis , Complement Activation/immunology , Diagnosis, Differential , Disease Progression , Fatal Outcome , Female , Humans , Inpatients , Platelet Aggregation/immunology , Purpura/virology , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Sacrum/virology , Skin/pathology , Skin Diseases, Vascular/etiology , Skin Diseases, Vascular/pathology
14.
Leg Med (Tokyo) ; 51: 101894, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1188870

ABSTRACT

SARS-CoV-2 infection was a leading cause of death in 2020 worldwide. It can evolve determining sudden dyspnea and death without hospitalization and/or a nasopharyngeal swab. These cases can need the intervention of forensic pathologists in order to identify causes of death and to clarify malpractice claims. For these reasons, it would be useful to identify immunohistochemistry patterns of SARS-CoV-2 deaths. Thus, the authors described immunohistochemistry findings of two Patients: perivascular recruitment of T-cells in lung parenchyma, massive activation of cytotoxic cells (especially in spleen's parenchyma), and diffuse platelet aggregation in medium/small vessels. In addition, they analyzed these data in the light of the scientific literature, pointing out meaningful immunohistochemistry patterns in order to better understand SARS-CoV-2 pathophysiology process and to clearly identify causes/contributing factors of death in forensic routine.


Subject(s)
COVID-19/immunology , COVID-19/metabolism , Forensic Pathology , Immunohistochemistry , SARS-CoV-2/immunology , Aged , Aged, 80 and over , Antigens, CD20 , Autopsy , CD3 Complex , COVID-19/physiopathology , Female , Humans , Integrin beta3 , Male , Platelet Aggregation , T-Cell Intracellular Antigen-1 , T-Lymphocytes, Cytotoxic
15.
N Engl J Med ; 384(22): 2124-2130, 2021 06 03.
Article in English | MEDLINE | ID: covidwho-1174740

ABSTRACT

We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4-polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.


Subject(s)
Autoantibodies/blood , COVID-19 Vaccines/adverse effects , Platelet Factor 4/immunology , Thrombocytopenia/etiology , Thrombosis/etiology , Adult , Autoimmune Diseases/etiology , Blood Chemical Analysis , Enzyme-Linked Immunosorbent Assay , Fatal Outcome , Female , Humans , Male , Middle Aged , Platelet Aggregation , Platelet Count
16.
Anesthesiology ; 134(3): 457-467, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1075617

ABSTRACT

BACKGROUND: The hemostatic balance in patients with coronavirus disease 2019 (COVID-19) seems to be shifted toward a hypercoagulable state. The aim of the current study was to assess the associated coagulation alterations by point-of-care-diagnostics, focusing on details of clot formation and lysis in these severely affected patients. METHODS: The authors' prospective monocentric observational study included critically ill patients diagnosed with COVID-19. Demographics and biochemical data were recorded. To assess the comprehensive hemostatic profile of this patient population, aggregometric (Multiplate) and viscoelastometric (CloPro) measures were performed in the intensive care unit of a university hospital at a single occasion. Coagulation analysis and assessment of coagulation factors were performed. Data were compared to healthy controls. RESULTS: In total, 27 patients (21 male; mean age, 60 yr) were included. Impedance aggregometry displayed no greater platelet aggregability in COVID-19 in comparison with healthy controls (area under the curve [AUC] in adenosine diphosphate test, 68 ± 37 U vs. 91 ± 29 U [-27 (Hodges-Lehmann 95% CI, -48 to -1); P = 0.043]; AUC in arachidonic acid test, 102 ± 54 U vs. 115 ± 26 U [-21 (Hodges-Lehmann 95% CI, -51 to 21); P = 0.374]; AUC in thrombin receptor activating peptide 6 test, 114 ± 61 U vs. 144 ± 31 U [-31 (Hodges-Lehmann 95% CI, -69 to -7); P = 0.113]). Comparing the thromboelastometric results of COVID-19 patients to healthy controls, the authors observed significant differences in maximum clot firmness in fibrin contribution to maximum clot firmness assay (37 ± 11 mm vs. 15 ± 4 mm [21 (Hodges-Lehmann 95% CI, 17 to 26); P < 0.001]) and lysis time in extrinsic activation and activation of fibrinolysis by tissue plasminogen activator assay (530 ± 327 s vs. 211 ± 80 s [238 (Hodges-Lehmann 95% CI, 160 to 326); P < 0.001]). CONCLUSIONS: Thromboelastometry in COVID-19 patients revealed greater fibrinolysis resistance. The authors did not find a greater platelet aggregability based on impedance aggregometric tests. These findings may contribute to our understanding of the hypercoagulable state of critically ill patients with COVID-19.


Subject(s)
COVID-19 , Fibrinolysis , Critical Illness , Humans , Male , Middle Aged , Platelet Aggregation , Prospective Studies , SARS-CoV-2 , Thrombelastography , Tissue Plasminogen Activator
18.
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
19.
J Thromb Thrombolysis ; 52(1): 105-110, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1002136

ABSTRACT

Patients with Coronavirus-associated disease-2019 (COVID-19) display alterations of the hemostatic system and the presence of a prothrombotic status frequently leading to vascular complications. However, the impact of COVID-19 on platelet activity, aggregation and agglutination still needs to be clarified. We measured total levels of von Willebrand factor (vWF) and vWF binding to the platelet glycoprotein (Gp) complex (GPIb-IX-V), in a cohort of COVID-19 patients admitted to the intensive care unit of our Institution. Moreover, we evaluated platelet aggregation in response to agonists (ADP, collagen, arachidonic acid) and platelet agglutination in response to ristocetin. We found that levels of vWF antigen and the active form of vWF binding to platelets (vWF:RCo), were markedly increased in these patients. These results were associated with higher agglutination rates induced by ristocetin, thereby indirectly indicating an increased capability of vWF to bind to platelets. Conversely, we found that platelet aggregation in response to both ADP and collagen was lower in COVID-19 patients compared to healthy volunteers. This study shows that COVID-19 is associated with increased vWF-induced platelet agglutination but reduced platelet responsivity to aggregation stimuli. Our findings have translational relevance since platelet adhesion to vWF may represent a marker to predict possible complications and better delineate therapeutic strategies in COVID-19 patients.


Subject(s)
Blood Platelets/metabolism , COVID-19/blood , Platelet Aggregation , von Willebrand Factor/metabolism , Adult , Aged , Aged, 80 and over , Agglutination , Blood Platelets/virology , COVID-19/diagnosis , COVID-19/virology , Female , Host-Pathogen Interactions , Humans , Male , Middle Aged , Platelet Function Tests , Protein Binding , SARS-CoV-2/pathogenicity , Thrombosis/blood , Thrombosis/diagnosis , Thrombosis/virology
20.
Platelets ; 32(4): 560-567, 2021 May 19.
Article in English | MEDLINE | ID: covidwho-998117

ABSTRACT

The aim of this study (NCT04343053) is to investigate the relationship between platelet activation, myocardial injury, and mortality in patients affected by Coronavirus disease 2019 (COVID-19). Fifty-four patients with respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were enrolled as cases. Eleven patients with the same clinical presentation, but negative for SARS-CoV-2 infection, were included as controls. Blood samples were collected at three different time points (inclusion [T1], after 7 ± 2 days [T2] and 14 ± 2 days [T3]). Platelet aggregation by light transmittance aggregometry and the circulating levels of soluble CD40 ligand (sCD40L) and P-selectin were measured. Platelet biomarkers did not differ between cases and controls, except for sCD40L which was higher in COVID-19 patients (p = .003). In COVID-19 patients, P-selectin and sCD40L levels decreased from T1 to T3 and were higher in cases requiring admission to intensive care unit (p = .004 and p = .008, respectively). Patients with myocardial injury (37%), as well as those who died (30%), had higher values of all biomarkers of platelet activation (p < .05 for all). Myocardial injury was an independent predictor of mortality. In COVID-19 patients admitted to hospital for respiratory failure, heightened platelet activation is associated with severity of illness, myocardial injury, and mortality.ClinicalTrials.gov number: NCT04343053.


Subject(s)
Blood Platelets/metabolism , COVID-19 , Heart Injuries , Myocardium , Respiratory Insufficiency , SARS-CoV-2/metabolism , Aged , Aged, 80 and over , Biomarkers/blood , CD40 Ligand/blood , COVID-19/blood , COVID-19/mortality , COVID-19/pathology , Female , Heart Injuries/blood , Heart Injuries/mortality , Heart Injuries/pathology , Heart Injuries/virology , Humans , Male , Middle Aged , Myocardium/metabolism , Myocardium/pathology , P-Selectin/blood , Platelet Aggregation , Respiratory Insufficiency/blood , Respiratory Insufficiency/mortality , Respiratory Insufficiency/pathology , Respiratory Insufficiency/virology
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