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1.
Curr Opin Nephrol Hypertens ; 31(1): 36-46, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1612725

ABSTRACT

PURPOSE OF REVIEW: Severe COVID-19 disease is often complicated by acute kidney injury (AKI), which may transition to chronic kidney disease (CKD). Better understanding of underlying mechanisms is important in advancing therapeutic approaches. RECENT FINDINGS: SARS-CoV-2-induced endothelial injury initiates platelet activation, platelet-neutrophil partnership and release of neutrophil extracellular traps. The resulting thromboinflammation causes ischemia-reperfusion (I/R) injury to end organs. Severe COVID-19 induces a lipid-mediator storm with massive increases in thromboxane A2 (TxA2) and PGD2, which promote thromboinflammation and apoptosis of renal tubular cells, respectively, and thereby enhance renal fibrosis. COVID-19-associated AKI improves rapidly in the majority. However, 15-30% have protracted renal injury, raising the specter of transition from AKI to CKD. SUMMARY: In COVID-19, the lipid-mediator storm promotes thromboinflammation, ischemia-reperfusion injury and cytotoxicity. The thromboxane A2 and PGD2 signaling presents a therapeutic target with potential to mitigate AKI and transition to CKD. Ramatroban, the only dual antagonist of the thromboxane A2/TPr and PGD2/DPr2 signaling could potentially mitigate renal injury in acute and long-haul COVID. Urgent studies targeting the lipid-mediator storm are needed to potentially reduce the heavy burden of kidney disease emerging in the wake of the current pandemic.


Subject(s)
Acute Kidney Injury , COVID-19 , Renal Insufficiency, Chronic , Thrombosis , Acute Kidney Injury/etiology , COVID-19/complications , Fibrosis , Humans , Inflammation , Kidney/pathology , Lipids , Renal Insufficiency, Chronic/pathology , SARS-CoV-2 , Thrombosis/pathology
2.
PLoS One ; 17(1): e0262352, 2022.
Article in English | MEDLINE | ID: covidwho-1606851

ABSTRACT

INTRODUCTION: COVID-19 infection has been hypothesized to precipitate venous and arterial clotting events more frequently than other illnesses. MATERIALS AND METHODS: We demonstrate this increased risk of blood clots by comparing rates of venous and arterial clotting events in 4400 hospitalized COVID-19 patients in a large multisite clinical network in the United States examined from April through June of 2020, to patients hospitalized for non-COVID illness and influenza during the same time period and in 2019. RESULTS: We demonstrate that COVID-19 increases the risk of venous thrombosis by two-fold compared to the general inpatient population and compared to people with influenza infection. Arterial and venous thrombosis were both common occurrences among patients with COVID-19 infection. Risk factors for thrombosis included male gender, older age, and diabetes. Patients with venous or arterial thrombosis had high rates of admission to the ICU, re-admission to the hospital, and death. CONCLUSION: Given the ongoing scientific discussion about the impact of clotting on COVID-19 disease progression, these results highlight the need to further elucidate the role of anticoagulation in COVID-19 patients, particularly outside the intensive care unit setting. Additionally, concerns regarding clotting and COVID-19 vaccines highlight the importance of addressing the alarmingly high rate of clotting events during actual COVID-19 infection when weighing the risks and benefits of vaccination.


Subject(s)
COVID-19/pathology , Thrombosis/pathology , Aged , COVID-19/mortality , Cohort Studies , Comorbidity , Female , Hospitalization , Humans , Male , New Jersey , Retrospective Studies , Thrombosis/mortality , United States
3.
Int J Mol Sci ; 22(24)2021 Dec 20.
Article in English | MEDLINE | ID: covidwho-1580687

ABSTRACT

COVID-19 infection is associated with a broad spectrum of presentations, but alveolar capillary microthrombi have been described as a common finding in COVID-19 patients, appearing as a consequence of a severe endothelial injury with endothelial cell membrane disruption. These observations clearly point to the identification of a COVID-19-associated coagulopathy, which may contribute to thrombosis, multi-organ damage, and cause of severity and fatality. One significant finding that emerges in prothrombotic abnormalities observed in COVID-19 patients is that the coagulation alterations are mainly mediated by the activation of platelets and intrinsically related to viral-mediated endothelial inflammation. Beyond the well-known role in hemostasis, the ability of platelets to also release various potent cytokines and chemokines has elevated these small cells from simple cell fragments to crucial modulators in the blood, including their inflammatory functions, that have a large influence on the immune response during infectious disease. Indeed, platelets are involved in the pathogenesis of acute lung injury also by promoting NET formation and affecting vascular permeability. Specifically, the deposition by activated platelets of the chemokine platelet factor 4 at sites of inflammation promotes adhesion of neutrophils on endothelial cells and thrombogenesis, and it seems deeply involved in the phenomenon of vaccine-induced thrombocytopenia and thrombosis. Importantly, the hyperactivated platelet phenotype along with evidence of cytokine storm, high levels of P-selectin, D-dimer, and, on the other hand, decreased levels of fibrinogen, von Willebrand factor, and thrombocytopenia may be considered suitable biomarkers that distinguish the late stage of COVID-19 progression in critically ill patients.


Subject(s)
Blood Platelets/physiology , COVID-19/blood , Thrombosis/pathology , Blood Coagulation , Blood Coagulation Disorders/etiology , Blood Platelets/metabolism , Blood Platelets/virology , COVID-19/metabolism , Cytokine Release Syndrome , Endothelial Cells/pathology , Fibrin Fibrinogen Degradation Products , Hemostasis , Humans , Inflammation , Phenotype , Platelet Activation/physiology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Thrombocytopenia/metabolism , Thrombosis/metabolism , Thrombosis/virology
4.
Clin Appl Thromb Hemost ; 27: 10760296211051764, 2021.
Article in English | MEDLINE | ID: covidwho-1511654

ABSTRACT

The precise mechanisms of pathology in severe COVID-19 remains elusive. Current evidence suggests that inflammatory mediators are responsible for the manifestation of clinical symptoms that precedes a fatal response to infection. This review examines the nature of platelet activating factor and emphasizes the similarities between the physiological effects of platelet activating factor and the clinical complications of severe COVID-19.


Subject(s)
COVID-19/metabolism , Platelet Activating Factor/metabolism , Animals , COVID-19/complications , COVID-19/mortality , COVID-19/pathology , Humans , Inflammation/complications , Inflammation/metabolism , Inflammation/mortality , Inflammation/pathology , Multiple Organ Failure/complications , Multiple Organ Failure/metabolism , Multiple Organ Failure/mortality , Multiple Organ Failure/pathology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/mortality , Respiratory Distress Syndrome/pathology , SARS-CoV-2/physiology , Severity of Illness Index , Thrombosis/complications , Thrombosis/metabolism , Thrombosis/mortality , Thrombosis/pathology
5.
Blood ; 138(16): 1481-1489, 2021 10 21.
Article in English | MEDLINE | ID: covidwho-1484294

ABSTRACT

A subset of patients with coronavirus disease 2019 (COVID-19) become critically ill, suffering from severe respiratory problems and also increased rates of thrombosis. The causes of thrombosis in severely ill patients with COVID-19 are still emerging, but the coincidence of critical illness with the timing of the onset of adaptive immunity could implicate an excessive immune response. We hypothesized that platelets might be susceptible to activation by anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies and might contribute to thrombosis. We found that immune complexes containing recombinant SARS-CoV-2 spike protein and anti-spike immunoglobulin G enhanced platelet-mediated thrombosis on von Willebrand factor in vitro, but only when the glycosylation state of the Fc domain was modified to correspond with the aberrant glycosylation previously identified in patients with severe COVID-19. Furthermore, we found that activation was dependent on FcγRIIA, and we provide in vitro evidence that this pathogenic platelet activation can be counteracted by the therapeutic small molecules R406 (fostamatinib) and ibrutinib, which inhibit tyrosine kinases Syk and Btk, respectively, or by the P2Y12 antagonist cangrelor.


Subject(s)
Blood Platelets/pathology , COVID-19/complications , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/pathology , von Willebrand Factor/metabolism , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antigen-Antibody Complex/immunology , Blood Platelets/immunology , Blood Platelets/metabolism , COVID-19/immunology , COVID-19/virology , Glycosylation , Humans , Platelet Activation/immunology , Thrombosis/immunology , Thrombosis/virology , von Willebrand Factor/genetics
6.
Clin Appl Thromb Hemost ; 27: 10760296211042940, 2021.
Article in English | MEDLINE | ID: covidwho-1484251

ABSTRACT

The world is in a hard battle against COVID-19. Endothelial cells are among the most critical targets of SARS-CoV-2. Dysfunction of endothelium leads to vascular injury following by coagulopathies and thrombotic conditions in the vital organs increasing the risk of life-threatening events. Growing evidences revealed that endothelial dysfunction and consequent thrombotic conditions are associated with the severity of outcomes. It is not yet fully clear that these devastating sequels originate directly from the virus or a side effect of virus-induced cytokine storm. Due to endothelial dysfunction, plasma levels of some biomarkers are changed and relevant clinical manifestations appear as well. Stabilization of endothelial integrity and supporting its function are among the promising therapeutic strategies. Other than respiratory, COVID-19 could be called a systemic vascular disease and this aspect should be scrutinized in more detail in order to reduce related mortality. In the present investigation, the effects of COVID-19 on endothelial function and thrombosis formation are discussed. In this regard, critical players, laboratory findings, clinical manifestation, and suggestive therapies are presented.


Subject(s)
Blood Coagulation , COVID-19/virology , Endothelial Cells/virology , Endothelium, Vascular/virology , SARS-CoV-2/pathogenicity , Thrombosis/virology , Animals , COVID-19/blood , COVID-19/pathology , COVID-19/physiopathology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Host-Pathogen Interactions , Humans , Signal Transduction , Thrombosis/blood , Thrombosis/pathology , Thrombosis/physiopathology
7.
Eur Rev Med Pharmacol Sci ; 25(19): 5904-5912, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1478932

ABSTRACT

OBJECTIVE: Liver injury has been reported in patients with COVID-19. This condition is characterized by severe outcome and could be related with the ability of SARS-CoV-2 to activate cytotoxic T cells. The purpose of this study is to show the histological and scanning electron microscopy features of liver involvement in COVID-19 to characterize the liver changes caused by the activation of multiple molecular pathways following this infection. PATIENTS AND METHODS: Liver biopsies from 4 patients (3 post-mortems and 1 in vivo) with COVID-19 were analyzed with histology and by scanning electron microscopy. RESULTS: The liver changes showed significant heterogeneity. The first case showed ground glass hepatocytes and scattered fibrin aggregates in the sinusoidal lumen. The second evidenced intra-sinusoidal thrombi. The third was characterized by sinusoidal dilatation, atrophy of hepatocytes, Disse's spaces dilatation and intra-sinusoidal aggregates of fibrin and red blood cells. The fourth case exhibited diffuse fibrin aggregates in the dilated Disse spaces and microthrombi in the sinusoidal lumen. CONCLUSIONS: In COVID-19-related liver injury, a large spectrum of pathological changes was observed. The most peculiar features were very mild inflammation, intra-sinusoidal changes, including sinusoidal dilatation, thrombotic sinusoiditis and diffuse intra-sinusoidal fibrin deposition. These findings suggested that a thrombotic sinusoiditis followed by a local diffuse intra-vascular (intra-sinusoidal) coagulation could be the typical features of the SARS-CoV-2-related liver injury.


Subject(s)
Blood Coagulation Disorders/pathology , COVID-19/pathology , Liver Diseases/pathology , Liver/pathology , Thrombosis/pathology , Aged , Autopsy , Biopsy , Erythrocytes/pathology , Fibrin , Hepatocytes/pathology , Humans , Male , Microscopy, Electron, Scanning , Middle Aged , Thrombosis/complications , Young Adult
8.
Front Immunol ; 12: 735922, 2021.
Article in English | MEDLINE | ID: covidwho-1477823

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. COVID-19 is considered an airway/multi-systemic disease, and demise has been associated with an uncontrolled immune response and a cytokine storm in response to the virus. However, the lung pathology, immune response, and tissue damage associated with COVID-19 demise are poorly described and understood due to safety concerns. Using post-mortem lung tissues from uninfected and COVID-19 deadly cases as well as an unbiased combined analysis of histology, multi-viral and host markers staining, correlative microscopy, confocal, and image analysis, we identified three distinct phenotypes of COVID-19-induced lung damage. First, a COVID-19-induced hemorrhage characterized by minimal immune infiltration and large thrombus; Second, a COVID-19-induced immune infiltration with excessive immune cell infiltration but no hemorrhagic events. The third phenotype correspond to the combination of the two previous ones. We observed the loss of alveolar wall integrity, detachment of lung tissue pieces, fibroblast proliferation, and extensive fibrosis in all three phenotypes. Although lung tissues studied were from lethal COVID-19, a strong immune response was observed in all cases analyzed with significant B cell and poor T cell infiltrations, suggesting an exhausted or compromised immune cellular response in these patients. Overall, our data show that SARS-CoV-2-induced lung damage is highly heterogeneous. These individual differences need to be considered to understand the acute and long-term COVID-19 consequences.


Subject(s)
COVID-19/mortality , COVID-19/pathology , Lung Injury/pathology , Pulmonary Alveoli/pathology , Pulmonary Fibrosis/pathology , Aged , Aged, 80 and over , Autopsy , CD8-Positive T-Lymphocytes/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/pathology , Epithelial Cells/pathology , Female , Hemorrhage/pathology , Humans , Inflammation/pathology , Lung/pathology , Lung Injury/virology , Lymphopenia/pathology , Macrophage Activation/immunology , Macrophages/immunology , Male , Middle Aged , Myocytes, Smooth Muscle/pathology , Neutrophils/immunology , SARS-CoV-2 , Thrombosis/pathology
9.
Int J Mol Sci ; 22(20)2021 Oct 13.
Article in English | MEDLINE | ID: covidwho-1470887

ABSTRACT

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has infected >235 million people and killed over 4.8 million individuals worldwide. Although vaccines have been developed for prophylactic management, there are no clinically proven antivirals to treat the viral infection. Continuous efforts are being made all over the world to develop effective drugs but these are being delayed by periodic outbreak of mutated SARS-CoV-2 and a lack of knowledge of molecular mechanisms underlying viral pathogenesis and post-infection complications. In this regard, the involvement of Annexin A2 (AnxA2), a lipid-raft related phospholipid-binding protein, in SARS-CoV-2 attachment, internalization, and replication has been discussed. In addition to the evidence from published literature, we have performed in silico docking of viral spike glycoprotein and RNA-dependent RNA polymerase with human AnxA2 to find the molecular interactions. Overall, this review provides the molecular insights into a potential role of AnxA2 in the SARS-CoV-2 pathogenesis and post-infection complications, especially thrombosis, cytokine storm, and insulin resistance.


Subject(s)
Annexin A2/metabolism , COVID-19/pathology , Annexin A2/chemistry , COVID-19/virology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/pathology , Humans , Molecular Docking Simulation , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/metabolism , Thrombosis/pathology , Virus Internalization
10.
Ophthalmic Res ; 64(5): 785-792, 2021.
Article in English | MEDLINE | ID: covidwho-1443682

ABSTRACT

INTRODUCTION: In December 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic broke out. The virus rapidly spread globally, resulting in a major world public-health crisis. The major disease manifestation occurs in the respiratory tract. However, further studies documented other systemic involvement. This study investigates histopathologic eye changes in postmortem material of coronavirus disease 2019 (COVID-19) patients. METHODS: Sections of formalin-fixed, paraffin-embedded eyes from 5 patients (10 eyes) who died of COVID-19 at the University Hospital in Basel were included. Gross examination and histological evaluation were performed by 3 independent ophthalmopathologists. Immunohistochemical staining was performed using antibodies against fibrin, cleaved caspase 3, and ACE-2. Five enucleated eyes of patients not infected with SARS-CoV-2 served as control group. All cases have been studied for presence of SARS-CoV-2 RNA by means of reverse transcription PCR and RNA in situ hybridization (ISH). The choroidal vessels of one case were analyzed with electron microscope. RESULTS: Ophthalmopathologically, 8 eyes from 4 patients displayed swollen endothelial cells in congested choroidal vessels. No further evidence of specific eye involvement of SARS-CoV-2 was found in any of the patients. In the 8 eyes with evidence of changes due to SARS-CoV-2, immunohistochemical staining demonstrated fibrin microthrombi, apoptotic changes of endothelial and inflammatory cells. In control eyes, ACE-2 was detectable in the conjunctiva, cornea, retina, and choroidea and displayed significantly lower amounts of stained cells as in COVID-19 eyes. SARS-CoV-2 RNA was detectable in both bulbi of 2/5 patients, yet ISH failed to visualize viruses. Electron microscopy showed no significant results due to the artifacts. DISCUSSION/CONCLUSION: As already described in other organs of COVID-19 patients, the ophthalmological examination revealed-microthrombi, that is, hypercoagulation and vasculopathy most probably due to endothelial damage. A possible viral spread to the endothelial cells via ACE-2 provides one pathophysiological explanation. The expression of ACE-2 receptors in the conjunctiva hints toward its susceptibility to infection. To what extend eyes, function is disrupted by SARS-CoV-2 is subject to further studies, especially in the clinic.


Subject(s)
COVID-19/pathology , Choroid Diseases/pathology , Eye Infections, Viral/pathology , RNA, Viral/genetics , Retinal Diseases/pathology , SARS-CoV-2/genetics , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , COVID-19 Nucleic Acid Testing , Caspase 3/metabolism , Choroid/blood supply , Choroid/pathology , Choroid Diseases/virology , Ciliary Body/blood supply , Ciliary Body/pathology , Conjunctiva/metabolism , Cornea/metabolism , Endothelial Cells/metabolism , Eye Infections, Viral/virology , Female , Fibrin/metabolism , Humans , Immunohistochemistry , In Situ Hybridization , Male , Real-Time Polymerase Chain Reaction , Retinal Diseases/virology , Retinal Vessels/pathology , Thrombosis/metabolism , Thrombosis/pathology
11.
JCI Insight ; 6(18)2021 09 22.
Article in English | MEDLINE | ID: covidwho-1435144

ABSTRACT

Neutrophils provide a critical line of defense in immune responses to various pathogens, inflicting self-damage upon transition to a hyperactivated, procoagulant state. Recent work has highlighted proinflammatory neutrophil phenotypes contributing to lung injury and acute respiratory distress syndrome (ARDS) in patients with coronavirus disease 2019 (COVID-19). Here, we use state-of-the art mass spectrometry-based proteomics and transcriptomic and correlative analyses as well as functional in vitro and in vivo studies to dissect how neutrophils contribute to the progression to severe COVID-19. We identify a reinforcing loop of both systemic and neutrophil intrinsic IL-8 (CXCL8/IL-8) dysregulation, which initiates and perpetuates neutrophil-driven immunopathology. This positive feedback loop of systemic and neutrophil autocrine IL-8 production leads to an activated, prothrombotic neutrophil phenotype characterized by degranulation and neutrophil extracellular trap (NET) formation. In severe COVID-19, neutrophils directly initiate the coagulation and complement cascade, highlighting a link to the immunothrombotic state observed in these patients. Targeting the IL-8-CXCR-1/-2 axis interferes with this vicious cycle and attenuates neutrophil activation, degranulation, NETosis, and IL-8 release. Finally, we show that blocking IL-8-like signaling reduces severe acute respiratory distress syndrome of coronavirus 2 (SARS-CoV-2) spike protein-induced, human ACE2-dependent pulmonary microthrombosis in mice. In summary, our data provide comprehensive insights into the activation mechanisms of neutrophils in COVID-19 and uncover a self-sustaining neutrophil-IL-8 axis as a promising therapeutic target in severe SARS-CoV-2 infection.


Subject(s)
COVID-19/metabolism , Interleukin-8/metabolism , Lung/immunology , Neutrophils/immunology , SARS-CoV-2 , Thrombosis/etiology , Animals , COVID-19/complications , COVID-19/pathology , Humans , Lung/pathology , Mice , Neutrophil Activation , Neutrophils/pathology , Phenotype , Thrombosis/pathology
12.
Int J Mol Sci ; 22(2)2021 Jan 08.
Article in English | MEDLINE | ID: covidwho-1389386

ABSTRACT

Neutrophils are primary effector cells of innate immunity and fight infection by phagocytosis and degranulation. Activated neutrophils also release neutrophil extracellular traps (NETs) in response to a variety of stimuli. These NETs are net-like complexes composed of cell-free DNA, histones and neutrophil granule proteins. Besides the evolutionarily conserved mechanism to capture and eliminate pathogens, NETs are also associated with pathophysiological processes of various diseases. Here, we elucidate the mechanisms of NET formation and their different implications in disease. We focused on autoinflammatory and cardiovascular disorders as the leading cause of death. Neutrophil extracellular traps are not only present in various cardiovascular diseases but play an essential role in atherosclerotic plaque formation, arterial and venous thrombosis, as well as in the development and progression of abdominal aortic aneurysms. Furthermore, NETosis can be considered as a source of autoantigens and maintains an inflammatory milieu promoting autoimmune diseases. Indeed, there is further need for research into the balance between NET induction, inhibition, and degradation in order to pharmacologically target NETs and their compounds without impairing the patient's immune defense. This review may be of interest to both basic scientists and clinicians to stimulate translational research and innovative clinical approaches.


Subject(s)
Autoimmune Diseases/immunology , Extracellular Traps/immunology , Neutrophils/immunology , Aortic Aneurysm, Abdominal/pathology , Autoimmune Diseases/pathology , Autoimmunity/immunology , COVID-19/immunology , COVID-19/pathology , Humans , Neutrophil Activation/immunology , Plaque, Atherosclerotic/pathology , Thrombosis/pathology
14.
J Autoimmun ; 121: 102662, 2021 07.
Article in English | MEDLINE | ID: covidwho-1385817

ABSTRACT

Herein, we consider venous immunothrombotic mechanisms in SARS-CoV-2 infection and anti-SARS-CoV-2 DNA vaccination. Primary SARS-CoV-2 infection with systemic viral RNA release (RNAaemia) contributes to innate immune coagulation cascade activation, with both pulmonary and systemic immunothrombosis - including venous territory strokes. However, anti-SARS-CoV-2 adenoviral-vectored-DNA vaccines -initially shown for the ChAdOx1 vaccine-may rarely exhibit autoimmunity with autoantibodies to Platelet Factor-4 (PF4) that is termed Vaccine-Induced Thrombotic Thrombocytopenia (VITT), an entity pathophysiologically similar to Heparin-Induced Thrombocytopenia (HIT). The PF4 autoantigen is a polyanion molecule capable of independent interactions with negatively charged bacterial cellular wall, heparin and DNA molecules, thus linking intravascular innate immunity to both bacterial cell walls and pathogen-derived DNA. Crucially, negatively charged extracellular DNA is a powerful adjuvant that can break tolerance to positively charged nuclear histone proteins in many experimental autoimmunity settings, including SLE and scleroderma. Analogous to DNA-histone interactons, positively charged PF4-DNA complexes stimulate strong interferon responses via Toll-Like Receptor (TLR) 9 engagement. A chain of events following intramuscular adenoviral-vectored-DNA vaccine inoculation including microvascular damage; microbleeding and platelet activation with PF4 release, adenovirus cargo dispersement with DNA-PF4 engagement may rarely break immune tolerance, leading to rare PF4-directed autoimmunity. The VITT cavernous sinus cerebral and intestinal venous territory immunothrombosis proclivity may pertain to venous drainage of shared microbiotal-rich areas of the nose and in intestines that initiates local endovascular venous immunity by PF4/microbiotal engagement with PF4 autoantibody driven immunothrombosis reminiscent of HIT. According to the proposed model, any adenovirus-vectored-DNA vaccine could drive autoimmune VITT in susceptible individuals and alternative mechanism based on molecular mimicry, vaccine protein contaminants, adenovirus vector proteins, EDTA buffers or immunity against the viral spike protein are secondary factors. Hence, electrochemical DNA-PF4 interactions and PF4-heparin interactions, but at different locations, represent the common denominator in HIT and VITT related autoimmune-mediated thrombosis.


Subject(s)
Autoantibodies/immunology , COVID-19/immunology , Purpura, Thrombocytopenic, Idiopathic/immunology , SARS-CoV-2/immunology , Thrombosis/immunology , Vaccines/adverse effects , COVID-19/pathology , COVID-19/prevention & control , Humans , Platelet Activation/immunology , Platelet Factor 4/immunology , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/pathology , Thrombosis/chemically induced , Thrombosis/pathology , Vaccines/immunology
15.
J Leukoc Biol ; 109(1): 35-47, 2021 01.
Article in English | MEDLINE | ID: covidwho-1372745

ABSTRACT

The SARS-CoV-2 pandemic has led to hundreds of thousands of deaths and billions of dollars in economic damage. The immune response elicited from this virus is poorly understood. An alarming number of cases have arisen where COVID-19 patients develop complications on top of the symptoms already associated with SARS, such as thrombosis, injuries of vascular system, kidney, and liver, as well as Kawasaki disease. In this review, a bioinformatics approach was used to elucidate the immune response triggered by SARS-CoV-2 infection in primary human lung epithelial and transformed human lung alveolar. Additionally, examined the potential mechanism behind several complications that have been associated with COVID-19 and determined that a specific cytokine storm is leading to excessive neutrophil recruitment. These neutrophils are directly leading to thrombosis, organ damage, and complement activation via neutrophil extracellular trap release.


Subject(s)
COVID-19/immunology , SARS-CoV-2/immunology , Signal Transduction/immunology , Thrombosis/immunology , Vascular System Injuries/immunology , COVID-19/pathology , Cytokines/immunology , Humans , Mucocutaneous Lymph Node Syndrome/immunology , Mucocutaneous Lymph Node Syndrome/pathology , Mucocutaneous Lymph Node Syndrome/virology , Pulmonary Alveoli/immunology , Pulmonary Alveoli/pathology , Pulmonary Alveoli/virology , Thrombosis/pathology , Thrombosis/virology , Vascular System Injuries/pathology , Vascular System Injuries/virology
16.
J Korean Med Sci ; 36(31): e223, 2021 Aug 09.
Article in English | MEDLINE | ID: covidwho-1360701

ABSTRACT

Vaccination with an adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can result in the rare development of thrombosis with thrombocytopenia mediated by platelet-activating antibodies against platelet factor 4 (PF4). This is a life-threating condition that may be accompanied by bleeding due to thrombocytopenia with thrombosis of the cerebral venous sinus or splanchnic vein. Herein, we describe the first fatal case of thrombosis with thrombocytopenia syndrome in Korea, presenting with intracranial hemorrhage caused by cerebral venous sinus thrombosis. A 33-year-old Korean man received the first dose of the ChAdOx1 nCoV-19 vaccination. He developed severe headache with vomiting 9 days after the vaccination. Twelve days after vaccination, he was admitted to the hospital with neurological symptoms and was diagnosed with cerebral venous sinus thrombosis, which was accompanied by intracranial hemorrhage. Thrombocytopenia and D-dimer elevation were observed, and the result of the PF4 enzyme-linked immunosorbent assay antibody test was reported to be strongly positive. Despite intensive treatment, including intravenous immunoglobulin injection and endovascular mechanical thrombectomy, the patient died 19 days after vaccination. Physicians need to be aware of thrombosis with thrombocytopenia syndrome (TTS) in adenoviral vector-vaccinated patients. Endovascular mechanical thrombectomy might be a useful therapeutic option for the treatment of TTS with cerebral venous sinus thrombosis.


Subject(s)
COVID-19 Vaccines/adverse effects , Cerebral Hemorrhage/mortality , Cerebral Hemorrhage/pathology , Thrombocytopenia/pathology , Thrombosis/pathology , Adenoviridae/immunology , Adult , COVID-19/immunology , COVID-19/prevention & control , Humans , Male , Platelet Factor 4/antagonists & inhibitors , Platelet Factor 4/immunology , Republic of Korea , SARS-CoV-2/immunology , Thrombosis/mortality , Vaccination/adverse effects
17.
Int J Mol Sci ; 22(16)2021 Aug 09.
Article in English | MEDLINE | ID: covidwho-1348646

ABSTRACT

The rare but dangerous adverse events evidenced after massive vaccination against SARS-CoV-2 are represented by thrombosis and thrombocytopenia. The patients diagnosed with severe COVID-19 may develop a pro-thrombotic state with a much higher frequency, thus we decided to investigate the role of Spike protein (the only common product of the two conditions) or the anti-Spike antibodies in the etiopathogenesis of thrombosis. A pathogenic Platelet Factor 4 (PF4)-dependent syndrome, unrelated to the use of heparin therapy, has been reported after the administration of vaccines in the patients manifesting acute thrombocytopenia and thrombosis. Thus, we aimed at shedding light on the structural similarities of Spike of SARS-CoV-2 and PF4 on their eventual biochemical interactions and on the role of their specific antibodies. The similarities between PF4 and Spike-RBD proteins were evaluated by a comparison of the structures and by testing the cross-reactivity of their specific antibodies by ELISA assays. We found that the anti-Spike antibodies do not recognize PF4, on the contrary, the anti-PF4 antibodies show some cross-reactivity for Spike-RBD. More interestingly, we report for the first time that the PF4 and Spike-RBD proteins can bind each other. These data suggest that the interaction of the two proteins could be involved in the generation of anti-PF4 antibodies, their binding to Spike-RBD, which could lead to platelets aggregation due also to their high expression of ACE2.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/immunology , Platelet Factor 4 , Spike Glycoprotein, Coronavirus , Cross Reactions , Humans , Platelet Factor 4/chemistry , Platelet Factor 4/immunology , Protein Binding , Protein Conformation , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Thrombocytopenia/pathology , Thrombosis/pathology
18.
Int J Mol Sci ; 21(21)2020 Nov 03.
Article in English | MEDLINE | ID: covidwho-1344351

ABSTRACT

Progressive respiratory failure is seen as a major cause of death in severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection. Relatively little is known about the associated morphologic and molecular changes in the circulation of these patients. In particular, platelet and erythrocyte pathology might result in severe vascular issues, and the manifestations may include thrombotic complications. These thrombotic pathologies may be both extrapulmonary and intrapulmonary and may be central to respiratory failure. Previously, we reported the presence of amyloid microclots in the circulation of patients with coronavirus disease 2019 (COVID-19). Here, we investigate the presence of related circulating biomarkers, including C-reactive protein (CRP), serum ferritin, and P-selectin. These biomarkers are well-known to interact with, and cause pathology to, platelets and erythrocytes. We also study the structure of platelets and erythrocytes using fluorescence microscopy (using the markers PAC-1 and CD62PE) and scanning electron microscopy. Thromboelastography and viscometry were also used to study coagulation parameters and plasma viscosity. We conclude that structural pathologies found in platelets and erythrocytes, together with spontaneously formed amyloid microclots, may be central to vascular changes observed during COVID-19 progression, including thrombotic microangiopathy, diffuse intravascular coagulation, and large-vessel thrombosis, as well as ground-glass opacities in the lungs. Consequently, this clinical snapshot of COVID-19 strongly suggests that it is also a true vascular disease and considering it as such should form an essential part of a clinical treatment regime.


Subject(s)
Blood Platelets/pathology , Cardiovascular Diseases/virology , Coronavirus Infections/blood , Coronavirus Infections/pathology , Erythrocytes/pathology , Ferritins/blood , P-Selectin/blood , Pneumonia, Viral/blood , Pneumonia, Viral/pathology , Betacoronavirus/isolation & purification , Blood Coagulation/physiology , Blood Platelets/virology , COVID-19 , Cardiovascular Diseases/blood , Cardiovascular Diseases/pathology , Coronavirus Infections/virology , Erythrocytes/virology , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Thrombosis/pathology , Thrombosis/virology
20.
Biosci Rep ; 41(8)2021 08 27.
Article in English | MEDLINE | ID: covidwho-1334001

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients. Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation. Using platelet-poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to ß and γ fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1. Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.


Subject(s)
COVID-19/pathology , Fibrin/metabolism , Fibrinolysis/physiology , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/pathology , Adult , Aged , Amyloid/metabolism , Blood Platelets/metabolism , Complement C3/metabolism , Female , Fibrinogen/metabolism , Humans , Lung/pathology , Male , Microfluidic Analytical Techniques , Middle Aged , Prothrombin/metabolism , SARS-CoV-2/metabolism , Thrombosis/virology , Trypsin/metabolism
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