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1.
Blood ; 138(22): 2256-2268, 2021 12 02.
Article in English | MEDLINE | ID: covidwho-1443788

ABSTRACT

SARS-CoV-2 vaccine ChAdOx1 nCoV-19 (AstraZeneca) causes a thromboembolic complication termed vaccine-induced immune thrombotic thrombocytopenia (VITT). Using biophysical techniques, mouse models, and analysis of VITT patient samples, we identified determinants of this vaccine-induced adverse reaction. Super-resolution microscopy visualized vaccine components forming antigenic complexes with platelet factor 4 (PF4) on platelet surfaces to which anti-PF4 antibodies obtained from VITT patients bound. PF4/vaccine complex formation was charge-driven and increased by addition of DNA. Proteomics identified substantial amounts of virus production-derived T-REx HEK293 proteins in the ethylenediaminetetraacetic acid (EDTA)-containing vaccine. Injected vaccine increased vascular leakage in mice, leading to systemic dissemination of vaccine components known to stimulate immune responses. Together, PF4/vaccine complex formation and the vaccine-stimulated proinflammatory milieu trigger a pronounced B-cell response that results in the formation of high-avidity anti-PF4 antibodies in VITT patients. The resulting high-titer anti-PF4 antibodies potently activated platelets in the presence of PF4 or DNA and polyphosphate polyanions. Anti-PF4 VITT patient antibodies also stimulated neutrophils to release neutrophil extracellular traps (NETs) in a platelet PF4-dependent manner. Biomarkers of procoagulant NETs were elevated in VITT patient serum, and NETs were visualized in abundance by immunohistochemistry in cerebral vein thrombi obtained from VITT patients. Together, vaccine-induced PF4/adenovirus aggregates and proinflammatory reactions stimulate pathologic anti-PF4 antibody production that drives thrombosis in VITT. The data support a 2-step mechanism underlying VITT that resembles the pathogenesis of (autoimmune) heparin-induced thrombocytopenia.


Subject(s)
Antigen-Antibody Complex/immunology , Autoantibodies/immunology , COVID-19/prevention & control , Capsid Proteins/adverse effects , Drug Contamination , Genetic Vectors/adverse effects , HEK293 Cells/immunology , Immunoglobulin G/immunology , Platelet Factor 4/immunology , Purpura, Thrombocytopenic, Idiopathic/etiology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/adverse effects , Adenoviridae/immunology , Animals , Antigen-Antibody Complex/ultrastructure , Autoantibodies/biosynthesis , Capillary Leak Syndrome/etiology , Capsid Proteins/immunology , Cell Line, Transformed , /immunology , Dynamic Light Scattering , Epitopes/chemistry , Epitopes/immunology , Extracellular Traps/immunology , Extravasation of Diagnostic and Therapeutic Materials/etiology , Genetic Vectors/immunology , HEK293 Cells/chemistry , Humans , Imaging, Three-Dimensional , Immunoglobulin G/biosynthesis , Inflammation , Mice , Microscopy/methods , Platelet Activation , Proteomics , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/immunology , Sinus Thrombosis, Intracranial/diagnostic imaging , Sinus Thrombosis, Intracranial/immunology , Spike Glycoprotein, Coronavirus/immunology , Virus Cultivation
3.
Mol Cells ; 44(6): 392-400, 2021 Jun 30.
Article in English | MEDLINE | ID: covidwho-1249738

ABSTRACT

It has been more than a year since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged. Many studies have provided insights into the various aspects of the immune response in coronavirus disease 2019 (COVID-19). Especially for antibody treatment and vaccine development, humoral immunity to SARS-CoV-2 has been studied extensively, though there is still much that is unknown and controversial. Here, we introduce key discoveries on the humoral immune responses in COVID-19, including the immune dynamics of antibody responses and correlations with disease severity, neutralizing antibodies and their cross-reactivity, how long the antibody and memory B-cell responses last, aberrant autoreactive antibodies generated in COVID-19 patients, and the efficacy of currently available therapeutic antibodies and vaccines against circulating SARS-CoV-2 variants, and highlight gaps in the current knowledge.


Subject(s)
Antibodies, Neutralizing/biosynthesis , B-Lymphocytes/immunology , COVID-19/immunology , Immunoglobulin Class Switching , Immunoglobulin G/biosynthesis , SARS-CoV-2/pathogenicity , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/biosynthesis , Antibody-Dependent Enhancement , Autoantibodies/biosynthesis , B-Lymphocytes/virology , COVID-19/drug therapy , COVID-19/mortality , COVID-19/virology , Host-Pathogen Interactions/immunology , Humans , Immunity, Humoral/drug effects , Immunoglobulin A/biosynthesis , Immunoglobulin M/biosynthesis , Immunologic Memory , SARS-CoV-2/immunology , Severity of Illness Index , Survival Analysis
4.
Clin Appl Thromb Hemost ; 27: 10760296211021498, 2021.
Article in English | MEDLINE | ID: covidwho-1249538

ABSTRACT

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


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , SARS-CoV-2 , Thrombosis/etiology , Autoantibodies/biosynthesis , COVID-19/epidemiology , COVID-19/physiopathology , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Clinical Trials as Topic , Disseminated Intravascular Coagulation/epidemiology , Disseminated Intravascular Coagulation/etiology , Drug Approval , Female , Genetic Vectors , Glycosaminoglycans/immunology , Humans , Male , Models, Cardiovascular , Pandemics/prevention & control , Platelet Factor 4/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Safety , Sinus Thrombosis, Intracranial/epidemiology , Sinus Thrombosis, Intracranial/etiology , Thrombosis/epidemiology , Thrombosis/physiopathology , Vaccines, Inactivated/adverse effects , Vaccines, Inactivated/genetics , Vaccines, Inactivated/immunology , Vaccines, Synthetic/adverse effects , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology
5.
Blood ; 137(26): 3656-3659, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1215090

ABSTRACT

Vaccination is crucial in combatting the severe acute respiratory syndrome coronavirus 2 pandemic. The rare complication of thrombocytopenia and thrombotic complications at unusual sites after ChAdOx1 nCov-19 vaccination is caused by platelet-activating antibodies directed against platelet factor 4 (PF4). We present a widely applicable whole-blood standard flow cytometric assay to identify the pathogenic antibodies associated with vaccine-induced immune-mediated thrombotic thrombocytopenia (VITT) after ChAdOx1 nCov-19 vaccination. This assay will enable rapid diagnosis by many laboratories. This trial was registered at www.clinicaltrials.gov as #NCT04370119.


Subject(s)
Autoantibodies/blood , COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Flow Cytometry/methods , Immunoglobulin G/blood , Platelet Activation/immunology , Platelet Factor 4/immunology , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Receptors, IgG/immunology , SARS-CoV-2 , Vaccination/adverse effects , Antibody Specificity , Autoantibodies/biosynthesis , Autoantibodies/immunology , COVID-19 Vaccines/immunology , Heparin/adverse effects , Heparin/immunology , Humans , Immunoenzyme Techniques , Immunogenicity, Vaccine , Immunoglobulin G/biosynthesis , Immunoglobulin G/immunology , P-Selectin/analysis , Purpura, Thrombocytopenic, Idiopathic/etiology , Purpura, Thrombocytopenic, Idiopathic/immunology
6.
Blood Coagul Fibrinolysis ; 32(4): 294-297, 2021 Jun 01.
Article in English | MEDLINE | ID: covidwho-1066464

ABSTRACT

Factor V inhibitors are a rare cause of life-threatening bleeding. We present a case of an acquired factor V inhibitor likely caused by coronavirus disease 2019 infection. Bleeding was manifested by severe anemia requiring frequent red-cell transfusion, left psoas muscle hematoma, and left retroperitoneal cavity hematoma. Factor V activity was less than 1% and the factor V inhibitor titer was 31.6 Bethesda units. Severe acute respiratory syndrome coronavirus 2 RNA testing of the nasopharynx was positive 2 weeks before presentation and continued to be positive for 30 days. The patient failed treatment with intravenous immunoglobulin and dexamethasone. Three cycles of plasmapheresis with fresh frozen plasma replacement resulted in correction of the bleeding and laboratory coagulopathy. This is the first reported case of a factor V inhibitor in a coronavirus disease 2019 patient and suggests that plasmapheresis may be a successful treatment strategy.


Subject(s)
Autoantibodies/biosynthesis , COVID-19/blood , Factor V/immunology , Hemorrhagic Disorders/etiology , SARS-CoV-2 , Aged, 80 and over , Anemia/etiology , Anemia/therapy , Antibodies, Viral/blood , Antibody Specificity , Autoantibodies/immunology , COVID-19/complications , COVID-19/diagnosis , COVID-19/immunology , Combined Modality Therapy , Comorbidity , Delayed Diagnosis , Dexamethasone/therapeutic use , Erythrocyte Transfusion , Factor V/antagonists & inhibitors , Female , Hematoma/etiology , Hemorrhagic Disorders/drug therapy , Hemorrhagic Disorders/therapy , Humans , Immunoglobulins, Intravenous/therapeutic use , Lupus Coagulation Inhibitor/blood , Octreotide/therapeutic use , Plasma , Plasmapheresis , SARS-CoV-2/immunology , Vitamin K/therapeutic use
7.
Clin Appl Thromb Hemost ; 27: 1076029620977702, 2021.
Article in English | MEDLINE | ID: covidwho-1063146

ABSTRACT

The SARS-CoV-2 pandemic has focused attention on prevention, restriction and treatment methods that are acceptable worldwide. This means that they should be simple and inexpensive. This review examines the possible role of glycosaminoglycan (GAG) antithrombotics in the treatment of COVID-19. The pathophysiology of this disease reveals a complex interplay between the hemostatic and immune systems that can be readily disrupted by SARS-CoV-2. Some of the GAG antithrombotics also possess immune-modulatory actions and since they are relatively inexpensive they could play an important role in the management of COVID-19 and its complications.


Subject(s)
COVID-19/drug therapy , Fibrinolytic Agents/therapeutic use , Heparin/therapeutic use , Autoantibodies/biosynthesis , COVID-19/complications , COVID-19/physiopathology , Endothelium, Vascular/immunology , Endothelium, Vascular/physiopathology , Endothelium, Vascular/virology , Female , Glycosaminoglycans/therapeutic use , Hemorrhage/etiology , Hemostatic Disorders/drug therapy , Hemostatic Disorders/etiology , Hemostatic Disorders/physiopathology , Humans , Immunologic Factors/therapeutic use , Inflammation/drug therapy , Inflammation/etiology , Inflammation/physiopathology , Male , Pandemics , Risk Factors , SARS-CoV-2/pathogenicity , Thrombin/biosynthesis , Thrombosis/etiology
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