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1.
Acta Neuropathol Commun ; 9(1): 199, 2021 12 23.
Article in English | MEDLINE | ID: covidwho-1581995

ABSTRACT

Apolipoprotein E ε4 allele (APOE4) has been shown to associate with increased susceptibility to SARS-CoV-2 infection and COVID-19 mortality in some previous genetic studies, but information on the role of APOE4 on the underlying pathology and parallel clinical manifestations is scarce. Here we studied the genetic association between APOE and COVID-19 in Finnish biobank, autopsy and prospective clinical cohort datasets. In line with previous work, our data on 2611 cases showed that APOE4 carriership associates with severe COVID-19 in intensive care patients compared with non-infected population controls after matching for age, sex and cardiovascular disease status. Histopathological examination of brain autopsy material of 21 COVID-19 cases provided evidence that perivascular microhaemorrhages are more prevalent in APOE4 carriers. Finally, our analysis of post-COVID fatigue in a prospective clinical cohort of 156 subjects revealed that APOE4 carriership independently associates with higher mental fatigue compared to non-carriers at six months after initial illness. In conclusion, the present data on Finns suggests that APOE4 is a risk factor for severe COVID-19 and post-COVID mental fatigue and provides the first indication that some of this effect could be mediated via increased cerebrovascular damage. Further studies in larger cohorts and animal models are warranted.


Subject(s)
Apolipoprotein E4/genetics , COVID-19/complications , COVID-19/genetics , Cerebral Hemorrhage/genetics , Mental Fatigue/genetics , Patient Acuity , Adult , Aged , Autopsy , Biological Specimen Banks , COVID-19/diagnosis , COVID-19/epidemiology , Cerebral Hemorrhage/diagnosis , Cerebral Hemorrhage/epidemiology , Cohort Studies , Female , Finland/epidemiology , Genetic Association Studies/methods , Heterozygote , Humans , Male , Mental Fatigue/diagnosis , Mental Fatigue/epidemiology , Microvessels/pathology , Middle Aged , Prospective Studies , Risk Factors , Young Adult
2.
Nat Neurosci ; 24(11): 1522-1533, 2021 11.
Article in English | MEDLINE | ID: covidwho-1500484

ABSTRACT

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , Coronavirus 3C Proteases/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Microvessels/metabolism , SARS-CoV-2/metabolism , Animals , Blood-Brain Barrier/pathology , Brain/pathology , Chlorocebus aethiops , Coronavirus 3C Proteases/genetics , Cricetinae , Female , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Mesocricetus , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microvessels/pathology , SARS-CoV-2/genetics , Vero Cells
3.
Eur Rev Med Pharmacol Sci ; 25(20): 6439-6442, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1503076

ABSTRACT

Arterial thromboembolic complications reported in patients with COVID-19 infection suggested that SARS-CoV-2 can trigger atherosclerotic plaque vulnerability. While endothelial cells in healthy subjects protect against thrombus formation, after injury they show prothrombotic activity. In addition, it has been hypothesized that "cytokine storm" might stimulate the production of neo-platelets triggering an abnormal "immunothrombosis" responsible for the hypercoagulable state induced in COVID-19 patients. The aim of this study is to report a case of severe COVID-19 infection characterized by the occurrence of microthrombosis in the vasa vasorum of the aorta. A 67-year-old male patient, in good health status and without comorbidities, who underwent a severe COVID-19 infection with fatal outcome, showed scattered aortic atherosclerotic plaques, characterized by multiple occlusive micro-thromboses in the vasa vasorum, spread out lymphocytic infiltrates and foci of endotheliitis and endothelial detachment. This case report confirms the previously described thrombotic involvement of vasa vasorum in COVID-19. The occurrence of the synchronous damage involving both the lumen surface (endothelial dysfunction, endotheliitis and endothelial detachment) and the adventitia (inflammation and occlusive thrombosis of vasa vasorum) could be the key points related to the fatal outcome of the SARS-CoV-2 patients. In our opinion, vasa vasorum thrombosis may thus initiate an atherogenic process that could be characterized by a much more rapid development.


Subject(s)
Aortic Diseases/complications , COVID-19/pathology , Microvessels/pathology , Plaque, Atherosclerotic/pathology , Vasa Vasorum/pathology , Aged , Aortic Diseases/pathology , Humans , Male
4.
Hamostaseologie ; 41(5): 387-396, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1483190

ABSTRACT

Hypercoagulability and vascular injury, which characterize morbidity in COVID-19 disease, are frequently observed in the skin. Several pathomechanisms, such as inflammation caused by angiotensin-converting enzyme 2-mediated uptake into endothelial cells or SARS-CoV-2-initiated host immune responses, contribute to microthrombus formation and the appearance of vascular skin lesions. Besides pathophysiologic mechanisms observed in the skin, this review describes the clinical appearance of cutaneous vascular lesions and their association with COVID-19 disease, including acro-ischemia, reticular lesions, and cutaneous small vessel vasculitis. Clinicians need to be aware that skin manifestations may be the only symptom in SARS-CoV-2 infection, and that inflammatory and thrombotic SARS-CoV-2-driven processes observed in multiple organs and tissues appear identically in the skin as well.


Subject(s)
COVID-19/complications , SARS-CoV-2 , Skin/blood supply , Angiotensin-Converting Enzyme 2/physiology , Antibodies, Antiphospholipid/blood , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/pathology , COVID-19/pathology , COVID-19/physiopathology , Complement Activation , Cytokines/metabolism , Host Microbial Interactions/immunology , Host Microbial Interactions/physiology , Humans , Microvessels/immunology , Microvessels/pathology , Microvessels/physiopathology , Pandemics , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Skin/immunology , Vasculitis/etiology , Vasculitis/pathology , Vasculitis/physiopathology , Virus Internalization
5.
Nat Neurosci ; 24(11): 1522-1533, 2021 11.
Article in English | MEDLINE | ID: covidwho-1483143

ABSTRACT

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , Coronavirus 3C Proteases/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Microvessels/metabolism , SARS-CoV-2/metabolism , Animals , Blood-Brain Barrier/pathology , Brain/pathology , Chlorocebus aethiops , Coronavirus 3C Proteases/genetics , Cricetinae , Female , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Mesocricetus , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microvessels/pathology , SARS-CoV-2/genetics , Vero Cells
6.
Cells ; 10(9)2021 08 31.
Article in English | MEDLINE | ID: covidwho-1390541

ABSTRACT

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.


Subject(s)
COVID-19/pathology , Cerebral Cortex/pathology , Aged , Aged, 80 and over , Autopsy , Brain/pathology , Brain/virology , Brain Diseases/pathology , Brain Diseases/virology , CD8-Positive T-Lymphocytes/pathology , Cerebral Cortex/virology , Female , Humans , Inflammation , Macrophages/pathology , Male , Microvessels/pathology , Microvessels/virology , Middle Aged , Nervous System Diseases/pathology , Nervous System Diseases/virology , SARS-CoV-2/pathogenicity
7.
Tissue Barriers ; 9(4): 1937013, 2021 10 02.
Article in English | MEDLINE | ID: covidwho-1298924

ABSTRACT

Blood-gas barrier (BGB) or alveolar-capillary barrier is the primary tissue barrier affected by coronavirus disease 2019 (COVID-19). Comprising alveolar epithelial cells (AECs), endothelial cells (ECs) and the extracellular matrix (ECM) in between, the BGB is damaged following the action of multiple pro-inflammatory cytokines during acute inflammation. The infection of AECs and ECs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen behind COVID-19, triggers an inflammatory response at the BGB, inducing the release of interleukin 1 (IL-1), IL-6, tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-ß), high mobility group box 1 (HMGB1), matrix metalloproteinases (MMPs), intercellular adhesion molecule-1 (ICAM-1) and platelet activating factor (PAF). The end result is the disassembly of adherens junctions (AJs) and tight junctions (TJs) in both AECs and ECs, AEC hyperplasia, EC pyroptosis, ECM remodeling and deposition of fibrin clots in the alveolar capillaries, leading to disintegration and thickening of the BGB, and ultimately, hypoxia. This commentary seeks to provide a brief account of how the BGB might become affected in COVID-19.


Subject(s)
Blood-Air Barrier/metabolism , COVID-19/metabolism , Pulmonary Gas Exchange , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , Blood-Air Barrier/pathology , COVID-19/pathology , Humans , Microvessels/metabolism , Microvessels/pathology
8.
Cells ; 10(4)2021 04 15.
Article in English | MEDLINE | ID: covidwho-1232577

ABSTRACT

Thrombin, the ligand of the protease-activated receptor 1 (PAR1), is a well-known stimulator of proangiogenic responses in vascular endothelial cells (ECs), which are mediated through the induction of vascular endothelial growth factor (VEGF). However, the transcriptional events underlying this thrombin-induced VEGF induction and angiogenic response are less well understood at present. As reported here, we conducted detailed promotor activation and signal transduction pathway studies in human microvascular ECs, to decipher the transcription factors and the intracellular signaling events underlying the thrombin and PAR-1-induced endothelial VEGF induction. We found that c-FOS is a key transcription factor controlling thrombin-induced EC VEGF synthesis and angiogenesis. Upon the binding and internalization of its G-protein-coupled PAR-1 receptor, thrombin triggers ERK1/2 signaling and activation of the nuclear AP-1/c-FOS transcription factor complex, which then leads to VEGF transcription, extracellular secretion, and concomitant proangiogenic responses of ECs. In conclusion, exposure of human microvascular ECs to thrombin triggers signaling through the PAR-1-ERK1/2-AP-1/c-FOS axis to control VEGF gene transcription and VEGF-induced angiogenesis. These observations offer a greater understanding of endothelial responses to thromboinflammation, which may help to interpret the results of clinical trials tackling the conditions associated with endothelial injury and thrombosis.


Subject(s)
Gene Expression Regulation , Neovascularization, Physiologic/genetics , Thrombin/pharmacology , Transcription, Genetic/drug effects , Vascular Endothelial Growth Factor A/metabolism , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation/drug effects , Humans , Microvessels/pathology , Neovascularization, Physiologic/drug effects , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins c-jun/metabolism , Receptor, PAR-1/metabolism , Transcription Factor AP-1/metabolism , Vascular Endothelial Growth Factor A/genetics
9.
Physiol Rep ; 9(5): e14796, 2021 03.
Article in English | MEDLINE | ID: covidwho-1120167

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to be a world-wide pandemic with overwhelming socioeconomic impact. Since inflammation is one of the major causes of COVID-19 complications, the associated molecular mechanisms have been the focus of many studies to better understand this disease and develop improved treatments for patients contracting SARS-CoV-2. Among these, strong emphasis has been placed on pro-inflammatory cytokines, associating severity of COVID-19 with so-called "cytokine storm." More recently, peptide bradykinin, its dysregulated signaling or "bradykinin storm," has emerged as a primary mechanism to explain COVID-19-related complications. Unfortunately, this important development may not fully capture the main molecular players that underlie the disease severity. To this end, in this focused review, several lines of evidence are provided to suggest that in addition to bradykinin, two closely related vasoactive peptides, substance P and neurotensin, are also likely to drive microvascular permeability and inflammation, and be responsible for development of COVID-19 pathology. Furthermore, based on published experimental observations, it is postulated that in addition to ACE and neprilysin, peptidase neurolysin (Nln) is also likely to contribute to accumulation of bradykinin, substance P and neurotensin, and progression of the disease. In conclusion, it is proposed that "vasoactive peptide storm" may underlie severity of COVID-19 and that simultaneous inhibition of all three peptidergic systems could be therapeutically more advantageous rather than modulation of any single mechanism alone.


Subject(s)
Bradykinin/metabolism , COVID-19/complications , Neprilysin/metabolism , Neurotensin/metabolism , Substance P/metabolism , Animals , COVID-19/metabolism , COVID-19/pathology , Cytokines/metabolism , Humans , Microvessels/metabolism , Microvessels/pathology
10.
Cells ; 10(2)2021 02 10.
Article in English | MEDLINE | ID: covidwho-1094233

ABSTRACT

Clinical manifestations of coronavirus disease 2019 (COVID-19) in pregnant women are diverse, and little is known of the impact of the disease on placental physiology. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been detected in the human placenta, and its binding receptor ACE2 is present in a variety of placental cells, including endothelium. Here, we analyze the impact of COVID-19 in placental endothelium, studying by immunofluorescence the expression of von Willebrand factor (vWf), claudin-5, and vascular endothelial (VE) cadherin in the decidua and chorionic villi of placentas from women with mild and severe COVID-19 in comparison to healthy controls. Our results indicate that: (1) vWf expression increases in the endothelium of decidua and chorionic villi of placentas derived from women with COVID-19, being higher in severe cases; (2) Claudin-5 and VE-cadherin expression decrease in the decidua and chorionic villus of placentas from women with severe COVID-19 but not in those with mild disease. Placental histological analysis reveals thrombosis, infarcts, and vascular wall remodeling, confirming the deleterious effect of COVID-19 on placental vessels. Together, these results suggest that placentas from women with COVID-19 have a condition of leaky endothelium and thrombosis, which is sensitive to disease severity.


Subject(s)
COVID-19/complications , Placenta/blood supply , Placenta/pathology , Pregnancy Complications, Cardiovascular/etiology , Pregnancy Complications, Infectious/etiology , Thrombosis/etiology , Adult , Antigens, CD/analysis , COVID-19/pathology , COVID-19/virology , Cadherins/analysis , Claudin-5/analysis , Endothelium/blood supply , Endothelium/pathology , Endothelium/virology , Female , Humans , Infant, Newborn , Microvessels/pathology , Microvessels/virology , Pregnancy , Pregnancy Complications, Cardiovascular/pathology , Pregnancy Complications, Cardiovascular/virology , Pregnancy Complications, Infectious/pathology , Pregnancy Complications, Infectious/virology , SARS-CoV-2/isolation & purification , Thrombosis/pathology , Thrombosis/virology , Young Adult , von Willebrand Factor/analysis
11.
Physiol Rep ; 9(3): e14726, 2021 02.
Article in English | MEDLINE | ID: covidwho-1058653

ABSTRACT

Corona virus disease 2019 (COVID-19) causes symptoms from multiple organs after infection by severe acute respiratory syndrome corona virus 2 (SARS CoV-2). They range from early, low blood oxygen levels (hypoxemia) without breathlessness ("silent hypoxia"), delirium, rashes, and loss of smell (anosmia), to persisting chest pain, muscle weakness and -pain, fatigue, confusion, memory problems and difficulty to concentrate ("brain fog"), mood changes, and unexpected onset of hypertension or diabetes. SARS CoV-2 affects the microcirculation, causing endothelial cell swelling and damage (endotheliitis), microscopic blood clots (microthrombosis), capillary congestion, and damage to pericytes that are integral to capillary integrity and barrier function, tissue repair (angiogenesis), and scar formation. Similar to other instances of critical illness, COVID-19 is also associated with elevated cytokine levels in the systemic circulation. This review examines how capillary damage and inflammation may contribute to these acute and persisting COVID-19 symptoms by interfering with blood and tissue oxygenation and with brain function. Undetectable by current diagnostic methods, capillary flow disturbances limit oxygen diffusion exchange in lungs and tissue and may therefore cause hypoxemia and tissue hypoxia. The review analyzes the combined effects of COVID-19-related capillary damage, pre-existing microvascular changes, and upstream vascular tone on tissue oxygenation in key organs. It identifies a vicious cycle, as infection- and hypoxia-related inflammation cause capillary function to deteriorate, which in turn accelerates hypoxia-related inflammation and tissue damage. Finally, the review addresses the effects of low oxygen and high cytokine levels in brain tissue on neurotransmitter synthesis and mood. Methods to assess capillary functions in human organs and therapeutic means to protect capillary functions and stimulate capillary bed repair may prove important for the individualized management of COVID-19 patients and targeted rehabilitation strategies.


Subject(s)
COVID-19/complications , Microvessels/pathology , Oxygen Consumption , Oxygen/metabolism , Animals , COVID-19/metabolism , COVID-19/pathology , Humans , Inflammation , Microvessels/metabolism , Microvessels/virology , Oxygen/blood , SARS-CoV-2/pathogenicity
12.
Curr Neurovasc Res ; 17(5): 784-792, 2020.
Article in English | MEDLINE | ID: covidwho-999945

ABSTRACT

A pericyte-centered theory suggesting that embolisms occurring within the microvasculature of a neurovascular unit that can result in either parenchymal hemorrhage or intravascular congestion is presented here. Dysfunctional microvascular pericytes are characterized by their location in the neurovascular unit, either on the arteriole or venule side. Pathophysiological and pathological changes caused by coronavirus disease 2019 (COVID-19) include pulmonary hypertension, edema, focal hemorrhage, microvascular congestion, and thrombosis. In this paper, the application of the pericytes-centered hypothesis to COVID-19 has been presented by proposing the concept of a pulmonary neurovascular unit (pNVU). The application of this concept implies that human lungs contain approximately 300 million pNVUs. This concept of existing local regulation of microvascular blood flow is supported by the observation of pathophysiology in pulmonary embolism and in acute high-altitude illness. The autonomic control seen in these three disease states matches blood flow with oxygen supply in each pNVU to maintain physiological blood oxygen saturation level. This paper illustrates how the malfunction of microvascular pericytes may cause focal hemorrhage, edema or microvascular congestion and thrombosis. A bypass existing in each pNVU would autonomically deviate blood flow from a COVID-19-affected pNVU to other healthy pNVUs. This action would prevent systemically applied medicines from reaching the therapeutic threshold in COVID-19-affected pNVUs. While testing this hypothesis with experimental evidence is urgently needed, supporting therapy aimed at improving microcirculation or rebuilding the physiological function of microvascular pericytes is recommended as a potentially effective treatment of COVID 19.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , COVID-19/metabolism , Neurovascular Coupling/physiology , Pericytes/metabolism , Animals , Blood-Brain Barrier/pathology , Brain/pathology , COVID-19/pathology , Humans , Microcirculation/physiology , Microvessels/metabolism , Microvessels/pathology , Pericytes/pathology
14.
Int J Cardiol ; 326: 243-247, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-917306

ABSTRACT

We concisely review clinical, autopsy, experimental and molecular data of 2019 coronavirus disease (COVID-19). Angiotensin-converting enzyme 2 disruption and thromboinflammatory microangiopathy emerge as distinctive features. Briefly, entry of the virus into microvessels can profoundly disrupt the local renin-angiotensin system, cause endothelial injury, activate the complement cascade and induce powerful thromboinflammatory reactions, involving, in particular, von Willebrand factor, that, if widespread, may lead to microvascular plugging, ischemia and, ultimately, organ failure. We believe the current COVID-19 data consolidate a widely unrecognised paradigm of potentially fatal thromboinflammatory microvascular disease.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Inflammation Mediators/metabolism , Microvessels/metabolism , Thrombosis/metabolism , COVID-19/diagnosis , COVID-19/epidemiology , Humans , Microvessels/pathology , Renin-Angiotensin System/physiology , Thrombosis/diagnosis , Thrombosis/epidemiology
17.
Neurol Sci ; 41(12): 3401-3404, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-842509

ABSTRACT

We describe the case of a COVID-19 patient with severely impaired consciousness after sedation hold, showing magnetic resonance imaging (MRI) findings of (i) acute bilateral supratentorial ischemic lesions involving the fronto-parietal white matter and the corpus callosum and (ii) multiple diffuse susceptibility weighted imaging (SWI) hypointense foci, infra and supratentorial, predominantly bithalamic, suggestive of microhemorrhage or alternatively microthrombi. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA was detected in the cerebrospinal fluid. Our findings suggest the occurrence of vascular damage, predominantly involving microvessels. The underlying mechanisms, which include direct and indirect penetration of the virus to the central nervous system and systemic cardiorespiratory complications, are yet to be elucidated, and a direct correlation with SARS-CoV-2 infection remains uncertain.


Subject(s)
Brain Ischemia/pathology , Brain Ischemia/virology , Coronavirus Infections/complications , Microvessels/pathology , Pneumonia, Viral/complications , Aged , Betacoronavirus , COVID-19 , Diabetes Mellitus , Fatal Outcome , Humans , Hypertension/complications , Male , Pandemics , SARS-CoV-2
18.
Thromb Haemost ; 120(12): 1668-1679, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-729018

ABSTRACT

Coronavirus disease of 2019 (COVID-19) is the clinical manifestation of the respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While primarily recognized as a respiratory disease, it is clear that COVID-19 is systemic illness impacting multiple organ systems. One defining clinical feature of COVID-19 has been the high incidence of thrombotic events. The underlying processes and risk factors for the occurrence of thrombotic events in COVID-19 remain inadequately understood. While severe bacterial, viral, or fungal infections are well recognized to activate the coagulation system, COVID-19-associated coagulopathy is likely to have unique mechanistic features. Inflammatory-driven processes are likely primary drivers of coagulopathy in COVID-19, but the exact mechanisms linking inflammation to dysregulated hemostasis and thrombosis are yet to be delineated. Cumulative findings of microvascular thrombosis has raised question if the endothelium and microvasculature should be a point of investigative focus. von Willebrand factor (VWF) and its protease, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13), play important role in the maintenance of microvascular hemostasis. In inflammatory conditions, imbalanced VWF-ADAMTS-13 characterized by elevated VWF levels and inhibited and/or reduced activity of ADAMTS-13 has been reported. Also, an imbalance between ADAMTS-13 activity and VWF antigen is associated with organ dysfunction and death in patients with systemic inflammation. A thorough understanding of VWF-ADAMTS-13 interactions during early and advanced phases of COVID-19 could help better define the pathophysiology, guide thromboprophylaxis and treatment, and improve clinical prognosis.


Subject(s)
COVID-19/complications , Disseminated Intravascular Coagulation/etiology , Microvessels/pathology , SARS-CoV-2/physiology , Thrombosis/etiology , ADAMTS13 Protein/metabolism , Animals , Blood Coagulation/immunology , Humans , von Willebrand Factor/metabolism
19.
EBioMedicine ; 58: 102925, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-701831

ABSTRACT

BACKGROUND: Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood. METHODS: Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry. PATIENT FINDINGS: Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage. INTERPRETATION: These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage. FUNDING: Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung.


Subject(s)
Coronavirus Infections/pathology , Extracellular Traps/metabolism , Microvessels/pathology , Neutrophils/metabolism , Pneumonia, Viral/pathology , Thrombosis/metabolism , COVID-19 , Cells, Cultured , Coronavirus Infections/complications , Coronavirus Infections/metabolism , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Humans , Microvessels/metabolism , Neutrophils/pathology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/metabolism , Thrombosis/etiology , Thrombosis/pathology
20.
Transl Res ; 225: 105-130, 2020 11.
Article in English | MEDLINE | ID: covidwho-343377

ABSTRACT

A significant amount of clinical and research interest in thrombosis is focused on large vessels (eg, stroke, myocardial infarction, deep venous thrombosis, etc.); however, thrombosis is often present in the microcirculation in a variety of significant human diseases, such as disseminated intravascular coagulation, thrombotic microangiopathy, sickle cell disease, and others. Further, microvascular thrombosis has recently been demonstrated in patients with COVID-19, and has been proposed to mediate the pathogenesis of organ injury in this disease. In many of these conditions, microvascular thrombosis is accompanied by inflammation, an association referred to as thromboinflammation. In this review, we discuss endogenous regulatory mechanisms that prevent thrombosis in the microcirculation, experimental approaches to induce microvascular thrombi, and clinical conditions associated with microvascular thrombosis. A greater understanding of the links between inflammation and thrombosis in the microcirculation is anticipated to provide optimal therapeutic targets for patients with diseases accompanied by microvascular thrombosis.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Pneumonia, Viral/complications , Thrombosis/etiology , Animals , COVID-19 , Endothelium, Vascular/pathology , Endothelium, Vascular/physiopathology , Humans , Microcirculation , Microvessels/pathology , Microvessels/physiopathology , Models, Cardiovascular , Pandemics , SARS-CoV-2 , Thrombosis/pathology , Thrombosis/physiopathology
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