Splanchnic vein thrombosis in COVID-19: A review of literature

Singh, Balraj; Kaur, Parminder; Maroules, Michael

doi:10.1016/j.dld.2020.09.025

Cited by 28 publications

(30 citation statements)

References 14 publications

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“…An intriguing feature of VITT not seen in HIT is the predilection for causing CVST and/or SVT, the latter encompassing mesenteric and portal vein thrombosis and Budd‐Chiari syndrome. 56 , 57 Although the mechanism behind this remains undetermined, NETs likely form important constituents of thrombi in both locations. A recent review article exploring the role of NETs in different forms of liver disease showed that liver damage secondary to portal vein thrombi and intravascular sinusoidal microthrombi in various diseases, including portal hypertension (PHTN) and sepsis, could be mitigated through inhibition of NETs via sivelstat, an NE inhibitor.…”

Section: Hit and Vitt: The Role Of Netsmentioning

confidence: 99%

Scientific premise for the involvement of neutrophil extracellular traps (NETs) in vaccine-induced thrombotic thrombocytopenia (VITT)

Kashir

Ambia

Shafqat

et al. 2021

Journal of Leukocyte Biology

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Following on from the devastating spread of COVID-19, a major global priority has been the production, procurement, and distribution of effective vaccines to ensure that the global pandemic reaches an end. However, concerns were raised about worrying side effects, particularly the occurrence of thrombosis and thrombocytopenia after administration of the Oxford/AstraZeneca and Johnson & Johnson's Janssen COVID-19 vaccine, in a phenomenon being termed vaccine-induced thrombotic thrombocytopenia (VITT). Similar to heparin-induced thrombocytopenia (HIT), this condition has been associated with the development of anti-platelet factor 4 antibodies, purportedly leading to neutrophil-platelet aggregate formation. Although thrombosis has also been a common association with COVID-19, the precise molecular mechanisms governing its occurrence are yet to be established. Recently, increasing evidence highlights the NLRP3 (NOD-like, leucine-rich repeat domains, and pyrin domain-containing protein) inflammasome complex along with IL-1β and effete neutrophils producing neutrophil extracellular traps (NETs) through NETosis. Herein, we propose and discuss that perhaps the incidence of VITT may be due to inflammatory reactions mediated via IL-1β/NLRP3 inflammasome activation and consequent overproduction of NETs, where similar autoimmune mechanisms are observed in HIT. We also discuss avenues by which such modalities could be treated to prevent the occurrence of adverse events and ensure vaccine rollouts remain safe and on target to end the current pandemic. INTRODUCTIONEver since COVID-19, caused by SARS-CoV-2, was declared by the World Health Organization (WHO) as a global pandemic, the leading global strategy against this disease has been the effective development, procurement, and distribution of vaccines. Indeed, many vaccines have been authorized by global regulatory authorities since December 2020. 1,2 Coronaviruses are large single-stranded positive-sense RNA viruses with a helical nucleocapsid (N) and an envelope composed of matrix protein (M), an envelope protein (E), and spike protein (S). The spike protein is the receptor-binding site for angiotensin-converting enzyme 2 for viral entry into the cell.The developmental stage of the COVID-19 vaccine saw various approaches, all of which utilize S protein as the immunogen: recombinant vaccines using viral vectors; nucleic acid vaccines or mRNA vaccines; inactivated vaccines; nanoparticle or virus-like particle vaccines; protein subunit vaccines; and live attenuated vaccines. 3,4 However, as one would expect from vaccines developed at such an unprecedented pace, several side effects have been reported termed adverse events of special interests (AESI). Variable AESIs observed include acute myocardial infarction, hemorrhagic/nonhemorrhagic stroke, deep vein thrombosis, pulmonary embolism, Bell's palsy,

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Section: Hit and Vitt: The Role Of Netsmentioning

confidence: 99%

Scientific premise for the involvement of neutrophil extracellular traps (NETs) in vaccine-induced thrombotic thrombocytopenia (VITT)

Kashir

Ambia

Shafqat

et al. 2021

Journal of Leukocyte Biology

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“…Post-mortem wedge liver biopsies from 48 patients who died from severe COVID-19 disease showed vascular alterations characterized by an increased number of portal vein branches associated with massive lumen dilatation, partial or complete luminal thrombosis of portal and sinusoidal vessels, and marked focal enlargement and fibrosis of the portal tract[ 41 ]. In addition, transaminitis has been reported in some cases of portal thrombosis due to SARS-CoV-2 infection[ 42 , 43 ].…”

Section: Sars-cov-2 Infection and Liver Dysfunction In Patients With No Previous Liver Diseasementioning

confidence: 99%

Liver dysfunction and SARS-CoV-2 infection

Gracia‐Ramos¹,

Jáquez-Quintana²,

Contreras-Omaña³

et al. 2021

WJG

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Severe acute respiratory syndrome coronavirus 2 infection is the cause of coronavirus disease 2019 (COVID-19), which predominantly affects the respiratory system; it also causes systemic and multi-organic disease. Liver damage is among the main extrapulmonary manifestations. COVID-19-associated liver injury is defined as any liver damage occurring during the disease course and treatment of COVID-19 in patients with or without pre-existing liver disease, and occurs in approximately one in five patients. Abnormal liver test results have been associated with a more severe course of COVID-19 and other complications, including death. Mechanisms linking COVID-19 to liver injury are diverse. Particular consideration should be made for patients with pre-existing liver disease, such as metabolic dysfunction-associated fatty liver disease, chronic liver disease due to viral or autoimmune disease, liver transplant carriers, or cirrhosis, given the risk for more severe outcomes. This manuscript summarizes the current lines of evidence on COVID-19-associated liver injury regarding pathophysiology, clinical significance, and management in both patients with or without pre-existing liver disease, to facilitate clinicians’ access to updated information and patient care. Finally, we mention the ideas and recommendations to be considered for future research.

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“…We previously dubbed the pattern of SARS-CoV-2-associated lung immunothrombosis as Pulmonary Intravascular Coagulopathy (PIC) and deliberately chose this acronym to differentiate this pathology from Disseminated Intravascular Coagulation (DIC), the latter of which leads to severe platelet consumption [ 23 , 24 ]. It is increasingly appreciated that direct endothelial SARS-CoV-2 infection is not necessary for the PIC pathology [ 25 , 26 ], which points towards innate immunity mechanisms underlying the prothrombotic state [ [27] , [28] , [29] , [30] ]. A contemporary model for severe COVID-19 pneumonia has proposed: i) that natural SARS-CoV-2 infection in close juxtaposition to the circulation leads to early immunothrombosis aimed at containment of thrombogenic SARS-CoV-2 RNA; but ii) that alveolar-vascular barrier disruption in severe COVID-19 pneumonia may instead lead to circulation of viral debris, including viral RNA that is termed “RNAaemia” [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Immunothrombosis in Vaccine-Induced Thrombotic Thrombocytopenia (VITT) Compared to Natural SARS-CoV-2 Infection

McGonagle

Marco

Bridgewood

2021

Journal of Autoimmunity

139

128

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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.

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Splanchnic vein thrombosis in COVID-19: A review of literature

Cited by 28 publications

References 14 publications

Scientific premise for the involvement of neutrophil extracellular traps (NETs) in vaccine-induced thrombotic thrombocytopenia (VITT)

Scientific premise for the involvement of neutrophil extracellular traps (NETs) in vaccine-induced thrombotic thrombocytopenia (VITT)

Liver dysfunction and SARS-CoV-2 infection

Mechanisms of Immunothrombosis in Vaccine-Induced Thrombotic Thrombocytopenia (VITT) Compared to Natural SARS-CoV-2 Infection

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