Elevated levels of d-dimer are associated with inflammation and disease activity rather than risk of venous thromboembolism in patients with granulomatosis with polyangiitis in long term observation

Borowiec, Anna; Dąbrowski, Rafał; Kowalik, Ilona; Rusinowicz, Tomasz; Hadzik-Błaszczyk, Małgorzata; Krupa, Renata; Życińska, Katarzyna

doi:10.1016/j.advms.2019.12.007

Cited by 30 publications

(27 citation statements)

References 19 publications

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“…In the current study, the elevation of D-dimer in the early phase post-immunization might indicate the activation of the body homeostasis induced by vaccines’ inherited property as inducers of inflammatory and immunization response [ 14 , 19 ]. In line with our explanation, many studies showed that elevated levels of D-dimer are associated in some cases with disease activity and inflammation, rather than with the risk of venous thromboembolism [ 20 , 21 ]. Markedly, the normalization of its level in the later stages of the current study reflects the limitation of that effect and excludes the risk of thrombosis and/or thrombotic embolism, as the value of D-dimer eliminates the possibility of a thromboembolic event when in the normal range [ 18 ].…”

Section: Discussionsupporting

confidence: 88%

“…The desired amount of viral antigen (3,6,10,15,20,30, 50, 100 µg) was diluted in 1X PBS, then mixed with Imject Alum adjuvant (Invitrogen) in a ratio of 2:1 (v/v). The formulated NRC-VACC-01 adjuvanted inactivated vaccine was mixed for 30 min under cooling conditions to confirm adsorption of viral antigen into the surface of the alum.…”

Section: Preparation Of Nrc-vacc-01 Inactivated Candidate Vaccinementioning

confidence: 99%

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Immunogenicity and Safety of an Inactivated SARS-CoV-2 Vaccine: Preclinical Studies

et al. 2021

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Since the emergence of SARS-CoV-2 at the end of 2019, 64 candidate vaccines are in clinical development and 173 are in the pre-clinical phase. Five types of vaccines are currently approved for emergency use in many countries (Inactivated, Sinopharm; Viral-vector, Astrazeneca, and Gamaleya Research Institute; mRNA, Moderna, and BioNTech/Pfizer). The main challenge in this pandemic was the availability to produce an effective vaccine to be distributed to the world’s population in a short time. Herein, we developed a whole virus NRC-VACC-01 inactivated candidate SARS-CoV-2 vaccine and tested its safety and immunogenicity in laboratory animals. In the preclinical studies, we used four experimental animals (mice, rats, guinea pigs, and hamsters). Antibodies were detected as of week three post vaccination and continued up to week ten in the four experimental models. Safety evaluation of NRC-VACC-01 inactivated candidate vaccine in rats revealed that the vaccine was highly tolerable. By studying the effect of booster dose in the immunological profile of vaccinated mice, we observed an increase in neutralizing antibody titers after the booster shot, thus a booster dose was highly recommended after week three or four. Challenge infection of hamsters showed that the vaccinated group had lower morbidity and shedding than the control group. A phase I clinical trial will be performed to assess safety in human subjects.

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Section: Discussionsupporting

confidence: 88%

Section: Preparation Of Nrc-vacc-01 Inactivated Candidate Vaccinementioning

confidence: 99%

Immunogenicity and Safety of an Inactivated SARS-CoV-2 Vaccine: Preclinical Studies

et al. 2021

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“…However, such observations remain largely anecdotal, and reliable data implicating an acquired prothrombotic state and/or VTE as a primary factor in COVID-19 pathogenesis remains lacking with further studies needed in this regard. Additionally, it should be noted that elevated D-dimer is a highly non-specific marker of VTE and may be a manifestation of inflammation rather than thrombosis [ 19 , 20 ]. In a study of 449 COVID-19 patients, there was no difference in admission D-dimer as compared with 104 patients with non-COVID pneumonia [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Admission D-dimer levels, D-dimer trends, and outcomes in COVID-19

Naymagon

Zubizarreta

Feld

et al. 2020

Thrombosis Research

107

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Observational data suggest an acquired prothrombotic state may contribute to the pathophysiology of COVID-19. These data include elevated D-dimers observed among many COVID-19 patients. We present a retrospective analysis of admission D-dimer, and D-dimer trends, among 1065 adult hospitalized COVID-19 patients, across 6 New York Hospitals. The primary outcome was all-cause mortality. Secondary outcomes were intubation and venous thromboembolism (VTE). Three-hundred-thirteen patients (29.4%) died, 319 (30.0%) required intubation, and 30 (2.8%) had diagnosed VTE. Using Cox proportional-hazard modeling, each 1 μg/ml increase in admission D-dimer level was associated with a hazard ratio (HR) of 1.06 (95%CI 1.04–1.08, p < 0.0001) for death, 1.08 (95%CI 1.06–1.10, p < 0.0001) for intubation, and 1.08 (95%CI 1.03–1.13, p = 0.0087) for VTE. Time-dependent receiver-operator-curves for admission D-dimer as a predictor of death, intubation, and VTE yielded areas-under-the-curve of 0.694, 0.621, and 0.565 respectively. Joint-latent-class-modeling identified distinct groups of patients with respect to D-dimer trend. Patients with stable D-dimer trajectories had HRs of 0.29 (95%CI 0.17–0.49, p < 0.0001) and 0.22 (95%CI 0.10–0.45, p = 0.0001) relative to those with increasing D-dimer trajectories, for the outcomes death and intubation respectively. Patients with low-increasing D-dimer trajectories had a multivariable HR for VTE of 0.18 (95%CI 0.05–0.68, p = 0.0117) relative to those with high-decreasing D-dimer trajectories. Time-dependent receiver-operator-curves for D-dimer trend as a predictor of death, intubation, and VTE yielded areas-under-the-curve of 0.678, 0.699, and 0.722 respectively. Although admission D-dimer levels, and D-dimer trends, are associated with outcomes in COVID-19, they have limited performance characteristics as prognostic tests.

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“…This is a limit of our study. Coagulation biomarkers, including D-dimers, are frequently altered during severe inflammation [67][68][69][70]. In patients with severe COVID-19, genetic variants studied here may be involved in more severe inflammatory conditions perhaps through STING signaling-mediated altered type I IFN production [31].…”

Section: Discussionmentioning

confidence: 91%

C9orf72 Intermediate Repeats Confer Genetic Risk for Severe COVID-19 Pneumonia Independently of Age

Zanella

Zacchi

Piva

et al. 2021

IJMS

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A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lysosome functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.

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Elevated levels of d-dimer are associated with inflammation and disease activity rather than risk of venous thromboembolism in patients with granulomatosis with polyangiitis in long term observation

Cited by 30 publications

References 19 publications

Immunogenicity and Safety of an Inactivated SARS-CoV-2 Vaccine: Preclinical Studies

Immunogenicity and Safety of an Inactivated SARS-CoV-2 Vaccine: Preclinical Studies

Admission D-dimer levels, D-dimer trends, and outcomes in COVID-19

C9orf72 Intermediate Repeats Confer Genetic Risk for Severe COVID-19 Pneumonia Independently of Age

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