9 research outputs found
Genetic prediction of ICU hospitalization and mortality in COVID-19 patients using artificial neural networks
There is an unmet need of models for early prediction of morbidity and mortality of Coronavirus disease-19 (COVID-19). We aimed to a) identify complement-related genetic variants associated with the clinical outcomes of ICU hospitalization and death, b) develop an artificial neural network (ANN) predicting these outcomes and c) validate whether complement-related variants are associated with an impaired complement phenotype. We prospectively recruited consecutive adult patients of Caucasian origin, hospitalized due to COVID-19. Through targeted next-generation sequencing, we identified variants in complement factor H/CFH, CFB, CFH-related, CFD, CD55, C3, C5, CFI, CD46, thrombomodulin/THBD, and A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS13). Among 381 variants in 133 patients, we identified 5 critical variants associated with severe COVID-19: rs2547438 (C3), rs2250656 (C3), rs1042580 (THBD), rs800292 (CFH) and rs414628 (CFHR1). Using age, gender and presence or absence of each variant, we developed an ANN predicting morbidity and mortality in 89.47% of the examined population. Furthermore, THBD and C3a levels were significantly increased in severe COVID-19 patients and those harbouring relevant variants. Thus, we reveal for the first time an ANN accurately predicting ICU hospitalization and death in COVID-19 patients, based on genetic variants in complement genes, age and gender. Importantly, we confirm that genetic dysregulation is associated with impaired complement phenotype.- Pfizer Pharmaceuticals(undefined
Platelet, Fibrinolytic and Other Coagulation Abnormalities in Newly-Diagnosed Patients with Chronic Thromboembolic Pulmonary Hypertension
The pathophysiological background of chronic thromboembolic pulmonary hypertension (CTEPH) has not been fully elucidated. Evidence suggests that abnormal platelet function and ineffective fibrinolysis may play a key role in the development of the disease. The purpose of this study was to evaluate platelet and coagulation function in CTEPH, using non-conventional global coagulation assays, and platelet activation and endothelial dysfunction laboratory markers. A total of 40 newly-diagnosed CTEPH patients were studied, along with 35 healthy controls. Blood samples from CTEPH patients were taken directly from the pulmonary artery. All subjects were assessed with platelet function analyzer-100, light transmission aggregometry, thromboelastometry, endogenous thrombin potential. von Willebrand antigen and activity, p-selectin, thromboxane A2 and serotonin levels were also assessed. The results showed that CTEPH patients present diminished platelet aggregation, presence of disaggregation, decreased rate of fibrinolysis, defective thrombin generation and increased levels of thromboxane A2, p-selectin, von Willebrand antigen and activity. Serotonin levels did not present any differences between the two groups. The results of this study suggest that CTEPH patients present platelet function, fibrinolytic, thrombin generation and other clot formation abnormalities. Well-designed clinical studies are needed to further evaluate the complex hemostatic abnormalities in the CTEPH setting and assess their potential clinical applications
Association between the plasminogen activator inhibitor-I 4G/5G polymorphism and venous thrombosis - A meta-analysis
The effect of the 675 insertion/deletion (4G/5G) polymorphism of
plasminogen activator inhibitor-1 (PAI-1) gene on the risk of venous
thromboembolism (VTE) remains controversial. In this study, we performed
a meta-analysis of published data regarding this issue. A comprehensive
electronic search was carried out up until September 2006.A total of 22
articles were included in the analysis that was performed using random
effects models. Eighteen papers, concerning patients without another
known risk factor, comprised 2,644 cases and 3,739 controls.The alleles
contrast (4G vs. 5G allele) yielded a statistically significant odds
ratio (OR) of 1.153 (95% confidence interval [Cl]: 1.068-1.246). In a
sub-analysis of five studies that included 256 cases with another
genetic risk factor and 147 controls, the combined per-allele OR was
still significant (OR: 1.833,95% CI: 1.325-2.536). On the contrary, the
analysis of five studies regarding cases with a non-genetic risk factor
for VTE (antiphospholipid antibody syndrome, Behcet disease) provided
insignificant results in all aspects.There was no evidence for
heterogeneity and publication bias in all analyses. Based on our
findings, the 4G allele appears to increase the risk of venous
thrombosis, particularly in subjects with other genetic thrombophilic
defects. Recommendation for detection of this polymorphism in evaluating
thrombophilia in such patients might be considered
The impact of the PAI-1 4G/5G polymorphism on the outcome of patients with ALI/ARDS
Intoduction: Increased levels of plasminogen activator inhibitor-1
(PAI-1) have been associated with worse outcome in ALI/ARDS. A single
guanosine insertion/deletion (4G/5G) polymorphism in the promoter region
of the PAI-1 gene, may play an important role in the regulation of PAI-1
expression. The objective of the study was to evaluate the effect of
this polymorphism on the outcome of critically ill patients with
ALI/ARDS.
Materials and Methods: 52 consecutive ventilated patients with ALI/ARDS
were studied. Bronchoalveolar lavage was performed within 48 hours from
diagnosis. Measurement of plasma and BALF PAI-1 activity and D-dimers
levels, and 4G/5G genotyping of PAI-1 were carried out. The primary
outcome was 28-day mortality, and secondary outcomes included organ
dysfunction and ventilator-free days.
Results: 17 patients were homozygotes for the 4G allele. Severity scores
were not different between subgroups upon study enrollment. 28-day
mortality was 70.6% and 42.9% for the 4G-4G and the non-4G-4G
patients, respectively (p = 0.06). PAI-1 activity levels and D-dimer in
plasma and BALF were not significantly different between the 4G-4G and
the non-4G-4G subgroups. In the multivariate analysis, genotype 4G/4G
was the only variable independently associated with 28-day mortality
(Odds Ratio = 9.95, 95% CI: 1.79-55.28, p = 0.009). Furthermore,
genotype 4G/4G and plasma PAI-1 activity levels were independently
negatively associated with ventilator free days (p = 0.033 and p =
0.008, respectively).
Conclusions: ALI/ARDS patients, homozygous for the 4G allele of the
PAI-1 gene, experienced higher 28-day mortality. This genotype was
associated with a reduction in the number of days of unassisted
ventilation and was inversely associated with the number of days without
organ failure. (C) 2008 Elsevier Ltd. All rights reserved
Haemostatic profile of riboflavin-treated apheresis platelet concentrates.
BACKGROUND: The haemostatic activity of platelet concentrates (PCs) treated with pathogen reduction technology (PRT) remains a subject of debate. Our aim was to investigate the effect of Mirasol PRT on the haemostatic properties of PCs stored in plasma. MATERIAL AND METHODS: Untreated and Mirasol-treated platelets stored in plasma and derived from ten split double-dose apheresis PCs were evaluated in vitro on days 1, 3 and 5 post collection for functionality, microparticle procoagulation activity (MPA), endogenous thrombin potential (ETP), and haemostatic profile using rotational thromboelastometry (ROTEM). RESULTS: P-selectin expression was significantly higher in Mirasol-treated platelets compared with untreated counterparts on days 3 and 5 (p=0.003 and p=0.002, respectively). Clot strength, as shown by EXTEM maximum clot firmness (MCF), was significantly lower in the Mirasol-treated platelets at all time points (days 1, 3, 5) than in untreated platelets (p=0.009, p<0.001, p<0.001, respectively). There was a considerable increase in MPA over time (p<0.001) and this was significantly higher in the Mirasol-treated platelets on day 5 (p=0.015). A notable acceleration of decrease in ETP values was observed for Mirasol-treated PCs over time (p<0.001), with significant differences between PRT-treated and untreated PCs on days 3 and 5 (p=0.038 and p=0.019, respectively). Clot strength attenuation was significantly associated with pH reduction (p<0.001, Spearman’s rho: 0.84), increased microparticle procoagulant activity (p<0.001, Spearman’s rho: -0.75), and with decreased ETP (p<0.032, Spearman’s rho: 0.41). DISCUSSION: Increased platelet activation induced by PRT treatment leads to a decrease in in vitro haemostatic capacity as seen by reduced clot strength and thrombin generation capacity over time. The clinical relevance of this needs to be investigated
Genetic prediction of ICU hospitalization and mortality in COVID-19 patients using artificial neural networks
There is an unmet need of models for early prediction of morbidity and
mortality of Coronavirus disease-19 (COVID-19). We aimed to a) identify
complement-related genetic variants associated with the clinical
outcomes of ICU hospitalization and death, b) develop an artificial
neural network (ANN) predicting these outcomes and c) validate whether
complement-related variants are associated with an impaired complement
phenotype. We prospectively recruited consecutive adult patients of
Caucasian origin, hospitalized due to COVID-19. Through targeted
next-generation sequencing, we identified variants in complement factor
H/CFH, CFB, CFH-related, CFD, CD55, C3, C5, CFI, CD46,
thrombomodulin/THBD, and A Disintegrin and Metalloproteinase with
Thrombospondin motifs (ADAMTS13). Among 381 variants in 133 patients, we
identified 5 critical variants associated with severe COVID-19:
rs2547438 (C3), rs2250656 (C3), rs1042580 (THBD), rs800292 (CFH) and
rs414628 (CFHR1). Using age, gender and presence or absence of each
variant, we developed an ANN predicting morbidity and mortality in
89.47% of the examined population. Furthermore, THBD and C3a levels
were significantly increased in severe COVID-19 patients and those
harbouring relevant variants. Thus, we reveal for the first time an ANN
accurately predicting ICU hospitalization and death in COVID-19
patients, based on genetic variants in complement genes, age and gender.
Importantly, we confirm that genetic dysregulation is associated with
impaired complement phenotype
Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial
Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1 alpha/beta inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR >= 6 ng ml(-1), 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.The SAVE-MORE phase 3 study demonstrates the efficacy of anakinra, an IL-1 alpha/beta inhibitor, in patients with COVID-19 and high serum levels of soluble plasminogen activator receptor
Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial
Early increase of soluble urokinase plasminogen activator receptor
(suPAR) serum levels is indicative of increased risk of progression of
coronavirus disease 2019 (COVID-19) to respiratory failure. The
SAVE-MORE double-blind, randomized controlled trial evaluated the
efficacy and safety of anakinra, an IL-1 alpha/beta inhibitor, in 594
patients with COVID-19 at risk of progressing to respiratory failure as
identified by plasma suPAR >= 6 ng ml(-1), 85.9% (n = 510) of whom were
receiving dexamethasone. At day 28, the adjusted proportional odds of
having a worse clinical status (assessed by the 11-point World Health
Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as
compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The
median WHO-CPS decrease on day 28 from baseline in the placebo and
anakinra groups was 3 and 4 points, respectively (odds ratio (OR) =
0.40, P < 0.0001); the respective median decrease of Sequential Organ
Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1
points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased
(hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.
The SAVE-MORE phase 3 study demonstrates the efficacy of anakinra, an
IL-1 alpha/beta inhibitor, in patients with COVID-19 and high serum
levels of soluble plasminogen activator receptor