Changes of histidine-rich glycoprotein levels in critically ill septic patients

doi:10.21203/rs.3.rs-3240691/v1

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Changes of histidine-rich glycoprotein levels in critically ill septic patients

https://doi.org/10.21203/rs.3.rs-3240691/v1

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Histidine-rich glycoprotein (HRG) has been reported as a prognostic factor in patients with sepsis. However, the relevance of HRG to the pathogenesis of septic-induced shock, disseminated intravascular coagulopathy (DIC), and acute respiratory distress syndrome (ARDS) is unknown. In 53 critically ill patients, we examined the association between HRG concentrations and the pathogenesis of these conditions. Serum HRG concentrations were significantly lower on days 3, 5, and 7 than on day 1 in patients with septic shock and in those with DIC, but not in those with ARDS. Although HRG concentrations on day 1 were not associated with survival, HRG concentrations were decreased in non-survivors, with a significant decline on days 3, 5, and 7 after admission to the intensive care unit. Whereas, HRG concentrations did not change in survivors. Decreased HRG concentrations may independently play a role in the pathogenesis of DIC in patients with sepsis and may relate to DIC-related mortality. A progressive decrease in HRG concentrations, especially on days 5 and 7, may affect the mortality rate. Therefore, supplemental HRG treatment may become a new strategy for critically ill patients with sepsis.

Health sciences/Diseases/Infectious diseases

Health sciences/Pathogenesis/Inflammation/Sepsis

Sepsis is a fatal syndrome characterized by infection and organ dysfunction that affects approximately 19 million people worldwide each year¹. The clinical characteristics and disease processes of patients with sepsis are highly variable because of the diversity of these patients^2,3. In 2017, sepsis occurred in more than 48.9 million people and was responsible for more than 11 million deaths worldwide, contributing to more than 20% of all deaths worldwide, according to the World Health Organization⁴. The Global Burden of Disease study on data from more than 100 million individual deaths across 195 countries estimated 48.9 million incident cases of sepsis worldwide⁵. In particular, patients with sepsis who presented with septic shock, acute respiratory distress syndrome (ARDS), or disseminated intravascular coagulation (DIC) had a worse prognosis^2,3,6. Therefore, various therapeutic modalities have been developed against severe sepsis. Treatment bundles, such as catecholamines and steroids, have improved the prognosis of patients with septic shock⁶. Recombinant human thrombomodulin and plasma-derived or recombinant antithrombin drugs have been applied for DIC, and they improve the prognosis in these patients, especially in Japan^6,7.

Histidine-rich glycoprotein (HRG) is a plasma glycoprotein produced by the liver. HRG is approximately 75 kDa in size and has many roles in physiological and pathological processes in the human body, such as coagulation, fibrinolysis, immunology, and the vascularature^8,9. HRG concentrations in plasma are approximately 60–150 µg/mL^8,10. A recent study showed that HRG concentrations were decreased during septic conditions, and patients with HRG concentrations < 20 µg/mL on day 1 after ICU admission had higher mortality with multiple organ failure^11,12. However, the relation of HRG concentrations to sepsis-related DIC, shock, and ARDS remains unknown. These concomitant conditions are associated with the prognosis in patients with sepsis^6,13,14. Therefore, we aimed to examine the change in HRG concentrations and their relationship to concomitant DIC, ARDS, and septic shock.

Patients’ characteristics

As shown in Table 1, the mean age of the patients was 63.0 ± 14.8 years and 60.4% were men (32 men and 21 women). The mean Acute Physiology and Chronic Evaluation (APACHE) II score was 27 ± 7.6, mean Sequential Organ Failure Assessment (SOFA) score was 9 ± 3.9, and mean acute DIC score was 2 ± 2.5 at 1 day after admission to the ICU. Twenty-nine (54.7%) patients presented with septic shock, 34 (64.2%) with ARDS, and 25 (47.2%) with DIC. ARDS in 20 patients was due to coronavirus disease 2019 (COVID-19). Of these patients, 12 (22.6%) died within 28 days.

Table 1

**Patients’ characteristics.** Data are reported as the mean ± standard deviation.
Factor	All n = 53	Survivor n = 41	Non-Survivor n = 12	P value
Age, years	63.6 ± 14.8	61.9 ± 15.4	69.4 ± 10.7	0.125
Male/Female, (%)	32/21 (60.4/39,6)	24/17 (58.5/41.5)	8/4 (66.7/33.3)	0.612
Site of infection	53
- Lung	30	24	6
- Abdomen	15	11	4
- Urinary tract	3	3	0
- Soft Tissues	5	3	2
SOFA	9.7 ± 3.9	9.2 ± 3.7	11.4 ± 3.9	0.08
APACHE II	27.7 ± 7.6	26 ± 7.4	33.5 ± 4.9	0.002*
Acute DIC score	2.6 ± 2.5	2.6 ± 2.7	2.7 ± 1.7	0.9
Platelet (x10³)	167.5 ± 90.8	171.3 ± 87.1	154.3 ± 105.3	0.573
ICU stays, days	14.6 ± 13.3	15.3 ± 14.6	12.5 ± 7.7	0.529
Diagnosis
Septic shock, (%) ARDS, (%) DIC, (%)	29 (54.7) 34 (64.2) 25 (47.2)	19 (46.3) 25 (61) 16 (39)	10 (83.3) 9 (75) 9 (75)	0.04* 0.5 0.04*

Association between serum and plasma HRG concentrations

We analyzed plasma and serum HRG concentrations in blood samples from patients and volunteers. Plasma and serum HRG concentrations showed a positive correlation, with a coefficient (r) of 0.9486. (Y = 0.911X + 4.57, P < 0.0001) (Fig. 1).

Changes in serum HRG concentrations in survivors and non-survivors

In survivors, mean HRG concentrations were 32.5, 28.6, 30.3, and 32.6 µg/mL on days 1, 3, 5, and 7, respectively (Fig. 2). In non-survivors, mean HRG concentrations were 36.3, 23.3, 19.7, and 20.3 µg/mL on days 1, 3, 5, and 7, respectively. In non-survivors, HRG concentrations were significantly lower on days 3 (P < 0.05), 5 (P < 0.01), and 7 (P < 0.05) than on day 1. HRG concentrations were significantly lower in non-survivors than in survivors on days 5 and 7.

Changes in HRG concentrations in patients with septic shock, DIC, and ARDS

HRG concentrations on days 1, 3, 5, and 7 were 35.3, 25.0, 24.1 and 24.3 µg/mL in patients with shock and 31.0, 30.4, 34.0, and 34.4 µg/mL in patients without shock. There was a significant decrease in HRG concentrations in patients with septic shock on days 3, 5, and 7 compared to day 1 (all P < 0.01). In addition, the HRG concentrations were significantly lower in patients with septic shock than in those without septic shock on days 5 and 7 (Fig. 3A).

Mean HRG concentrations were 29.0, 22.7, 22.3, and 22.1 µg/mL in patients with DIC and 35.5, 31.0, 32.5, and 34.9 µg/mL in patients without DIC on days 1, 3, 5, and 7, respectively. In patients with DIC, there was no significant difference in HRG concentrations on days 3, 5, or 7 compared with day 1. The patients with DIC showed significantly lower HRG concentrations than patients without DIC on days 3, 5, and 7 (Fig. 3B).

Mean HRG concentrations were 31.3, 27.6, 29.4, and 28.9 µg/mL in patients with ARDS and 36.9, 27.2, 26.0, and 29.9 µg/mL in patients without ARDS on days 1, 3, 5, and 7, respectively. Although the mean HRG concentration was significantly lower on day 5 than on day 1 in patients without ARDS, no significant difference was found in patients with ARDS. There was no significant difference in HRG concentrations at any time point between patients with ARDS and those without ARDS (Fig. 3C).

HRG concentrations between survivors and non-survivors in patients with septic shock, DIC, and ARDS

Mean HRG concentrations were 35.3, 28.0, 27.4, and 29.6 µg/mL in survivors with septic shock and 35.4, 19.0, 16.6, and 16.4 µg/mL in non-survivors with septic shock on days 1, 3, 5, and 7, respectively. HRG concentrations were lower on days 3, 5 and 7 than on day 1 in non-survivors with septic shock. HRG concentrations were also significantly lower in non-survivors than in survivors with septic shock on days 5 and 7 (both P < 0.05, Fig. 4A).

Mean HRG concentrations were 29.5, 26.0, 26.4, and 27.0 µg/mL in survivors with DIC and 28.1, 14.5, 16.6, and 16.4 µg/mL in non-survivors with DIC on days 1, 3, 5, and 7, respectively. HRG concentrations in non-survivors with DIC were lower than those in survivors with DIC, but significant differences were only observed on days 3 and 5 (both P < 0.05, Fig. 4B).

Mean HRG concentrations were 29.3, 28.9, 32.5, and 34.3 µg/mL in survivors with ARDS and 36.3, 24.2, 20.6, and 20.3 µg/mL in non-survivors with ARDS on days 1, 3, 5, and 7, respectively. HRG concentrations were significantly lower on days 5 and 7 than on day 1 in non-survivors with ARDS, but there was no difference between the time points in survivors with ARDS (Fig. 4C). HRG concentrations were also significantly lower in non-survivors with ARDS than in survivors with ARDS on days 5 and 7.

Receiver operator characteristic analysis to predict the prognosis of critically ill patients with sepsis

We analyzed the predictive ability of HRG concentrations for the prognosis using receiver operator characteristic (ROC) curves (Fig. 5a). The areas under the curve of HRG concentrations were 0.566, 0.651, 0.764, and 0.798 on days 1, 3, 5, and 7, respectively. The sensitivity and specificity of HRG concentrations were 0.77 and 0.75, respectively, on day 5, with a cut-off level of 25.5 µg/mL The sensitivity and specificity of HRG concentrations were 0.75 and 0.81, respectively, on day 7, with a cut-off level of 25.7 µg/mL. It was very close in two cut-off levels. Therefore, Kaplan–Meier analysis was performed by using an HRG concentration of 25.5 µg/mL on day 5. Patients with an HRG concentration < 25.5 µg/mL showed a significantly lower survival curve (log-rank test, P < 0.05) (Fig. 5b).

We showed the changes in serum HRG concentrations in critically ill patients with sepsis in a single-center observational study. To the best of our knowledge, only one multicenter, observational study showed the changes in plasma HRG concentrations¹⁵. Previous studies on sepsis measured HRG concentrations in plasma^11,12. In our preliminary experiments, we measured serum and plasma HRG concentrations and found a strong positive correlation between them. Since serum samples are more stable and preservable than plasma samples, we measured them in this study.

The most important finding in our study was that regarding HRG concentrations in survivors and non-survivors with sepsis. The HRG concentrations of non-survivors were significantly lower than those of survivors on days 3, 5, and 7 after admission to the ICU but not on day 1. In contrast to our results, a previous study showed a significant difference in HRG concentrations in survivors and non-survivors on day 1, and a low HRG concentration on day 1 was a significant prognostic factor¹². One reason for this discrepancy between studies could be due to the sample size. Another possible reason is that the previous study was a multicenter registered study. The patients in this previous study may have had selection bias¹². In our study, ROC and Kaplan–Meier analysis suggested that HRG concentrations on days 5 and 7 may be more predictive of patients’ outcomes than those on days 1 and 3 in the ICU. Changes in HRG concentrations in patients with septic shock and in patients with DIC, which decreased progressively, especially on day 5, may worsen the patient’s prognosis. Previous clinical studies showed that HRG concentrations are decreased not only in sepsis,^11,12 but also in pregnancy and preeclampsia¹⁶. Decreased HRG concentrations also correlated with survival in patients with severe community-acquired pneumonia and ventilator-associated pneumonia^17,18.

In this study, we analyzed HRG concentrations in septic shock, ARDS, and DIC conditions. In patients with septic shock, HRG concentrations were decreased on days 3, 5, and 7. HRG concentrations in patients with DIC were significantly lower than those in patients without DIC on days 3, 5, and 7. Unlike the changes in septic shock, HRG concentrations did not significantly change on days 3, 5, and 7 compared with those on day 1 in the patients with DIC. This finding could be because the mean HRG concentration was low since day 1 in patients with DIC. HRG may have some relationship with the formation of DIC. Previous studies have shown that patients with sepsis induced DIC have a much higher mortality rate than those without DIC^6,19. HRG has been identified as a coagulation-related protein that regulates the intrinsic pathway of coagulation by binding to factor (F) XIIa and attenuating its ability to induce coagulation²⁰. Additionally, HRG-deficient families have severe thrombotic disease²¹. Therefore, a low HRG concentration might increase the risk of thrombosis, resulting in DIC. Further study is necessary to explain the precise relationship between HRG and DIC.

A significant decrease in HRG concentrations was not observed in patients with ARDS who did not have shock or DIC in this study. Inflammation associated with ARDS is primarily confined to the lungs. Therefore, HRG concentrations may not decrease as much as in septic shock and DIC. COVID-19 is a recently discovered cause of ARDS¹⁴ and is known to cause coagulopathy^14,22. We included 20 (58.8%) patients with COVID-19 among 34 patients with ARDS in our study. Two of these patients died and three were not extubated within 28 days of admission to the ICU. Patients with ARDS who died or were not extubated had lower HRG values on days 5 and 7 than on day 1 (Supplementary Fig. S1 and S2). Völlmy et al. conducted a proteomic analysis on 33 patients with severe COVID-19 and found that HRG concentrations were lower in non-survivors than in survivors²³.

HRG also has antibacterial effects against Gram-positive bacteria (Enterococcus faecalis and Staphylococcus aureus), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and systemic candida infections^24,25. Therefore, HRG supplementation may contribute to bacterial sepsis. In basic research, HRG administration in septic rats changed the neutrophil shape from irregular to spherical, reducing their diameter and suppressing adhesion to the vascular wall²⁶. Guo et al. also reported that HRG has therapeutic potential to reduce liver damage in mice with nonalcoholic steatohepatitis and hepatic ischemia/reperfusion injury by reducing neutrophil extracellular traps (NETS) formation²⁷. Therefore, therapeutic supplementation of HRG may be useful in patients with sepsis and decreased HRG concentrations. HRG is easy to extract and purify from blood as shown in previous studies^26,27. Therefore, HRG is thought to be a relatively readily available blood product. The administration of HRG may be considered a new therapeutic approach, especially in patients with sepsis and DIC. Further research on a larger scale is required to determine the exact period and cut-off of HRG concentrations that require additional HRG administration.

The concentration of HRG was significantly lower in non-survivors than in survivors, particularly on days 5 and 7. The HRG concentrations of patients with septic shock and DIC were significantly lower than those without, and this was related to their prognosis. Therefore, HRG supplementation therapy may become a promising drug for patients with sepsis.

Patients and data collection

Our study was a single-center, retrospective, observational study. Sixty-five critically ill patients with sepsis were consecutively admitted to the emergency ICU of Kyushu University Hospital from June 2019 to October 2021. Patients aged < 20 years, those with terminal stage cancer, and those who died during an ICU stay < 3 days were excluded. Fifty-three patients were included in this study. The reason for ICU admission was septic shock requiring adrenalin > 0.1 γ or acute respiratory distress syndrome requiring a mechanical ventilator. Twenty-four patients had septic shock, 16 had DIC, and 28 had ARDS. Most of the patients showed overlap of these diseases (Table 1).

Septic shock

The diagnosis of sepsis and septic shock was made based on the criteria of Sepsis-3, which defines sepsis as a dysregulated host response to infection that causes life-threatening organ dysfunction ¹. Sepsis-3 defines septic shock as a subset of sepsis in which there is a substantial increase in mortality due to considerable abnormalities of the underlying circulation and cellular metabolism ¹.

DIC

DIC was diagnosed using the Japanese Association for Acute Medicine DIC score (Supplementary Table 1)¹³. The Japanese Association for Acute Medicine DIC score consists of the platelet count, the prothrombin time, fibrin degradation products (FDP) or D dimer, and systemic inflammatory response syndrome. This score was developed for the early diagnosis of DIC and is used in Japan.

ARDS

ARDS was diagnosed according to the Berlin definition. The Berlin definition of ARDS is the presence of symptoms or worsening of the respiratory system within 1 week, with diffuse bilateral opacities on chest radiographs, which are not attributed to congestive heart failure or intravascular volume overload. The Berlin definition categorizes ARDS as mild (200 mm Hg < PaO₂/FiO₂ ≤ 300 mm Hg), moderate (100 mm Hg < PaO₂/FiO₂ ≤ 200 mm Hg), and severe (PaO₂/FiO₂ ≤ 100 mm Hg)¹⁴. In the present study period, COVID-19 infection was prevalent; therefore, ARDS in most patients was due to COVID-19. The diagnosis of COVID-19 was made based on a positive polymerase chain reaction (PCR) result.

Other definitions

The SOFA and APACHE II scores were calculated from the patient’s clinical and laboratory data. The patient’s clinical and laboratory data were collected daily during the ICU stay. The patient’s condition was evaluated on day 28 after admission to determine the state of survival.

Sample collection

Blood samples were taken from patients on the first, third, fifth, and seventh days after admission to the ICU in Kyushu University Hospital. Blood samples were also taken from two healthy volunteers for comparison. Blood samples were collected in serum and EDTA plasma tubes. The plasma tubes were shaken slowly and centrifuged at 1000 x g for 15 minutes. The serum tubes were gently inverted twice and then remained at room temperature for 45 minutes to complete the coagulation process. The same centrifugation conditions as those for plasma samples were then carried out. We collected the supernatant and stored it at − 80°C.

Measurement of HRG

According to the manufacturer’s manual protocol, serum and plasma HRG concentrations were measured using a human HRG enzyme-linked immunoassay (ELISA) kit (Abcam, Cambridge, UK). Diluted blood samples and standards were placed into each well. The wells were gently shaken for 2.5 hours at room temperature. After washing the wells, biotinylated anti-human HRG antibody was added to each well, and the ELISA plate was gently shaken at room temperature for 1 hour. After rewashing, HRP-Streptavidin Concentrate was added to each well and left at room temperature for 45 minutes. TMB Substrate Reagent was used and then the plates were read immediately at 450 nm by an ELISA microplate reader (Tecan, Männedorf Switzerland).

Ethics statement

This study was conducted by following the ethical guidelines of the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The study was approved by Kyushu University Hospital Institutional Review Board (approval number: 21117-00), and informed consent was obtained before data collection.

Statistical analysis

Data are shown as the mean ± standard deviation. The correlation between serum and plasma HRG concentrations was analyzed using Pearson’s correlation matrix and simple linear regression. Pearson’s r values > 0.70 were considered a strong correlation. Differences between the two groups were analyzed using the unpaired Student t-test and two-way analysis of variance with Dunnett’s multiple comparisons test for three or more groups. Fisher’s exact probability test was used to compare ratios between two categorical groups. To predict the prognosis, we used a ROC curve analysis to assess HRG concentrations on days 1, 3, 5, and 7. The Kaplan–Meier survival curve and log-rank test were performed by dividing the patients into two groups using the cut-off levels obtained from the ROC curve analysis. All two-tailed tests with P < 0.05 were considered statistically significant. The statistical analyses were performed using GraphPad Prism (GraphPad Prism 9.5.1. for macOS; GraphPad Software, San Diego, California, USA).

Acknowledgments

The authors would like to thank the ICU medical and nursing teams at Kyushu University Hospital for their contributions to obtaining informed consent and collecting the blood samples. We thank Ellen Knapp, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Author contributions

A.N.K.P. and T.A. designed the study. A.N.K.P. and T.A. wrote the manuscript. A.N.K.P., J.G., Y.M., and S.N. performed the experiments. A.N.K.P, S.M., and K.Y. participated in data collection. A.N.K.P., T.A., and M.M. contributed to the statistical analysis. T.A. and M.M. supervised the study. All authors read and approved the final manuscript.

Data availability

The data for this study are available from the corresponding author upon reasonable request.

Additional information

Competing interests

The authors declare no potential conflicts of interest.

Funding

This research was supported by grants from the Japan Society for the Promotion of Science (JSPS) KAKENHI grant number JP22H03175.

Correspondence and requests for materials should be addressed to T.A.

Singer, M. et al. The third international consensus definition for sepsis and septic shock (Sepsis-3) JAMA 315, 801–810 (2016).
Iskander, K.N. et al. Sepsis: multiple abnormalities, heterogeneous responses, and evolving understanding. Physiol. Rev. 93, 1247–1288 (2013).
Cecconi, M., Evans, L., Levy, M. & Rhodes, A. Sepsis and septic shock. Lancet 392, 75–87 (2018).
Sepsis. World Health Organization https://www.who.int/news-room/fact-sheets/detail/sepsis. (2020)
Rudd, K. E. et al. The global burden of sepsis: barriers and potential solutions. Crit. Care 22, (2018).
Gando, S. et al. Role of disseminated intravascular coagulation in severe sepsis. Thromb. Res. 178, 182–188 (2019).
Akahoshi, T. et al. Impact of antithrombin activity levels following recombinant antithrombin gamma therapy in patients with sepsis-induced disseminated intravascular coagulation. Clin. Appl. Thromb. Hemost. 28, 107602962211357 (2022).
Poon, I. K., Patel, K. K., Davis, D. S., Parish, C. R. & Hulett, M. D. Histidine-rich glycoprotein: the swiss army knife of mammalian plasma. Blood 117, 2093–2101 (2011).
Wake, H. Histidine-rich glycoprotein modulates the blood-vascular system in septic condition. Acta Med. Okayama 73, 379-382 (2019).
Takahashi, Y. et al. Histidine-rich glycoprotein stimulates human neutrophil phagocytosis and prolongs survival through clec1a. J. Immunol. 206, 737–750 (2021).
Kuroda, K. et al. Decrease in histidine-rich glycoprotein as a novel biomarker to predict sepsis among systemic inflammatory response syndrome. Crit. Care Med. 46, 570-576 (2018).
Kuroda, K. et al. Histidine-rich glycoprotein as a prognostic biomarker for sepsis. Sci. Rep. 11, (2021).
Iba, T. et al. Diagnosis of sepsis-induced disseminated intravascular coagulation and coagulopathy. Acute Med. Surg. 6, 223-232 (2019).
Meyer, N. J., Gattinoni, L. & Calfee, C. S. Acute respiratory distress syndrome. Lancet 398, 622-637 (2021).
Kawanoue, N. et al. Consistently low levels of histidine-rich glycoprotein as a new prognostic biomarker for sepsis: a multicenter prospective observational study. PLoS One 18, (2023).
Bolin, M., Akerud, P., Hansson, A., & Akerud, H. Histidine-rich glycoprotein as an early biomarker of preeclampsia. Am. J. Hypertens. 24, 496-501 (2011).
He, X., Luo, Q., Zhao, L., Shang, Y., & Gao, Z. Prognostic value of histidine-rich glycoprotein for community-acquired pneumonia. Dis. Markers 2022, 1-9 (2022).
Ding, H.G. et al. A novel biomarker of serum histidine-rich glycoprotein (HRG) for diagnosing and predicting prognosis of ventilator-associated pneumonia (VAP): a pilot study. Eur. Rev. Med. Pharmacol. Sci. 22, 7920-7927 (2018).
Iba, T., Umemura, Y., Wada, H., & Levy, J.H. Roles of coagulation abnormalities and microthrombosis in sepsis: pathophysiology, diagnosis, and treatment. Arch. Med. Res. 52, 788-797 (2021).
Iba, T. et al. Sepsis-associated disseminated intravascular coagulation and its differential diagnoses. J. Intensive Care 7, (2019).
Ogura, H. et al. Epidemiology of severe sepsis in Japanese intensive care units: a prospective multicenter study. J. Infect. Chemother. 20, 157-162 (2014).
MacQuarrie, J.L. et al. Histidine-rich glycoprotein binds factor XIIa with high affinity and inhibits contact-initiated coagulation. Blood 117, 4134-4141 (2011).
Shigekiyo, T. et al. Histidine-rich glycoprotein (HRG) Tokushima 2: novel HRG deficiency, molecular and cellular characterization. Thromb Haemost. 84, 675-679 (2000).
Weekly epidemiological update on COVID-19 - 11 May 2023. World Health Organization https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---11-may-2023. (2023)
Iba, T., Levy, J.H., Levi, M., Connors, J.M., & Thachil, J. Coagulopathy of coronavirus disease 2019. Crit. Care Med. 48, 1358-1364 (2020).
Völlmy, F. et al. A serum proteome signature to predict mortality in severe COVID-19 patients. Life Sci. Alliance 4, (2021).
Rydengård, V., Olsson, A.K., Mörgelin, M., & Schmidtchen, A. Histidine-rich glycoprotein exerts antibacterial activity. FEBS J. 274, 377-389 (2007).
Rydengård, V. et al. Histidine-rich glycoprotein protects from systemic Candida infection. PLoS Pathog. 4, (2008).
Wake, H. et al. Histidine-rich glycoprotein prevents septic lethality through regulation of immunothrombosis and inflammation. EBioMedicine 9, 180-194 (2016).
Guo, J. et al. Histidine-rich glycoprotein alleviates liver ischemia/reperfusion injury in mice with nonalcoholic steatohepatitis. Liver Transpl. 27, 840-853 (2021).

No competing interests reported.

SupplementaryinformationChangesofhistidinerichglycoproteinlevelsincriticallyillsepticpatients.docx

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Journal Publication

published 24 Jun, 2024

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Changes of histidine-rich glycoprotein levels in critically ill septic patients

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Results

Patients’ characteristics

Association between serum and plasma HRG concentrations

Changes in serum HRG concentrations in survivors and non-survivors

Changes in HRG concentrations in patients with septic shock, DIC, and ARDS

HRG concentrations between survivors and non-survivors in patients with septic shock, DIC, and ARDS

Receiver operator characteristic analysis to predict the prognosis of critically ill patients with sepsis

Discussion

Materials and methods

Patients and data collection

Septic shock

DIC

ARDS

Other definitions

Sample collection

Measurement of HRG

Ethics statement

Statistical analysis

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

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