An Exploratory, Observational Cohort Study on the Dynamics of Heparin Binding Protein in Cardiothoracic Surgery Using Cardiopulmonary Bypass

Abstract BackgroundSurgical trauma and cardiopulmonary bypass (CPB) cause an inflammatory response, difficult to differentiate from postoperative infections. Heparin-binding protein (HBP) is released from neutrophils and has been shown to predict infection-related organ dysfunction and disease progression to severe sepsis. In order to explore the potential of HBP as a biomarker for postoperative infections and asess possible confounding effects of concomitant medications, this study aimed to investigate the pre-, intra- and postoperative dynamics of HBP in cardiac surgery with CPB.Methods Thirty patients undergoing cardiac surgery with CPB were included, of which 15 underwent coronary artery bypass grafting (CABG) surgery and 15 underwent complex procedures with longer CPB duration. Ten patients undergoing lung surgery without CPB were also included as a conventional surgery reference group. HBP was measured at nine different perioperative time points.Results Our results showed that HBP levels were not affected by surgical trauma by itself. An increase in HBP levels was observed immediately following heparin administration and further increased during CPB. Prior to protaminization, we measured higher peak HBP-levels in the complex group (345.7 (287.8-472.6) ng/mL) compared with the CABG group (152.7 (85.3-204.0) ng/mL, p<0.001). HBP decreased rapidly following cessation of CPB and simultaneous protamine administration. Delay of protamine administration revealed that protamine, and not the cessation of CPB is primarily responsible for the rapidly reduced HBP concentration. At the arrival to the ICU, the median HBP levels were 24.8 (15.6-38.1) ng/mL for CABG patients compared with 50.5 (36.5-104.6) ng/mL for complex surgery patients (p=0.004). One day after surgery, HBP levels in all three groups were below the proposed cutoff of 30 ng/mL, previously found to predict development of organ dysfunction during infection, while other biomarkers for infections remained elevated.ConclusionsHBP levels are elevated by administration of heparin and the use of CPB but reduced by protamine administration. At postoperative day one, HBP levels were below the threshold for infection with organ dysfunction, indicating that postoperative HBP measurement may be a better screening tool for postoperative infections than other biomarkers of infections that remain elevated after surgery.

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Dynamics of heparin binding protein in cardiothoracic surgery using cardiopulmonary bypass – exploring its potential as a marker for postoperative infections.

10.21203/rs.3.rs-26369/v1 ◽

2020 ◽

Author(s):

Niklas Sterner ◽

Jane Fisher ◽

Louise Thelaus ◽

Carolin Ketteler ◽

Spela Lemez ◽

...

Keyword(s):

Cardiac Surgery ◽

Cardiopulmonary Bypass ◽

Organ Dysfunction ◽

Binding Protein ◽

Surgical Trauma ◽

Heparin Binding ◽

Postoperative Infections ◽

Heparin Binding Protein ◽

Heparin Administration ◽

Protamine Administration

Abstract Background Surgical trauma and cardiopulmonary bypass (CPB) cause an inflammatory response, difficult to differentiate from postoperative infections. Heparin-binding protein (HBP) is released from neutrophils and has been shown to predict infection-related organ dysfunction and disease progression to severe sepsis. The aim of this study was to investigate the pre-, intra- and postoperative dynamics of HBP in cardiac surgery using CPB, in order to explore the usefulness of HBP as a biomarker for postoperative infections. Methods and Results Thirty patients undergoing cardiac surgery with CPB were included, of which 15 underwent coronary artery bypass grafting (CABG) surgery and 15 underwent complex procedures with longer CPB time. A reference group of ten patients undergoing lung surgery without CPB was also included. HBP was measured at nine different time points during surgery. Our results showed that HBP levels were not affected by surgical trauma itself. An increase in HBP levels was observed immediately following heparin administration and further increased during CPB. Prior to protaminization, we measured higher peak in HBP-levels in the complex group 345.7 (287.8-472.6) ng/mL compared with the CABG group 152.7 (85.3-204.0) ng/mL, p <0.001. HBP decreased rapidly following end of CPB and simultaneous protamine administration. Delay of protamine administration revealed that protamine, and not the cessation of CPB is primarily responsible for the rapidly reduced HBP concentration. At the arrival to the ICU, the median HBP levels were 24.8 (15.6-38.1) ng/mL for CABG patients compared with 50.5 (36.5-104.6) ng/mL for complex surgery patients ( p =0.004). One day after surgery HBP levels in all three groups were below the proposed cutoff of 30 ng/mL previously found to predict development organ dysfunction during infection. There was a statistically significant correlation between CPB duration and peak HBP concentration (r=0.598, p =0.002). Conclusions HBP levels are elevated by administration of heparin and the use of CPB. However, at postoperative day one, HBP levels normalized regardless of surgical complexity, indicating that postoperative HBP measurement may be used as a screening tool for postoperative infections in cardiac surgery.

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Heparin Binding Protein and Endothelial Glycocalyx Markers in Severe COVID-19 – A Prospective Observational Cohort Study

10.21203/rs.3.rs-64087/v1 ◽

2020 ◽

Author(s):

Lisa Mellhammar ◽

Louise Thelaus ◽

Sixten Elén ◽

Jane Fisher ◽

Adam Linder

Keyword(s):

Organ Dysfunction ◽

Binding Protein ◽

Point Of Care ◽

Severe Disease ◽

Endothelial Glycocalyx ◽

Enzyme Linked Immunosorbent Assay ◽

Heparin Binding ◽

Convenience Sample ◽

Point Of Care Test ◽

Heparin Binding Protein

Abstract Background: The pathophysiology of severe COVID-19 has been implicated to involve neutrophil activation in the blood and in the lungs and endothelial dysfunction. Heparin binding protein (HBP) is a neutrophil protein that plays an important role in bacterial sepsis and is a promising biomarker in severe infections. Syndecans and glypicans are potential markers of sheeding of the glycocalyx and endothelial dysfunction.The primary aims of this study were to assess whether HBP or syndecans and glypicans are involved in the pathophysiology of COVID-19 and if so, whether they can be used to predict severe disease preferably using a point-of-care test (POC) that can substitute more time-consuming analysis with enzyme-linked immunosorbent assay (ELISA).Methods: A prospective convenience sample study of biomarkers. The main cohort consisted of patients admitted to hospital with a confirmed COVID-19 diagnosis. Samples and clinical data were collected at admission, during admission and at discharge and samples were analyzed with ELISA kit (Axis-Shield Diagnostics) for measuring HBP concentration and a novel dry immunofluorescence analyzer (Jet-iStar 800) (Joinstar) for point-of-care testing.Results: Thirty-five COVID-19 patients were prospectively enrolled in the study. HBP was significantly elevated in COVID-19 patients with organ dysfunction (n= 23) compared to those without organ dysfunction (n=6), 24.7 ng/mL (95% CI 17.3-48.4) vs 10.6 ng/mL (95% CI 6.2-17.1 ng/mL), p=0.03. Syndecan-1 and Glypican-4 were not significantly elevated in patients with organ dysfunction. Syndecan-1, 62.1 ng/mL (44.4-102.0) vs 57.5 ng/mL (95% CI 46.0- 63.7), p=0.44 and glypican-4, 3292.4 pg/mL (95% CI 1707.5- 6790.6) vs 3962.7 pg/mL (95% CI 2653.6- 5823.5), p=0.80. The point-of-care (POC) HBP test showed good correlation to the standard ELISA with an R-value of 0.83. HBP measured by the POC device predicted development of COVID-induced organ dysfunction within 72 hours with an AUC of 0.88.Conclusions: The neutrophil-derived HBP is elevated prior to onset of organ dysfunction in patients with severe COVID-19 using a newly developed point-of-care test and hence HBP could be used in a clinical setting as a prognostic marker in COVID-19.

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Heparin-Binding Protein Performs Better for Detecting Sepsis Among Patients Presenting With Signs of Systemic Infection Compared With Procalcitonin, C-Reactive Protein, and Lactate Level, and Heparin-Binding Protein Is Sufficient for Both Ruling in and Out Sepsis With Organ Dysfunction: Beware of Potential Confounding Factors!

Critical Care Medicine ◽

10.1097/ccm.0000000000005005 ◽

2021 ◽

Vol 49 (7) ◽

pp. e733-e734

Author(s):

Patrick M. Honore ◽

Sebastien Redant ◽

Thierry Preseau ◽

Keitiane Kaefer ◽

Leonel Barreto Gutierrez ◽

...

Keyword(s):

Organ Dysfunction ◽

Lactate Level ◽

Binding Protein ◽

Systemic Infection ◽

Confounding Factors ◽

Heparin Binding ◽

C Reactive Protein ◽

Reactive Protein ◽

Heparin Binding Protein

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Heparin-binding protein: a key player in the pathophysiology of organ dysfunction in sepsis

Journal of Internal Medicine ◽

10.1111/joim.12604 ◽

2017 ◽

Vol 281 (6) ◽

pp. 562-574 ◽

Cited By ~ 26

Author(s):

J. Fisher ◽

A. Linder

Keyword(s):

Organ Dysfunction ◽

Binding Protein ◽

Protein A ◽

Heparin Binding ◽

Heparin Binding Protein

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Heparin-Binding Protein Measurement Improves the Prediction of Severe Infection With Organ Dysfunction in the Emergency Department

Critical Care Medicine ◽

10.1097/ccm.0000000000001265 ◽

2015 ◽

Vol 43 (11) ◽

pp. 2378-2386 ◽

Cited By ~ 40

Author(s):

Adam Linder ◽

Ryan Arnold ◽

John H. Boyd ◽

Marko Zindovic ◽

Igor Zindovic ◽

...

Keyword(s):

Emergency Department ◽

Organ Dysfunction ◽

Binding Protein ◽

Severe Infection ◽

Heparin Binding ◽

Heparin Binding Protein ◽

Protein Measurement

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Heparin binding protein in severe COVID-19—A prospective observational cohort study

PLoS ONE ◽

10.1371/journal.pone.0249570 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0249570

Author(s):

Lisa Mellhammar ◽

Louise Thelaus ◽

Sixten Elén ◽

Jane Fisher ◽

Adam Linder

Keyword(s):

Organ Dysfunction ◽

Binding Protein ◽

Point Of Care ◽

Severe Disease ◽

University Hospital ◽

Enzyme Linked Immunosorbent Assay ◽

Heparin Binding ◽

Convenience Sample ◽

Point Of Care Test ◽

Heparin Binding Protein

Background and aims Neutrophil-derived heparin binding protein (HBP; also known as azurocidin or CAP-37) is a key player in bacterial sepsis and a promising biomarker in severe infections. The aims of this study were to assess whether HBP is involved in the pathophysiology of COVID-19 and, if so, whether it can be used to predict severe disease preferably using a point-of-care test. Methods This was a prospective convenience sample study of biomarkers in patients admitted to Skåne University hospital in Sweden with a confirmed COVID-19 diagnosis. Plasma samples and clinical data were collected within 72h after admission, during hospital stay and at discharge. Plasma HBP concentrations samples were measured both with enzyme-linked immunosorbent assay (ELISA) and with a novel dry immunofluorescence analyzer (Joinstar) point-of-care test. Results Thirty-five COVID-19 patients were enrolled in the study. Twenty-nine patients had blood samples taken within 72h after admission. We compared the highest HBP value taken within 72h after admission in patients who eventually developed organ dysfunction (n = 23) compared to those who did not (n = 6), and found that HBP was significantly elevated in those who developed organ dysfunction (25.0 ng/mL (interquartile range (IQR) 16.6–48.5) vs 10.6 ng/mL (IQR 4.8–21.7 ng/mL), p = 0.03). Point-of-care test measurements correlated well with ELISA measurements (R = 0.83). HBP measured by the POC device predicted development of COVID-induced organ dysfunction with an AUC of 0.88 (95% confidence interval (CI) 0.70–1.0). Conclusions HBP is elevated prior to onset of organ dysfunction in patients with severe COVID-19 using a newly developed point-of-care test and hence HBP could be used in a clinical setting as a prognostic marker in COVID-19.

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O-44 Release of heparin binding protein during cardiac surgery: a new mediator of systemic inflammatory response?

Journal of Cardiothoracic and Vascular Anesthesia ◽

10.1053/j.jvca.2011.03.057 ◽

2011 ◽

Vol 25 (3) ◽

pp. S19

Author(s):

Ruth Bundy ◽

Sharif Al-Ruzzeh ◽

Mohamed Amrani ◽

Heiko Herwald ◽

Lennart Lindbom ◽

...

Keyword(s):

Cardiac Surgery ◽

Inflammatory Response ◽

Binding Protein ◽

Systemic Inflammatory Response ◽

Heparin Binding ◽

Heparin Binding Protein

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Repeated measures of Heparin-binding protein (HBP) and procalcitonin during septic shock: biomarker kinetics and association with cardiovascular organ dysfunction

Intensive Care Medicine Experimental ◽

10.1186/s40635-020-00338-8 ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Jonas Tverring ◽

Niklas Nielsen ◽

Josef Dankiewicz ◽

Adam Linder ◽

Fredrik Kahn ◽

...

Keyword(s):

Septic Shock ◽

Organ Dysfunction ◽

Repeated Measures ◽

Binding Protein ◽

Heparin Binding ◽

Heparin Binding Protein ◽

Crude Model ◽

Adjusted Model ◽

Kinetics Of ◽

Over Time

Abstract Background Heparin-binding protein (HBP) is a neutrophil-derived pro-inflammatory protein, an inducer of endothelial dysfunction and vascular permeability and a promising prognostic biomarker in sepsis. This exploratory study aims to describe the kinetics of plasma HBP during septic shock and investigate an association between repeated measures of HBP concentration and cardiovascular organ dysfunction severity. Methods We included patients at or above 18 years with suspected septic shock on admission to the intensive care unit (ICU) during 2014 and 2016 to 2018. Plasma samples were collected from ICU admission and every 4 h for 72 h or until death or ICU discharge and batch analysed for HBP. Mean arterial blood pressure (MAP) and noradrenaline dose (NA dose) were recorded at each sampling time point, and systemic vascular resistance index (SVRI) was recorded when available from non-invasive monitoring. The association between HBP, NA dose, MAP and SVRI was assessed respectively using mixed-effects linear regression models. Procalcitonin (PCT) was used as a comparator. Results A total of 24 patients were included. The kinetics of plasma HBP was highly variable over time, with occasional >2-fold increases and decreases in between 4-h measurements. Every 100 ng/mL increase in HBP corresponded to a 30% increase in NA dose in a crude model (95% CI 3 to 60%, p = 0.03, nobs = 340), a 1.4-mmHg decrease in MAP in an adjusted model (95% CI − 1 to − 2.3 mmHg, p = 0.04) or a 99 dyne s cm−5 m−2 decrease in SVRI in another adjusted model (95% CI − 36 to − 162, p = 0.002, npat = 13). PCT had a stronger association to NA dose than HBP in a crude model but was not significantly associated to NA dose, MAP or SVRI in any time-adjusted model. Conclusions Plasma HBP displayed a highly variable kinetic pattern during septic shock and was significantly associated to cardiovascular organ dysfunction severity over time.

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