Fibrinolytic Capacity and Risk of Bleeding in Intensive Care Patients with Acute Kidney Injury

Abstract

Background

Acute kidney injury (AKI) is common among intensive care unit (ICU) patients and is associated with increased bleeding risk. The impact of fibrinolysis in AKI-related bleeding has not been explored previously.

Objectives

(1) Compare fibrinolytic capacity in ICU patients with and without AKI. (2) Investigate the association between fibrinolytic capacity, as well as other laboratory and clinical variables, and bleeding within the first 7 ICU days in AKI patients.

Methods

Adult ICU patients were prospectively enrolled and stratified by AKI presence and severity at ICU admission. On the morning after admission, fibrinolytic capacity was assessed using a modified rotational thromboelastometry (ROTEM-tPA) assay. The primary outcome was the difference in ROTEM-tPA lysis time on day 1 of ICU admission between AKI and non-AKI patients.

Results

AKI patients (n = 160) had more bleedings and higher 30-day mortality than non-AKI patients (n = 99). ROTEM-tPA analysis showed progressively impaired fibrinolysis with increasing AKI severity. AKI stage 3 patients (n = 53) demonstrated significant impairment across all fibrinolysis parameters compared with non-AKI patients. Among AKI stage 2 to 3 patients (n = 106), bleeding patients (n = 61) had more pronounced fibrinolytic impairment than non-bleeding patients (n = 45). Bleeding risk in AKI stage 2 to 3 was associated with increasing severity of illness (OR: 1.21 (95%CI 1.04–1.42) per 1 point increase in non-renal Sequential Organ Failure Assessment (SOFA) score, p = 0.01).

Conclusions

AKI severity in ICU patients was associated with progressively impaired fibrinolysis. Despite this, AKI patients had more bleedings within the first 7 days of ICU admission.

 

Scroll to top

Keywords

acute kidney injury - blood coagulation tests - critical care - fibrinolysis - thrombelastography

Introduction

Acute kidney injury (AKI) occurs in more than half of patients admitted to the intensive care unit (ICU).[1] It encompasses a heterogeneous group of conditions characterized by an abrupt decline in kidney function, manifesting as elevated serum creatinine and/or oliguria.[2]

Several studies have reported an increased risk of bleeding in AKI patients.[3] [4] [5] [6] [7] Potential risk factors include advanced age, chronic liver disease, coronary artery disease, severe sepsis, use of anticoagulant or antiplatelet therapy, and long-term use of corticosteroids.[3] [6] Moreover, AKI often develops as part of multiorgan failure, particularly in critically ill patients, which may itself contribute to increased bleeding risk.[8] [9] However, no specific hemostatic mechanisms have been identified to explain AKI-related bleeding, making prevention and treatment in this patient group challenging. AKI has been associated with reduced platelet count in both non-ICU and ICU settings.[4] Furthermore, reduced platelet aggregation in AKI patients has been found in non-ICU settings[10] [11] and in a study by Wiegele et al, which compared ICU patients with AKI with healthy controls.[12] However, a recent study did not confirm an association between reduced platelet function and bleeding in ICU AKI patients.[4] The fibrinolytic system has only been sparsely investigated in AKI. A study conducted by Larsson et al found that patients with acute uremia exhibited decreased fibrinolytic activity.[13] However, Zanetto et al demonstrated that both hypofibrinolytic and hyperfibrinolytic alterations were present in patients with AKI, but elevated plasmin–antiplasmin complex levels suggested an overall hyperfibrinolytic state.[10] By contrast, chronic kidney disease (CKD) has previously been associated with hypofibrinolysis, which may increase the risk of thromboembolic events in these patients.[11] [14] [15]

The overall aim of this study was to investigate the fibrinolytic status of AKI patients in an ICU setting and to identify factors associated with bleeding in this population. The primary objective was to employ a modified rotational thromboelastometry (ROTEM-tPA) assay to investigate whole-blood fibrinolytic capacity in AKI ICU patients compared with non-AKI ICU patients. Second, we aimed to investigate whether fibrinolytic capacity on the first ICU day, along with other laboratory and clinical variables, was associated with increased bleeding during the first 7 ICU days in AKI patients.

 

Scroll to top

Materials and Methods

Design and Study Population

We conducted a single-center prospective cohort study, enrolling adult patients admitted to the 22-bed multidisciplinary ICU at Aarhus University Hospital, a tertiary referral hospital in Denmark. Written informed consent was obtained from the patient or the next of kin, as well as from an independent ICU physician. Patients admitted between September 2022 and October 2024 were screened for eligibility. For logistical reasons, recruitment was restricted to weekdays. Patients were excluded from the study if the duration of ICU admission was less than 12 hours, if they had been admitted to an ICU within the preceding 3 months (including transfers from other ICUs or prior participation in this study), or if they had received fibrinolytic or antifibrinolytic therapy within 24 hours before blood sampling. The blood sample was obtained on the morning following admission.

Patients were stratified according to AKI development within a 48-hour window before and after blood sampling. CKD stage 3 to 5 patients formed a separate group and were further stratified by the development of acute-on-chronic renal failure (ACRF).

AKI was defined and classified according to the KDIGO criteria[16]: AKI stage 1: either a 1.5- to 1.9-fold increase in plasma creatinine from baseline, an absolute creatinine increase ≥0.3 mg/dL (≥ 27 μmol/L) within 48 hours or a urine output <0.5 mL/kg/h for 6 to 12 hours; AKI stage 2: a 2.0- to 2.9-fold increase in creatinine from baseline or a urine output <0.5 mL/kg/h for ≥12 hours; AKI stage 3: either a 3.0-fold increase in creatinine from baseline, a concentration ≥4.0 mg/dL (≥354 μmol/L), initiation of renal replacement therapy, a urine output <0.3 mL/kg/h for ≥24 hours or anuria for ≥12 hours. Baseline creatinine was defined as the most recent plasma creatinine measured by the patient's general practitioner or at an outpatient clinic within 1 year prior to the ICU admission. To reflect habitual renal function, creatinine measurements obtained within 7 days prior to hospital admission were excluded. If baseline creatinine was not available, it was calculated using the “three-variable equation” based on the modification of diet in renal disease (MDRD) equation: baseline creatinine = 0.74 − 0.2 (if female) + 0.08 (if Black) + 0.003 × age (in years).[17] Ideal body weight was used to calculate body-weight normalized hourly urine output.[18]

CKD stage 3 to 5 patients were stratified using an ACRF classification adapted from The International Acute Dialysis Quality Initiative (ADQI).[19] [20] Patients were classified as having CKD stage 3 to 5 if the estimated glomerular filtration rate (eGFR), calculated from their baseline creatinine, was <60 mL/min/1.73 m.[2] [21] ACRF stage 1 was defined as a 1.5- to 1.9-fold increase in plasma creatinine from baseline or a reduction in eGFR of ≥25%. ACRF stage 2 was defined as a 2.0- to 2.9-fold increase in creatinine from baseline or a reduction in eGFR of ≥50%. ACRF stage 3 was defined as a 3.0-fold increase in creatinine from baseline or a reduction in eGFR of ≥75%. In addition, patients were classified as ACRF stage 3 if their creatinine concentration reached ≥350 µmol/L following a ≥1.5-fold increase from baseline.

 

Scroll to top

Clinical Data

Clinical data were collected from the patients' electronic medical records and ICU observation charts and managed using REDCap electronic data capture tools hosted at Aarhus University, Denmark.[22] [23] Information regarding age, sex, body mass index (BMI), smoking status, and comorbidities at enrollment was recorded. Sepsis and septic shock were assessed in accordance with the Sepsis-3 guidelines.[24] Treatment prior to blood sampling was documented, including extracorporeal membrane oxygenation, renal replacement therapy, major surgeries, and the use of anticoagulant medication, hemostatic agents, and blood products. Simplified Acute Physiology Score (SAPS) III was assessed by the attending ICU physician at the time of admission.[25] DIC score was calculated according to the International Society for Thrombosis and Haemostasis (ISTH).[26] The highest Sequential Organ Failure Assessment (SOFA) score[24] on the day of blood sampling was also evaluated. Non-renal SOFA score was calculated by excluding the renal component from the standard SOFA score. During the 30 days following ICU admission, data were prospectively collected regarding length of ICU stay, administration of vasopressor agents, renal replacement therapy or mechanical ventilation during admission, 30-day all-cause mortality, and venous thromboembolism (VTE) during the 30 days, verified by relevant imaging (e.g., ultrasound, computed tomography scan). Imaging was obtained at the discretion of the attending physician.

 

Scroll to top

Bleeding

The occurrence of bleeding (World Health Organization [WHO] Bleeding Score grade ≥2)[27] during the first 7 days of ICU admission was obtained. Grade 1 represents mild, self-limiting bleeding. Grade 2 bleeding represents moderate bleeding that does not require transfusion or cause severe hemodynamic instability. It includes prolonged epistaxis (>30 minutes), purpura >1 inch, joint bleeding, melena, hematemesis, macroscopic hematuria, abnormal vaginal bleeding, hemoptysis, visible blood in body cavities, retinal bleeding without visual impairment, and bleeding at invasive sites. Grade 3 represents severe bleeding, defined as red blood cell transfusion beyond routine requirements or moderate hemodynamic instability. Grade 4 represents life-threatening bleeding, defined by severe hemodynamic instability, fatal bleeding, or CNS bleeding identified on imaging. The bleeding score was determined by reviewing patients' journals for documented bleeding incidences, hemodynamic data, and blood transfusions.

 

Scroll to top

 

Scroll to top

Laboratory Methods

Rotational Thromboelastometry Modified with Tissue Plasminogen Activator

Blood was drawn from intra-arterial catheters or, if none were available, by venipuncture with minimal stasis into citrated tubes (1.8 mL BD Vacutainer 3.2% sodium citrate, Plymouth, United Kingdom). The collected samples were gently inverted and left to rest for 30 minutes. The ROTEM-tPA assay (Werfen, Barcelona, Spain) was performed as previously described.[28] Briefly, undiluted EXTEM reagent served as the tissue factor (TF) source, and STARTEM reagent provided the calcium, mirroring the standard EXTEM protocol. Human recombinant tPA (Calbiochem, Sigma-Aldrich, Merck, Darmstadt, Germany) was added to the STARTEM reagent immediately before analysis to achieve a final concentration of 125 ng/mL tPA in the cup. The ROTEM analysis was conducted at 37°C over 60 minutes, with all assays performed in duplicate.

The following standard ROTEM parameters were recorded: clotting time (CT, seconds), maximum clot firmness (MCF, mm), maximum velocity (MaxV, mm/min), lysis index 45 (LI45, %), maximum lysis (ML, %), lysis onset time (LOT, seconds), and lysis time (LT, seconds). ROTEM parameters are shown in [Fig. 1]. Patients who did not achieve an LOT or an LT within the 60-minute run due to hypofibrinolysis were assigned an LOT and/or an LT of 3,600 seconds.

Fig. 1 ROTEM coagulation and lysis parameters. CT, clotting time (seconds, time until an amplitude of 2 mm is reached); FS, fibrinolysis speed (mm/min, clot breakdown speed in mm/min between LOT and LT); LI45, lysis index 45 (% of clot amplitude of MCF at 45 minutes after CT); LOT, lysis onset time (seconds, time from CT to 15% decrease in amplitude of MCF); LT, lysis time (seconds, time from CT until clot firmness has decreased to 10% of MCF); MaxV, maximum velocity (mm/min, maximum clot formation speed); MCF, maximum clot firmness (mm, the maximum amplitude reached); ML, maximum lysis (%, maximum lysis detected during the runtime); t-AUCi, time to attain maximal clot amplitude after reaching maximal clot formation velocity (minutes, time from MAXV-t to MCF-t). (Figure from Brewer JS et al., TH Open, 2024. 8(1): p. e164-e174. Published under a CC-by license.[31])

Time to attain maximal clot amplitude after reaching maximal clot formation velocity (t-AUCi, min) was computed according to the methodology of Scarlatescu et al using the formula: t-AUCi = (MCF-t + CT) − MaxV-t.[29]

Fibrinolysis speed (FS, mm/min), the clot breakdown speed between LOT and LT, was calculated according to the approach for FS_c outlined by Kuiper et al[30]: FS Δamplitude (LT − LOT)/Δtime (LT – LOT). When LT was not available due to hypofibrinolysis, FS was calculated using the amplitude at 60 minutes: If LOT was unavailable due to hypofibrinolysis, FS was set to 0 mm/min.

ROTEM-tPA results from 38 blood donors from the Department of Clinical Immunology, Aarhus University Hospital, were included as healthy controls.[28]

The study was approved by the Central Denmark Region Committees on Health Research Ethics (file no. 1–10–72–162–20).

 

Scroll to top

Platelet Function Analysis

Platelet aggregation was assessed with whole blood impedance aggregometry (Multiplate, Roche, Basel, Switzerland). The following agonists were used: Adenosine diphosphate (6.5 μM, ADPtest), arachidonic acid (0.5 mM, ASPItest), and thrombin-receptor-activating peptide (32 μM, TRAPtest), according to the manufacturer's instructions.

 

Scroll to top

Routine Laboratory Analyses

Platelet count, activated partial thromboplastin time (aPTT), international normalized ratio (INR), antithrombin (functional), fibrinogen (functional, Clauss), arterial lactate, and routine laboratory markers of inflammation and organ dysfunction were analyzed in the automated routine laboratory of the Department of Clinical Biochemistry, following ISO15189:2022-accredited protocols.

 

Scroll to top

Statistical Analysis

The primary outcome was the difference in ROTEM-tPA lysis onset time on day 1 of ICU admission between AKI patients and non-AKI patients. Before commencing the study, we performed a sample size calculation to estimate feasibility. Based on preliminary data from 54 ICU patients, a mean (SD) lysis onset time of 30 (13) minutes was expected. With a significance level (2α) of 0.05, a study power (1 − β) of 0.90 and a minimal relevant difference of 25%, 31 AKI patients and 31 non-AKI patients had to be included. We were ultimately able to include more patients than minimally required, also when stratifying for AKI stages: stage 1, n = 54; stage 2, n = 53; stage 3, n = 53, non-AKI, n = 99, ensuring sufficient power to detect differences in lysis onset time between AKI stage 3 and non-AKI, as displayed in [Fig. 2].

Fig. 2 Coagulation and fibrinolysis parameters measured by ROTEM-tPA in patients with normal renal function, acute kidney injury stage 1, 2, and 3, chronic kidney disease with and without acute-on-chronic renal failure, and healthy individuals. Boxes show the medians and interquartile ranges, and whiskers represent the 2.5th and the 97.5th percentiles. p-values were calculated with the Kruskal-Wallis test. ACRF, acute-on-chronic renal failure; AKI, acute kidney injury; CKD, chronic kidney disease; t-AUCi, time to attain maximal clot amplitude after reaching maximal clot formation velocity.

Normal distribution was assessed visually with quantile–quantile plots. As the majority of the data were not normally distributed, the data were analyzed with non-parametric tests. Continuous data were described using median and interquartile range, and categorical data were presented as numbers and percentages. Differences in continuous variables between groups were tested with the Mann-Whitney test when comparing two groups, and the Kruskal-Wallis test when comparing three or more groups. Association between bleeding (WHO score ≥2) during the first 7 days on ICU and clinical and laboratory parameters was assessed with multiple logistic regression. All statistical analyses and graphs were generated using GraphPad Prism version 10.3.0 for macOS (GraphPad Software, San Diego, California, United States).

 

Scroll to top

 

Scroll to top

Results

Enrollment and Patient Characteristics

A total of 323 patients were recruited to the study. Of these, 159 patients had previously participated in a study by Brewer et al.[31] [Fig. 3] provides an overview of the inclusion and exclusion process and outlines patient stratification by renal function. Of the 160 AKI patients, 94% met the AKI criteria before or at the time of blood sampling.

Fig. 3 Flowchart of patient inclusion and stratification according to renal function. ^aMore than 48 hours before the blood sample obtained on day 1 of ICU admission. ^bWithin +/− 48 hours of the blood sample obtained on day 1 of ICU admission. Notes: Logistical reasons encompass foreign patients who did not understand Danish, patients admitted on weekdays when laboratory work was not conducted due to absence, instances where patient admission exceeded our laboratory capacity, and inclusion in other clinical studies where co-enrollment was not possible. ACRF, acute-on-chronic renal failure; AKI, acute kidney injury; CKD, chronic kidney disease; ICU, intensive care unit.

Patient characteristics by renal function group (AKI, CKD, or no AKI) are summarized in [Table 1], and biochemical measurements obtained on the first morning after ICU admission are presented in [Table 2]. AKI patients were in general more severely ill than non-AKI patients, with illness severity at ICU admission increasing with higher AKI stages. Patients with AKI stage 3 were frequently diagnosed with sepsis (46%) and septic shock (29%) on day 1. Their ICU stays were longer, and they generally required more advanced intensive care therapy than the other groups. They exhibited elevated inflammatory markers (C-reactive protein and leucocyte count), increased fibrinogen, low antithrombin, and high D-dimer levels. Further, stage 3 AKI patients had the highest incidence of both bleeding and VTE development among all groups, and 30-day mortality was 30%.

Table 1 Demographic and clinical characteristics of intensive care unit patients

		AKI within +/− 48 hours of the blood sample obtained on day 1			CKD stages 3–5 (n = 64)
	Non-AKI (n = 99)	AKI stage 1 (n = 54)	AKI stage 2 (n = 53)	AKI stage 3 (n = 53)
Demographics
Age, y	63 (54–72)	67 (58–77)	71 (60–76)	67 (52–75)	76 (69–82)
Female sex	44 (44%)	25 (46%)	23 (43%)	22 (42%)	20 (31%)
BMI, kg/m2	25 (23–30)	27 (24–30)	25 (23–28)	26 (22–31)	27 (23–32)
Illness severity and sepsis
SAPS III score	50 (41–66)	53 (43–62)	58 (46–72)	67 (53–76)	60 (50–71)
SOFA score day 1	5 (3–9)	7 (4–10)	7 (5–11)	11 (8–13)	9 (7–11)
Non-renal SOFA score day 1	5 (3–9)	6 (3–10)	7 (4–10)	8 (7–11)	7 (5–9)
Days in hospital before ICU admission	0 (0–3)	0 (0–0)	1 (0–3)	0 (0–1)	0 (0–1)
Length of ICU stay (d)	1 (1–4)	2 (1–4)	2 (1–4)	5 (2–7)	2 (1–4)
Sepsis on day 1	14 (14%)	7 (13%)	16 (30%)	24 (46%)	19 (30%)
Septic shock on day 1	7 (7%)	3 (6%)	9 (17%)	15 (29%)	10 (16%)
Arterial lactate at admission (mmol/L)	1 (1–2)	2 (1–2)	2 (1–4)	3 (2–7)	1 (1–3)
Comorbidities
Hypertension	33 (22%)	28 (52%)	25 (47%)	23 (43%)	36 (56%)
Diabetes	20 (20%)	9 (17%)	10 (19%)	6 (11%)	21 (33%)
Ischemic heart disease	13 (13%)	9 (17%)	8 (15%)	8 (15%)	23 (36%)
Heart failure	7 (7%)	5 (9%)	2 (4%)	4 (8%)	16 (25%)
Cirrhosis of the liver	4 (4%)	1 (2%)	3 (6%)	2 (4%)	0 (0%)
Solid cancer	16 (16%)	1 (2%)	11 (21%)	8 (15%)	5 (8%)
Hematologic cancer	3 (3%)	2 (4%)	4 (8%)	3 (6%)	7 (11%)
Rheumatologic disease	5 (5%)	8 (15%)	5 (9%)	2 (4%)	7 (11%)
Interventions and medication before blood sample obtained on day 1
Renal replacement therapy (24 hours)	0 (0%)	0 (0%)	0 (0%)	7 (13%)	1 (2%)
ECMO (24 hours)	0 (0%)	3 (6%)	4 (8%)	8 (15%)	2 (3%)
Major surgery (7 days)	27 (27%)	17 (31%)	15 (28%)	9 (17%)	17 (27%)
Platelet inhibitors (10 days)	22 (22%)	24 (44%)	13 (25%)	15 (28%)	25 (39%)
Vitamin K antagonists (14 days)	6 (6%)	2 (4%)	1 (2%)	1 (2%)	8 (13%)
Direct oral anticoagulants (3 days)	16 (16%)	10 (19%)	5 (9%)	8 (15%)	13 (20%)
Heparins
Low molecular weight, prophylactic dose (24 hours)	23 (23%)	5 (9%)	10 (19%)	12 (23%)	14 (22%)
Low molecular weight, therapeutic dose (24 hours)	12 (12%)	6 (11%)	5 (9%)	5 (9%)	3 (5%)
Unfractionated (24 hours)	6 (6%)	4 (7%)	7 (13%)	11 (21%)	8 (13%)
No heparin (24 hours)	60 (61%)	40 (74%)	32 (60%)	26 (49%)	39 (61%)
Erythrocyte transfusion (24 hours)	20 (20%)	15 (28%)	15 (28%)	13 (25%)	18 (28%)
Plasma transfusion (24 hours)	20 (20%)	11 (20%)	10 (19%)	8 (15%)	9 (14%)
Platelet transfusion (24 hours)	15 (15%)	10 (19%)	7 (13%)	4 (8%)	11 (17%)
Interventions during ICU admission
Mechanical ventilation	49 (49%)	36 (67%)	29 (55%)	41 (77%)	42 (66%)
Renal replacement therapy	1 (1%)	2 (4%)	2 (4%)	22 (42%)	2 (3%)
Vasopressor treatment	9 (9%)	9 (17%)	16 (30%)	16 (30%)	24 (33%)
ECMO	0 (0%)	4 (17%)	4 (8%)	8 (15%)	2 (3%)
Erythrocyte transfusion	25 (25%)	16 (30%)	22 (42%)	26 (49%)	21 (33%)
Plasma transfusion	15 (15%)	8 (15%)	9 (17%)	13 (25%)	5 (8%)
Platelet transfusion	8 (8%)	7 (13%)	8 (15%)	10 (19%)	5 (8%)
Events and mortality
Any bleeding, WHO bleeding score ≥1 (within 7 days of ICU admission)	42 (42%)	29 (54%)	36 (68%)	39 (74%)	35 (55%)
WHO bleeding score 1	11 (11%)	8 (15%)	9 (17%)	5 (9%)	7 (11%)
WHO bleeding score 2	24 (24%)	14 (26%)	22 (42%)	28 (53%)	24 (38%)
WHO bleeding score 3	7 (7%)	7 (13%)	4 (8%)	5 (9%)	4 (6%)
WHO bleeding score 4	0 (0%)	0 (0%)	1 (2%)	1 (2%)	0 (0%)
Occurrence of VTE (within 30 days of ICU admission)	7 (7%)	2 (4%)	3 (6%)	7 (13%)	2 (3%)
Mortality (within 30 days of ICU admission)	9 (9%)	9 (16%)	16 (30%)	16 (30%)	24 (38%)

Abbreviations: AKI, acute kidney injury; BMI, body mass index; CKD, chronic kidney disease; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment; VTE, venous thromboembolism; WHO, World Health Organization.

Notes: Continuous variables are reported as medians (interquartile range) while categorical variables are presented as numbers and percentages. Non-renal SOFA score was calculated by excluding the renal component from the standard SOFA score. The following parameters have missing data: Arterial lactate at admission (n = 2), BMI (n = 27), SAPS (n = 2). Length of ICU stay for patients still admitted to the ICU after 30 days was registered as 30 days (n = 4). Patients who died during ICU admission (n = 36) were excluded from the length of stay calculation to prevent survivor bias. Further, there are missing SOFA score component values on five patients and a score of 0 was imputed for missing variables.

Table 2 Routine laboratory measurements on day 1 of intensive care unit admission

	Reference interval	Non-AKI	AKI stage 1	AKI stage 2	AKI stage 3	CKD stages 3–5
Lactate (mmol/L)	0.5–2.5	1.2 (0.9–1.7)	1.2 (0.9–1.9)	1.6 (1.1–2.7)	2.0 (1.2–3.2)	1.2 (0.8–1.9)
Bilirubin (µmol/L)	5–25	13 (9–18)	14 (10–21)	13 (10–24)	20 (13–33)	12 (7–19)
Albumin (g/L)	36–48	30 (26–34)	31 (28–34)	30 (27–33)	30 (25–34)	31 (27–33)
Creatinine (µmol/L)	45–105*	73 (56–88)	89 (77–111)	99 (76–135)	178 (152–268)	175 (137–231)
Urea (mmol/L)	2.6–8.1*	5.5 (4.1–7.6)	7.0 (5.6–8.8)	8.6 (7.0–11.9)	11.6 (9.0–17.3)	13.2 (9.4–20.7)
eGFR (mL/min/1.73 m2)	>60	89 (75–91)	63 (53–87)	56 (35–77)	28 (20–39)	29 (22–41)
C-reactive protein (mg/L)	<8.0	54.0 (15.4–149.3)	43.8 (18.8–137.0)	112.2 (40.0–206.8)	115.9 (56.1–265.3)	58.3 (23.7–153.7)
Leukocyte count (109/L)	3.5–10.0	10.8 (8.7–13.8)	12.4 (8.5–16.9)	12.7 (9.0–17.2)	14.4 (11.1–21.2)	12.0 (9.0–16.4)
Hemoglobin (mmol/L)	7.3–10.5*	7.2 (6.1–7.8)	6.8 (6.1–7.7)	6.5 (5.7–7.1)	7.1 (5.7–7.8)	6.6 (5.9–7.5)
Platelet count (109/L)	145–400*	231 (172–281)	214 (167–281)	208 (120–291)	208 (153–261)	215 (160–287)
Mean platelet volume, MPV (fL)	6.5–11.0	10.3 (9.4–11.0)	10.2 (9.8–10.7)	10.4 (9.7–11.1)	10.4 (9.8–11.1)	10.5 (10.1–11.3)
Immature platelet fraction	0.016–0.126	0.047 (0.027–0.065)	0.046 (0.034–0.069)	0.049 (0.036–0.079)	0.055 (0.031–0.078)	0.046 (0.030–0.066)
International normalized ratio, INR	<1.2	1.2 (1.1–1.3)	1.2 (1.1–1.3)	1.3 (1.2–1.4)	1.3 (1.1–1.5)	1.2 (1.1–1.3)
Activated partial thromboplastin time, aPTT (s)	20–29	25 (22–29)	26 (23–28)	27 (26–33)	29 (25–37)	25 (23–29)
Antithrombin (103 IU/L)	0.80–1.20	0.85 (0.77–0.96)	0.83 (0.71–0.95)	0.80 (0.67–0.93)	0.64 (0.58–0.83)	0.9 (0.8–1.0)
Fibrinogen (µmol/L)	5.5–12.0	11.7 (9.0–15.2)	11.3 (8.5–13.5)	12.6 (9.3–15.0)	12.1 (7.3–15.4)	13.2 (10.2–17.4)
Fibrin D-dimer (mg/L FEU)	<0.5	2.4 (1.0–4.5)	3.2 (1.0–9.5)	3.6 (2.0–9.2)	8.4 (3.8–20.1)	3.1 (1.1–7.4)

Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; FEU, fibrinogen equivalent unit; IU, international units.

Notes: Reported as medians (interquartile range). The following has missing data: bilirubin (n = 4), albumin (n = 3), creatinine (n = 3), eGFR (n = 3), C-reactive protein (n = 3), leukocyte count (n = 3), hemoglobin (n = 6), mean platelet volume (n = 14).

*Reference interval contains both females and males.

Compared with AKI patients, CKD patients were older (median age 76 years), predominantly male (69%), and had higher prevalences of comorbidities, including hypertension, diabetes, ischemic heart disease, and heart failure. This group had the highest 30-day mortality (38%) of all groups.

 

Scroll to top

 

Scroll to top

Rotem-tPA Results

Fibrinolysis in Patients with Normal Renal Function and Acute Kidney Injury

Higher stages of AKI were associated with progressively impaired fibrinolysis, and stage 3 AKI patients showed significant impairment across all fibrinolysis parameters compared with non-AKI patients ([Fig. 2] and [Supplementary Table S1]). In non-AKI patients, a lysis time above the 97.5th percentile of the 38 healthy individuals (50 minutes[28]) was observed in 42%. This was seen in 54% of patients with AKI stage 1, 72% with stage 2, and 85% with stage 3, demonstrating an increasing prevalence of impaired fibrinolysis with increasing severity of AKI. Furthermore, maximum lysis and fibrinolysis speed were significantly lower, and lysis onset time, lysis index 45, and t-AUCi were significantly higher in stage 3 AKI patients versus non-AKI patients, indicating an overall impaired fibrinolysis in these patients. CT was significantly longer in AKI stage 3 patients versus non-AKI patients; however, no significant differences between these patients were observed in MCF or MaxV.

We performed a subgroup analysis excluding patients who had sepsis at the time of blood sampling. The results are shown in [Supplementary Fig. S1]. Patients with AKI stage 3 still had significantly impaired fibrinolysis across every fibrinolysis parameter compared with patients with non-AKI when excluding sepsis patients. No differences were observed in CT, MCF, or MaxV between the groups.

In conclusion, increasing AKI severity in ICU patients was associated with progressively impaired fibrinolysis in the ROTEM-tPA analysis, whereas coagulation parameters remained largely unchanged.

 

Scroll to top

Patients with Chronic Kidney Disease and Acute-on-chronic Renal Failure

ROTEM-tPA results of patients with CKD stages 3 to 5 and ACRF ≤stage 1 (CKD non-ACRF + ACRF stage 1) showed impaired fibrinolysis across all parameters compared with patients with normal renal function; however, a significant difference was only seen in maximum lysis, lysis onset time, and t-AUCi ([Fig. 2] and [Supplementary Table S1]). When excluding sepsis patients, the difference was no longer significant ([Supplementary Fig. S1]). The reduction in fibrinolysis was slightly more pronounced in CKD patients with ACRF stages 2 to 3 than in patients with ACRF ≤stage 1, but not significantly. The coagulation parameters CT, MCF, and MaxV were significantly increased in patients with ACRF stages 2 to 3 compared with patients with normal renal function. No significant difference was found in CKD patients with ACRF ≤stage 1 compared with the other groups.

 

Scroll to top

Bleeding in Acute Kidney Injury Patients

To investigate fibrinolysis in patients with AKI-related bleeding, we compared ROTEM-tPA results in patients with AKI stages 2 to 3 (n = 106), stratified by a WHO bleeding score ≥2 within the 7 days following admission to the ICU ([Fig. 4]). A bleeding score ≥2 was observed in 61 of the 106 AKI stage 2 to 3 patients. Of these, 82% had a score of 2, 15% a score of 3, and 3% a score of 4. The most common presentation of grade 2 bleeding was bleeding at invasive sites (57%), visible blood in body cavity fluid (21%), hemoptysis (18%), and macroscopic hematuria (16%). Of the 106 patients with AKI stages 2 to 3, 20% died within 7 days (17% of stage 2 and 23% of stage 3).

Fig. 4 Coagulation and fibrinolysis parameters measured by ROTEM-tPA in patients with acute kidney injury stages 2 and 3, stratified by the occurrence of bleeding within the 7 days following admission to the intensive care unit. Boxes show the medians and interquartile ranges, and whiskers represent the 2.5th and the 97.5th percentiles. p-values were calculated with the Mann-Whitney test.

In both groups, a lysis time above 3,000 seconds (the 97.5th percentile of the 38 healthy individuals[28]) was seen in the majority of patients (67% of non-bleeding patients versus 87% of bleeding patients). Thus, hypofibrinolysis was present in most patients; however, those who experienced bleeding showed a more pronounced impairment of fibrinolysis compared with patients who did not bleed. The difference was only statistically significant in lysis time. No difference was observed in the coagulation parameters CT, MCF, and MAXV between the two groups.

 

Scroll to top

Thrombosis in Acute Kidney Injury Patients

To investigate the association between fibrinolytic abnormalities and thrombosis in patients with AKI, we compared ROTEM-tPA results in AKI patients who developed VTE within 30 days of ICU admission (n = 12) with AKI patients who did not develop VTE (n = 148).

Both groups exhibited impaired fibrinolysis, with a lysis time above 3,000 seconds in 83% of VTE patients versus 60% of non-VTE patients. Across all fibrinolysis parameters, VTE patients demonstrated greater fibrinolytic impairment than non-VTE patients, although the difference was only statistically significant for maximum lysis and lysis index 45 ([Supplementary Fig. S2]). This is in accordance with previous results from our group from a mixed ICU cohort, shown by Brewer et al[31]; it should be noted that some of the patients included in the study by Brewer et al were also included in the present study. No difference was observed in the coagulation parameters between the two groups.

 

Scroll to top

 

Scroll to top

Platelet Function in Acute Kidney Injury

Platelet aggregation was significantly reduced in patients with AKI stage 3 compared with non-AKI patients when using ADP as the agonist, but not when using AA or TRAP ([Supplementary Fig. S3]). The difference remained significant for ADP when adjusting for platelet count. However, after adjusting for the use of antiplatelet therapy within the past 10 days of blood sampling, no differences were observed between any of the groups.

In patients with AKI stages 2 to 3, a significantly reduced platelet aggregation was observed in bleeding patients compared with non-bleeding patients when using ADP and AA as agonists, but not when using TRAP ([Supplementary Fig. S4]). No difference was seen after adjusting for platelet count and the use of antiplatelet therapy.

In conclusion, AKI and AKI-related bleeding were not associated with reduced platelet function in ICU patients.

 

Scroll to top

Association between Clinical Characteristics and Bleeding in Patients with Acute Kidney Injury

[Table 3] summarizes the clinical characteristics of patients with AKI stages 2 to 3 and with ACRF stages 2 to 3, stratified by the occurrence of bleeding (WHO score ≥2) during the first 7 days in the ICU. The parameters displayed in [Table 3] were assessed for association with bleeding in a univariate analysis (except VTE occurrence and 30-day mortality), and the following four parameters showed a significant association with bleeding: non-renal SOFA score (OR for bleeding 1.21 [95%CI 1.08–1.39] pr. 1 point increase in SOFA score, p < 0.01); treatment with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) in therapeutic dose during the first 24 hours of admission (OR 3.67 [95%CI 1.41–10.85], p = 0.01); mean platelet volume (MPV) (OR 1.67 [95%CI 1.06–2.72] per 1 fL increase); ROTEM-tPA LT (OR 1.04 [95%CI 1.00–1.09] per 1 minute increase) ([Supplementary Table S2]). In multivariate analysis including these four parameters, only non-renal SOFA score remained statistically significant (OR: 1.21 [95%CI 1.04–1.42] per 1 point increase in SOFA score, p = 0.01). The use of UFH or therapeutic LMWH was still associated with an OR of 2.1 for bleeding, though no longer statistically significant ([Table 4]).

Table 3 Clinical characteristics and routine laboratory measurements on day 1 of ICU admission in patients with acute kidney injury stages 2 to 3, and chronic kidney disease with and without acute-on-chronic renal failure, stratified by the occurrence of bleeding within the 7 days following admission

	Patients who developed AKI stage 2 or 3 within +/− 48 hours of the blood sample obtained on day 1		CKD patients who developed ACRF stage 2 or 3 within +/− 48 hours of the blood sample obtained on day 1
	Non-bleeding (WHO bleeding score ≤1 within 7 days of ICU admission) (n = 45)	Bleeding (WHO bleeding score ≥2 within 7 days of ICU admission) (n = 61)	Non-bleeding (WHO bleeding score ≤1 within 7 days of ICU admission) (n = 10)	Bleeding (WHO bleeding score ≥2 within 7 days of ICU admission) (n = 8)
Demographics
Age, y	69 (52–74)	71 (57–75)	81 (66–86)	74 (65–79)
Female sex	23 (51%)	21 (34%)	1 (10%)	3 (38%)
BMI, kg/m2	27 (22–28)	26 (23–30)	29 (26–37)	30 (24–40)
Illness severity and sepsis
Non-renal SOFA score day 1	6 (4–10)	9 (7–11)	8 (5–9)	11 (10–12)
Sepsis on day 1	20 (44%)	22 (36%)	4 (40%)	4 (50%)
ISTH DIC score day 1	3 (2–4)	3 (2–5)	3 (2–4)	3 (2–4)
Interventions and medication before blood sample obtained on day 1
Renal replacement therapy (24 hour)	2 (4%)	5 (8%)	0 (0%)	1 (13%)
ECMO (24 hour)	2 (4%)	10 (16%)	0 (0%)	0 (0%)
Major surgery (7 days)	9 (20%)	15 (25%)	3 (30%)	1 (13%)
Platelet inhibitors (10 days)	10 (22%)	18 (30%)	5 (50%)	3 (38%)
Vitamin K antagonists (14 days)	0 (0%)	2 (3%)	0 (0%)	2 (25%)
Direct oral anticoagulants (3 days)	6 (13%)	7 (11%)	3 (30%)	1 (13%)
Heparins
Low molecular weight, prophylactic dose (24 hours)	10 (22%)	12 (20%)	2 (20%)	3 (38%)
Low molecular weight, therapeutic dose (24 hours)	3 (7%)	7 (11%)	0 (0%)	1 (13%)
Unfractionated (24 hours)	3 (7%)	15 (25%)	1 (10%)	0 (0%)
No heparin (24 hours)	30 (67%)	28 (46%)	7 (70%)	4 (50%)
Routine laboratory measurements on day 1 of intensive care unit admission
Platelet count (109/L)	226 (164–304)	190 (120–264)	228 (175–255)	219 (190–314)
Mean platelet volume, MPV (fL)	10.2 (9.6–10.9)	10.5 (10.1–11.3)	10.9 (10.5–11.5)	10.5 (10.3–10.7)
Immature platelet fraction	0.045 (0.027–0.071)	0.055 (0.038–0.080)	0.043 (0.031–0.079)	0.050 (0.035–0.065)
International normalized ratio, INR	1.3 (1.2–1.5)	1.3 (1.1–1.5)	1.2 (1.0–1.4)	1.2 (1.1–1.8)
Activated partial thromboplastin time, aPTT (s)	28 (26–32)	30 (25–37)	25 (22–28)	34 (29–42)
Antithrombin (IU/L)	0.77 (0.65–0.92)	0.69 (0.58–0.87)	0.90 (0.82–1.05)	0.86 (0.78–0.94)
Fibrinogen (µmol/L)	12.8 (9.9–15.0)	12.0 (7.5–15.4)	16.7 (13.1–19.5)	13.9 (12.9–18.6)
Fibrin D-dimer (mg/L FEU)	5.0 (2.0–14.1)	5.2 (2.6–16.2)	3.6 (1.6–5.3)	4.7 (2.6–6.4)
Events and mortality
Occurrence of VTE (within 30 days of ICU admission)	3 (7%)	7 (11%)	0 (0%)	0 (0%)
Mortality (within 30 days of ICU admission)	8 (18%)	24 (39%)	7 (70%)	5 (63%)

Abbreviations: ACRF, acute-on-chronic renal failure; AKI, acute kidney injury; BMI, body mass index; CKD, chronic kidney disease; DIC, disseminated intravascular coagulation; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; FEU, fibrinogen equivalent unit; ISTH, International Society on Thrombosis and Haemostasis; IU, international units; SOFA, sequential organ failure assessment; VTE, venous thromboembolism; WHO, World Health Organization.

Notes: Reported as medians (interquartile range). The following has missing data: BMI (n = 16), SAPS (n = 1), mean platelet volume (n = 9).

Table 4 Odds ratio for bleeding during the first 7 days in patients with AKI stages 2 to 3 in the intensive care unit with a multivariate logistic regression model

Parameter	OR (95% CI)	p
Non-renal SOFA score day 1, per 1 point increase	1.208 (1.043–1.417)	0.01
LMWH (therapeutic dose) or UFH (within 24 hours)	2.122 (0.706–6.954)	0.19
MPV on day 1, per 1 fL increase	1.410 (0.858–2.373)	0.18
LT, per 1 minute increase	1.025 (0.984–1.070)	0.24

Abbreviations: CI, confidence interval; LMWH, low-molecular-weight heparin; LT, lysis time; MPV, mean platelet volume; OR, odds ratio; SOFA, sequential organ failure assessment; UFH, unfractionated heparin.

 

Scroll to top

Discussion

The present study found that the fibrinolytic capacity in ICU patients with AKI was significantly impaired compared with ICU patients with normal renal function. Notably, these results were independent of the presence of sepsis, which has previously been associated with impaired fibrinolysis.[31] Furthermore, despite the impaired fibrinolysis, AKI patients experienced more bleeding events within the first 7 days of ICU admission.

Few studies have previously investigated the fibrinolytic changes in AKI. In line with our results, Larsson et al[13] studied the fibrinolytic system in 18 patients with acute uremia and found a decreased fibrinolytic activity in these patients. Similar findings were reported by Malyszko et al[11] who included 17 patients requiring dialysis for acute renal failure and compared them with healthy controls. Both studies reported increased levels of plasminogen activator inhibitors in AKI patients, suggesting a potential mechanism underlying the impaired fibrinolysis. None of the previous studies included critically ill non-AKI patients as controls, and all were characterized by relatively small sample sizes. In addition, they utilized plasma-based assays to assess fibrinolytic capacity, potentially overlooking important cellular interactions. We extend previous findings by including a large cohort of ICU patients with and without AKI and by using a modified viscoelastic whole-blood analysis to provide a global assessment of the fibrinolytic system in AKI-related bleeding.

Zanetto et al[10] investigated different aspects of hemostasis in 80 patients with decompensated cirrhosis with and without AKI (40 patients in each group). Cirrhosis patients with AKI showed mixed hypofibrinolytic (lower plasminogen and increased levels of activated–inactivated thrombin activatable fibrinolysis inhibitor) and hyperfibrinolytic (lower antiplasmin and increased tPA and plasmin–antiplasmin complex) alterations compared with cirrhosis patients without AKI. They proposed that cirrhosis patients with AKI were characterized by an overall state of hyperfibrinolysis, but observed impaired fibrinolysis when comparing 10 AKI patients without liver disease with healthy controls. Their findings of hyperfibrinolysis in AKI are confined to cirrhotic patients and cannot be directly extrapolated to our ICU cohort with AKI, in which only a few patients had cirrhosis.

CKD has previously been associated with hypofibrinolysis.[11] [14] Our results support this, as the fibrinolytic alterations observed in patients with AKI were similar to those seen in patients with CKD. However, the degree of fibrinolytic impairment in CKD and ACRF was less pronounced than in AKI, and not all fibrinolytic parameters reached statistical significance, indicating a more substantial disruption of the fibrinolytic system in the context of acute injury to otherwise normal renal function. An increased inflammatory response in AKI may contribute to the pathophysiology of this finding.

Consistent with previous research, we found that AKI was associated with an increased prevalence of bleeding risk. However, AKI patients who experienced bleeding showed significantly impaired fibrinolysis compared with non-bleeding patients, suggesting that the fibrinolytic system may not be the driver of AKI-related bleeding. On the contrary, hypofibrinolysis may be an adaptive response to an increased bleeding tendency in AKI, potentially driven by endothelial dysfunction triggering the release of fibrinolysis inhibitors. Moreover, in agreement with Jensen et al,[4] we found that AKI and AKI-related bleeding was not associated with reduced platelet aggregation or thrombocytopenia in ICU patients, indicating that the increased bleeding frequency is not driven by platelet dysfunction. The ROTEM-tPA coagulation parameters CT, MCF, and MaxV were closely aligned with the established reference values for standard EXTEM, thus providing no clinically relevant explanation for the increased bleeding tendency in AKI. These findings indicate that the pathophysiology of the increased bleeding in AKI may be independent of the hemostatic system. Rather, bleeding may be attributed to marked inflammation as seen in other critically ill patients.[32]

As bleeding was not associated with coagulation dynamics, decreased platelet function, or increased fibrinolysis, we performed a multivariate regression analysis and found that bleeding in AKI patients correlated with severity of illness. We observed a 20% increase in bleeding risk for each point increase in non-renal SOFA score. This indicates that critical illness itself, regardless of the underlying cause or the presence of AKI, is associated with an increased risk of bleeding. Consequently, bleeding in AKI may primarily reflect critical illness rather than hemostatic failure. Additionally, therapeutic doses of LMWH and UFH further increased the risk of bleeding, although not statistically significant. These findings suggest that the general bleeding risk associated with therapeutic LMWH and UFH increases with the severity of illness.

Patients with AKI stages 2 to 3 had a three times higher 30-day mortality compared with patients with normal renal function. CKD patients had a four times higher mortality, which can potentially be attributed to baseline differences in age and comorbidities. Further, mortality was markedly higher in AKI patients who experienced bleeding compared with non-bleeding patients, emphasizing the seriousness of AKI-related bleeding. Notably, the risk of venous thrombosis was increased in patients with AKI stage 3 and AKI patients who experienced bleeding, indicating a complex hemostatic derangement with both hypo- and hypercoagulable features that complicates treatment strategies in these patients. The increased risk of VTE in AKI may in part be driven by fibrinolytic impairment. AKI patients who developed VTE within 30 days of ICU admission showed a more pronounced impairment of fibrinolysis compared with AKI patients without VTE. This was previously demonstrated by our research group, where impaired fibrinolysis on day 1 of ICU admission was linked with increased risk of VTE in an overall ICU cohort.[31]

Key strengths of this study are a large, diverse ICU cohort, a comprehensive collection of clinical and biochemical data, including bleeding and thrombosis, and a global evaluation of fibrinolysis using ROTEM-tPA. Additionally, we stratified patients by consensus AKI criteria, separating mild and severe AKI. However, some limitations must be considered. In several cases, information on renal function for the days immediately preceding hospitalization was unavailable (17% of AKI stage 1, 19% of stage 2, and 40% of stage 3). Some of these patients may have developed AKI more than 48 hours before the blood sample was obtained on day 1 of ICU admission. Consequently, the impaired fibrinolysis observed in AKI stage 3 could partly reflect a longer duration of AKI. When no baseline creatinine was available, it was estimated using an adaptation of the MDRD equation. This approach might misclassify some cases of AKI; however, it is unlikely to incorrectly classify stage 1 AKI as stage 2 or 3.[17] We included patients who fulfilled AKI criteria +/− 48 hours within blood sampling so as not to misclassify any AKI patients as non-AKI, since changes in creatinine following AKI may be delayed. This could theoretically mean that some AKI patients had not yet developed AKI at the time of blood sampling; however, 94% of patients fulfilled the AKI criteria before or at the time of blood sampling. Bleeding was defined according to WHO bleeding scale and patients' journals were used to identify bleeding incidents. This is dependent on clinician interpretation, and there may be an underreporting of bleeding incidence in patients' journals. Further, as 20% of patients with AKI stages 2 to 3 died within 7 days, bleeding could be underreported in the most critically ill patients due to survivorship bias. The occurrence of VTE may also be underreported, as routine ultrasound screening was not performed; on the other hand, this ensured that we only included symptomatic, clinically significant VTE events. Moreover, when comparing groups with different renal functions, we did not account for the severity of critical illness as a potential confounder. Extracorporeal membrane oxygenation (ECMO) was more common among AKI patients than non-AKI patients. ECMO is a well-established risk factor for bleeding, involving multiple mechanisms such as anticoagulation therapy, coagulopathy, and platelet abnormalities, and may therefore have confounded the observed association between AKI and bleeding.[33] Several hemostatic markers were not included in this study, for instance, different coagulation factors and pro- and antifibrinolytic proteins such as tPA and plasminogen activator inhibitor-1 (PAI-1). Further research could include these when investigating AKI-related bleeding to identify potential therapeutic targets.

 

Scroll to top

Conclusion

This study demonstrates that AKI in ICU patients is associated with an increased risk of bleeding and higher 30-day mortality. ROTEM-tPA shows impaired fibrinolysis in AKI patients and therefore cannot explain AKI-related bleeding. Rather, bleeding risk in AKI patients seems to be influenced mainly by severity of illness and anticoagulant use.

 

Scroll to top

 

Scroll to top

Conflict of Interest

R.R.M., T.G., and C.L.H. declare no conflicts of interest. J.B.L. has no conflicts of interest pertaining to the present paper, but has the following general conflicts of interest: Has received lecture honoraria from Bristol-Myers Squibb and Merck (payment made to her institution).

Acknowledgments

The authors gratefully acknowledge Vivi Bo Mogensen and Tine Kusk Jørgensen for their invaluable support and assistance in the laboratory.

• References

• 1 Hoste EA, Bagshaw SM, Bellomo R. et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med 2015; 41 (08) 1411-1423
• 2 Levey AS, James MT. Acute kidney injury. Ann Intern Med 2017; 167 (09) ITC66-ITC80
• 3 Zarka F, Tayler-Gomez A, Ducruet T. et al. Risk of incident bleeding after acute kidney injury: a retrospective cohort study. J Crit Care 2020; 59: 23-31
• 4 Jensen JLS, Hviid CVB, Hvas CL, Christensen S, Hvas AM, Larsen JB. Platelet function in acute kidney injury: a systematic review and a cohort study. Semin Thromb Hemost 2023; 49 (05) 507-522
• 5 Hung A, Garcia-Tsao G. Acute kidney injury, but not sepsis, is associated with higher procedure-related bleeding in patients with decompensated cirrhosis. Liver Int 2018; 38 (08) 1437-1441
• 6 Wu PC, Wu CJ, Lin CJ, Wu VC. National Taiwan University Study Group on Acute Renal Failure Group. Long-term risk of upper gastrointestinal hemorrhage after advanced AKI. Clin J Am Soc Nephrol 2015; 10 (03) 353-362
• 7 Decousus H, Tapson VF, Bergmann JF. et al; IMPROVE Investigators. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 2011; 139 (01) 69-79
• 8 Vigneron C, Devautour C, Charpentier J, Birsen R, Jamme M, Pène F. Severe bleeding events among critically ill patients with haematological malignancies. Ann Intensive Care 2024; 14 (01) 155
• 9 Barea-Mendoza JA, Chico-Fernández M, Molina-Díaz I. et al; Neurointensive Care and Trauma Working Group of the Spanish Society of Intensive Care Medicine (SEMICYUC). Risk factors associated with early and late posttraumatic multiorgan failure: an analysis from RETRAUCI. Shock 2021; 55 (03) 326-331
• 10 Zanetto A, Rinder HM, Campello E. et al. Acute kidney injury in decompensated cirrhosis is associated with both hypo-coagulable and hyper-coagulable features. Hepatology 2020; 72 (04) 1327-1340
• 11 Malyszko J, Malyszko JS, Pawlak D, Pawlak K, Buczko W, Mysliwiec M. Hemostasis, platelet function and serotonin in acute and chronic renal failure. Thromb Res 1996; 83 (05) 351-361
• 12 Wiegele M, Infanger L, Lacom C, Koch S, Baierl A, Schaden E. Thrombin generation and platelet function in ICU patients undergoing CVVHD using regional citrate anticoagulation. Front Med (Lausanne) 2021; 8: 680540
• 13 Larsson SO, Hedner U, Nilsson IM. On coagulation and fibrinolysis in acute renal insufficiency. Acta Med Scand 1971; 189 (06) 443-451
• 14 Mörtberg J, Blombäck M, Wallén Å, He S, Jacobson SH, Spaak J. Increased fibrin formation and impaired fibrinolytic capacity in severe chronic kidney disease. Blood Coagul Fibrinolysis 2016; 27 (04) 401-407
• 15 Olesen JB, Lip GY, Kamper AL. et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012; 367 (07) 625-635
• 16 Kellum JA, Lameire N, Aspelin P. et al. Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012; 2 (01) 1-138
• 17 Závada J, Hoste E, Cartin-Ceba R. et al; AKI6 investigators. A comparison of three methods to estimate baseline creatinine for RIFLE classification. Nephrol Dial Transplant 2010; 25 (12) 3911-3918
• 18 Jiang J, Zhang J, Liu Y, Xu D, Peng Z. Urine output calculated using actual body weight may result in overestimation of acute kidney injury for obese patients. Shock 2021; 56 (05) 737-743
• 19 Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute Dialysis Quality Initiative workgroup. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8 (04) R204-R212
• 20 Ali T, Khan I, Simpson W. et al. Incidence and outcomes in acute kidney injury: a comprehensive population-based study. J Am Soc Nephrol 2007; 18 (04) 1292-1298
• 21 Stevens PE, Levin A. Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med 2013; 158 (11) 825-830
• 22 Harris PA, Taylor R, Minor BL. et al; REDCap Consortium. The REDCap consortium: building an international community of software platform partners. J Biomed Inform 2019; 95: 103208
• 23 Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42 (02) 377-381
• 24 Singer M, Deutschman CS, Seymour CW. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315 (08) 801-810
• 25 Moreno RP, Metnitz PG, Almeida E. et al; SAPS 3 Investigators. SAPS 3—From evaluation of the patient to evaluation of the intensive care unit. Part 2: Development of a prognostic model for hospital mortality at ICU admission. Intensive Care Med 2005; 31 (10) 1345-1355
• 26 Taylor Jr FB, Toh CH, Hoots WK, Wada H, Levi M. Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86 (05) 1327-1330
• 27 Kaufman RM, Djulbegovic B, Gernsheimer T. et al; AABB. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2015; 162 (03) 205-213
• 28 Larsen JB, Hvas CL, Hvas AM. Modified rotational thromboelastometry protocol using tissue plasminogen activator for detection of hypofibrinolysis and hyperfibrinolysis. Methods Mol Biol 2023; 2663: 763-773
• 29 Scarlatescu E, Kim PY, Marchenko SP, Tomescu DR. Validation of the time to attain maximal clot amplitude after reaching maximal clot formation velocity parameter as a measure of fibrinolysis using rotational thromboelastometry and its application in the assessment of fibrinolytic resistance in septic patients: a prospective observational study: communication from the ISTH SSC Subcommittee on Fibrinolysis. J Thromb Haemost 2024; 22 (04) 1223-1235
• 30 Kuiper GJ, Kleinegris MC, van Oerle R. et al. Validation of a modified thromboelastometry approach to detect changes in fibrinolytic activity. Thromb J 2016; 14: 1
• 31 Brewer JS, Hvas CL, Hvas AM, Larsen JB. Impaired whole-blood fibrinolysis is a predictor of mortality in intensive care patients. TH Open 2024; 8 (01) e164-e174
• 32 Stravitz RT, Ellerbe C, Durkalski V. et al; Acute Liver Failure Study Group. Bleeding complications in acute liver failure. Hepatology 2018; 67 (05) 1931-1942
• 33 Thomas J, Kostousov V, Teruya J. Bleeding and thrombotic complications in the use of extracorporeal membrane oxygenation. Semin Thromb Hemost 2018; 44 (01) 20-29

Publication History

Received: 19 September 2025

Accepted: 22 September 2025

Accepted Manuscript online:
13 October 2025

Article published online:
29 October 2025