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.
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.
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.
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.
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 FSc 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).
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.
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.
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).
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.
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.
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.
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.
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.
Platelet Function in Acute Kidney Injury
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.
Association between Clinical Characteristics and Bleeding in Patients with Acute Kidney
Injury
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.
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.
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.
What is Known About this Topic?
-
AKI is common in ICU patients and associated with higher bleeding risk.
-
The underlying pathophysiology of AKI-related bleeding is poorly understood.
-
The fibrinolytic system has only been sparsely investigated in AKI.
What Does this Paper Add?
-
Assesses fibrinolysis in AKI in a large ICU cohort using a modified rotational thromboelastometry
(ROTEM-tPA) assay.
-
Demonstrates that fibrinolysis is impaired in AKI and cannot explain AKI-related bleeding.
-
Suggests that bleeding risk in AKI is influenced mainly by severity of illness and
use of therapeutic LMWH and UFH.
Bibliographical Record
Rasmus R. Mikkelsen, Christine L. Hvas, Tua Gyldenholm, Julie Brogaard Larsen. Fibrinolytic
Capacity and Risk of Bleeding in Intensive Care Patients with Acute Kidney Injury.
TH Open 2025; 09: a27199152.
DOI: 10.1055/a-2719-9152
