
==== Front
Res Pract Thromb Haemost
Res Pract Thromb Haemost
Research and Practice in Thrombosis and Haemostasis
2475-0379
Elsevier

S2475-0379(24)00215-2
10.1016/j.rpth.2024.102520
102520
Brief Report
Spontaneous bleeding in chronic kidney disease: global coagulation assays may predict bleeding risk
Brook Rowena rowena.brook@nh.org.au
1234∗
Wang Julie 1234
Barit David 5
Ho Prahlad 1234
Lim Hui Yin 1234
1 Northern Clinical Diagnostics & Thrombovascular Research (NECTAR), Northern Health, Epping, Victoria, Australia
2 Haematology Department, Northern Health, Epping, Victoria, Australia
3 Northern Pathology Victoria, Epping, Victoria, Australia
4 Department of Medicine, Northern Health, University of Melbourne, Melbourne, Victoria, Australia
5 Renal Department, Northern Health, Epping, Victoria, Australia
∗ Correspondence Rowena Brook, Haematology Department, Northern Health, 185 Cooper Street, Epping, VIC 3076, Australia. rowena.brook@nh.org.au
22 7 2024
7 2024
22 7 2024
8 5 10252021 4 2024
20 6 2024
10 7 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

Chronic kidney disease (CKD) is associated with increased bleeding and thrombotic risks. Standard blood tests do not sufficiently quantify these risks. Global coagulation assays (GCAs) provide a more comprehensive assessment of coagulation.

Objectives

We aimed to evaluate if GCAs are predictive of spontaneous major bleeding (sMB) in CKD.

Methods

Adult patients with CKD (estimated glomerular filtration rate, <30 mL/min/1.73m2) were recruited to this pilot prospective observational study. Testing with GCAs (thromboelastography, overall hemostatic potential, calibrated automated thrombogram, and plasminogen activator inhibitor-1) was performed, and the results were correlated to sMB events.

Results

Eighty-seven CKD patients (median age, 67 years; 67.8% male) were included, with median follow-up of 3.1 years. CKD patients demonstrated elevated fibrinogen, factor VIII, and von Willebrand factor antigen levels, while other conventional coagulation test results were within reference intervals. Ten episodes of sMB (11.5%) were captured (3.0/100 person-years), with no significant association demonstrated between sMB and antiplatelet use (P = .36), platelet count (P = .14), or renal function (urea, P = .27; estimated glomerular filtration rate, P = .09). CKD patients with sMB had more hypocoagulable GCA parameters compared with those without sMB. The lowest quartiles of endogenous thrombin potential (subhazard ratio [sHR], 7.11; 95% CI, 1.84-27.45), overall hemostatic potential (sHR, 6.81; 95% CI, 1.77-26.16), and plasminogen activator inhibitor-1 (sHR, 5.26; 95% CI, 1.55-17.91) were associated with sMB.

Conclusion

This pilot study demonstrates that GCAs such as thrombin and fibrin generation may predict sMB risk in patients with CKD, which has potential to be practice-changing. Larger studies are required to validate these findings.

Essentials

• Chronic kidney disease (CKD) patients are at increased risk of bleeding and thrombotic events.

• Global coagulation assays and plasminogen activator inhibitor-1 quantification were performed.

• CKD patients had baseline testing with follow-up for spontaneous major bleeding events.

• Key hypocoagulable global coagulation assay parameters and plasminogen activator inhibitor-1 were associated with future spontaneous major bleeding events in CKD.

Keywords

chronic kidney disease
coagulation
fibrin
global coagulation assays
hemorrhage
plasminogen activator inhibitor 1
thrombin
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pmc1 Introduction

A major challenge in managing chronic kidney disease (CKD) is the delicate balance between hypercoagulability and bleeding risk. Up to half of patients with advanced-stage CKD have cardiovascular disease, with cardiovascular mortality accounting for 40% to 50% of all deaths [1]. Paradoxically, patients with CKD also have an up to 35% increased risk of bleeding [2]. This clinical conundrum is compounded by the frailty of these patients and because management of cardiovascular disease often involves antiplatelets and/or anticoagulants, and yet, there are no accurate clinical tools to predict individual risk of bleeding [3].

Basic coagulation tests such as prothrombin time and activated partial thromboplastin time measure the time to commencement of clot formation, capturing only approximately 5% of thrombin formation, providing an incomplete coagulation assessment [4]. These tests, designed for specific clinical contexts such as monitoring anticoagulation, are inadequate to predict general bleeding risks [5]. Platelet dysfunction, resulting in abnormal platelet-platelet and platelet-vessel wall interactions secondary to the effects of uremia and anemia, is frequently considered the most important contributor to renal bleeding [6]. However, studies to date exploring platelet function in CKD have reported heterogeneous results and have not linked platelet function testing results to clinical outcomes [7].

Global coagulation assays (GCAs) measuring thrombin and fibrin generation provide a more comprehensive assessment of clot formation and lysis [8]. Although viscoelastic testing is already used clinically in transfusion settings [9], GCAs have not been collectively studied to assess bleeding risk. GCAs appear to discriminate between healthy and hypercoagulable populations such as CKD and type 2 diabetes [10,11], and we have shown that GCAs are predictive of arterial thrombosis in dialysis patients [12]. We hypothesize that GCAs may provide a superior prediction of individual bleeding risk compared with standard blood tests. Using a pilot prospective observational study, we aimed to assess the utility of GCAs in predicting risk of spontaneous major bleeding (sMB) in CKD.

2 Methods

Adult patients aged ≥18 years with estimated glomerular filtration rate <30 mL/min/1.73m2 were recruited from renal outpatients and dialysis centers at Northern Health, Victoria, Australia, between March 2017 and July 2021. Exclusion criteria included patients with active malignancy or on therapeutic anticoagulation (unfractionated heparin/enoxaparin administration during hemodialysis [HD] was allowed). Informed consent was obtained from participants. This study was approved by the Austin Health Human Research Ethics Committee (HREC/Austin/16/459).

At the time of recruitment, a baseline clinical assessment was performed, and blood samples were collected for routine laboratory testing including full blood count, renal and liver function, and coagulation panels. Additional citrated plasma was collected for GCAs including viscoelastic testing with thromboelastography (TEG); calibrated automated thrombogram (CAT), which measures thrombin generation; overall hemostatic potential (OHP), which measures fibrin generation along with fibrinolytic potential; and human plasminogen activator inhibitor-1 (PAI-1) antigen level (using human PAI-1 total antigen assay enzyme-linked immunosorbent assay kit, Molecular Innovations). TEG was performed within 4 hours on whole blood while remaining plasma was double centrifuged at 2500g for 10 minutes to obtain platelet-poor plasma (PPP) stored at −80 °C for batch testing of CAT, OHP, and PAI-1. Figure 1 describes the GCAs in detail and key reported parameters. The primary outcome was sMB events (as per the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee definition) [13].Figure 1 Explanation of global coagulation assays. CAT, calibrated automated thrombogram; ETP, endogenous thrombin potential; MA, maximum amplitude; OCP, overall coagulation potential; OFP, overall fibrinolytic potential; OHP, overall hemostatic potential; PPP, platelet-poor plasma; TEG, thromboelastography; t-PA, tissue plasminogen activator.

Statistical analysis was performed using Stata version 13.0 (StataCorp). Follow-up was censored at the date of last documented contact with the health service or death. Statistical significance was set at P value <.05. A univariate competing-risk model using the Fine and Gray method was used to evaluate sMB events within the CKD cohort with death as a competing event.

3 Results and Discussion

3.1 Demographics and clinical outcomes

Eighty-seven patients were recruited, which included 67.8% male (n = 59) with a median age of 67 years (range, 31-86 years). Median follow-up was 3.1 years (IQR, 1.9-4.0 years); 74.7% (n = 65) of CKD patients were dialysis-dependent, with 61.5% (n = 40) receiving HD and 38.5% (n = 25) receiving peritoneal dialysis.

Ten episodes of sMB were captured (11.5%; 3.0/100 person-years) during follow-up. The median time of recruitment to event was 2.3 years, with renal function during this period remaining unchanged (urea, P = .17; estimated glomerular filtration rate, P = .32). Six episodes of sMB occurred in dialysis-dependent patients (5 HD and 1 peritoneal dialysis). Five patients who experienced sMB were on aspirin. The majority of sMB events were gastrointestinal (n = 5), followed by intracranial bleeding (n = 3) and menorrhagia (n = 2). The all-cause mortality was 39.1% (n = 34) with no bleeding-related mortality.

Overall, 44.8% (n = 39; 17.5/100 person-years) experienced arterial thrombosis, including acute myocardial infarction, thrombotic stroke, and critical limb ischemia (vascular access thrombosis was excluded). This included 3 sMB patients (3/10 vs 36/77 in those without sMB; P = .40).

3.2 Standard laboratory testing and GCAs

3.2.1 Comparison of CKD patients with sMB

Age (P = .22), sex (P = .20), antiplatelet use (P = .36), urea (P = .27), creatinine (P = .07), and dialysis modality (P = .26) were not associated with sMB, although there was a trend toward lower body mass index (P = .06; Table 1). Fibrinogen was lower in the sMB group (P = .01), although the mean value (3.8 g/L) was within the reference interval (2.0-4.0 g/L). The lowest quartile of fibrinogen was, however, associated with sMB events with a subhazard ratio (sHR) of 3.79 (95% CI, 1.08-13.22; P = .04). There were no significant differences in platelet count or other conventional coagulation testing parameters between both subgroups, the majority of which were within reference intervals.Table 1 Comparison of demographics, standard laboratory testing parameters, and global coagulation assay parameters between groups.

Parameters	Laboratory reference interval	All CKD (N = 87)	CKD without sMB (n = 77)	CKD with sMB (n = 10)	P value	
Demographics and standard laboratory parameters	
Age (y)	-	67.0 (56.0-77.0)	66.0 (56.0-74.0)	76.5 (67.0-79.0)	.22	
Male sex, n (%)	-	59 (67.8)	54 (70.1)	5 (50.0)	.20	
Body mass index (kg/m2)	-	29.9 (26.1-34.3)	30.1 (26.5-35.3)	26.9 (25.0-30.4)	.06	
Dialysis dependency, n (%)	-	65 (74.7)	59 (76.6)	6 (60.0)	.26	
Antiplatelet use, n (%)	-	55 (63.2)	50 (64.9)	5 (50.0)	.36	
Dual antiplatelet use, n (%)	-	9 (10.3)	8 (10.4)	1 (10.0)	.97	
Hemoglobin (g/L)	128-175 (M)	112 (105-120)	113 (105-120)	110 (102-118)	.54	
115-155 (F)	
Platelets (×109/L)	150-400	209 (177-254)	215 (179-254)	178 (127-243)	.14	
PT (s)	11.0-17.0	12.3 (11.1-13.2)	12.3 (11.1-13.2)	11.8 (11.0-14.1)	.95	
aPTT (s)	25.0-38.0	28.7 (26.8-31.1)	28.7 (26.8-31.1)	28.9 (25.1-32.5)	.96	
Fibrinogen (g/L), mean (SD)	2.0-4.0	4.7 (1.1)	4.8 (1.1)	3.8 (1.2)	.01	
D-dimer (ng/mL)	<500	920 (595-1330)	900 (590-1320)	970 (610-1390)	.83	
Factor VIII (%), mean (SD)	50-150	198.7 (68.7)	202.7 (69.7)	166.3 (52.5)	.13	
VWF antigen (%)	50-150	180.0 (149.0-242.0)	185.0 (150.5-242.5)	154.0 (121.0-202.0)	.29	
Urea (mmol/L)	3.0-9.2	21.1 (15.9-25.3)	21.1 (17.2-25.3)	17.7 (15.7-22.5)	.27	
Creatinine (μmol/L)	60-110	529.0 (320.0-805.0)	544.0 (376.0-811.0)	379.0 (264.0-602.0)	.07	
eGFR (mL/min/1.73m2)	>89	8.0 (5.0-14.0)	7.0 (5.0-13.0)	11.0 (8.0-19.0)	.09	
Albumin (g/L), mean (SD)	-	35.2 (4.4)	35.0 (4.3)	37.0 (4.2)	.17	
Global coagulation assays and PAI-1	
PAI-1 (ng/mL)	-	7.8 (3.7-19.5)	8.6 (4.8-19.5)	3.1 (1.0-16.4)	.08	
Thromboelastography	
R-time (min)	-	6.5 (5.8-7.7)	6.5 (5.8-7.5)	6.4 (5.5-7.9)	.98	
K-time (min)	-	1.4 (1.2-1.7)	1.4 (1.2-1.6)	1.7 (1.3-1.8)	.36	
Maximum amplitude (mm), mean (SD)	-	70.0 (6.4)	70.5 (5.8)	66.6 (9.5)	.08	
Alpha angle (°)	-	58.8 (51.1-68.7)	59.8 (50.8-70.4)	56.2 (52.0-58.9)	.41	
Lysis 30 (%)	-	0.0 (0.0-0.4)	0.0 (0.0-0.4)	0.0 (0.0-0.2)	.52	
Calibrated automated thrombogram	
Lag time, mean (SD)	-	4.4 (0.9)	4.5 (0.9)	4.0 (0.8)	.10	
ETP (nM·min), mean (SD)	-	1297.1 (218.5)	1317.8 (212.2)	1137.5 (209.3)	.01	
Peak (nM), mean (SD)	-	236.3 (67.6)	240.7 (68.5)	203.1 (52.2)	.10	
Velocity index (nM/min)	-	72.5 (56.6-103.2)	73.3 (57.6-106.7)	61.3 (49.0-87.2)	.19	
Overall hemostatic potential	
OCP (units), mean (SD)	-	46.6 (12.8)	47.5 (12.8)	39.9 (11.7)	.08	
OHP (units)	-	16.2 (10.9-21.2)	17.0 (11.8-21.2)	7.7 (5.5-19.3)	.01	
OFP (%)	-	65.1 (54.4-74.2)	63.8 (54.3-71.7)	75.4 (64.3-81.8)	.03	
Clinical outcomes	
Arterial thrombotic event, n (%)	-	39 (44.8)	36 (46.8)	3 (30.0)	.40	
All-cause mortality, n (%)	-	34 (39.1)	29 (37.7)	5 (50.0)	.45	
Values are reported as median (IQR) unless otherwise specified. Significant P values <.05 are in bold.

aPTT, activated partial thromboplastin time; CKD, chronic kidney disease; ETP, endogenous thrombin potential; eGFR, estimated glomerular filtration rate; F, female; M, male; OCP, overall coagulation potential; OFP, overall fibrinolytic potential; OHP, overall hemostatic potential; PAI-1, plasminogen activator inhibitor-1; PT, prothrombin time; sMB, spontaneous major bleeding; VWF, von Willebrand factor.

Importantly, patients with sMB demonstrated more hypocoagulable key GCA parameters compared with those without sMB, including significantly lower endogenous thrombin potential (ETP; 1137.5 vs 1317.8 nM; P = .01), lower fibrinogen generation (OHP, 7.7 vs 17.0 units; P = .01), and increased overall fibrinolytic potential (OFP, 75.4% vs 63.8%; P = .03). The lowest quartiles of ETP (sHR, 7.11; 95% CI, 1.84-27.45; P = .004), OHP (sHR, 6.81; 95% CI, 1.77-26.16; P = .005), and PAI-1 (sHR, 5.26; 95% CI, 1.55-17.91; P = .008; Table 2, Figure 2) were predictive of sMB events while the lowest quartile of maximum amplitude was not statistically significant (sHR, 3.15; 95% CI, 0.92-10.85; P = .07).Table 2 Key parameters by most hypocoagulable quartiles.

Parameters	Subhazard ratio	95% CI	P value	
Demographics and standard laboratory parameters	
Body mass index Q1 (≤26.1 kg/m2)	1.99	0.58-6.82	.27	
Urea Q4 (≥25.3 mmol/L)	0.31	0.04-2.30	.25	
Hemoglobin Q1 (≤105 g/L)	1.12	0.30-4.22	.87	
Platelets Q1 (≤177 × 109/L)	3.14	0.91-10.83	.07	
PT Q1 (≤11.1 s)	1.00	0.25-4.01	>0.99	
aPTT Q1 (≤26.8 s)	1.23	0.32-4.73	.77	
Fibrinogen Q1 (≤3.9 g/L)	3.79	1.08-13.22	.04	
Factor VIII Q1 (≤151%)	1.20	0.30-4.84	.80	
VWF antigen (≤149%)	1.27	0.33-4.87	.73	
Global coagulation assays and PAI-1	
Maximum amplitude Q1 (≤65.7 mm)	3.15	0.92-10.85	.07	
Endogenous thrombin potential Q1 (≤1139.62 nM·min)	7.11	1.84-27.45	.004	
Overall hemostatic potential Q1 (≤10.94 Units)	6.81	1.77-26.16	.005	
PAI-1 Q1 (≤3.69 ng/mL)	5.26	1.55-17.91	.008	
Significant P values <.05 are in bold.

aPTT, activated partial thromboplastin time; PAI-1, plasminogen activator inhibitor-1; PT, partial thromboplastin time; Q, quartile; VWF, von Willebrand factor.

Figure 2 Competing risks regression curves for spontaneous major bleeding of key most hypocoagulable quartiles within the chronic kidney disease cohort including (A) maximum amplitude (MA) on thromboelastography, (B) endogenous thrombin potential (ETP) on calibrated automated thrombogram, (C) overall hemostatic potential (OHP) on OHP, and (D) plasminogen activator inhibitor-1 (PAI-1). SHR, subhazard ratio.

To the best of our knowledge, our pilot study provides first-in-human, novel evidence that GCAs may be predictive of bleeding outcomes in our complex renal population, where balancing bleeding and thrombotic risk is challenging but clinically critical [14]. While patients with CKD appear to be hypercoagulable compared with healthy controls, as published in the literature and our previous work [12,15], CKD patients who experienced sMB events demonstrated hypocoagulable GCA parameters. This is despite the majority of the standard laboratory tests being nondiscerning. This novel finding may a herald of the promise of practice-changing personalized risk assessment for CKD patients.

The bleeding phenotype in CKD has traditionally been attributed to anemia as well as uremia-associated impaired platelet function and platelet-vessel wall interactions [14]. Apart from fibrinogen level, which demonstrated association with sMB events within the CKD cohort, our results did not demonstrate a significant difference in standard laboratory markers including hemoglobin, platelet count, and urea. Furthermore, most conventional coagulation tests were within reference intervals except for von Willebrand factor antigen and factor VIII levels, which were all elevated in the CKD group, consistent with previous literature [16]. Previous studies utilizing bleeding time as a surrogate marker for hemorrhagic risk also did not demonstrate an association with renal function in patients with CKD [17]. Moreover, bleeding time is highly subjective and operator-dependent and has additional patient risks such as permanent scarring from the incision [18].

The results of platelet function test have been conflicting—a meta-analysis by Baaten et al. [7] reported that while the majority reported impaired function, significant numbers of studies have found platelet function to be unchanged or even increased. Few studies correlated platelet function testing with clinical outcomes and found that the outcomes were not predictive of bleeding risks [19,20]. Kuiper et al. [21] reported that PFA-100 (Siemans) and platelet aggregometry results did not predict kidney biopsy-associated hemorrhage. In addition, antiplatelet use, age, sex, and use of dialysis were also not associated with increased bleeding risk. Nopp et al. [3] also did not find clinical-based bleeding scores with incorporation of basic laboratory results to be predictive of hemorrhage.

GCAs can provide a more comprehensive assessment of the coagulation process including fibrinolysis and thus is likely a superior alternative to standard coagulation testing for reflecting the complex coagulation status in CKD. Whole blood viscoelastic testing is the most commonly used GCA in clinical practice, particularly in guiding massive transfusion management [22], although limited studies have investigated its association with risk of bleeding. TEG and rotational thromboelastometry have been reported to be hypercoagulable in CKD patients [12,23], although bleeding outcomes were not reported. In our study, the CKD patients in the lowest quartile maximum amplitude, a measure of the strength of clot formation and a surrogate marker of platelet and fibrinogen function, showed a trend toward sMB events (P = .07).

More importantly, contrary to the traditional hypothesis of platelet dysfunction being the key contributor to renal bleeding [6], we found PPP assays measuring thrombin and fibrin generation (CAT and OHP) to be most discriminatory of the sMB group. Patients who experienced sMB were associated with the most hypocoagulable quartiles of ETP (marker of reduced total thrombin production) and OHP (denoting increased response to tissue plasminogen activator [tPA]). Of note, we have previously reported increased OHP and decreased OFP to be associated with increased risk of thrombotic events within the dialysis cohort [12]. Most other studies lack clinical outcome data and compare with healthy controls. Gäckler et al. [24] demonstrated that patients with CKD showed elevated fibrinogen levels and hypofibrinolysis using clot lysis time, and Matusik et al. [25] similarly found an association with increased ETP and prolonged clot lysis time with stage 4 vs stage 3 CKD.

The decreased PAI-1 levels may partly be explained by the trend toward lower body mass index in this group, as PAI-1 is synthesized in adipose tissue [26]. PAI-1 is an inhibitor of intravascular fibrinolysis through inhibition of tPA and urokinase plasminogen activator, 2 enzymes involved in converting plasminogen to plasmin, a key enzyme of the fibrinolytic system that breaks down fibrin clots [27]. While congenital PAI-1 deficiency is a rare genetic bleeding disorder [28], PAI-1 has not been well studied as a predictive marker of bleeding risk. In CKD, the net proteolytic activity is dependent on the balance between PAI-1 and activation of tPA/urokinase plasminogen activator.

Uremia and chronic inflammation typically upregulate tissue factor, PAI-1, and coagulation factor expression, resulting in increased thrombogenicity in CKD [29]. Despite this, we found that patients with sMB have hypocoagulable GCA parameters performed on PPP. These findings suggest an important role of thrombin and fibrin pathway dysregulation in CKD bleeding, which occurs independently of platelets. However, endothelial dysfunction in CKD can also increase plasma levels of anticoagulants such as tissue factor pathway inhibitor [12] and thrombomodulin [30]. We postulate that plasmatic coagulation factor imbalance favoring net anticoagulation tendency may be an important supplemental mechanism of bleeding in addition to platelet-dependent mechanisms in some patients with CKD. This hemostatic disequilibrium likely results from a complex interplay of multiple processes and warrants further elucidation.

Nevertheless, our observations suggest that GCAs could be a more complete assessment tool for evaluating both bleeding and thrombotic risk in individual CKD patients. We acknowledge some limitations including small patient numbers, single-site design, and low numbers of sMB events, because of which the study had insufficient power to perform multivariate risk analysis. Nevertheless, this pilot study highlighted novel findings that may significantly improve outcomes for CKD patients and is an important step toward personalized medicine. Furthermore, our study population is relatively larger than most other studies of GCAs in CKD patients. Combining several GCAs also offers a comprehensive assessment of the hemostasis system beyond conventional coagulation tests, befitting the complexity of the coagulopathy seen in CKD.

4 Conclusion

This pilot study highlights the potential of multimodal GCA assessment in predicting bleeding outcomes within the complex CKD population, where balancing bleeding and thrombosis risk is clinically challenging but critically important. Traditional markers of hypocoagulability in CKD including hemoglobin, urea, platelet, and basic coagulation test parameters did not predict bleeding risks, with most parameters falling within reference intervals. Importantly, GCA parameters were able to discern increased bleeding risk, with decreased total thrombin production (ETP), decreased fibrin generation (OHP), and increased fibrinolysis (OFP) as well as reduced PAI-1 being associated with sMB events. Larger studies are needed to validate these findings and to explore the potential of GCAs in other coagulopathic states beyond CKD.

Relationship Disclosure

The authors have no further conflicts of interest to declare beyond those outlined in Funding.

Funding

R.B. is a recipient of a Heart Foundation of Australia Professional Scholarship. H.Y.L. was a recipient of the cofunded National Health and Medical Research Council Postgraduate Scholarship and Heart Foundation Health Professional Scholarship.

Author contributions

P.H. and H.Y.L. conceived and designed the study. H.Y.L. and R.B. acquired data. R.B. and J.W. analyzed data. All authors interpreted the data. R.B. and H.Y.L. wrote the manuscript. H.Y.L., D.B., J.W., and P.H. edited the manuscript. H.Y.L. and P.H. provided supervision for the project.

Relationship Disclosure

The authors have no further conflicts of interest to declare beyond those outlined in Funding.

Handling Editor: Dr Johnny Mahlangu
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