a b s t r a c t

Background: In acute aortic syndrome (AAS) screening, D-dimer is a well-established biomarker whose useful- ness has been scarcely studied with respect to its measurement timing. We aimed to evaluate the effectiveness of D-dimer-based AAS screening focused on the time interval between AAS onset and D-dimer measurement. Methods: We retrospectively analyzed consecutive patients diagnosed with AAS who visited our hospital be- tween 2011 and 2021. For the primary analysis, we divided patients according to the quartiles of the time interval between AAS symptom onset and D-dimer measurement. D-dimer level >= 0.5 ug/mL and age-adjusted D- dimer >= [age (years) x 0.01] ug/mL (minimum of 0.5 ug/mL) were defined as positive. The primary endpoint was the comparative ability of D-dimer to detect AAS within and between each time quartile. In an exploratory secondary analysis, we reported patient and AAS characteristics in the subgroup of patients who underwent repeat D-dimer measurement within 48 h of the first D-dimer measure.

Results: The 273 AAS patients were divided into four groups based on quartiles of the time interval (Group 1, <=1 h;

Group 2, 1-2 h; Group 3, 2-5 h; and Group 4, >5 h). There were no significant differences in D-dimer levels or in the proportions with positive D-dimer (Group 1: 97%, Group 2: 96%, Group 3: 99%, Group 4: 99%; P = 0.76) or

positive age-adjusted D-dimer (Group 1: 96%, Group 2: 90%, Group 3: 96%, Group 4: 97%; P = 0.32) between the groups. Of the 147 patients who had D-dimer re-measured, nine had negative D-dimer levels on either the primary or secondary measurement. Of these nine patients, eight had AAS with a thrombosed false lumen and one with a patent false lumen had a short length of dissection. In all nine patients, D-dimer levels remained low (maximum of 1.4 ug/mL).

Conclusion: D-dimer levels were elevated from the early stages of AAS. The clinical utility of D-dimer is not affected

by the time interval from AAS onset to D-dimer measurement, but rather is influenced by AAS characteristics.

(C) 2023

1. Introduction

Acute aortic syndrome is a life-threatening emergency in which diagnostic delay and misdiagnosis represent a substantial con- cern [1,2]. Contrast-enhanced computed tomography (CE-CT) is the gold standard modality for AAS diagnosis. The clinical presentation of AAS may be non-specific, leading to unnecessary CE-CT testing in many patients [1-3]. Thus, appropriate patient selection for diagnostic CE-CT remains challenging, and physicians are required for AAS screen- ing to balance the risks of misdiagnosis and overtesting [1-3].

* Corresponding author at: 7-33 Motomachi, Naka-ku, Hiroshima-city, Hiroshima 730- 8518, Japan.

E-mail address: [email protected] (T. Otani).

One potential method for AAS screening before undergoing CE-CT is using the clinical prediction rule, known as the aortic dissection detec- tion risk score (ADD-RS) [4-10]. The ADD-RS is highly sensitive for de- tecting AAS; however, it has poor specificity, and about 4% of patients who are classified as low risk still have AAS [4]. In addition to the ADD-RS, D-dimer is known to be a useful screening biomarker for AAS prior to CE-CT with a sensitivity of >95% [11-18]. However, its specific- ity is low as D-dimer can also be elevated in several other situations, in- cluding in the elderly [11-18]. To address this problem, age-adjusted D- dimer cut-offs may be considered to increase specificity; however, it is important to note that some patients with AAS still have negative D- dimer results [19]. Previous studies have correlated negative D-dimer results in AAS to short dissection lengths, younger populations, and thrombosed false lumens including intramural haematoma (IMH) [11-15,20]. Conversely, the impact of D-dimer measurement timing on

https://doi.org/10.1016/j.ajem.2023.05.044

0735-6757/(C) 2023

its value for AAS screening has not been well studied, including its screening usefulness in early-stage AAS (e.g., <1 h from AAS symptom onset) and the D-dimer level trends after AAS diagnosis, especially in patients with negative results on initial D-dimer measurement.

To address these knowledge gaps in the literature, we conducted a study: 1) to investigate the comparative ability of D-dimer to detect AAS according to the time interval between D-dimer measurement and AAS symptom onset, and 2) to examine the D-dimer level trends in patients who underwent remeasurement within 48 h of initial mea- surement, with a focus on the patients with AAS who had negative D- dimer results on either the primary or secondary measurement.

1. Methods
   1. Study design and setting

This retrospective, single-center, observational study was a post hoc analysis of our prior study [3]. We retrospectively analyzed consecutive AAS patients aged >=15 years who visited our hospital between April 2011 and March 2021 using the same dataset from our previous study [3]. Patients with traumatic aortic dissection or those who experienced cardiac arrest before undergoing CT were not included in this study. Only those who underwent both a CE-CT and an unenhanced CT were included in this study, because both imaging modalities are crucial for diagnosing AAS variants [1]. Additionally, those who did not have D- dimer measurements upon arrival and those whose time from AAS symptom onset to D-dimer measurement was unknown were also ex- cluded from this study. All patients were diagnosed with AAS using non-electrocardiogram-gated CT with multi-slice CT scanners and a slice thickness of 5 mm. The following factors were investigated: base- line characteristics, AAS-associated symptoms, Stanford type of dissec- tion, AAS variants with false lumen status in Acute aortic dissection , time from the onset of AAS symptoms to D-dimer measurement, and measured D-dimer concentration. Time intervals were extracted from physicians’ and nurses’ documentation in the electronic medical re- cords, and the initial D-dimer results closest to hospital arrival and re- measured D-dimer results were also extracted from these records. The onset time of AAS was obtained through clinical history-taking from pa- tients and their families regarding symptoms associated with AAS, such as chest or back pain, syncope, or stroke. The time of D-dimer measure- ment was taken as the time of blood sample collection. The study protocol was approved by the Ethics Board of Hiroshima City Hiroshima Citizens Hospital (reference 2022-82) and conformed to the principles of the Dec- laration of Helsinki and its amendments. The requirement for written informed consent was waived because of the retrospective study design.

• 1. Definitions

Radiologists or vascular surgeons in our hospital diagnosed AAS based on CT findings in symptomatic patients. The diagnosis of AAS var- iants, such as classic AAD, IMH, and penetrating aortic ulcer (PAU), was performed according to the 2014 guidelines of the European Society of Cardiology [1]. The status of the false lumen in AAD was divided into three categories (patent, thrombosis, and partial thrombosis) deter- mined by early phase CE-CT findings [21]. AAS with patent false lumen was defined as AAD patients with patent or partial thrombosis in the false lumen; while AAS with thrombosed false lumen was defined as AAD patients with thrombosed false lumen, IMH, and PAU. The dis- tinction between AAD with thrombosed false lumen and IMH was based on the presence or absence of an intimal tear and high- attenuation hematoma [1]. AAS that involved the Ascending aorta was classified as Stanford type A dissection, while those limited to the de- scending aorta (distal to the left subclavian artery) were classified as Stanford type B dissection [1]. D-dimer levels were measured using the latex agglutination method with the LIAS AUTO D-dimer NEO (Sysmex, Kobe, Japan). The coefficient of variation was <10%. The

measurable range for D-dimer values was 0.5 to 200 ug/mL. D-dimer values below 0.5 ug/mL and above 200 ug/mL could not be measured. D-dimer test results with a level < 0.5 ug/mL were defined as negative, and a level >= 0.5 ug/mL as positive. Age adjusted D-dimer was defined as positive with a level >= [age (years) x 0.01] ug/mL (with a minimum of 0.5 ug/mL for patients aged <=50 years) [19]. Most of these definitions were taken from our previous study [3].

• 1. Statistical analyses

The study patients were divided into four groups based on the quar- tile of the time interval between the onset of AAS symptoms and D- dimer measurement. The relationship between this time interval and patient characteristics, as well as D-dimer levels, was analyzed using univariate analysis. Data are presented as medians and interquartile ranges (IQRs) for continuous variables and as numbers and percentages for categorical variables. Continuous variables were compared using the Mann-Whitney U test, and categorical variables were compared using the chi-square or Fisher’s exact test. For the subgroup analysis, we se- lected only patients who underwent D-dimer remeasurement within 48 h of the initial D-dimer measurement without Surgical repair. We com- pared the characteristics of patients with elevated or decreased D-dimer levels and evaluated the characteristics of patients with negative D-dimer levels on either the primary or secondary measurement. The pri- mary endpoint of this study was the comparative ability of D-dimer to detect AAS within and between time quartiles. In an exploratory second- ary analysis, we reported patient and AAS characteristics in the subgroup of patients who underwent repeat D-dimer measurement within 48 h of the initial D-dimer measurement. All statistical analyses were performed using R software package (version 4.0.2, R Development Core Team; https://www.r-project.org/). Statistical significance was set at p < 0.05.

1. Results
   1. Patient characteristics

A total of 344 patients with AAS visited our hospital during the study period. Of these, 273 patients (79%) whose D-dimer levels were mea- sured on arrival were included in the primary analysis. Among these 273 patients, 147 (54%) had their D-dimer levels re-measured within 48 h of their initial measurement (Fig. 1). The median age of the 273 pa- tients in the primary analysis was 71 years (IQR, 61-80), and 168 (62%) were male. Of these, 116 (42%) had Stanford type A dissection and 220 (81%) had classic AAD, including 57 (21%) with patent false lumen, 97 (36%) with complete thrombosis, and 66 (24%) with partial thrombosis of the false lumen. Additionally, 40 (15%) patients had IMH, and 13 (5%) had PAU. The median time from the onset of AAS symptoms to primary D-dimer measurement was 2 h (IQR 1-5) and the median D-dimer level on arrival was 6.3 ug/mL (IQR 2.2-21.9). D-dimer testing was positive in 266 patients (97%), and age-adjusted D-dimer was positive in 258 patients (94%) (Table 1).

• 1. Comparisons between four groups stratified by D-dimer measurement timing

For the primary analysis, we divided patients into quartiles of the time interval between AAS symptom onset and D-dimer measurement [group 1: <=1 h, group 2: 1-2 h (>1 h and <=2 h), group 3: 2-5 h (>2 h and <= 5 h), and group 4: >5 h] (Table 2). There were no significant dif- ferences in patient age, sex, Stanford type of AAS, or AAS variants be- tween the four groups. Additionally, there were no significant differences in D-dimer levels [Group 1: 6.6 ug/mL (IQR 2.3-29.2), Group 2: 4.3 ug/mL (IQR 1.3-16.0), Group 3: 6.6 ug/mL (IQR 2.1-26.7),

Group 4: 7.2 ug/mL (IQR 3.1-15.1); P = 0.32] or in the proportion of pa- tients with positive D-dimer (Group 1: 97%, Group 2: 96%, Group 3: 99%, Group 4: 99%; P = 0.76) or positive age-adjusted D-dimer (Group 1:

Fig. 1. Flow chart of participant inclusion.

CT, computed tomography.

96%, Group 2: 90%, Group 3: 96%, Group 4: 97%; P = 0.32) between the groups (Fig. 2).

• 1. Comparison between patients with up- and down-trending D-dimer levels

Of the 147 patients who had D-dimer levels re-measured, 74 (50%) had elevated D-dimer levels compared to their primary measurements

Table 1

Baseline characteristics of study participants.

(Table 3). There was no significant difference in the time from onset to primary D-dimer measurement (median 2 [IQR1-4] vs. 3 [IQR 2-6] h, P = 0.050) and the time to secondary D-dimer measurement (me- dian 19 [IQR 13-34] vs. 21 [IQR14-29] h, P = 0.43) between the two groups. Additionally, there were no significant differences in median age, sex, Stanford type A dissection, or AAS variants between the two groups. The proportion of positive D-dimer and age-adjusted D-dimer was also similar between the two groups, with 97% (143/147) of pa- tients having positive D-dimer and 95% (139/147) having positive age-adjusted D-dimer at the time of remeasurement.

n = 273

Age, years 71 (61-80)

Male sex 168 (62)

Hypertension 198 (73)

Dyslipidemia 67 (25)

Diabetes mellitus 16 (6)

Current smoker 61 (22)

Back pain 187 (69)

Chest pain 120 (44)

Abdominal pain 35 (13)

Painless AAS 13 (5)

Syncope 16 (6)

Stroke 9 (3)

Stanford type A 116 (42)

AAS variants

AAD 220 (81)

Patent 57 (21)

Thrombosis 97 (36)

Partial thrombosis 66 (24)

intramural hematoma 40 (15)

Penetrating aortic ulcer 13 (5)

AAS with patent false lumen 123 (45)

Onset to primary D-dimer measured, hours 2 (1-5)

D-dimer on arrival, ug/mL 6.3 (2.2-21.9)

Positive D-dimer on arrival 266 (97)

Positive age-adjusted D-dimer on arrival 258 (94)

Data are presented as the number (column %) of patients or median (interquartile range). AAS, Acute aortic syndromes; AAD, acute aortic dissection.

• 1. Presentation of patients with negative D-dimer levels on either primary or secondary D-dimer measurement

Out of 147 patients who underwent repeat D-dimer measurement, nine patients were found to have negative D-dimer levels (<0.5 ug/mL) on either the primary or secondary measurement, as shown in Table 4. Of these nine patients, 8 had AAS with a thrombosed false lumen and one patient with a patent false lumen had a short length of dissection (patient no. 7). Only one patient had negative D-dimer levels in both the primary and secondary measurements (patient no. 1). D-dimer levels changed from negative to positive in five patients (patient nos. 2-6) and from positive to negative in three patients (pa- tient nos. 7-9). In all nine patients, D-dimer levels remained low (max- imum of 1.4 ug/mL). The AAD-RS was 1 in six patients and 2 in three patients.

1. Discussions

The major findings of this study were as follows: 1) D-dimer levels were sufficiently elevated for effective AAS screening regardless of the time interval between the onset of AAS symptoms and D-dimer mea- surement, and D-dimer levels were useful for AAS screening even within 1 h of onset. 2) In selected AAS patients who did not undergo sur- gical repair, re-measured D-dimer levels decreased from their initial

Table 2

Comparisons among four groups divided based on the time of D-dimer measurement.

	Group 1		Group 2		Group 3		Group 4	P-value
	<=1 h n = 70		1-2 h n = 68		2-5 h n = 67		>5 h n = 68
Age, years	69 (61-79)		72 (63-79)		70 (61-80)		72 (62-80)	0.92
Male sex	45 (64)		42 (62)		40 (60)		41 (60)	0.95
Stanford type A	32 (46)		27 (40)		26 (39)		31 (46)	0.77
AAS variants AAD	62 (89)		54 (79)		52 (78)		52 (76)	0.24
Patent	15 (21)		9 (13)		14 (21)		19 (28)
Thrombosis	28 (40)		31 (46)		24 (36)		14 (21)
Partial thrombosis	19 (27)		14 (21)		14 (21)		19 (28)
Intramural hematoma	5 (7)		13 (19)		11 (16)		11 (16)
Penetrating aortic ulcer	3 (4)		1 (1)		4 (6)		5 (7)
AAS with patent false lumen	34 (49)		23 (34)		28 (42)		38 (56)	0.063
D-dimer, ug/mL	6.6 (2.3-29.2)		4.3 (1.3-16.0)		6.6 (2.1-26.7)		7.2 (3.1-15.1)	0.32
Positive D-dimer	68 (97)		65 (96)		66 (99)		67 (99)	0.76
Positive age-adjusted D-dimer	67 (96)		61 (90)		64 (96)		66 (97)	0.32

Data are presented as the number (column %) of patients or median (interquartile range). AAS, acute aortic syndromes; AAD, acute aortic dissection.

levels in half of the patients with AAS; however, re-measured D-dimer levels remained useful for AAS screening. 3) AAS patients with low D- dimer levels maintained these low levels throughout the disease course. In the field of emergency medicine, accurate and Timely diagnosis of AAS can be challenging because of its nonspecific symptoms, which may range from sudden severe chest or back pain accompanied by a pulse deficit to painless presentations [1-3]. This results in difficulties in opti- mal patient selection for urgent CE-CT and raises concerns regarding

misdiagnosis and overtesting [1-3].

D-dimer, a plasma fibrin degeneration product, is a well-established biomarker for ruling out pulmonary embolism [19,22]. Elevated D- dimer levels indicate the fibrinolysis of thrombus following activation of the coagulation cascade, and many AAS patients also have elevated D-dimer levels [11-18,23]. Over 95% of AAS patients have positive D- dimer results at a cut-off of >=0.5 ug/mL and D-dimer is commonly used as a rule-out diagnostic tool for AAS. Conversely, the relationship between the time of the onset of AAS symptoms and D-dimer measure- ment and has not been well discussed [12,15-17,24]. Previous studies have shown that D-dimer can become elevated within 1-6 h of AAS

symptom onset and remain positive for up to 10 days [12,15-17,24]. One study showed no relationship between onset to D-dimer measure- ment and positive D-dimer test in multivariate analysis; however, this report did not address D-dimer levels [15]. Another study suggested that the onset of AAS symptoms within 2 h was associated with rela- tively low D-dimer levels, but there was no significant difference, and the sample size was small [12]. AAS is often accompanied by sudden symptoms, and patients may present to the hospital early, making it im- portant to study the usefulness of D-dimer levels in the early stages of AAS. In this study, we found that D-dimer was positive in 97% of cases with a level of >=0.5, and 94% of cases when adjusted for age, which is consistent with previous reports [11-18]. The median time from the onset of AAS symptoms to D-dimer measurement was 2 (IQR 1-5) hours, indicating that AAS patients were found to have visited the hos- pital early. When comparing the four groups divided according to the quartiles of the time interval between AAS symptom onset to D-dimer measurement, the time from AAS symptom onset to D-dimer measure- ment did not affect the D-dimer levels or positivity rate. Even when D- dimer was measured within an hour of onset, D-dimer was positive in

Fig. 2. D-dimer levels in each group divided based on the time interval between the onset of AAS symptoms and D-dimer measurement. Box plot graph showing median, interquartile range, and 10th and 90th percentiles of D-dimer levels. There were no significant differences in D-dimer levels (P = 0.32) or in the propor- tion of patients with positive D-dimer (P = 0.76) or positive age-adjusted D-dimer (P = 0.32) between the groups. D-dimer levels were compared using the Mann-Whitney U test, and the proportion of patients with positive D-dimer (with or without age-adjustment) were compared using the Fisher’s exact test.

Table 3

Comparison between patients with elevated and decreased re-measured D-dimer levels.

	Elevated D-dimer n = 74		Decreased D-dimer n = 73	P-value
Age, years	71 (62-79)		72 (64-80)	0.71
Male sex	48 (65)		46 (63)	0.87
Onset to primary D-dimer measured, hours	2 (1-4)		3 (2-6)	0.050
Onset to secondary D-dimer measured, hours	19 (13-24)		21 (14-29)	0.43
Stanford type A	8 (11)		9 (12)	0.80
AAS variants AAD	61 (82)		57 (78)	0.55
Patent	14 (19)		8 (11)
Thrombosis	30 (41)		37 (51)
Partial thrombosis	17 (23)		12 (16)
Intramural hematoma	11 (15)		11 (15)
Penetrating aortic ulcer	2 (3)		5 (7)
AAS with patent false lumen	32 (43)		19 (26)	0.056
Primary D-dimer, ug/mL	3.3 (1.4-7.0)		5.3 (2.3-20.3)	0.006
Secondary D-dimer, ug/mL	5.2 (2.6-10.2)		3.3 (1.7-11.9)	0.081
Positive primary D-dimer	69 (93)		72 (99)	0.21
Positive secondary D-dimer	74 (100)		69 (95)	0.058
Positive age-adjusted primary D-dimer	64 (86)		69 (95)	0.158
Positive age-adjusted secondary D-dimer	72 (97)		67 (92)	0.166

Data are presented as the number (column %) of patients or median (interquartile range). AAS, acute aortic syndromes; AAD, acute aortic dissection.

97% of cases and 96% when age was adjusted. Our results suggest that D- dimer levels become elevated in the early stage following AAS symptom onset, and D-dimer levels become sufficiently elevated for effective screening of AAS even within one hour after the onset of AAS symptoms. D-dimer level trends after hospital admission also remain unclear due to the limited number of reports on this topic. We investigated 127 cases (excluding those who underwent emergency surgery) that were re-measured for D-dimer within 48 h and found that approxi- mately half of the cases showed a D-dimer peak within 48 h. There were no significant differences between the D-dimer increased and de- creased groups, and the diagnostic sensitivity of D-dimer of AAS was maintained when re-measured. This result suggests that D-dimer is use- ful not only in the early stages, but also beyond 48 h, and that the posi-

tivity rate of D-dimer is not affected by the passage of time.

In a small percentage of AAS cases, D-dimer results can yield nega- tive results, and similar results were obtained in this study [11-18,20]. It is important for physicians to be aware of the types of AAS that may result in negative D-dimer results, as misdiagnosis must be avoided due to the severity of AAS. The D-dimer results in AAS are influenced by the status of the false lumen [11-14,20]. Previous reports have

shown that AAS with a thrombosed false lumen, including IMH and PAU, could have negative D-dimer results [11-14,20]. This could be ex- plained by the fact that fibrin degeneration products do not leak into the bloodstream in these types of AAS, resulting in no D-dimer eleva- tion. Additionally, AAS with a short dissection length and young popula- tion may also have negative D-dimer results [12-15]. However, subsequent trends in D-dimer levels among AAS patients who initially tested negative for D-dimer levels have not been reported. In our study, of the seven cases with a negative initial D-dimer result, D- dimer was re-measured in six cases. Only one case showed a negative D-dimer test on re-examination, while the others had persistently low D-dimer levels (maximum, 1.4 ug/mL). Five of these cases had false lumen thrombosis, suggesting that D-dimer levels remained low in AAS patients with negative initial results. The same results were found in cases where the initial D-dimer level was positive, but subsequent tests were negative. As reported in previous studies, certain AAS types could have negative D-dimer results, and positive or negative D-dimer results in these AAS types may be influenced by the timing of D-dimer measurement [11-15,20]. However, remeasurement of D-dimer is not recommended for AAS screening due to its life-threatening course and

Table 4

Presentations of patients with negative D-dimer levels on either the primary or secondary D-dimer measurement.

No.	Age	Sex	ADD-RS	Onset to primary D-dimer measurement, hours	Onset to secondary D-dimer measurement, hours	Stanford type	AAS variants	The extent of dissection	Primary D-dimer, ug/mL	Secondary D-dimer, ug/mL
1	64	Female	2	2	15	B	AAD with thrombosed false lumen	Descending thoracic aorta to renal artery	<0.5	<0.5
2	56	Female	1	2	17	B	IMH	Descending thoracic aorta to renal artery	<0.5	0.5
3	58	Male	1	1	21	B	PAU	Only in descending thoracic aorta (short	<0.5	0.6
4	67	Female	2	10	50	B	IMH	length) Descending thoracic aorta to renal artery	<0.5	0.6
5 6	60 71	Male Female	1 2	4 2	40 9	B B	AAD with thrombosed false lumen IMH	Descending thoracic aorta to coeliac artery Descending thoracic aorta to renal artery	<0.5 <0.5	0.7 1.4
7	77	Male	1	23	33	B	AAD with patent false	Only in descending abdominal aorta	0.5	<0.5
8	59	Female	1	2	20	B	lumen AAD with thrombosed	(short length) Descending thoracic aorta to renal artery	0.7	<0.5
9	72	Female	1	2	14	B	false lumen AAD with thrombosed	Descending thoracic aorta to coeliac	1.3	<0.5
							false lumen	artery

AAD-RS, aortic dissection detection risk score; AAS, acute aortic syndromes; AAD, acute aortic dissection; IMH, intramural hematoma; PAU, penetrating aortic ulcer.

the mortality rate increases with the passage of time from onset. Alter- native Screening tools, such as the AAD-RS or unenhanced CT, should be used for these types of AAS [3-10]. Previous reports have indicated that combining ADD-RS and D-dimer, particularly in low- to moderate-risk cases, provides a higher sensitivity in excluding AAS [6-10] In this study, all 9 cases, who underwent repeat D-dimer measurement and had negative D-dimer levels on either the primary or secondary mea- surement, had an ADD-RS of >=1.

The findings of this study indicate that the timing of D-dimer mea- surement is not critical for its usefulness in AAS screening, but rather is influenced by AAS characteristics (e.g., false lumen status or dissec- tion extent). Additionally, cases with low D-dimer levels maintained these low levels throughout the disease course.

This study had several limitations. First, this was a retrospective ob- servational study conducted at a single institution. Second, this study in- cluded only patients diagnosed with AAS and retrospectively analyzed the usefulness of D-dimer. Therefore, the specificity of D-dimer for AAS was not evaluated. Third, we excluded 36 AAS cases that did not have D-dimer measurements in the primary analysis, and remeasure- ment of D-dimer was performed in about half of the cases. Fourth, the impact of comorbidities on D-dimer level was not considered. Fifth, we divided the study patients into four groups based on the quartiles of the time interval between AAS symptom onset and D-dimer mea- surement. This was because there were no previous reports to provide a basis for other appropriate deviation; however, it is important to note that this grouping itself may have influenced the results of our study. Finally, the influence of treatments after hospitalization, except for surgery, on re-measured D-dimer levels has not been considered.

1. Conclusions

In patients with AAS, D-dimer levels can become sufficiently elevated for effective AAS screening even within one hour after the onset of symp- toms. The clinical utility of D-dimer level is not affected by the time inter- val from the onset of AAS symptoms to D-dimer measurement, but rather is influenced by AAS characteristics, and cases with low D-dimer levels maintained these low levels throughout the disease course.

Funding

This research did not receive any specific grants from funding agen- cies in the public, commercial, or not-for-profit sectors.

Credit author statement

All authors contributed to the conception of the analysis, data analy- sis, and Data interpretation, as well as the writing and revision of the manuscript. TO and TA conducted the statistical analysis and verified the underlying data. TO, TI, KK, and HN were involved in the study de- sign, coordination, data collection, and data interpretation. All authors critically reviewed and revised the manuscript. TO handle the manu- script submission. All authors have read and approved the final version.

CRediT authorship contribution statement Takayuki Otani: Writing - review & editing, Writing - original draft,

Formal analysis, Data curation, Conceptualization. Toshikazu Abe:

Writing - review & editing, Formal analysis. Toshihisa Ichiba: Writing - review & editing. Kenichiro Kashiwa: Writing - review & editing. Hiroshi Naito: Writing - review & editing.

Data availability

The submission of raw data was not permitted by the Hiroshima City Hi- roshima Citizens Hospital Ethics Board.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influ- ence the work reported in this paper.

Acknowledgments

We thank Editage (www.editage.jp) for the English language editing.

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