Edited by: Gerald A. Meininger, University of Missouri, United States
Reviewed by: Barbara Ruszkowska-Ciastek, Nicolaus Copernicus University in Toruń, Poland; Sivareddy Kotla, University of Texas MD Anderson Cancer Center, United States
†First author
This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology
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In the present study, we investigated the associations between D-dimer levels at admission and early adverse events in patients with acute type A aortic dissection undergoing arch replacement and the frozen elephant trunk (FET).
We retrospectively analyzed data of patients with acute type A aortic dissection undergoing aortic arch surgery and FET from July 2017 to December 2018 at Beijing Anzhen Hospital. D-dimer levels were evaluated within 24 h of admission. Multivariate Cox regression analysis was used to determine independent predictors of early postoperative adverse events.
A total of 347 patients were included in the study. The average age of the patients was 48.07 ± 10.56 years, with male predominance (79.25%). The incidence of 90-day postoperative adverse events was 18.7%, consisting of 14.7% mortality and 4.0% permanent neurological dysfunction (PND). The median D-dimer level was 1.95 ug/ml (interquartile range, 0.77–3.16 ug/ml). Multivariable Cox regression analysis revealed that D-dimer level was independently associated with 90-day postoperative adverse events after adjustment for confounding factors (hazard ratio = 1.19 per 10 ug/ml increase in D-dimer, 95% confidence interval: 1.01–1.41;
Increased D-dimer levels at admission were associated with 90-day postoperative adverse events in patients with acute type A aortic dissection undergoing arch replacement and FET. These results may help clinicians optimize the risk evaluation and perioperative clinical management to reduce early adverse events.
Explore the relationship between D-dimer and early outcomes in patients with aortic dissection with arch replacement.
Increased D-dimer at admission was associated with adverse events in patients with aortic dissection with arch surgery.
The high-risk patients deserve close medical monitoring.
The incidence of aortic dissection markedly increases with atherosclerosis and hypertension. Although surgical treatment significantly reduces the mortality of patients with aortic dissection compared with medical management, short-term mortality (30-day or in-hospital mortality) remains high (13–17%) (
D-dimer, a specific degradation product of cross-linked fibrin, represents the coagulation and fibrinolytic system activation (
For these reasons, we conducted a retrospective cohort study to investigate the association between D-dimer levels and 90-day postoperative adverse events in patients undergoing arch replacement and FET using a multivariate Cox regression model containing all known associated major perioperative predictors. Our hypothesis was that the risk of 90-day postoperative adverse events would increase as D-dimer levels increased.
From July 1, 2017, to December 31, 2018, consecutive patients with aortic disease undergoing aortic arch surgery were retrospectively identified at the aortic center in the Beijing Anzhen Hospital (Capital Medical University of Beijing, China). Patients with acute type A aortic dissection who underwent total arch replacement and the frozen elephant trunk (FET) technique were recruited into this observational retrospective cohort study. Patients who (1) underwent hemi-arch replacement (
The endpoint of this observational retrospective study was defined as early all-cause mortality or permanent neurological dysfunction (PND) during the hospital stay or within 90 days after surgery. PND was defined as the presence of permanent neurologic deficits, including abnormal movement of limbs, coma, and sensory loss affecting one side of the body, within postoperative 90-day. Confirmation of the diagnosis was made by a neurologist or by means of computed tomographic scanning or magnetic resonance imaging of the brain.
The type of aortic dissection was classified according to Stanford classification (
Within 24 h after admission, whole-blood samples were drawn into blood collection tubes containing sodium citrate (3.2%, 109 mmol/L) as the anticoagulant (9:1 ratio of blood:anticoagulant) to measure prothrombin time (PT), activated partial thromboplastin time (APTT), fibrin degradation products (FDP), and D-dimer. Venous blood was immediately sent to the clinical laboratory center of the Anzhen hospital. Plasma PT, APTT, FDP, and D-dimer were measured using the commercially available automated latex immunoturbidimetric assay (Werfen ACL TOP 700, United States) (
Clinical, operative, perfusion, and postoperative data have been retrospectively collected in a department database, and further data were extracted from operation reports, perfusion reports, intraoperative computerized records, and review of medical records. Data were compiled via the Empower Dataweb data collection management system (X&Y Solutions, Inc., Boston, MA, United States). The current study was approved by the Human Subjects Review Committee at Anzhen Hospital (Approval No. 2017058X). Follow-up data were obtained from medical records and telephone calls.
Categorical variables were presented as frequencies or percentages, whereas continuous variables were expressed as means ± standard deviations (normal distribution) or medians and interquartile ranges (skewed distribution). First, we grouped D-dimer levels in tertiles. The significant differences between the means and proportions of the tertiles in baseline characteristics were analyzed using a Student’s
Baseline characteristics of patients according to D-dimer tertiles.
Characteristics | Total |
Lowest tertile |
Median tertile |
Highest tertile |
|
D-Dimer (ug/ml) | 1.95 (0.77–3.16) | 0.51 (0.33–0.77) | 1.95 (1.26–2.28) | 6.27 (3.16–13.27) | < 0.001 |
Age, |
48.07 ± 10.56 | 46.43 ± 10.69 | 47.43 ± 11.39 | 50.34 ± 9.17 | 0.013 |
Sex (men),% | 275 (79.25%) | 90 (77.59%) | 94 (81.74%) | 91 (78.45%) | 0.714 |
BMI (kg/m2) | 26.75 ± 4.35 | 27.00 ± 5.04 | 26.85 ± 4.22 | 26.39 ± 3.69 | 0.552 |
Smoking history | 175 (51.47%) | 54 (47.79%) | 66 (57.39%) | 55 (49.11%) | 0.290 |
Comorbidities | |||||
Diabetes mellitus | 13 (3.75%) | 3 (2.59%) | 5 (4.35%) | 5 (4.31%) | 0.722 |
Hypertension | 280 (80.69%) | 89 (76.72%) | 94 (81.74%) | 97 (83.62%) | 0.388 |
Coronary artery disease | 23 (6.63%) | 6 (5.17%) | 8 (6.96%) | 9 (7.76%) | 0.720 |
Acute cardiac tamponade | 14 (4.03%) | 3 (2.59%) | 2 (1.74%) | 9 (7.76%) | 0.073 |
Cerebrovascular disease | 20 (5.76%) | 7 (6.03%) | 7 (6.09%) | 6 (5.17%) | 0.959 |
Acute visceral ischemia | 8 (2.31%) | 0 (0.00%) | 3 (2.61%) | 5 (4.31%) | 0.088 |
Lower-extremity ischemia | 26 (7.49%) | 2 (1.72%) | 9 (7.83%) | 15 (12.93%) | 0.003 |
Spinal cord injury | 1 (0.32%) | 0 (0.00%) | 1 (0.94%) | 0 (0.00%) | 1.000 |
Marfan syndrome | 3 (0.86%) | 2 (1.72%) | 1 (0.87%) | 0 (0.00%) | 0.552 |
Chronic kidney disease | 58 (16.71%) | 10 (8.62%) | 22 (19.13%) | 26 (22.41%) | 0.013 |
LVEF% | 62.49 ± 5.43 | 62.06 ± 6.27 | 62.47 ± 5.01 | 62.93 ± 4.91 | 0.492 |
Severe aortic regurgitation | 51 (15.32%) | 22 (19.82%) | 14 (12.96%) | 15 (13.16%) | 0.502 |
WBC (g/L) | 11.60 ± 4.06 | 9.53 ± 3.63 | 12.07 ± 4.09 | 13.21 ± 3.56 | < 0.001 |
NE(∗10−9/L) | 9.61 ± 4.04 | 7.33 ± 3.68 | 10.10 ± 3.97 | 11.39 ± 3.37 | < 0.001 |
Creatinine (μmol/L) | 91.79 ± 50.96 | 83.02 ± 45.94 | 96.93 ± 64.17 | 95.45 ± 38.75 | 0.074 |
APTT (sec) | 29.68 ± 4.15 | 29.67 ± 4.72 | 29.03 ± 3.70 | 30.32 ± 3.90 | 0.064 |
PT (sec) | 12.76 ± 2.52 | 12.73 ± 3.01 | 12.47 ± 1.33 | 13.08 ± 2.83 | 0.183 |
0.200 | |||||
Ascending aorta replacement | 183 (52.89%) | 60 (51.72%) | 71 (61.74%) | 52 (45.22%) | |
Bentall’s procedure | 138 (39.88%) | 47 (40.52%) | 40 (34.78%) | 51 (44.35%) | |
Aortic root repair | 23 (6.65%) | 8 (6.90%) | 4 (3.48%) | 11 (9.57%) | |
Other | 2 (0.58%) | 1 (0.86%) | 0 (0.00%) | 1 (0.87%) | |
Concomitant procedures (CABG and valve surgery) | 32 (9.22%) | 14 (12.07%) | 9 (7.83%) | 9 (7.76%) | 0.430 |
Lowest nasopharygeal temperature (.C) | 24.31 ± 1.54 | 24.34 ± 1.38 | 24.40 ± 1.70 | 24.19 ± 1.53 | 0.578 |
Lowest bladder temperature (.C) | 25.68 ± 1.67 | 25.59 ± 1.38 | 25.93 ± 1.85 | 25.52 ± 1.72 | 0.137 |
Cross-clamp time (min) | 115.45 ± 28.84 | 113.55 ± 28.95 | 111.22 ± 25.23 | 121.54 ± 31.21 | 0.017 |
CPB time (min) | 207.63 ± 50.61 | 201.17 ± 44.88 | 206.20 ± 45.47 | 215.52 ± 59.47 | 0.091 |
MHCAT (min) | 27.18 ± 9.81 | 28.28 ± 9.61 | 27.12 ± 9.62 | 26.16 ± 10.16 | 0.258 |
Multivariable cox regression analyses of 90-day postoperative adverse events in patients with acute type A aortic dissection undergoing arch replacement and FET.
Non-adjusted |
Adjust I |
Adjust II |
||||
HR 95% CI | HR 95% CI | HR 95% CI | ||||
D-dimer ug/ml per 10 ug/ml | 1.28 (1.11, 1.48) | 0.001 | 1.26 (1.09, 1.45) | 0.002 | 1.19 (1.01, 1.41) | 0.039 |
Lowest tertile (T1) | Reference | Reference | Reference | |||
Median tertile (T2) | 2.13 (1.03, 4.38) | 0.041 | 2.01 (0.97, 4.17) | 0.058 | 1.58 (0.73, 3.39) | 0.242 |
Highest tertile (T3) | 3.30 (1.66, 6.55) | 0.001 | 3.16 (1.59, 6.29) | 0.001 | 2.41 (1.15, 5.06) | 0.019 |
0.0004 | 0.001 | 0.015 |
Effects of D-dimer on 90-day postoperative adverse events in each subgroup by multivariable Cox model.
CPB per 10 min | No. of participants | HR (95% CI) | ||
0.814 | ||||
≤43 | 106 | 1.14 (0.84, 2.38) | 0.197 | |
44–52 | 128 | 1.19 (0.90, 1.58) | 0.231 | |
≥53 | 113 | 1.25 (1.04, 1.50) | 0.015 | |
0.831 | ||||
Male | 275 | 1.25 (1.05, 1.49) | 0.011 | |
Female | 72 | 1.38 (1.07, 1.79) | 0.014 | |
0.534 | ||||
≤24 | 104 | 1.76 (1.36, 2.27) | <0.0001 | |
24–27 | 117 | 1.12 (0.89, 1.42) | 0.332 | |
≥27 | 124 | 1.30 (0.89, 1.88) | 0.170 | |
0.105 | ||||
No | 327 | 1.19 (0.99, 1.43) | 0.064 | |
Yes | 20 | 7.03 (1.10, 44.98) | 0.039 | |
0.885 | ||||
No | 324 | 1.26 (1.08, 1.48) | 0.004 | |
Yes | 23 | 1.24 (0.87, 1.76) | 0.236 | |
0.072 | ||||
No | 339 | 1.33 (1.15, 1.54) | 0.0001 | |
Yes | 8 | –& | –& | |
0.655 | ||||
No | 321 | 1.31 (1.12, 1.54) | 0.001 | |
Yes | 26 | 1.06 (0.73, 1.56) | 0.750 | |
0.558 | ||||
<60 | 58 | 1.33 (1.08, 1.65) | 0.008 | |
≥60 | 289 | 1.18 (0.95, 1.46) | 0.139 |
From July 1, 2017, to December 31, 2018, 510 consecutive patients received aortic arch surgery at the cardiac surgery center in the Beijing Anzhen Hospital. We excluded patients who underwent hemi-arch replacement (
Flow chart.
The final analysis included 347 patients with acute type A aortic dissection who underwent total arch replacement and FET implantation (
At the time of presentation, no difference was found in the patients’ sex, BMI, LVEF, and clinical status regarding diabetes mellitus, hypertension, coronary artery disease, cerebrovascular disease, the type of aortic root procedure, and concomitant procedures. However, lower-extremity ischemia and CKD were more common among those with higher D-dimer. Further, higher white blood cell counts and longer cross-clamp times were also associated with higher D-dimer.
Sixty-five (18.7%) patients developed 90-day postoperative mortality and PND, consisting of 51 (14.7%) patient deaths and 14 (4.0%) patients with PND.
The results of univariate analyses of 90-day postoperative adverse events are summarized in the
Kaplan–Meier analysis of freedom from 90-day postoperative adverse events based on D-dimer tertile (Log-rank,
To evaluate the potential influence of other factors, a sub-analysis was conducted stratifying patients by age tertiles, sex, BMI tertiles, history of cerebrovascular disease, history of coronary artery disease, acute visceral ischemia, lower-extremity ischemia, and chronic kidney disease, as presented in
The results of this study show that serum D-dimer level upon admission is independently associated with 90-day postoperative adverse events in patients with acute type A aortic dissection undergoing arch surgery with FET. For every 10 ug/mL increase in plasma D-dimer concentration, the risk of 90-day postoperative adverse events increased by 19%, after adjusting for multiple factors. To the best of our knowledge, this is the first study to show an association between D-dimer level and 90-day postoperative adverse events in patients with acute type A aortic dissection undergoing arch surgery with FET.
D-dimer is a degradation product of cross-linked fibrin. Elevated D-dimer levels are generally thought to be the result of intravascular activation of the coagulation system and secondary fibrinolysis. Several studies have shown that D-dimer is a good diagnostic test for diverse thrombotic conditions, such as ischemic stroke (
The present study confirmed that D-dimer remains an independent predictor of 90-day postoperative adverse events in patients with type A aortic dissection despite surgical treatment. Although the mechanism of this relationship is not yet clear, some possible explanations may clarify its existence. Firstly, D-dimer concentrations may reflect the anatomical extent of the dissection, which represents the extent of the aortic injury (
In our center, over the past 10 years, although arch replacement with FET under moderate hypothermic circulatory arrest (MHAC) plus ante-grade cerebral perfusion has already become a standard procedure for aortic dissection (
There are several limitations in this study. First, this study is a retrospective design from a single center, and our results may not be extendable to patients in other centers. Second, we measured D-dimer only on admission, and a series of measurements after arch replacement might be more valuable for evaluation of the association between D-dimer level and 90-day postoperative adverse events. Third, for the treatment of acute type A aortic dissection, aortic arch replacement combined with FET is a preferred choice at our center, while other centers may select more conventional procedures. This might lead to differences in study results. Fourth, this study lacks data on aortic computed tomography angiography (CTA). Because our center is the largest referral center for aortic disease in China, we only referred to the images from the local hospitals, as we can’t repeat the imaging examination for patients with type A aortic dissection given a limited time. Post-operative CTA was also not collected in every patient. The relationship between the level of D-dimer and CTA was not analyzed. Finally, other coagulation factors and tissue factors, such as factor II, V, VII, VIII, IX et al., were not collected because it was not the routine items of the clinical practice in the Beijing Anzhen Hospital (Capital Medical University of Beijing, China).
D-dimer is easily available in routine medical practice. Our results show that increased D-dimer levels at admission were associated with 90-day postoperative adverse events in patients with type A aortic dissection undergoing arch surgery with FET. This indicates that such high-risk patients deserve close medical monitoring.
The datasets generated for this study are available on request to the corresponding author.
The studies involving human participants were reviewed and approved by the Beijing Anzhen Hospital. The patients/participants provided their written informed consent to participate in this study.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We would like to thank Chen Chang-zhong MD, Ph.D. and Chen Xinlin MD, Ph.D. (Department of Epidemiology and Biostatistics, X&Y Solutions Inc., Boston, MA, United States) and for their helpful review and comments about the manuscript. We also thank the Dr. Jie Liu from the Chinese PLA General Hospital for his advice and support.
The Supplementary Material for this article can be found online at: