Elevated plasma D-dimer level is associated with short-term poor outcome in patients with acute ischemic stroke: a prospective, observational study

doi:10.21203/rs.2.9184/v2

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Elevated plasma D-dimer level is associated with short-term poor outcome in patients with acute ischemic stroke: a prospective, observational study

https://doi.org/10.21203/rs.2.9184/v2

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published 22 Jul, 2019

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Background: Elevated level of plasma D-dimer increases the risk of ischemic stroke, stroke severity and progression of stroke status, but the association between plasma D-dimer level and functional outcome is unclear. The aim of this study is to investigate whether Plasma D-dimer level is a determinant of short-term poor functional outcome in patients with acute ischemic stroke (AIS). Methods: This prospective study included 877 Chinese patients with AIS admitted to Renmin Hospital of Wuhan University within 72 hours of symptom onset. Patients were categorized per plasma D-dimer level: Quartile 1(0.24 mg /L), Quartile 2 (0.25–0.56 mg /L), Quartile 3 (0.57–1.78 mg /L), and Quartile 4 (1.78mg /L). Each patient’s medical record was reviewed, and demographic, clinical, laboratory and neuroimaging information was abstracted. Functional outcome at 90 days was assessed with the modified Rankin Scale (mRS). Results: Of 877 patients were included (mean age, 64 years; male, 68.5%), poor outcome was present in 302 (34.4%) patients. After adjustment for potential confounding variables, higher plasma D-dimer level on admission was associated with poor outcome (adjusted odds ratio [aOR] 2.257, 95% CI1.349-3.777 for Q4:Q1; P trend = 0.004). According to receiver operating characteristic (ROC) analysis, the best discriminating factor was a plasma D-dimer level 0.315 mg/L for pour outcome [area under the ROC curve (AUC) 0.657; sensitivity 83.8%; specificity 41.4%]. Conclusion: Elevated plasma D-dimer level on admission was significantly associated with increased poor outcome after admission for AIS, suggesting the potential role of plasma D-dimer as a predictive marker for short-term poor outcome in patients with AIS.

Internal Medicine Specialties

Acute ischemic stroke

D-dimer

Outcome

modified Rankin Scale

Epidemiological investigations have concluded that stroke is a leading cause of adult disability and mortality, and it poses a serious public health burden worldwide [1-3]. Recently the multicenter Global Burden Disease (GBD 2016) Study found that risk of ischemic stroke was 18.3% ，the risk of hemorrhagic stroke was 8.2% among adults 25 years of age or older [4]. As a predominant stroke subtype in Chinese populations[5], acute ischemic stroke (AIS) was up to 66.4% among the stroke subtypes between September 2007 and August 2008 in the Chinese National Stroke Registry [6]. Because of the high morbidity of AIS and high risk of disability after AIS, the estimation of prognosis is an emergent issue when physicians confront with these concerns from patients and families after AIS. Recent studies have found prognostic factors such as glycemic index, BMI and uric acid, but their prognostic values on AIS was inconsistent [7-12]. For better specific management of stroke rehabilitation regarding neurological functional outcome, identifying more powerful predictors of clinical prognosis is indispensable.

D-dimer is a final soluble fibrin degradation product and derived from the cross-linked fibrin network undergoes plasmin-mediated degradation. As plasma D-dimer level reflects increases in blood thrombosis and degradation of fibrin, plasma D-dimer could be a biological marker of hemostatic abnormalities and thrombosis[ 13]. Elevated plasma D-dimer level is reportedly a determinant of stroke progression [ 14], and infarction volume [ 15] and the incidence of stroke [ 16]. There are recently many studies about whether plasma D-dimer level is a determinant of poor functional outcomes after AIS, however, the conclusions of studies were controversial [ 17-20]. Some investigators found that plasma D-dimer level could predict independently poor functional outcomes in patients with AIS[ 17, 18], while other investigators reported the conflicting results[ 19, 20].

Accordingly, the aim of this study was to investigate whether elevated plasma D-dimer level could be a significant determinant of poor outcome after admission for AIS.

Study population

This was a prospective follow-up study.Date were retrospectively analyzed from a prospective registry. We enrolled 877 consecutive Chinese patients with AIS at Renmin Hospital of Wuhan University from January 2017 to August 2018. All patients were admitted within 72 hours of experiencing a new focal or global neurological event. Acute ischemic stroke was diagnosed according to the World Health Organization criteria [

                 21
              </a>] combined with brain computed tomography or magnetic resonance confirmation within
           72 hours. Patients were excluded if any of the following criteria were met: a delay
           of 72 hours from symptom recognition to admission, age younger than 18 years, preexisting
           significant disability (defined as modified Rankin scale, mRS2) from any condition,
           intracranial hemorrhage, malignancy, febrile disorders, and acute or chronic inflammatory
           disease at study enrollment. Each participant was followed up after 3 months via telephone,
           email, and face to face. The study protocol complied with the Declaration of Helsinki and was approved by the
           Wuhan University Ethics Committee.</p>

Demographic and clinical assessment

Socio-demographic, self-reported medical history and vascular risk biomarker data were assessed and included: age, sex, body mass index (BMI), histories of hypertension, diabetes, alcohol consumption, smoking, dyslipidemia, atrial fibrillation, previous stroke, and coronary artery disease (CAD). The National Institutes of Health Stroke Scale (NIHSS) scores were used by stroke neurologists to assess neurological deficit when the patients were admitted [ 22]. Stroke subtype was classified according to Trial of Org 10172 in acute stroke treatment (TOAST classification) criteria [ 23], which distinguished large-artery arteriosclerosis, small-artery occlusion, cardio-embolism, other causative factor, and undetermined causative factor.

Fasting plasma glucose (FPG) was measured in each patient after at least 8 h of fastingon the first or second day of admissionPlasma D-dimer level was measured for all patients at admission with a particle-enhanced, immunoturbidimetric assay in a calibrated SYSMEX7000 analyzer (Sysmex Corporation, Hyogo, Japan). The normal range of morning plasma D-dimer concentration in our hospital laboratory is 0–0.55 mg/L.

Follow‑up and short term outcomes

Patient follow-up was performed at 90 days after stroke onset. The prognosis outcome was assessed with the modified Rankin Scale (mRS) viatelephone interview, email, and face to face by a trained research nurse or neurologist, a good functional outcome was defined as a mRS of 0–2 points, whereas a poor outcome was defined as a mRS of 3–6 points.

Statistical analysis

For continuous variables, data are expressed either as the means ± standard deviations (SD) or medians (interquartile ranges, IQR). Categorical variables are expressed as frequencies and percentages. The patients were categorized into two groups according to prognosis outcome (good outcome group vs poor outcome group) , Two-group comparison of normally distributed continuous variables was assessed using independent t-tests, non-parametric Mann–Whitney U test was used for not normally distributed continuous variables, and χ 2 test for categorical variables. Furthermore ,we categorized the patients into four quartiles groups according to their plasma D-dimer level at admission. Four-group comparison was assessed using the χ 2 test, one-way analysis of variance(ANOVA) and Mann–Whitney U tests, as appropriate. Multivariate analysis adjustment for variables was performed for the correlation between the quartiles of plasma D-dimer level and poor outcome by logistic regression analysis, which used methods from previous studies [ 24, 25] . Results were expressed as adjusted odds ratios (OR) with the corresponding 95% confidence intervals (CIs). Receiver operating characteristic (ROC) curves were utilized to evaluate the accuracy of plasma D-dimer level to predict AIS poor neurological outcome. The area under the curve (AUC) was calculated as measurements of the accuracy of the test. All statistical analysis was performed with SPSS for Windows, version 22.0 (SPSS Inc., Chicago, IL, USA). P<0.05 was considered statistically significant.

Baseline characteristics of the patients

A total of 877 AIS patients (median age 64 years,68.5% male) who met the inclusion criteria were recruited for this study，and we collected variables associated with functional outcome of AIS included sex, age, BMI, vascular risk factors( smoker, Alcohol drinker, atrial fibrillation, diabetes, hypertension, CAD, dyslipidemia, previous stroke),baseline Systolic blood pressure(SBP) , baseline Systolic diastolic blood pressure(DBP) , FBG , baseline NIHSS scores and stroke subtype. The median plasma D-dimer level on admission was 0.56 (0.24-1.79) mg /L, and the median NIHSS score on admission was 5(3–8). In this study, 575 patients(65.6%) presented with good outcomes, 302 patients(34.4%) presented with poor outcome and 77 patients(8.8%) had died among the 877 patients whthin 90 days. The baseline characteristics and outcome of the patients with AIS are described in Table 1. The sex, age, BMI, smoker, history of atrial fibrillation, FBG, plasma D-dimer level, baseline NIHSS scores and stroke etiology were markedly associated with the outcomes of AIS at 90 days (P<0.05 for all).

Figure 1 shows the plasma D-dimer level between two functional outcome groups. In the patients with poor outcome, plasma D-dimer level were significantly higher compared with those in patients with good outcome [0.88(IQR, 0.42–2.72) mg/L vs 0.46 (IQR, 0.21–1.32) mg/L; Z=-7.655,P=0.000]

Correlation between plasma D-dimer level and 90-Day functional outcome

Patients were stratified into four groups according to plasma D-dimer quartiles: Plasma D-dimer level 0.24(n=226), 0.25–0.56(n=213), 0.57–1.78(n=219), and 1.78mg /L(n=219) (Table 2). Among the four groups, there were no significant differences in the history of hypertension, diabetes, dyslipidemia, previous stroke, Alcohol drinker, FBG, and baseline SBP (P0.05 for all). Age, sex, BMI, smoker, atrial fibrillation, baseline DBP, baseline NIHSS scores, stroke etiology, and mortality differed among the four groups (P<0.05 for all). The unadjusted comparisons of the four groups revealed more poor outcomes among the higher quartiles of Plasma D-dimer (χ2=53.724, P = 0.000 ). (Figure 2).

Functional outcome stratified for plasma D-dimer Level is shown in Figure 3,univariate analysis shows a clear relationship between admission plasma D-dimer level and mRS using χ2 Test (χ2=877.000, P trend = 0.000). Furthermore, the correlation between plasma D-dimer level and pooroutcome after adjustment for variables are detailed in Table 3. In patients with high plasma D-dimer level, the risk of poor functional outcome at 90 days was significantly increased as compared with the group with low plasma D-dimer level (P trend = 0.000, OR = 3.800, 95% CI = 2.420-5.965 for Q4: Q1; adjusted for age, sex and BMI). Additional adjustment for smoker, alcohol drinker, atrial fibrillation, diabetes, hypertension, CAD, dyslipidemia ,previous stroke, baseline SBP , baseline DBP, FBG , baseline NIHSS scores and stroke etiology did not influence this finding, an overall OR of 2.257 (P trend = 0.004, 95% CI = 1.349-3.777 for Q4: Q1) was found for patients with high plasma D-dimer level.

Predictive values of plasma D-dimer level for outcome

To further evaluate the predictive values of Plasma D-dimer level in patients with AIS, the ROC curves and AUCs were created and are depicted (Figure 4). Based on the ROC curve, the optimal cut-off value of plasma D-dimer level as an indicator for diagnosis of unfavorable functional outcome was projected to be 0.315 mg/L, which yielded a sensitivity of 83.8% and a specificity of 41.4%, the area under the curve was 0.657 (95%CI, 0.620–0.694; P=0.000).

In the present study, higher plasma D-dimer level on admission was a significant independent determinant of short-term neurological dysfunction in patients with AIS within 90 days in the Chinese population. After adjusting for various confounders, the correlationremained significant.

Previous prospective epidemiological investigations have concluded that there is a positive association between plasma D-dimer level and stroke [ 26-28]. In some studies, the results showing that plasma D-dimer level was associated with stroke severity [ 29, 30], infarct volume [ 15, 31, 32] and progression of stroke status [ 14, 33, 34]. However, the relationship between plasma D-dimer level and functional outcome in patients with AIS has been poorly studied.

The available investigations of stroke have shown relationships-between plasma D-dimer level and functional outcome in several different types of population with AIS [ 35-39]. Nam et al. [ 35] and Nezu et al. [ 36] found a predictive role of plasma D-dimer level only in patients with cryptogenic stroke. A Canadian study by Kim et al. [ 37] reported prognostic Value of plasma D-dimer level in patients with noncardioembolic stroke. In the study of the Chinese population complicating coronary heart disease, the result indicated that higher plasma D-dimer level had worst outcome within 90 days after initial onset of AIS[ 38]. A Swiss study by Hsu et al. reported high plasma D-dimer level indicates unfavorable outcome of in patients with AIS receiving intravenous thrombolysis[ 39]. But review previous literature, we also found that some other studies have reported conflicting results in comparison. A report by Squizzato et al. [ 19] revealed that plasma D-dimer level with AIS probably do not predict the functional outcome after adjustment for age and stroke subtype. Furthermore, two other studies did not even find a meaningful association between plasma D-dimer level and the prognosis of patients with AIS[ 40, 41].

In this study, because the prognostic did not alter even if adjusted various confounders such as age, sex, BMI, vascular risk factors, baseline NIHSS scores, and stroke etiology, our results revealed plasma D-dimer level is an independent biological prognostic marker of AIS. Actually, the positive value of plasma D-dimer in patients with all subtypes of AIS was indicated in the previous several studies [33, 41, 42], which is consistent with our findings.

D-dimer derived from the cross-linked fibrin network is a final soluble fibrin degradation product undergoes plasmin-mediated degradation [ 13]. Plasma D-dimer could be elevated in population with thrombotic diseases such as pulmonary embolism and venous thromboembolism [ 42, 43], however, the mechanism remains unclear. There are several possible explanations for why plasma D-dimer level might be relevant to poor functional outcome in patient with AIS. First of all, plasma D-dimer level increases in blood coagulation and degradation of fibrin and could be a marker of thrombosis based on the underlying mechanisms [ 44, 45]. Moreover, high plasma D-dimer level may result in resistant to the endogenous fibrinolytic system and influence thromboembolism formation [ 40, 46]. Furthermore, plasma D-dimer level also stimulates the immune system and lead to changes in inflammatory mediators levels such as IL-1, TNF-alpha, IL-6, and IL-8 [ 47, 48]. Activated inflammation may contribute to the pathological alteration in patients with AIS [ 49]. In addition, infarct volume, initial stroke severity, and progression of stroke status were correlated with high plasma D-dimer level [ 14, 29-34], therefore elevated plasma D-dimer level may predict poor outcome through the aggravation of cerebral tissue damage by disturbing recanalization and increasing reperfusion injury. Additionally, plasma D-dimer level in patients with AIS may identify patients who may benefit from additional interventions, targeting some of the mechanisms mentioned above. This needs be explored in further studies.

This current study has several limitations. First, this is a single-center, observational study. The sample sizes of patients are small, and selection bias was a major concern, therefore limiting the power to generalize our results. Second, the plasma D-dimer level was measured only at admission in our study, however ,recording the serial change of plasma D-dimer level might be better explored the correlation between D-dimer and outcomeafter AIS. Finally, our study did explore short-term outcome whose end-point was defined at 90 days. The correlation between plasma D-dimer level and long-term prognosis require further confirmation in our study population. Therefore, further larger sample size, multicenter studiesneed to be conducted.

Elevated plasma D-dimer level on admission was significantly associated with increased poor outcome after admission for AIS, suggesting the positive role of plasma D-dimer level within 72-hours of a stroke as a predictive marker for short-term poor outcome after 90 days in patients with AIS. Plasma D-dimer level isa convenient and economical biological indicator could be used for better specific management of stroke rehabilitation regarding functional outcome.

AIS :acute ischemic stroke; mRS :modified Rankin Scale ;NIHSS: National Institutes of Health Stroke Scale; TOAST: Trial of Org 10,172 in Acute Stroke Treatment ;OR: Odds ratio; aOR: adjusted odds ratio; ROC :receiver operating characteristic; AUC: area under the ROC curve；BMI :body mass index ; CAD: coronary artery disease; SBP :systolic blood pressure; DBP :diastolic blood pressure;FPG :fasting plasma glucose; SD ：standard deviations ;IQR ： interquartile ranges ;ANOVA: analysis of variance； CI: Confidence interval

Ethics approval

This study is approved by the Ethics Committee of Wuhan University, Wuhan, China.

Consent to participate

All participants gave written informed consent for participation and to publication.

Consent for publication

Not applicable.

Authors’ contributions

TY interpreted the patient data and were the main contributors in writing the manuscript. TY, BLT, GL, DH, and YQZ performed the statistical analysis and were a major contributor in writing the manuscript. QC, CFW, QZ, BP, YG, and LX collected the data and were the major contributors in writing the manuscript. GHW participated in study design, data interpretation and revise the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

Funding

This research was supported by the National Natural Science Foundation of China (No. 81401051) and the Hubei Provincial Natural Science Foundation of China (No. 2016CFB575).

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgments

We thank all the participants for their participation in this study.

Author details

1 Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China

2 Department of Neurology, Dawu County Hospital of Traditional Chinese Medicine, Hubei 432800, China

3 Emergency Department, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430061, China

4 Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan 430060, China

5 Institute of Neuropsychiatry, Renmin Hospital of Wuhan University, Wuhan 430060, China

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Table 1 Baseline characteristics of the study patients grouped by 90-day functional outcome

Variable	all （n=877)	good outcome (n=575)	poor outcome (n=302)	P value
Age (years) , median (IQR)	64.00 (54.50-73.00)	62(52-70)	68(60-77.25)	0.000
Sex (male) , n (%)	601(68.5)	413(71.8)	188(62.3)	0.004
BMI (kg/m2) ,(Mean± SD)	25.09±3.64	24.76±3.54	25.70±3.74	0.000
Smoker , n (%)	337(38.4)	217(37.7)	120(39.7)	0.307
Alcohol drinkers , n (%)	192(21.9)	137(23.8)	55(18.2)	0.056
Hypertension , n (%)	531(60.5)	336(58.4)	195(64.6)	0.077
Diabetes mellitus , n (%)	281(32.0)	172(29.9)	109(36.1)	0.062
CAD , n (%)	106(12.1)	61(10.6)	45(14.9)	0.064
Atrial fibrillation , n (%)	110(12.5)	44(7.7)	66(21.9)	0.000
Dyslipidemia , n (%)	309(35.2)	209(36.3)	100(33.1)	0.341
Previous stroke , n (%)	116(13.2)	73(12.7)	43(14.2)	0.522
NIHSS on admission , median (IQR)	5(3-8)	5(3-7)	7(5-8)	0.000
SBP(mmHg) , median (IQR)	147(131-164)	147(132-162)	147(130-165)	0.949
DBP (mmHg) , median (IQR)	83(75-92)	83(75-92)	83(74-92)	0.229
FBG (mmol/L) , median (IQR)	6(4.81-8.22)	5.62(4.63-7.50)	6.70(5.46-9.50)	0.000
D-dimer (mg /L) , median (IQR)	0.56(0.24-1.79)	0.46(0.21-1.32)	0.88(0.42_2.72)	0.000
Stroke etiology , n (%)				0.000
Large-vessel occlusive	344(39.2)	176(30.6)	168(55.6)
Small-vessel occlusive	366(41.7)	312(54.3)	54(17.9)
Cardioembolic	88(10)	32(5.6)	56(18.5)
Other	30(3.4)	21(3.7)	9(3.0)
Undetermined	49(5.6)	34(5.9)	15(5.0)

BMI:body mass index; CAD:coronary artery disease; NIHSS: National Institutes of Health Stroke Scale; SBP: systolic blood pressure ;DBP: diastolic blood pressure ; IQR : interquartile range ;SD: standard deviation.

a χ 2 test, independent t-tests, or Mann-Whitney U test , as appropriate .

Table 2 Baseline characteristics of the study patients grouped by plasma D-dimer Quartile

	Quartile 1	Quartile 2	Quartile 3	Quartile 4
	(≤ 0.24) n=226	(0.25-0.56) n=213	(0.57-1.78) n=219	(＞1.78) n=219	Pvaluea
Age (years), median (IQR)	59(50-66)	66(58-74)	66(53-76)	66(57-76)	0.000
Sex (male) , n (%)	172(76.1)	152(71.4)	142(64.8)	135(61.6)	0.005
BMI(kg/m2) ,(Mean± SD)	24.89±3.52	24.79±3.56	24.99±3.64	25.69±3.78	0.040
Smoker , n (%)	102(45.1)	90(42.3)	74(33.8)	71(32.4)	0.012
Alcohol drinker , n (%)	56(24.8)	51(23.9)	44(20.1)	41(18.7)	0.344
Hypertension , n (%)	138(61.1)	131(63.5)	130(59.4)	133(60.7)	0.972
Diabetes mellitus , n (%)	83(36.7)	71(33.3)	55(25.1)	72(32.9)	0.062
CAD, n (%)	18(8.0)	24(11.3)	27(12.3)	37(16.9)	0.036
Atrial fibrillation , n (%)	10(4.4)	23(10.8)	30(13.7)	47(21.5)	0.000
Dyslipidemia , n (%)	90(39.8)	80(37.6)	63(28.8)	76(34.7)	0.085
Previous stroke , n (%)	22(9.7)	38(17.8)	28(12.8)	28(12.8)	0.093
NIHSS on admission, median (IQR)	4(3-7)	5(3-7)	6(3-7)	7(5-10)	0.000
SBP (mmHg), median (IQR)	148(134-165)	145(131-162)	144(130-162)	152(134-166)	0.221
DBP (mmHg), median (IQR)	85(78-95)	82(76-90)	80(74-90)	84(76-93)	0.001
FBG (mmol/L), median (IQR)	5.7(4.66-8.23)	6.01(4.95-7.85)	5.90(4.78-7.46)	6.23(5.00-9.10)	0.089
D-dimer (mg /L), median (IQR)	0.17（0.12-0.21）	0.38（0.31-0.48）	0.92（0.72-1.27）	3.06（2.45-3.97）	0.000
Stroke etiology, n (%)					0.000
Large-vessel occlusive	81(35.8)	82(38.5)	86(39.3)	95(43.4)
Small-vessel occlusive	118(52.2)	93(43.7)	91(41.6)	64(29.2)
Cardioembolic	7(3.1)	18(8.5)	24(11)	39(19.8)
Other	12(5.3)	7(3.3)	5(2.3)	6(2.7)
Unknown	8(3.5)	13(6.1)	13(5.9)	15(6.8)
Mortality, n (%)	4(1.8)	13(6.1)	24(11)	36(16.4)	0.000

a χ 2 test, ANOVA or Mann–Whitney U tests, as appropriate .

Table 3 Adjusted odds ratios for poor outcome according to plasma D-dimer levels

	Quartile 1	Quartile 2	P value	Quartile 3	P value	Quartile 4	P value	P for trend
OR (95% CI)a	1	2.139（1.348-3.393）	0.001	2.518（1.596-3.974）	0.000	3.800（2.420-5.965）	0.000	0.000
OR (95% CI)b	1	2.021（1.225-3.334）	0.006	2.503（1.527-4.105）	0.000	3.181（1.964-5.201）	0.000	0.000
OR (95% CI)c	1	2.028（1.208-3.405）	0.007	2.246（1.345-3.749）	0.002	2.257（1.349-3.777）	0.002	0.004

OR: odds ratio;CI :confidence interval; ORa, adjusted for age, sex, and BMI. ORb, as note a with additional adjustment for smoker, Alcohol drinker, atrial fibrillation, diabetes, hypertension, CAD, dyslipidemia, previous stroke, and stroke etiology. ORc, as note b with additional adjustment for baseline SBP, DBP, FBG andbaseline NIHSS scores.

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published 22 Jul, 2019

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Editorial decision: Minor revision
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Elevated plasma D-dimer level is associated with short-term poor outcome in patients with acute ischemic stroke: a prospective, observational study

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