Plasma D‐dimer predicts poor outcome and mortality after spontaneous intracerebral hemorrhage

Abstract Background The elevation of plasma D‐dimer levels may predict a higher risk of thrombosis and play a role in the pathological process of patients after spontaneous intracerebral hemorrhage (ICH). However, its function in predicting the prognosis of ICH has not been verified on large cases. Patients and Methods Retrospective cohort study of 1,332 consecutive patients with spontaneous ICH at an academic medical center was conducted. Functional outcome at three months after ICH was dichotomized using the modified Rankin Scale (0–2 versus 3–6). D‐dimer level in blood was analyzed within 1 hr of admission. An ICH outcome score combining D‐dimer level for evaluating poor functional outcome and mortality was tested. Results The proportion of patients with poor functional outcome and mortality at three months was significantly higher in patients with elevated D‐dimer level (p < .001). Multivariable analysis demonstrated that elevated D‐dimer level was an independent predictor of poor functional outcome (odds ratio 1.486, 95% confidence interval 1.086–2.060, p = .014) and mortality (odds ratio 2.015, 95% confidence interval 1.186–3.423, p = .01). An increasing ICH outcome score combining D‐dimer level was associated with increased poor functional outcome and mortality. Conclusions Elevated plasma D‐dimer level after spontaneous ICH is associated with poor functional outcome and mortality. The study suggests that elevated D‐dimer level has a predictive value for outcome and mortality in patients with spontaneous ICH.


| INTRODUC TI ON
Spontaneous intracerebral hemorrhage (ICH) is one of the leading causes of stroke-related fatality and disability, which affects approximately 2 million people in the world each year (Cordonnier et al., 2018). In spite of advances in acute treatment strategies, prevention remains the most effective approach to reduce the significant impact of ICH (Hemphill et al., 2015).
There have been several reports assessing the risk factors for patients with ICH (Guo et al., 2017;Shoamanesh et al., 2018).
Coagulation disorders and impaired hemostasis are established risk factors associated with ICH (Carpenter et al., 2016). Because endothelial injury often occurs after ICH which may lead to coagulation and fibrinolysis activation, D-dimer will be released into the bloodstream as a fibrin degradation product. The elevation of plasma D-dimer levels has been associated with a higher risk of thrombosis and an unfavorable neurologic outcome (Fukuda et al., 2018). Moreover, D-dimer is also easily measurable in routine medical practice; therefore, the utility of D-dimer as a blood biomarker assessing late clinical severity of ICH may add early prognostic information and be a suitable target for therapeutic research.
Recently, several studies reported that an elevated serum D-dimer level could predict poor functional outcomes after ICH; however, there was limited data regarding the association between D-dimer and outcome of ICH patients in any large study (Delgado et al., 2006;Hu et al., 2014). Therefore, the purpose of this study was to investigate whether D-dimer level, detected within 1 hr of admission, can be an effective early indicator for poor functional outcome and mortality at three months in ICH patients based on large number of cases in a single center. Patients,aged ≥18 years,presenting

| D-dimer measurement
Blood samples were obtained within 1 hr of admission and to analyze D-dimer concentrations using standard techniques (CA-7000 Sysmex; Dade Behring). D-dimer was treated as a dichotomous variable. The value of D-dimer ≥ 0.55 mg/L fibrinogen equivalent units (FEU) was defined as elevated.

| Statistical analysis
Statistical analysis was performed using SPSS for Mac (version 21.0, IBM Corp.). Categorical variables were expressed as counts (percentage), whereas continuous variables were expressed as mean ± SD or median (interquartile range [IQR]) values. The differences between patients with and without high D-dimer level on admission were examined using the χ 2 test, the t test, or the Mann-Whitney U test as appropriate. Multiple logistic regression was calculated to identify predictors for poor functional outcome and mortality after incorporating the variables that revealed to be associated with mortality and poor outcome after three months in univariate analyses (p < .05).
An ICH outcome score combining D-dimer level was conducted by predictors which were screened using a multiple logistic regression analysis. The c-statistic (area under the curve) was used to measure the goodness of fit. Statistical significance was defined as p < .05 for all tests.
Conclusions: Elevated plasma D-dimer level after spontaneous ICH is associated with poor functional outcome and mortality. The study suggests that elevated D-dimer level has a predictive value for outcome and mortality in patients with spontaneous ICH.

K E Y W O R D S
D-dimer, mortality, outcome, spontaneous intracerebral hemorrhage

| RE SULTS
We included 1,332 patients (mean 65 ± 14 years old, 52.1% female) with requisite data for analysis. D-dimer was elevated in 540 of 1,332 patients with SICH (40.5%). Age, sex, heart rate, initial neurological status (NIHSS and GCS), hematoma location, midline shift, HCT, glucose, and fibrinogen were significantly associated with elevated plasma D-dimer level. Patients with higher initial hematoma volume were more likely presented with D-dimer elevation   (Table 3).
To compare the impact of D-dimer on the multivariable model, a sub-analysis without D-dimer was showed in Table S1.
Finally, to evaluate the impact of D-dimer on the accuracy of poor functional outcome and mortality assessment, we designed an ICH outcome score combining D-dimer level (ICH-CDD). In multivariable logistic regression analysis, age, first systolic BP, admission GCS, initial hematoma volume, admission PT, intraventricular hemorrhage, and D-dimer levels were also associated with poor functional outcome or mortality (Table 3). Each of these factors was incorporated into ICH-CDD (total score ranging from 0-8 points; Table 4).
The probability for poor functional outcome and mortality at three months for ICH-CDD category is shown in Figure 2. A receiver operating characteristic (ROC) curve was created to assess the ability of ICH-CDD to predict poorer functional outcome and mortality. ICH-CDD showed an area under the curve (AUC) to predict functional outcome of 0.743 (95% CI: 0.692-0.795) and mortality of 0.826 (95% CI 0.782-0.871). In order to objectively evaluate ICH-CDD, we assessed traditional ICH Score (Hemphill et al., 2001)  ICH-CDD showed a potential advantage to predict poorer functional outcome and mortality relative to ICH Score and ICH-FOS.  Values are n (%), mean ± SD, or median (interquartile range).

TA B L E 2
Univariate associations with poor functional outcome (mRS 3-6) and mortality study demonstrated that higher plasma D-dimer level, which is a fibrin degradation product, measured within 1 hr of admission, was significantly associated with poor functional outcome and increased mortality at three months in 1,332 patients with ICH, which is consistent with previous reports. More specifically, we further found that plasma D-dimer levels were independent risk factors of mortality and poor outcome.  . Similarly, recent studies showed that elevated D-dimer increased incidence of thromboembolic events and systemic complications in subarachnoid hemorrhage (SAH) (Fukuda et al., 2017(Fukuda et al., , 2018Zheng et al., 2018). In our results, the elevation of D-dimer showed a strong association with higher initial hematoma volume and intraventricular hemorrhage. To the best of our knowledge, our conclusion that D-dimer is useful in predicting poor prognosis is based on the largest clinical sample data so far; however, the mechanism that elevated D-dimer affects the prognoses of ICH patients still has not yet been established. F I G U R E 2 Probability of poor functional outcome and mortality according to ICH outcome score combining D-dimer level category Although we have made significant progress in the management of ICH and monitoring patients throughout their hospitalization, the initial assessment of clinical prognosis using ICH score remains poor. Since D-dimer levels have been demonstrated to be an independent predictor of poor outcome in ICH, they have not been previously incorporated into relevant prediction scores for functional outcomes and mortality of ICH patients (Chen et al., 2016;Hu et al., 2014). Considering D-dimer's important ability to predict prognosis and because its levels are easily acquired in routine medical practice, we set a new ICH-CDD for evaluating poor functional outcome and mortality in ICH patients.
An increasing ICH outcome score combining D-dimer level was associated with increased poor functional outcome and mortality. Although the AUC for poor functional outcome is not robust, ICH-CDD could effectively evaluate and predict mortality at three months post event. Therefore, our data suggests that D-dimer has an additive predictive value for outcome and mortality on conventional risk factors, but further studies still are needed to investigate whether this modified ICH score could replace or improve the contemporary prediction models.
We also acknowledge that our study has some limitations. First, although D-dimer's role in coagulation and fibrinolytic systems is attractive, the pathophysiologic mechanism of D-dimer in ICH has not been fully elucidated. Further studies need to reveal how D-dimer levels affect hematoma enlargement. Second, our analysis was a retrospective design and conducted at a single institution. Further studies with a prospective and multicenter trial are needed to confirm our findings.
In conclusion, our study showed that elevated plasma D-dimer level after spontaneous ICH is an independent risk factor for poor functional outcome and mortality. In addition, our findings also indicated that elevated D-dimer level has an additive predictive value for outcome and mortality in patients with spontaneous ICH.

CO N FLI C T O F I NTE R E S T
The authors have no conflict of interest to declare.

PEER R E V I E W
The peer review history for this article is available at https://publo ns.com/publo n/10.1002/brb3.1946.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.