Lower Serum Calcium Level Is Associated With Hemorrhagic Transformation After Thrombolysis
Background and Purpose—We aim to investigate whether lower admission serum calcium levels are associated with hemorrhagic transformation (HT) after intravenous thrombolysis (IVT).
Methods—A total of 362 patients treated with IVT was divided into 4 quartiles based on admission serum calcium levels (Q1[<2.16], Q2[2.16, 2.23], Q3[2.24, 2.31], and Q4[>2.31] mmol/L). HT was classified as hemorrhagic infarction and parenchymal hemorrhage. Logistic regression was applied to assess the association between serum calcium levels and the incidence of HT.
Results—Compared with Q4, HT was more common in Q1 (odds ratio, 2.580; 95% CI, [1.258–5.292]; P=0.010), Q2 (odds ratio, 2.382; 95% CI, [1.163–4.877]; P=0.018), and Q3 (odds ratio, 2.293; 95% CI, [1.133–4.637]; P=0.021). Hemorrhagic infarction was more common in Q1 (P=0.037), and Q2 (P=0.018), compared with Q4, and parenchymal hemorrhage was more common in Q1 (P=0.029) than Q4.
Conclusions—Lower admission serum calcium level is independently associated with HT after IVT, and this hypothesis needs larger confirmatory trials.
Hemorrhagic transformation (HT) is the main complication of intravenous thrombolysis (IVT) after ischemic stroke.1–3 Previous studies have demonstrated that low serum calcium level is associated with poor outcome, extensive infarction in patients with ischemic stroke, and large hematoma volumes in patients with intracerebral hemorrhage.4–7 As an essential cofactor in the coagulation cascade, calcium ion plays an important role in the conversion of prothrombin to thrombin. The association of decreased calcium levels with prolonged clotting time and bleeding tendency has been shown in rodent models.8 We, therefore, hypothesized that patients with lower serum calcium levels may be more likely to experience HT after IVT.
Subjects and Methods
Consecutive patients admitted to our department from March 2010 to August 2014 were prospectively considered. The inclusion criteria for enrollment were (1) age ≥18 years; (2) diagnosis of acute ischemic stroke and treatment with IV recombinant tissue-type plasminogen activator within 6 hours of symptom onset; (3) serum calcium level collected on admission; and (4) computed tomography/magnetic resonance imaging performed 24 hours after IVT. Patients were excluded if endovascular interventions were performed. IV recombinant tissue-type plasminogen activator (alteplase, 0.9 mg/kg up to a maximum of 90 mg/kg) was used with 10% of the total dosage as a bolus and the rest >1 hour.
We used DWI lesion volume on magnetic resonance imaging or the volume of the brain tissue with a relative cerebral blood flow <30% on perfusion computed tomography together as the volume of the infarct core.9 We divided HT within 24 hours after thrombolysis into hemorrhagic infarction (HI) and parenchymal hemorrhage (PH) on the basis of imaging characteristics, referring to the European Cooperative Acute Stroke Study II (ECASS II) definition.10
Fisher exact test was used to compare the dichotomous variables between groups, whereas t test, or Mann–Whitney U test was used for the continuous variables. One-way ANOVA or Kruskal–Wallis test was used between multiple groups. For multivariate analysis, the pool of covariates were determined based on univariate analysis at P<0.1 level and previous literature. All statistical analyses were performed by SPSS 19.0.
A total of 362 patients met the study criteria, HT was evaluated on magnetic resonance imaging (n=259) and computed tomographic scan (n=103) within 24 hours after IVT, affecting 115 (31.8%) patients, among whom 80 (22.1%) had HI and 35 (9.7%) had PH. Incidence of HT in each calcium quartile was 40.2% in Q1, 33.0% in Q2, 33.3% in Q3, and 21.5% in Q4, respectively. Incidence of HI in each calcium quartile was 25.6% in Q1, 26.6% in Q2, 22.6% in Q3, and 14.0% in Q4, respectively. Incidence of PH in each calcium quartile was 14.6% in Q1, 6.4% in Q2, 10.8% in Q3, and 7.5% in Q4, respectively.
Table I in the online-only Data Supplement gives the demographic characteristics and clinical variables by calcium quartiles. Logistic regression found that compared with Q4, the incidence of HT was significantly higher in Q1, Q2, and Q3, as shown in Table. HI is more common in Q1, and Q2, compared with Q4. Q3 has a tendency to have more HI than Q4, but failed to reach a statistical significance. Q1 was more likely to have PH than Q4, whereas Q2 and Q3 did not reach statistical significance (Table). The results were similar when infarct volume was included in the logistic regression model (Table II in the online-only Data Supplement).
To our knowledge, this is the first study investigating the relationship between admission serum calcium level and HT after IVT. We found that a lower admission serum calcium level was associated with a higher incidence of HT within 24 hours after IVT.
In previous studies, a lower admission serum calcium level within 24 hours after ischemic stroke onset is associated with higher baseline National Institutes of Health Stroke Scale (NIHSS) score, larger infarct volume, and poor discharge functional outcome.4,5 In our study, we found that lower admission serum calcium level was associated with HT after IVT. Micozkadioglu et al11 found a slight elevation in admission serum calcium level in 27 patients with HT out of 160 patients with stroke. However, multivariate analysis was not performed and the percentage of patients treated with IVT was not mentioned. In patients with acute intracerebral hemorrhage, admission serum calcium level was also found to be negatively related to hematoma volume.6
There are 2 possible mechanisms which may explain the association between serum calcium level and HT after IVT. First, calcium ion is an essential cofactor in the coagulation cascade and plays an important role in the conversion of prothrombin to thrombin. In rodent models, decreased calcium levels was found to be associated with prolonged clotting time and bleeding tendency.8 Second, evidence demonstrated that the activation of extracellular calcium receptors located in the perivascular sensory nerves could lead to the release of vasodilator substance, which mediated the relaxation of isolated arteries.12 Therefore, because of the decreased Ca2+-induced relaxation of isolated arteries, lower serum calcium level may result in the persistent constriction of the blood vessels in the peri-ischemic zone, which subsequently elevates local blood pressure and causes HT.6
Our study has limitations. First, it is limited by the single-center, hospital-based, retrospective design. Second, our study only focused on total serum calcium, whereas ionized calcium, the physiologically active compartment, was not measured. Third, a progressive decrease along the 1 to 4 quartiles was followed in the proportion of HI, but not in the PH quartiles. This nonproportional effect could be because of the relatively low incidence of PH. Studies based on larger population is thus needed.
In conclusion, lower admission serum calcium level is independently associated with HT in 24 hours after thrombolysis. Admission serum calcium level might be used as one of the predictors for HT after thrombolysis. Further investigations will be needed to test this hypothesis and then elucidate the potential neuroprotective mechanism of serum calcium.
Sources of Funding
Dr Lou was supported by Zhejiang Provincial Natural Science Foundation of China (LR12H09001), the Science Technology Department of Zhejiang Province (2013C03043-3), the National Natural Science Foundation of China (81171095 and 81471170). Dr Liebeskind was supported by National Institutes of Health/National Institute of Neurological Disorders and Stroke (K24NS072272 and R13NS089280).
Dr Liebeskind is a consultant/advisory board (modest)-Stryker and Covidien and he was employed by the University of California, which holds a patent on retriever devices for stroke, at the time of this work. The other authors report no conflicts.
↵* Drs Guo and Yan contributed equally.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.115.008992/-/DC1.
- Received February 1, 2015.
- Revision received March 1, 2015.
- Accepted March 3, 2015.
- © 2015 American Heart Association, Inc.
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