Association between serum calcium and hemorrhagic transformation in ischemic stroke: A systematic review and meta-analysis


      • The relationship between serum calcium and hemorrhagic transformation remains controversial.
      • We conducted a meta-analysis to explore the relationship between serum calcium and hemorrhagic transformation.
      • The results of this study may provide a basis for the prevention of hemorrhagic transformation.
      • Serum calcium was related to hemorrhagic transformation and may be one of the risk factors for hemorrhagic transformation.



      Hemorrhagic transformation (HT) is a common complication of ischemic stroke. A growing number of studies have found that serum calcium levels are lower in HT groups than in control groups. However, the relationship between serum calcium and HT remains controversial. We performed a meta-analysis to assess the relationship between serum calcium levels and HT.

      Methods and results

      Electronic databases were searched for studies on serum calcium and HT from inception to November 6, 2021. Ten studies included in present meta-analysis with a total of 3212 participants. Due to the high heterogeneity (I2 = 81%), we chose the random effects model. The results showed that the serum calcium level in the HT group was significantly lower than that in the control group (pooled mean difference, −0.05; 95% confidence interval (CI), (−0.09, −0.02); P = 0.001). Whether thrombolytic or not the results were applied (pooled mean difference, −0.07; 95% CI, (−0.13, −0.01); P = 0.02 and pooled mean difference, −0.03; 95% CI, (−0.06, −0.01); P = 0.007).


      Serum calcium was related to HT and may be one of the risk factors for HT.



      AIS (acute ischemic stroke), asICH (asymptomatic intracranial hemorrhage), CBM (Chinese Biomedical Literature Database), CI (confidence interval), CNKI (China National Knowledge Infrastructure), CT (computed tomography), EVT (endovascular treatment), HT (hemorrhagic transformation), IVT (intravenous thrombolysis), MRI (magnetic resonance imaging), NA (not available), NOS (Newcastle Ottawa Scale), PRISMA (Preferred Reporting Items for Systematic Reviews and meta-Analyses)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Clinical Neuroscience
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • GBD 2019 Diseases and Injuries Collaborators
        Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019.
        Lancet. 2020; 396: 1204-1222
        • GBD 2016 Lifetime Risk of Stroke Collaborators
        Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016.
        N Engl J Med. 2018; 379: 2429-2437
        • Lindley R.I.
        • Wardlaw J.M.
        • Sandercock P.A.
        • et al.
        Frequency and risk factors for spontaneous hemorrhagic transformation of cerebral infarction.
        J Stroke Cerebrovasc Dis. 2004; 13: 235-246
        • Otsu Y.
        • Namekawa M.
        • Toriyabe M.
        • et al.
        Strategies to prevent hemorrhagic transformation after reperfusion therapies for acute ischemic stroke: A literature review.
        J Neurol Sci. 2020; 419: 117217
        • Shen A.Y.
        • Yao J.F.
        • Brar S.S.
        • et al.
        Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation.
        J Am Coll Cardiol. 2007; 50: 309-315
        • Mehta R.H.
        • Cox M.
        • Smith E.E.
        • et al.
        Race/Ethnic differences in the risk of hemorrhagic complications among patients with ischemic stroke receiving thrombolytic therapy.
        Stroke. 2014; 45: 2263-2269
        • van Kranendonk K.R.
        • Treurniet K.M.
        • Boers A.M.M.
        • et al.
        Hemorrhagic transformation is associated with poor functional outcome in patients with acute ischemic stroke due to a large vessel occlusion.
        J Neurointerv Surg. 2019; 11: 464-468
        • Andrade J.B.C.
        • Mohr J.P.
        • Lima F.O.
        • et al.
        Predictors of hemorrhagic transformation after acute ischemic stroke based on the experts' opinion.
        Arq Neuropsiquiatr. 2020; 78: 390-396
        • Guo Y.
        • Yan S.
        • Zhang S.
        • et al.
        Lower serum calcium level is associated with hemorrhagic transformation after thrombolysis.
        Stroke. 2015; 46: 1359-1361
        • Zhong T.T.
        • Wang G.
        • Wang X.Q.
        • et al.
        Serum calcium, albumin, globulin and matrix metalloproteinase-9 levels in acute cerebral infarction patients.
        World J Clin Cases. 2021; 9: 9070-9076
        • Sun R.N.
        • Zhao Y.Z.
        • Zhu Y.H.
        • et al.
        Value of serum calcium and UA levels before thrombolysis for predicting HT in AIS patients after intravenous thrombolysis.
        Chin J Geriatr Heart Brain Vessel Dis. 2021; 23: 617-620
        • Wei X.F.
        • Che C.H.
        • Liu C.Y.
        • et al.
        Analysis of risk factors related to hemorrhagic transformation after thrombolytic therapy in patients with acute ischemic stroke.
        Chin J Clin Rational Drug Use. 2017; 10: 15-18
        • Xing Y.
        • Guo Z.N.
        • Yan S.
        • et al.
        Increased globulin and its association with hemorrhagic transformation in patients receiving intra-arterial thrombolysis therapy.
        Neurosci Bull. 2014; 30: 469-476
        • Li S.Z.
        The study of serum magnesium and matrix metalloproteinase-9 in predicting hemorrhagic transformation after acute ischemic stroke.
        Wan Nan Med College. 2020; : 1-68
        • Liu L.J.
        • Liu X.Y.
        • Wu X.S.
        • et al.
        Influencing factors of hemorrhagic transformation in non-thrombolytic patients after acute large area cerebral infarction.
        Chinese J Gen Pract. 2021; 19: 898-907
        • Cheng Z.
        • Huang X.
        • Muse F.M.
        • et al.
        Low serum magnesium levels are associated with hemorrhagic transformation after thrombolysis in acute ischemic stroke.
        Front Neurol. 2020; 11: 962
        • Tan G.
        • Yuan R.
        • Wei C.
        • et al.
        Serum magnesium but not calcium was associated with hemorrhagic transformation in stroke overall and stroke subtypes: a case-control study in China.
        Neurol Sci. 2018; 39: 1437-1443
        • Kang X.
        Predictive value of amino-terminal B-type natriuretic peptide precursor for hemorrhagic transformation in patients with acute ischemic stroke.
        Chongqing Med Univ. 2019; : 1-40
        • Ma R.X.
        Analysis of transformation characteristics and risk factors of intracranial hemorrhage after intravenous thrombosis in acute cerebral infarction.
        Ning Xia Med Univ. 2021; : 1-35
        • Shamseer L.
        • Moher D.
        • Clarke M.
        • et al.
        Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation.
        BMJ. 2016; 350: g7647
        • Stang
        Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
        Eur J Epidemiol. 2010; 25: 603-605
        • Wan X.
        • Wang W.
        • Liu J.
        • et al.
        Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range.
        BMC Med Res Methodol. 2014; 14: 135
        • Luo D.
        • Wan X.
        • Liu J.
        • et al.
        Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range.
        Stat Methods Med Res. 2018; 27: 1785-1805
        • Robertson W.G.
        • Marshall R.W.
        Calcium measurements in serum and plasma–total and ionized.
        CRC Crit Rev Clin Lab Sci. 1979; 11: 271-304
        • Zhang Y.B.
        • Zheng S.F.
        • Yao P.S.
        • et al.
        Lower ionized calcium predicts hematoma expansion and poor outcome in patients with hypertensive intracerebral hemorrhage.
        World Neurosurg. 2018; 118: e500-e504
        • Morotti A.
        • Charidimou A.
        • Phuah C.L.
        • et al.
        Association between serum calcium level and extent of bleeding in patients with intracerebral hemorrhage.
        JAMA Neurol. 2016; 73: 1285-1290
        • Liu J.
        • Wang D.
        • Xiong Y.
        • et al.
        A cohort study of relationship between serum calcium levels and cerebral microbleeds (CMBs) in ischemic stroke patients with AF and/or RHD.
        Medicine (Baltimore). 2016; 95: e4033
        • Fukuda T.
        • Nakashima Y.
        • Harada M.
        • et al.
        Effect of whole blood clotting time in rats with ionized hypocalcemia induced by rapid intravenous citrate infusion.
        J Toxicol Sci. 2006; 31: 229-234
        • Wellman G.C.
        • Nathan D.J.
        • Saundry C.M.
        • et al.
        Ca2+ sparks and their function in human cerebral arteries.
        Stroke. 2002; 33: 802-808
        • Guo Y.
        • Yang X.
        • He J.
        • et al.
        Important roles of the Ca2+-sensing receptor in vascular health and disease.
        Life Sci. 2018; 209: 217-227
        • Ortiz-Capisano M.C.
        • Liao T.D.
        • Ortiz P.A.
        • Beierwaltes W.H.
        Calcium-dependent phosphodiesterase 1C inhibits renin release from isolated juxtaglomerular cells.
        Am J Physiol Regul Integr Comp Physiol. 2009; 297: R1469-R1476