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Impact of D-dimer levels for short-term or long-term outcomes in cryptogenic stroke patients

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Abstract

Background

D-dimer levels are used in several clinical settings, such as in predicting venous thrombosis, cardioembolic stroke and cancer status. In the present study, we investigated the associations between plasma D-dimer levels at admission, clinical characteristics and mortality at discharge in cryptogenic stroke patients. We also investigated whether D-dimer levels can predict long-term outcomes in those patients, including those with and without right-to-left shunt (RLS).

Methods

Acute cryptogenic stroke patients (n = 295, 72 ± 13 years old) were consecutively enrolled and retrospectively analyzed. We defined the cryptogenic stroke as an undetermined etiology according to the Trial of Org 10172 in Acute Stroke Treatment criteria. Plasma D-dimer levels at admission were evaluated. Assessments for RLS were performed using saline contrast-transcranial Doppler ultrasonography or contrast-transesophageal echography. Survivors (at discharge) underwent follow-up for up to 3 years after stroke onset.

Results

Of the total enrolled cohort, 17 patients died at discharge. D-dimer levels correlated with initial National Institutes of Health Stroke Scale (NIHSS) score (r = 0.391, P < 0.001) and were associated with mortality at discharge [odds ratio 1.04; 95% confidence interval (CI) 1.00–1.08, P = 0.049] after adjusting for age, sex and initial NIHSS score. Of the 278 survivors at discharge, 266 patients were evaluated to assess RLS during hospitalization, and 62 patients (23.3%) exhibited RLS. According to the median plasma D-dimer levels at admission (0.7 µg/ml), the patients were divided into a low D-dimer group (n = 136, < median) and a high D-dimer group (n = 130, ≥ median). Patients in the high D-dimer group were older, more frequently female, had a lower BMI, had a higher prevalence of cancer and had greater initial neurological severity compared to the patients in the low D-dimer group. During the follow-up period (median, 1093 days), 31 patients developed recurrent stroke and 33 patients died. High D-dimer levels at admission were independently associated with recurrent stroke and all-cause mortality [hazard ratio (HR) 3.76; 95% CI 1.21–14.1, P = 0.021) in patients with RLS, but not in those without RLS (HR 1.35; 95% CI 0.74–2.50, P = 0.335).

Conclusions

Increased D-dimer levels at admission were associated with mortality at discharge in cryptogenic stroke patients. In addition, high D-dimer levels were also associated with long-term outcomes in cryptogenic stroke patients with RLS.

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References

  1. Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24:35–41

    Article  PubMed  Google Scholar 

  2. Ageno W, Finazzi S, Steidl L, Biotti MG, Mera V, Melzi D’Eril G, Venco A (2002) Plasma measurement of D-dimer levels for the early diagnosis of ischemic stroke subtypes. Arch Intern Med 162:2589–2593

    Article  CAS  PubMed  Google Scholar 

  3. Castellanos M, Castillo J, García MM, Leira R, Serena J, Chamorro A, Dávalos A (2002) Inflammation-mediated damage in progressing lacunar infarctions: a potential therapeutic target. Stroke 33:982–987

    Article  PubMed  Google Scholar 

  4. Di Castelnuovo A, de Curtis A, Costanzo S, Persichillo M, Olivieri M, Zito F, Donati MB, de Gaetano G, Iacoviello L, Investigators M-SP (2013) Association of D-dimer levels with all-cause mortality in a healthy adult population: findings from the MOLI-SANI study. Haematologica 98:1476–1480

    Article  PubMed  PubMed Central  Google Scholar 

  5. Folsom AR, Gottesman RF, Appiah D, Shahar E, Mosley TH (2016) Plasma d-Dimer and incident ischemic stroke and coronary heart disease: the atherosclerosis risk in communities study. Stroke 47:18–23

    Article  CAS  PubMed  Google Scholar 

  6. Gladstone DJ, Spring M, Dorian P, Panzov V, Thorpe KE, Hall J, Vaid H, O’Donnell M, Laupacis A, Côté R, Sharma M, Blakely JA, Shuaib A, Hachinski V, Coutts SB, Sahlas DJ, Teal P, Yip S, Spence JD, Buck B, Verreault S, Casaubon LK, Penn A, Selchen D, Jin A, Howse D, Mehdiratta M, Boyle K, Aviv R, Kapral MK, Mamdani M, Coordinators EIa (2014) Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 370:2467–2477

    Article  CAS  PubMed  Google Scholar 

  7. Grau AJ, Weimar C, Buggle F, Heinrich A, Goertler M, Neumaier S, Glahn J, Brandt T, Hacke W, Diener HC (2001) Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke 32:2559–2566

    Article  CAS  PubMed  Google Scholar 

  8. Haapaniemi E, Tatlisumak T (2009) Is D-dimer helpful in evaluating stroke patients? A systematic review. Acta Neurol Scand 119:141–150

    Article  CAS  PubMed  Google Scholar 

  9. Huang YY, Shao B, Ni XD, Li JC (2014) Differential lesion patterns on T2-weighted magnetic resonance imaging and fluid-attenuated inversion recovery sequences in cryptogenic stroke patients with patent foramen ovale. J Stroke Cerebrovasc Dis 23:1690–1695

    Article  PubMed  Google Scholar 

  10. Iguchi Y, Kimura K, Kobayashi K, Aoki J, Sakai K, Terasawa Y, Uemura J, Shibazaki K (2010) Detection of right-to-left shunts may be associated with body size. J Neuroimaging 20:130–133

    Article  PubMed  Google Scholar 

  11. Iguchi Y, Kimura K, Kobayashi K, Ueno Y, Inoue T (2006) Ischaemic stroke with malignancy may often be caused by paradoxical embolism. J Neurol Neurosurg Psychiatry 77:1336–1339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, Fang MC, Fisher M, Furie KL, Heck DV, Johnston SC, Kasner SE, Kittner SJ, Mitchell PH, Rich MW, Richardson D, Schwamm LH, Wilson JA, American Heart Association Stroke Council CoCaSN, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease (2014) Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 45:2160–2236

    Article  PubMed  Google Scholar 

  13. Kim JW, Kim SJ, Yoon CW, Park CH, Kang KW, Kim SK, Kim YH, Bang OY (2013) Association between the amount of right-to-left shunt and infarct patterns in patients with cryptogenic embolic stroke: a transcranial Doppler study. Int J Stroke 8:657–662

    Article  PubMed  Google Scholar 

  14. Kim YD, Song D, Nam HS, Lee K, Yoo J, Hong GR, Lee HS, Nam CM, Heo JH (2015) D-dimer for prediction of long-term outcome in cryptogenic stroke patients with patent foramen ovale. Thromb Haemost 114:614–622

    Article  PubMed  Google Scholar 

  15. Kishore A, Vail A, Majid A, Dawson J, Lees KR, Tyrrell PJ, Smith CJ (2014) Detection of atrial fibrillation after ischemic stroke or transient ischemic attack: a systematic review and meta-analysis. Stroke 45:520–526

    Article  CAS  PubMed  Google Scholar 

  16. Kono T, Ohtsuki T, Hosomi N, Takeda I, Aoki S, Sueda Y, Ishihara K, Nakamura T, Yamawaki T, Matsumoto M (2012) Cancer-associated ischemic stroke is associated with elevated D-dimer and fibrin degradation product levels in acute ischemic stroke with advanced cancer. Geriatr Gerontol Int 12:468–474

    Article  PubMed  Google Scholar 

  17. Lee JK, Bettencourt R, Brenner D, Le TA, Barrett-Connor E, Loomba R (2012) Association between serum interleukin-6 concentrations and mortality in older adults: the Rancho Bernardo study. PLoS One 7:e34218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu LB, Li M, Zhuo WY, Zhang YS, Xu AD (2015) The role of hs-CRP, D-dimer and fibrinogen in differentiating etiological subtypes of ischemic stroke. PLoS One 10:e0118301

    Article  PubMed  PubMed Central  Google Scholar 

  19. Loscalzo J (1986) Paradoxical embolism: clinical presentation, diagnostic strategies, and therapeutic options. Am Heart J 112:141–145

    Article  CAS  PubMed  Google Scholar 

  20. Marnane M, Duggan CA, Sheehan OC, Merwick A, Hannon N, Curtin D, Harris D, Williams EB, Horgan G, Kyne L, McCormack PM, Duggan J, Moore A, Crispino-O’Connell G, Kelly PJ (2010) Stroke subtype classification to mechanism-specific and undetermined categories by TOAST, A-S-C-O, and causative classification system: direct comparison in the North Dublin population stroke study. Stroke 41:1579–1586

    Article  PubMed  Google Scholar 

  21. Matsumoto M, Sakaguchi M, Okazaki S, Furukado S, Tagaya M, Etani H, Shimazu T, Yoshimine T, Mochizuki H, Kitagawa K (2013) Relationship between plasma (D)-dimer level and cerebral infarction volume in patients with nonvalvular atrial fibrillation. Cerebrovasc Dis 35:64–72

    Article  PubMed  Google Scholar 

  22. Montaner J, Perea-Gainza M, Delgado P, Ribó M, Chacón P, Rosell A, Quintana M, Palacios ME, Molina CA, Alvarez-Sabín J (2008) Etiologic diagnosis of ischemic stroke subtypes with plasma biomarkers. Stroke 39:2280–2287

    Article  CAS  PubMed  Google Scholar 

  23. Robson SC, Shephard EG, Kirsch RE (1994) Fibrin degradation product D-dimer induces the synthesis and release of biologically active IL-1 beta, IL-6 and plasminogen activator inhibitors from monocytes in vitro. Br J Haematol 86:322–326

    Article  CAS  PubMed  Google Scholar 

  24. Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, Rymer MM, Thijs V, Rogers T, Beckers F, Lindborg K, Brachmann J, Investigators CA (2014) Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 370:2478–2486

    Article  CAS  PubMed  Google Scholar 

  25. Shin YW, Lee ST, Jung KH, Kim DY, Park CK, Kim TM, Choi SH, Chu K, Lee SK (2016) Predictors of survival for patients with cancer after cryptogenic stroke. J Neurooncol 128:277–284

    Article  CAS  PubMed  Google Scholar 

  26. Squizzato A, Ageno W, Finazzi S, Mera V, Romualdi E, Bossi A, Venco A (2006) D-dimer is not a long-term prognostic marker following acute cerebral ischemia. Blood Coagul Fibrinolysis 17:303–306

    Article  CAS  PubMed  Google Scholar 

  27. Ueno Y, Iguchi Y, Inoue T, Shibazaki K, Urabe T, Kimura K (2007) Paradoxical brain embolism may not be uncommon-prospective study in acute ischemic stroke. J Neurol 254:763–766

    Article  PubMed  Google Scholar 

  28. Wang J, Ning R, Wang Y (2016) Plasma D-dimer Level, the Promising Prognostic Biomarker for the Acute Cerebral Infarction Patients. J Stroke Cerebrovasc Dis 25:2011–2015

    Article  PubMed  Google Scholar 

  29. Wannamethee SG, Whincup PH, Lennon L, Papacosta O, Lowe GD (2014) Associations between fibrin D-dimer, markers of inflammation, incident self-reported mobility limitation, and all-cause mortality in older men. J Am Geriatr Soc 62:2357–2362

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yang XY, Gao S, Ding J, Chen Y, Zhou XS, Wang JE (2014) Plasma D-dimer predicts short-term poor outcome after acute ischemic stroke. PLoS One 9:e89756

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported in part by research grants from JSPS KAKENHI (Grant No. 17K17907) and the Japan Heart Foundation.

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Authors and Affiliations

Authors

Contributions

Study concept and design by Nezu and Yagita; acquisition of data by Nezu, Kitano, Kubo, Uemura, Yamashita, Iwanaga, Inoue; analysis and interpretation of data by Nezu and Yagita; manuscript drafting by Nezu; critical revision of the manuscript for important intellectual content by all the coauthors; study supervision by Kimura and Yagita.

Corresponding author

Correspondence to Tomohisa Nezu.

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Conflicts of interest

Naohisa Hosomi reports an honorarium from Mochida Pharmaceutical Co., Ltd which is outside the submitted work. Hirofumi Maruyama reports grants from Daiichi Sankyo Co., Ltd which is outside the submitted work. Masayasu Matsumoto reports grants from Takeda Pharmaceutical Co., LTD., Sanofi K.K., Mochida Pharmaceutical Co., LTD., Otsuka Pharmaceutical, and Daiichi Sankyo Co., LTD. and honoraria from Sanofi K.K., Bayer Health Care, and Daiichi Sankyo Co., LTD, which is outside the submitted work. Yoshiki Yagita reports an honorarium from Daiichi Sankyo Co., Ltd which is outside the submitted work. Other authors declare that there is no conflict of interest.

Ethical standards

This study complied with the Declaration of Helsinki for investigations involving humans, and the study protocol was approved by the Ethics Committee of the Kawasaki Medical School Hospital (#2334).

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Nezu, T., Kitano, T., Kubo, S. et al. Impact of D-dimer levels for short-term or long-term outcomes in cryptogenic stroke patients. J Neurol 265, 628–636 (2018). https://doi.org/10.1007/s00415-018-8742-x

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  • DOI: https://doi.org/10.1007/s00415-018-8742-x

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