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Fibrinogen and LDL Influence on Blood Viscosity and Outcome of Acute Ischemic Stroke Patients in Indonesia

Fibrinogen and LDL Influence on Blood Viscosity and Outcome of Acute Ischemic Stroke Patients in... Background: To assess the role of risk factors of metabolic syndrome on blood viscosity and the prognosis of acute ischemic stroke in Indonesia based on the National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). Methods: This study included 135 patients with acute ischemic stroke. Patients underwent measurements of viscosity and risk factor assessment. Analysis was performed to assess the role of these risk factors for blood viscosity and outcomes of acute ischemic stroke with NIHSS and mRS as indicators. NIHSS was assessed at <3 days after onset and 7 days after onset, while mRS was assessed 1 month post treatment. Bivariate analysis was performed using chi-square test, and variables with p < 0.25 were further analyzed in multivariate analysis using logistic regression. Results: Factors affecting blood viscosity are fibrinogen, low-density lipoprotein (LDL), and hematocrit. Factors affecting NIHSS and mRS are fibrinogen and LDL. Conclusion: Fibrinogen and LDL affect the viscosity of blood and outcomes in acute ischemic stroke patients, so it is necessary to treat in the primary and secondary prevention of ischemic stroke. Keywords Acute ischemic stroke, blood viscosity, fibrinogen, LDL due to differences in speed. Several factors can affect blood Introduction viscosity including hematocrit, erythrocyte aggregation, erythrocyte deformability, fibrinogen levels, age, smoking, Every year, around 16 million people worldwide suffer a stroke 1 9,10 DM, dyslipidemia, and others. Hyperviscosity conditions for the first time. The prevalence of global stroke sufferers is are very important to be identified immediately, not only around 62 million people and the mortality rate from stroke to carry out several possible treatments that can affect the reaches 9.7%. In adults aged 45–64 years, vascular diseases, clinical improvement of the patient, but they are also expected including stroke, are a major cause of disability. In Indonesia, to be associated with clinical outcomes in patients with based on Riskesdas 2013, the prevalence of stroke (time >15 acute ischemic stroke that can be assessed clinically and by years) was 1.21% . The highest prevalence was found in laboratory measurements. Scoring systems used to assess people who were above 75 years (6.7%). clinical outcomes of acute ischemic stroke patients that have This pathophysiology of cerebral ischemia (ischemic been widely used include National Institute of Health Stroke penumbra) includes disorders of cellular perfusion and Scale (NIHSS) and Modified Rankin Scale (mRS). To prevent metabolism that are closely related to blood flow (including blood hyperviscosity and stroke, the target of treatment should collateral flow), blood vessels and blood viscosity (blood be risk factors that affect viscosity. Therefore, this study was hyperviscosity). Blood viscosity in acute ischemic stroke conducted to determine which factors are related to blood have been studied, both in Indonesia and other countries. 4 5 6 viscosity in stroke patients in the Indonesian population. Meliala, Rasyid, and Szapary et al., conducted studies of ischemic stroke patients and stated that blood hyperviscosity was found in patients with acute ischemic stroke. Ott in his study concluded that hyperviscosity occurs in more than 40% Department of Neurology, Cipto Mangunkusumo Hospital/Faculty of of patients with acute ischemic stroke in the first 24 hours of Medicine, Universitas Indonesia, Jakarta, Indonesia. onset, so it is important to know as early as possible because Corresponding author: it greatly affects cerebral blood flow. Al Rasyid, Department of Neurology, Cipto Mangunkusumo Hospital/Faculty Blood viscosity is resistance to blood flow due to friction of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia. E-mail: alrasyid50@yahoo.com of the lamina that moves along the axis of the blood vessel Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-Commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Rasyid et al. 31 Fatmawati Hospital. However, 15 of the subjects dropped Methods out, due to discharge at their own request, incomplete data, death before a month after onset, and unability to be contacted Study Subjects during the study period. A total of 135 patients with acute ischemic stroke from March to August 2013 were included in this cross-sectional study. Subjects Characteristics Sample size was calculated using the rules of thumb. The study participants were at Cipto Mangunkusumo Hospital Most of the study subjects were 60–83 years old (mean 57.9 in Jakarta, Fatmawati Hospital Jakarta, Prikasih Jakarta ± 11.9) and men. Most of them were smokers. In laboratory Hospital, and Bhakti Yuda Depok Hospital. tests, most of them had high fibrinogen levels associated with Inclusion criteria were age of 35–74 years, diagnosis hyperviscosity. of acute ischemic stroke within 3 days of onset, clinical manifestations of partial anterior or lacunar stroke according Table 1. Factors that Affect Blood Viscosity to Bamford’s definition, and no history of using drugs Characteristics (n = 135) with hemorrheological effects. The exclusion criteria were Demography as follows: a history of transient ischemic attack (TIA); Age, mean (SD) 57.9 (11.9) disorders that affect blood and plasma viscosity in stroke, Age, n (%) such as anemia, polycythemia, dengue hemorrhagic fever, 60-80 60 (44.4 %) massive bleeding, and diarrhea; seizures; head trauma; brain 35-59 75 (55.6 %) tumor; and lung cancer. Gender, n (%) Male 83 (61.5 %) Female 52 (38.5 %) Procedures Smoking, n (%) Patients underwent blood viscosity examination using Moderate-severe 24 (17.8 %) digital microcapillary instrument, and assessments of Mild 111 (82.2 %) risk factors, including age, smoking, hypertension, DM, Clinical Characteristics cardiovascular diseases, hematocrit levels, fibrinogen, low- Onset, hrs, mean(SD) 28.05 (22.13) density lipoprotein (LDL), high-density lipoprotein (HDL), Stroke subtypes, n (%) and triglycerides. Stroke outcome was assessed using clinical LACS 33 (24.4 %) assessment (NIHSS score 3 days and 1 week after onset; mRS PACS 102 (75.6 %) score 1 month after discharge from hospital). The clinical Hypertension, n (%) conditions were considered to be improved if the NIHSS Yes 112 (82.96 %) score was ≤1 or improved by ≥4 and the mRS score was 0–2. No 23 (17.03 %) DM, n (%) Yes 40 (29,6 %) Statistical Analysis No 95 (70,3 %) Data were analyzed using Statistical Package for the Social Laboratory Characteristics Sciences (SPSS) software version 17. Bivariate analysis Hematocrit, vol %, median (range) 41.80 (21.00-56.60) was performed using chi-square and multivariate analysis High, n (%) 18 (13.3 %) Normal, n (%) 117 (86.7 %) was performed to assess variables with p < 0.25 to find Fibrinogen, mg/dL, median (range) 392.00 (92.60-651.00) independent risk factors using logistic regression. High, n (%) 92 (68.1 %) Normal, n (%) 43 (31.9 %) Ethics Blood glucose, mg/dL, median (range) 135 (66-447) HDL, mg/dL, mean (SD) 48.02 (14.02) The Research Committee at the Faculty of Medicine, Low, n (%) 30 (22.2 %) University of Indonesia, approved this study with ethical Normal, n (%) 105 (77.8 %) approval number 69/H2.F1/Etik/2013. All subjects gave LDL, mg/dL, mean (SD) 131.19 (44.58) informed consent to participate in this study. High, n (%) 69 (51.1 %) Normal, n (%) 66 (48.9 %) Trigliserida, mg/dL, mean (SD) 156.87 (89.78) Result High, n (%) 70 (51.9 %) Normal, n (%) 65 (48.1 %) Study subjects were 150 patients hospitalized around March– Viskositas Darah, mean (SD) 5.59 (1.20) August 2013 and were diagnosed with ischemic stroke: 59 Hyperviscosity, n (%) 77 (57.0 %) of them were treated at Cipto Mangunkusumo Hospital, 38 Normoviscosity, n (%) 58 (43.0 %) at Prikasih Hospital, 42 at Bhakti Yuda Hospital, and 11 at 32 Annals of Neurosciences 26(3–4) Factors expected to influence blood viscosity were analyzed In bivariate analysis, fibrinogen levels and LDL were using chi-square and logistic regression. From bivariate risk factors for higher NIHSS scores at 1-week follow-up. analysis, fibrinogen levels, hematocrit, and LDL were found Fibrinogen and LDL were also independent factors based on to be risk factors for blood viscosity. Candidate variables were multivariate analysis (p = 0.044 and p = 0.002). selected using chi-square, and those who were considered Fibrinogen and LDL levels were also risk factors for as risk factors for blood and plasma viscosity with p < 0.25 higher mRS scores at 1-month follow-up. From multivariate were then analyzed using logistic regression. Fibrinogen and analysis, only fibrinogen proved to be an independent risk hematocrit were found to be factors that affect blood viscosity factor (p < 0.001) independently (p < 0.001 and p = 0.019). Table 2. Blood Viscosity Factors that Affect Stroke Outcome Viskositas Darah RR Variable Normal Hyperviscosity p (95.0% CI) Fibrinogen High 27(29,3%) 65 (70,7%) <0,001 6,22 (2,78 – 13,88) Normal 31 (72,1%) 12 (27,9%) LDL High 57 (82.6%) 12 (17.4%) 0.001 3,723 (1,690 – 8,202) Normal 37 (56.1%) 29 (43.9%) Hematocrit High 2 (11,1%) 16 (88,9%) 0.003 7,344 (1,616– 33,381) Normal 56 (47,9%) 61 (52,1%) Table 3. Factors that Affect NIHSS NIHSS RR Variable No improvement Improvement p value (95.0% CI) Hypertension Hypertension 79 (70,5%) 33 (29,5%) 0,613 1,277 (0,494 – 3,299) Normal 15 (65,2%) 8 (34,8%) DM Yes 24 (61,5%) 15 (38,5%) 0,547 0,35 (0,29 – 1,02) No 70 (72,9%) 26 (27,1%) Fibrinogen High 70 (76,1%) 22 (23,9%) 0,017 2,519 (1,167 – 5,436) Normal 24 (55,8%) 19 (44,2%) LDL High 57 (82.6%) 12 (17.4%) 0.001 3,723 (1,690 – 8,202) Normal 37 (56.1%) 29 (43.9%) HDL Low 17 (56.7%) 13 (43.3%) 0.080 0,476 (0.205– 1,103) Normal 77 (73.3%) 28 (26.7%) Table 4. Factors that affect mRS mRS Adjusted RR Variable p (95.0% CI) High Low Hypertension Yes 70 (69,7%) 42(37,5%) 0.883 1,07 (0.43 – 2,69) No 14 (60,9%) 9 (39,1%) DM Yes 23 (54,8%) 19 (45,2%) 0.23 0,63 (0.30 – 1,33) No 60 (66.0%) 32 (34.0%) Fibrinogen High 71 (77.2%) 21 (22.8%) <0,001 7,80 (3,46– 17,6) Normal 13 (30.2%) 30 (69.8 %) LDL High 49 (71.0%) 20 (29.0%) 0,031 2,17 (1,06 – 4,41) Normal 35 (53.0%) 31 (47.0%) HDL Low 16 (53,3%) 14 (46,7%) 0,255 0,62(0,27-1,41) Normal 68 (65,3%) 37 (35,2%) Rasyid et al. 33 Table 5. Multivariate Analysis NIHSS RR Variable No Improvement Improvement p (95.0% CI) Fibrinogen High 70 (76,1%) 22 (23,9%) 0,044 2,326 (1,022 – 5,291) Normal 24 (55,8%) 19 (44,2%) LDL High 57 (82.6%) 12 (17.4%) 0.002 3,882 (1,680 – 8,970) Normal 37 (56.1%) 29 (43.9%) mRS High Low p RR (95.0% CI) Fibrinogen High 71 (77.2%) 21 (22.8%) <0,001 7,80 (3,46– 17,6) Normal 13 (30.2%) 30 (69.8 %) disorders and stroke outcomes, which can be assessed by Discussion NIHSS score and mRS. The relationship of lipid levels and blood viscosity, as Fibrinogen is a facilitator of the formation of rouleaux 10,16 found in our study, is in accordance with previous findings. through receptors on the erythrocyte membrane. It is High LDL/HDL ratios indicate high levels of circulating a factor that determines changes in blood and plasma cholesterol in blood vessels, including cerebral blood vessels. viscosity, and affects the aggregation of erythrocytes, On the surface of the erythrocytes, there are approximately which causes blood hyperviscosity. In the ischemic region, 200 bonding places for LDL or HDL molecules so that they more rouleaux is formed, and a higher number of fibrinogen can have an effect on blood viscosity in low blood flow bonds is found. High levels of fibrinogen, which has large conditions such as cerebral ischemia. High LDL levels molecular weight among plasma proteins, will increase induce erythrocyte aggregation, which causes increased plasma viscosity. blood viscosity. Thus, high LDL levels worsen the outcome Fibrinogen plays an important role as a medium for the of acute ischemic stroke. interaction of erythrocyte and platelet cells, so that if fibrinogen Fibrinogen and LDL/HDL measurements are not only levels increase, there will be an increase in erythrocyte relatively low cost but they are also universally available. In aggregation and an increase in platelet aggregation, which Indonesia, and most of the developing countries in Asia and often occur in acute stroke. Africa, a simple and low-cost diagnostic tool is what is needed, It has been observed that fibrinogen has an effect on especially in Indonesia since the health cost (laboratory erythrocyte aggregation by finding that fibrinogen has a specific examination, hospital care, drugs, medical rehabilitation, etc.) bond with erythrocyte membranes. Carvalho reported the for Indonesian are funded by the National Health Insurance fibrinogen receptor in erythrocytes by using the atomic force (Badan Penyelenggara Jaminan Sosial/BPJS). microscope, a nanodiagnostic device to see the interaction This study used digital microcapillary instrument to of a single molecule between fibrinogen and receptors in examine blood viscosity. “Digital Microcapillary” is a the erythrocyte membrane. The bonding strength between novel diagnostic instrument created by Al Rasyid et al. and fibrinogen and erythrocyte membrane receptors is relatively has been patented in Indonesia by the Ministry of Law and weaker than fibrinogen’s bond with platelets. Fibrinogen Human Rights of Republic of Indonesia since 2016. Digital receptors in erythrocyte membranes are αIIbβ3 integrins. This microcapillary is a simple portable device to measure blood fibrinogen receptor in the erythrocyte membrane is not as viscosity rapidly and cheaply. The use of this novel digital strong as the receptors on platelets whose bonds are affected microcapillary instrument is an advantage of this study by calcium in the αIIbβ3 specific inhibitor. because it has not been used in any previous studies. The effect of fibrinogen on blood viscosity has been widely studied. In one study, three groups of patients were divided based on fibrinogen levels. Blood viscosity was Conclusion significantly associated with blood fibrinogen levels in each group (p < 0.01). Increased blood viscosity was associated Fibrinogen and LDL levels are factors that can affect blood with an increase in fibrinogen levels and was more pronounced viscosity independently. Fibrinogen and LDL, through the in the hematocrit group with a higher value. High blood effect of increasing blood viscosity, also affect the outcome viscosity in acute stroke is responsible for low cerebral blood of acute ischemic stroke. Fibrinogen, dyslipidemia, and blood flow and impaired perfusion, which causes ischemia and hyperviscosity are factors that need to be managed in stroke infarction. This process affects the severity of neurological patients or patients at risk of stroke. 34 Annals of Neurosciences 26(3–4) Acknowledgements 6. Szapary L, Horvath B, Marton Z, et al. Hemorheological disturbances in patients with chronic cerebrovascular diseases. We would like to thank Cipto Mangunkusumo Hospital and Clin Hemorheol Microcirc 2004; 31 (1): 1-9. Department of Neurology Universitas Indonesia for facilitating this research. We would also like to thank Fatmawati Hospital, Prikasih 7. Ott E, Fazekas F, Tschinkel M, Bertha G, and Lechner H. Jakarta Hospital, and Bhakti Yuda Hospital for allowing us to collect Rheological aspect of cerebrovascular disease. Eur Neurol the required data for this research. 1983; 22: 35–37. 8. Rosencranz R, Steven A. Clinical laboratory measurement of Author Contributions serum, plasma, and blood viscosity. Am J Clin Pathol 2006;125 Al Rasyid conceived the study and was responsible of overall study (suppl 1): S78–86. direction and planning; Al Rasyid, Salim Harris, and Rakhmad 9. Chen G, Zhao L, Liu Y W, Liao F, Han D, and Zhou H. Hidayat designed the study; Salim Harris developed study flow and Regulation of blood viscosity in disease prevention and data analysis strategy; Rakhmad Hidayat reviewed and corrected treatment. Chin Sci Bull 2012; 57: 1946−1952. study hypothesis; Al Rasyid, Mohammad Kurniawan, and Taufik Mesiano collected and pooled the data; Al Rasyid and Taufik 10. Irace C, Carallo C, Scavelli F, Esposito T, De Franceschi MS, Mesiano performed and interpreted data analysis. All authors were and Tripolino C. Influence of blood lipids on plasma and blood involved in manuscript writing, with Mohammad Kurniawan and viscosity. Clin Hemorheol Microcirc 2014; 57 (3): 267–274. Taufik Mesiano edited the final manuscript. 11. Rasyid A and Soertidewi L. Managemen stroke komprehensif. Jakarta: Balai Penerbit FKUI, 2007, pp. 64–71. Declaration of Conflicting Interests 12. Rasyid A, Misbach J, Purba JS, Timan IS, Sukrisman L, The authors declared no potential conflicts of interest with respect to Mansyur M, Yudiarsyah E, and Suroto. The Role of a Novel the research, authorship and/or publication of this article. Digital Microcapillary Instrument in Detecting Blood and Plasma Hyperviscosity. Acta Medica Indonesiana 2014; 46 (3): Funding 226–232. The authors received no financial support for the research, authorship 13. Carvalho FA, de Oliveira S, Freitas T, Gonçalves S, and Santos and/or publication of this article. NC. Variations on fibrinogen-erythrocyte interactions during cell aging. PloS ONE 2011; 6 (3): 18167–1871. References 14. Matsuda T, Murakami M. Relationship between fibrinogen and 1. Ovbiagele B and Nguyen-Huynh MN. Stroke epidemiology: blood viscosity. Elsevier DOI: 10.1016/0049-3848(76)90044-X. advancing our understanding of mechanism and therapy. 15. De la Ossa NP, Sánchez-Ojanguren J, Palomeras E, et al. Neurotherapeutics 2011; 8 (3): 319–329. Influence of the stroke code activation source on the outcome of 2. Mihardja LK, Delima, Soetiarto F, Suhardi, and Kristanto acute ischemic stroke patient. Neurology 2008; 70: 1238–1243. AY. Riset Kesehatan Dasar Departemen Kesehatan. Jakarta: 16. Aloulou I, Varlet-Marie E, Mercier J, and Brun JF. Kemenkes, 2013. Hemorheological disturbances correlate with the lipid profile 3. Ahmed HS, Hu CJ, Paczynsky R, and Hsu CY. Patophysiology but not with the NCEPATPIII score of the metabolic syndrome. of ischemic injury. In: Marc Fisher. Stroke Therapy. 2nd ed. Clin Hemorheol Microcirc 2006; 35 (1–2): 207–212. London: Butterworth-Heinemann, 2001, pp. 25–32. 17. Cho Y, Cho D. Hemorheology and microvascular disorder. 4. Meliala C, Nuradyo D, and Suryatmojo B. Hiperviskositas Korean Circ J 2011; 4: 287–295. sebagai faktor risiko stroke infark di RSUP Dr. Sardjito FK 18. Rasyid A, Harris S, Nurhayati E, Prihartono J. Pentoxifylline in UGM Yogyakarta. Thesis, Yogyakarta, Universitas Gadjah acute ischemic stroke patients with blood hyperviscosity. Int J Mada, 1996. App Pharm 2018; 10 (1): 307–310. 5. Rasyid A, Nuradyo D, and Sutarni S. Realibilitas dan validitas mikrokapiler hematokrit pada pemeriksaan viskositas darah penderita stroke iskemik akut dan stroke infark. Berkala NeuroSains 2000; 1 (2): 97-102. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Neurosciences SAGE

Fibrinogen and LDL Influence on Blood Viscosity and Outcome of Acute Ischemic Stroke Patients in Indonesia

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© 2020 Indian Academy of Neurosciences (IAN)
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0972-7531
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0976-3260
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Abstract

Background: To assess the role of risk factors of metabolic syndrome on blood viscosity and the prognosis of acute ischemic stroke in Indonesia based on the National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). Methods: This study included 135 patients with acute ischemic stroke. Patients underwent measurements of viscosity and risk factor assessment. Analysis was performed to assess the role of these risk factors for blood viscosity and outcomes of acute ischemic stroke with NIHSS and mRS as indicators. NIHSS was assessed at <3 days after onset and 7 days after onset, while mRS was assessed 1 month post treatment. Bivariate analysis was performed using chi-square test, and variables with p < 0.25 were further analyzed in multivariate analysis using logistic regression. Results: Factors affecting blood viscosity are fibrinogen, low-density lipoprotein (LDL), and hematocrit. Factors affecting NIHSS and mRS are fibrinogen and LDL. Conclusion: Fibrinogen and LDL affect the viscosity of blood and outcomes in acute ischemic stroke patients, so it is necessary to treat in the primary and secondary prevention of ischemic stroke. Keywords Acute ischemic stroke, blood viscosity, fibrinogen, LDL due to differences in speed. Several factors can affect blood Introduction viscosity including hematocrit, erythrocyte aggregation, erythrocyte deformability, fibrinogen levels, age, smoking, Every year, around 16 million people worldwide suffer a stroke 1 9,10 DM, dyslipidemia, and others. Hyperviscosity conditions for the first time. The prevalence of global stroke sufferers is are very important to be identified immediately, not only around 62 million people and the mortality rate from stroke to carry out several possible treatments that can affect the reaches 9.7%. In adults aged 45–64 years, vascular diseases, clinical improvement of the patient, but they are also expected including stroke, are a major cause of disability. In Indonesia, to be associated with clinical outcomes in patients with based on Riskesdas 2013, the prevalence of stroke (time >15 acute ischemic stroke that can be assessed clinically and by years) was 1.21% . The highest prevalence was found in laboratory measurements. Scoring systems used to assess people who were above 75 years (6.7%). clinical outcomes of acute ischemic stroke patients that have This pathophysiology of cerebral ischemia (ischemic been widely used include National Institute of Health Stroke penumbra) includes disorders of cellular perfusion and Scale (NIHSS) and Modified Rankin Scale (mRS). To prevent metabolism that are closely related to blood flow (including blood hyperviscosity and stroke, the target of treatment should collateral flow), blood vessels and blood viscosity (blood be risk factors that affect viscosity. Therefore, this study was hyperviscosity). Blood viscosity in acute ischemic stroke conducted to determine which factors are related to blood have been studied, both in Indonesia and other countries. 4 5 6 viscosity in stroke patients in the Indonesian population. Meliala, Rasyid, and Szapary et al., conducted studies of ischemic stroke patients and stated that blood hyperviscosity was found in patients with acute ischemic stroke. Ott in his study concluded that hyperviscosity occurs in more than 40% Department of Neurology, Cipto Mangunkusumo Hospital/Faculty of of patients with acute ischemic stroke in the first 24 hours of Medicine, Universitas Indonesia, Jakarta, Indonesia. onset, so it is important to know as early as possible because Corresponding author: it greatly affects cerebral blood flow. Al Rasyid, Department of Neurology, Cipto Mangunkusumo Hospital/Faculty Blood viscosity is resistance to blood flow due to friction of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia. E-mail: alrasyid50@yahoo.com of the lamina that moves along the axis of the blood vessel Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-Commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Rasyid et al. 31 Fatmawati Hospital. However, 15 of the subjects dropped Methods out, due to discharge at their own request, incomplete data, death before a month after onset, and unability to be contacted Study Subjects during the study period. A total of 135 patients with acute ischemic stroke from March to August 2013 were included in this cross-sectional study. Subjects Characteristics Sample size was calculated using the rules of thumb. The study participants were at Cipto Mangunkusumo Hospital Most of the study subjects were 60–83 years old (mean 57.9 in Jakarta, Fatmawati Hospital Jakarta, Prikasih Jakarta ± 11.9) and men. Most of them were smokers. In laboratory Hospital, and Bhakti Yuda Depok Hospital. tests, most of them had high fibrinogen levels associated with Inclusion criteria were age of 35–74 years, diagnosis hyperviscosity. of acute ischemic stroke within 3 days of onset, clinical manifestations of partial anterior or lacunar stroke according Table 1. Factors that Affect Blood Viscosity to Bamford’s definition, and no history of using drugs Characteristics (n = 135) with hemorrheological effects. The exclusion criteria were Demography as follows: a history of transient ischemic attack (TIA); Age, mean (SD) 57.9 (11.9) disorders that affect blood and plasma viscosity in stroke, Age, n (%) such as anemia, polycythemia, dengue hemorrhagic fever, 60-80 60 (44.4 %) massive bleeding, and diarrhea; seizures; head trauma; brain 35-59 75 (55.6 %) tumor; and lung cancer. Gender, n (%) Male 83 (61.5 %) Female 52 (38.5 %) Procedures Smoking, n (%) Patients underwent blood viscosity examination using Moderate-severe 24 (17.8 %) digital microcapillary instrument, and assessments of Mild 111 (82.2 %) risk factors, including age, smoking, hypertension, DM, Clinical Characteristics cardiovascular diseases, hematocrit levels, fibrinogen, low- Onset, hrs, mean(SD) 28.05 (22.13) density lipoprotein (LDL), high-density lipoprotein (HDL), Stroke subtypes, n (%) and triglycerides. Stroke outcome was assessed using clinical LACS 33 (24.4 %) assessment (NIHSS score 3 days and 1 week after onset; mRS PACS 102 (75.6 %) score 1 month after discharge from hospital). The clinical Hypertension, n (%) conditions were considered to be improved if the NIHSS Yes 112 (82.96 %) score was ≤1 or improved by ≥4 and the mRS score was 0–2. No 23 (17.03 %) DM, n (%) Yes 40 (29,6 %) Statistical Analysis No 95 (70,3 %) Data were analyzed using Statistical Package for the Social Laboratory Characteristics Sciences (SPSS) software version 17. Bivariate analysis Hematocrit, vol %, median (range) 41.80 (21.00-56.60) was performed using chi-square and multivariate analysis High, n (%) 18 (13.3 %) Normal, n (%) 117 (86.7 %) was performed to assess variables with p < 0.25 to find Fibrinogen, mg/dL, median (range) 392.00 (92.60-651.00) independent risk factors using logistic regression. High, n (%) 92 (68.1 %) Normal, n (%) 43 (31.9 %) Ethics Blood glucose, mg/dL, median (range) 135 (66-447) HDL, mg/dL, mean (SD) 48.02 (14.02) The Research Committee at the Faculty of Medicine, Low, n (%) 30 (22.2 %) University of Indonesia, approved this study with ethical Normal, n (%) 105 (77.8 %) approval number 69/H2.F1/Etik/2013. All subjects gave LDL, mg/dL, mean (SD) 131.19 (44.58) informed consent to participate in this study. High, n (%) 69 (51.1 %) Normal, n (%) 66 (48.9 %) Trigliserida, mg/dL, mean (SD) 156.87 (89.78) Result High, n (%) 70 (51.9 %) Normal, n (%) 65 (48.1 %) Study subjects were 150 patients hospitalized around March– Viskositas Darah, mean (SD) 5.59 (1.20) August 2013 and were diagnosed with ischemic stroke: 59 Hyperviscosity, n (%) 77 (57.0 %) of them were treated at Cipto Mangunkusumo Hospital, 38 Normoviscosity, n (%) 58 (43.0 %) at Prikasih Hospital, 42 at Bhakti Yuda Hospital, and 11 at 32 Annals of Neurosciences 26(3–4) Factors expected to influence blood viscosity were analyzed In bivariate analysis, fibrinogen levels and LDL were using chi-square and logistic regression. From bivariate risk factors for higher NIHSS scores at 1-week follow-up. analysis, fibrinogen levels, hematocrit, and LDL were found Fibrinogen and LDL were also independent factors based on to be risk factors for blood viscosity. Candidate variables were multivariate analysis (p = 0.044 and p = 0.002). selected using chi-square, and those who were considered Fibrinogen and LDL levels were also risk factors for as risk factors for blood and plasma viscosity with p < 0.25 higher mRS scores at 1-month follow-up. From multivariate were then analyzed using logistic regression. Fibrinogen and analysis, only fibrinogen proved to be an independent risk hematocrit were found to be factors that affect blood viscosity factor (p < 0.001) independently (p < 0.001 and p = 0.019). Table 2. Blood Viscosity Factors that Affect Stroke Outcome Viskositas Darah RR Variable Normal Hyperviscosity p (95.0% CI) Fibrinogen High 27(29,3%) 65 (70,7%) <0,001 6,22 (2,78 – 13,88) Normal 31 (72,1%) 12 (27,9%) LDL High 57 (82.6%) 12 (17.4%) 0.001 3,723 (1,690 – 8,202) Normal 37 (56.1%) 29 (43.9%) Hematocrit High 2 (11,1%) 16 (88,9%) 0.003 7,344 (1,616– 33,381) Normal 56 (47,9%) 61 (52,1%) Table 3. Factors that Affect NIHSS NIHSS RR Variable No improvement Improvement p value (95.0% CI) Hypertension Hypertension 79 (70,5%) 33 (29,5%) 0,613 1,277 (0,494 – 3,299) Normal 15 (65,2%) 8 (34,8%) DM Yes 24 (61,5%) 15 (38,5%) 0,547 0,35 (0,29 – 1,02) No 70 (72,9%) 26 (27,1%) Fibrinogen High 70 (76,1%) 22 (23,9%) 0,017 2,519 (1,167 – 5,436) Normal 24 (55,8%) 19 (44,2%) LDL High 57 (82.6%) 12 (17.4%) 0.001 3,723 (1,690 – 8,202) Normal 37 (56.1%) 29 (43.9%) HDL Low 17 (56.7%) 13 (43.3%) 0.080 0,476 (0.205– 1,103) Normal 77 (73.3%) 28 (26.7%) Table 4. Factors that affect mRS mRS Adjusted RR Variable p (95.0% CI) High Low Hypertension Yes 70 (69,7%) 42(37,5%) 0.883 1,07 (0.43 – 2,69) No 14 (60,9%) 9 (39,1%) DM Yes 23 (54,8%) 19 (45,2%) 0.23 0,63 (0.30 – 1,33) No 60 (66.0%) 32 (34.0%) Fibrinogen High 71 (77.2%) 21 (22.8%) <0,001 7,80 (3,46– 17,6) Normal 13 (30.2%) 30 (69.8 %) LDL High 49 (71.0%) 20 (29.0%) 0,031 2,17 (1,06 – 4,41) Normal 35 (53.0%) 31 (47.0%) HDL Low 16 (53,3%) 14 (46,7%) 0,255 0,62(0,27-1,41) Normal 68 (65,3%) 37 (35,2%) Rasyid et al. 33 Table 5. Multivariate Analysis NIHSS RR Variable No Improvement Improvement p (95.0% CI) Fibrinogen High 70 (76,1%) 22 (23,9%) 0,044 2,326 (1,022 – 5,291) Normal 24 (55,8%) 19 (44,2%) LDL High 57 (82.6%) 12 (17.4%) 0.002 3,882 (1,680 – 8,970) Normal 37 (56.1%) 29 (43.9%) mRS High Low p RR (95.0% CI) Fibrinogen High 71 (77.2%) 21 (22.8%) <0,001 7,80 (3,46– 17,6) Normal 13 (30.2%) 30 (69.8 %) disorders and stroke outcomes, which can be assessed by Discussion NIHSS score and mRS. The relationship of lipid levels and blood viscosity, as Fibrinogen is a facilitator of the formation of rouleaux 10,16 found in our study, is in accordance with previous findings. through receptors on the erythrocyte membrane. It is High LDL/HDL ratios indicate high levels of circulating a factor that determines changes in blood and plasma cholesterol in blood vessels, including cerebral blood vessels. viscosity, and affects the aggregation of erythrocytes, On the surface of the erythrocytes, there are approximately which causes blood hyperviscosity. In the ischemic region, 200 bonding places for LDL or HDL molecules so that they more rouleaux is formed, and a higher number of fibrinogen can have an effect on blood viscosity in low blood flow bonds is found. High levels of fibrinogen, which has large conditions such as cerebral ischemia. High LDL levels molecular weight among plasma proteins, will increase induce erythrocyte aggregation, which causes increased plasma viscosity. blood viscosity. Thus, high LDL levels worsen the outcome Fibrinogen plays an important role as a medium for the of acute ischemic stroke. interaction of erythrocyte and platelet cells, so that if fibrinogen Fibrinogen and LDL/HDL measurements are not only levels increase, there will be an increase in erythrocyte relatively low cost but they are also universally available. In aggregation and an increase in platelet aggregation, which Indonesia, and most of the developing countries in Asia and often occur in acute stroke. Africa, a simple and low-cost diagnostic tool is what is needed, It has been observed that fibrinogen has an effect on especially in Indonesia since the health cost (laboratory erythrocyte aggregation by finding that fibrinogen has a specific examination, hospital care, drugs, medical rehabilitation, etc.) bond with erythrocyte membranes. Carvalho reported the for Indonesian are funded by the National Health Insurance fibrinogen receptor in erythrocytes by using the atomic force (Badan Penyelenggara Jaminan Sosial/BPJS). microscope, a nanodiagnostic device to see the interaction This study used digital microcapillary instrument to of a single molecule between fibrinogen and receptors in examine blood viscosity. “Digital Microcapillary” is a the erythrocyte membrane. The bonding strength between novel diagnostic instrument created by Al Rasyid et al. and fibrinogen and erythrocyte membrane receptors is relatively has been patented in Indonesia by the Ministry of Law and weaker than fibrinogen’s bond with platelets. Fibrinogen Human Rights of Republic of Indonesia since 2016. Digital receptors in erythrocyte membranes are αIIbβ3 integrins. This microcapillary is a simple portable device to measure blood fibrinogen receptor in the erythrocyte membrane is not as viscosity rapidly and cheaply. The use of this novel digital strong as the receptors on platelets whose bonds are affected microcapillary instrument is an advantage of this study by calcium in the αIIbβ3 specific inhibitor. because it has not been used in any previous studies. The effect of fibrinogen on blood viscosity has been widely studied. In one study, three groups of patients were divided based on fibrinogen levels. Blood viscosity was Conclusion significantly associated with blood fibrinogen levels in each group (p < 0.01). Increased blood viscosity was associated Fibrinogen and LDL levels are factors that can affect blood with an increase in fibrinogen levels and was more pronounced viscosity independently. Fibrinogen and LDL, through the in the hematocrit group with a higher value. High blood effect of increasing blood viscosity, also affect the outcome viscosity in acute stroke is responsible for low cerebral blood of acute ischemic stroke. Fibrinogen, dyslipidemia, and blood flow and impaired perfusion, which causes ischemia and hyperviscosity are factors that need to be managed in stroke infarction. This process affects the severity of neurological patients or patients at risk of stroke. 34 Annals of Neurosciences 26(3–4) Acknowledgements 6. Szapary L, Horvath B, Marton Z, et al. Hemorheological disturbances in patients with chronic cerebrovascular diseases. We would like to thank Cipto Mangunkusumo Hospital and Clin Hemorheol Microcirc 2004; 31 (1): 1-9. Department of Neurology Universitas Indonesia for facilitating this research. We would also like to thank Fatmawati Hospital, Prikasih 7. Ott E, Fazekas F, Tschinkel M, Bertha G, and Lechner H. Jakarta Hospital, and Bhakti Yuda Hospital for allowing us to collect Rheological aspect of cerebrovascular disease. Eur Neurol the required data for this research. 1983; 22: 35–37. 8. Rosencranz R, Steven A. Clinical laboratory measurement of Author Contributions serum, plasma, and blood viscosity. Am J Clin Pathol 2006;125 Al Rasyid conceived the study and was responsible of overall study (suppl 1): S78–86. direction and planning; Al Rasyid, Salim Harris, and Rakhmad 9. Chen G, Zhao L, Liu Y W, Liao F, Han D, and Zhou H. Hidayat designed the study; Salim Harris developed study flow and Regulation of blood viscosity in disease prevention and data analysis strategy; Rakhmad Hidayat reviewed and corrected treatment. Chin Sci Bull 2012; 57: 1946−1952. study hypothesis; Al Rasyid, Mohammad Kurniawan, and Taufik Mesiano collected and pooled the data; Al Rasyid and Taufik 10. Irace C, Carallo C, Scavelli F, Esposito T, De Franceschi MS, Mesiano performed and interpreted data analysis. All authors were and Tripolino C. Influence of blood lipids on plasma and blood involved in manuscript writing, with Mohammad Kurniawan and viscosity. Clin Hemorheol Microcirc 2014; 57 (3): 267–274. Taufik Mesiano edited the final manuscript. 11. Rasyid A and Soertidewi L. Managemen stroke komprehensif. Jakarta: Balai Penerbit FKUI, 2007, pp. 64–71. Declaration of Conflicting Interests 12. 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Thesis, Yogyakarta, Universitas Gadjah acute ischemic stroke patients with blood hyperviscosity. Int J Mada, 1996. App Pharm 2018; 10 (1): 307–310. 5. Rasyid A, Nuradyo D, and Sutarni S. Realibilitas dan validitas mikrokapiler hematokrit pada pemeriksaan viskositas darah penderita stroke iskemik akut dan stroke infark. Berkala NeuroSains 2000; 1 (2): 97-102.

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Published: Jul 1, 2019

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