1 original papers Adv Clin Exp Med 00, 9, 5, ISSN 30-05X Copyright by Wroclaw Medical University Anna B. Sobol, Krzysztof Selmaj, Alina Mochecka, Anna Kumor 3, Jerzy Loba Aspirin Responsiveness in Ischemic Stroke Patients in Relation to Diabetes Mellitus, Lipid and Hemostatic Profile* Odpowiedź na aspirynę w niedokrwiennym udarze mózgu w odniesieniu do cukrzycy, profilu lipidowego i profilu hemostazy Department of Internal Medicine and Diabetology, Medical University of Lodz, Poland Department of Neurology, Medical University of Lodz, Poland 3 Department of Laboratory Diagnostics, Medical University of Lodz, Poland Abstract Background. The problem of aspirin responsiveness in ischemic stroke patients is still not clear. Objectives. The aim of the study was to assess aspirin responsiveness in stroke patients in relation to diabetes mellitus, hemostatic and lipid profile. Material and Methods. 64 patients ( with diabetes, 4 men, mean age 57.9 ± 0.4 years) with ischemic stroke or transient ischemic attack treated with the routine dose of 50 mg acetylsalicylic acid (ASA) daily were included into this study. Aspirin responsiveness was assessed based on platelet reactivity using platelet function analyzer (PFA-00 TM ) with collagen/epinephrine cartridges and whole blood platelet aggregometry with 0.5 mm arachidonic acid on the first day of acute stroke and after 0 days of a 50 mg ASA intake. Lipid and hemostatic profiles were determined. Results. The authors observed ASA unresponsiveness in 6/ (7.3%) of diabetic and in 7/4 (40.5%) of non-diabetic patients (no significant differences). Lipoprotein(a) was higher in ASA-unresponsive compared with ASA-responsive patients before ASA treatment 43 (4 0) mg/dl vs. 7 (4 30) mg/dl, p = 0.03 as well after 0 days of ASA treatment 37 (4 94) mg/dl vs 7 ( 90) mg/dl, p = 0.0. Conclusions. The authors suggest that the prevalence of diabetes mellitus and hemostatic profile in ischemic stroke patients should not be associated with ASA unresponsiveness. The enhanced lipoprotein(a) might indicate ASA-unresponsive stroke patients (Adv Clin Exp Med 00, 9, 5, ). Key words: aspirin responsiveness, blood coagulation, diabetes mellitus, ischemic stroke, lipoprotein(a). Streszczenie Wprowadzenie. Problem odpowiedzi na aspirynę u pacjentów z niedokrwiennym udarem mózgu pozostaje niewyjaśniony. Cel pracy. Ustalenie, czy odpowiedź na aspirynę ma związek z występowaniem cukrzycy, profilem lipidowym i wskaźnikami hemostazy. Materiał i metody. Badaniami objęto 64 pacjentów ( chorych na cukrzycę, 4 M, średnia wieku 57,9 ± 0,4 lat) z niedokrwiennym udarem mózgu lub przejściowym atakiem niedokrwiennym (TIA), leczonych rutynową dawką 50 mg kwasu acetylosalicylowego (ASA) dziennie. Odpowiedź na aspirynę oceniano, badając reaktywność płytek krwi z wykorzystaniem analizatora czynności płytek krwi (PFA-00 TM ), z użyciem kartridży kolagen/epinefryna i na podstawie pomiaru agregacji we krwi pełnej z 0,5 mm kwasem arachidonowym w pierwszym dniu wystąpienia udaru i po 0 dniach przyjmowania 50 mg ASA. Oceniano profil lipidowy i wybrane wskaźniki hemostazy. Wyniki. Brak odpowiedzi na ASA stwierdzono u 6 (7.3%) spośród pacjentów chorych na cukrzycę i u 7 (40,5%) spośród 4 pacjentów niechorujących na cukrzycę (różnice nieistotne statystycznie). Lipoproteina (a) była wyższa * This study was supported by the Medical University of Lodz, grant no The preliminary results of this study were presented at the 4st European Association for the Study of Diabetes Annual Meeting, September 005, Athens, Greece.
2 594 A.B. Sobol et al. u pacjentów nieodpowiadających na ASA w porównaniu z pacjentami odpowiadającymi na ASA zarówno przed leczeniem: 43 (4 0) mg/dl vs 7 (4 30) mg/dl, p = 0,03, jak i po 0 dniach leczenia ASA: 37 (4 94) mg/dl vs 7 ( 90) mg/dl, p = 0,0. Wnioski. Badania mogą sugerować, że obecność cukrzycy, a także profil hemostazy u pacjentów z niedokrwiennym udarem mózgu nie są związane z brakiem odpowiedzi na ASA. Zwiększone stężenie lipoproteiny(a) może wskazywać pacjentów z niedokrwiennym udarem mózgu nieodpowiadających na ASA (Adv Clin Exp Med 00, 9, 5, ). Słowa kluczowe: odpowiedź na aspirynę, krzepnięcie krwi, cukrzyca, niedokrwienny udar mózgu, lipoproteina (a). The incidence of stroke in diabetic patients is 4 fold higher than in non-diabetic patients . The essential role in atherogenic pathogenesis in diabetes is played by platelets . The role of aspirin as an effective antiplatelet drug was confirmed in many clinical trials and is strongly recommended in diabetic patients in primary and secondary prophylaxis of cardiovascular complications [3 8]. However, in reflect of last results of a Swedish record linkage study published by Welin et al. the role of aspirin in diabetic patients in primary prevention seems to be controversial and showed that aspirin significantly increased mortality and the risk of serious bleeding in diabetic patients without cardiovascular disease . Despite therapeutic doses of ASA a group of patients does not respond to this drug presenting clinically or laboratory unresponsiveness . Among several risk factors for stroke diabetes was reported as associated with the diminished or the lack of ASA response [ 3]. However, there are only few data concerning ASA unresponsiveness in diabetic stroke patients [4 5]. Earlier we published our results based on the same group of stroke patients showing that aspirin unresponsiveness was associated with significantly worse neurological status according to Rankin Scale . The aim of this study was to answer whether diabetes mellitus is associated with ASA unresponsiveness in ischemic stroke patients. The role of lipid and hemostatic profile in relation to ASA unresponsiveness was also assessed. Material and Methods We enrolled 64 patients ( with diabetes and 4 without diabetes) hospitalized at the Department of Neurology, Medical University of Lodz, Poland, with diagnosis of ischemic stroke, with symptoms lasting < 7 hours or transient ischemic attack (TIA) and with recommended routine dose of ASA (50 mg daily) after obtaining their informed consent according to the local Ethical Committee. The diagnosis of stroke or TIA was based on neurological examination, laboratory parameters, computed tomography and/or magnetic resonance. The patients with infections, cancer, hepatic or renal failure, known hemostatic disorders and aspirin allergy, anticoagulant, thrombolytic or antiplatelet therapy ASA, clopidogrel, thienopyridine, non-steroidal anti-inflammatory drugs (NSDAIDs) for at least 0 days before the admission to hospital were excluded. 37 age and sex matched healthy volunteers (physicians and laboratory staff in this hospital) receiving the same dose of acetylsalicylic acid (50 mg daily) for the same time as the studied group were included into the control group, after obtaining their informed consent according to the local Ethical Committee. Exclusion criteria for the control group additionally included the history of stroke, ischemic heart disease, diabetes mellitus, hyperlipoproteinemia and hypertension. Blood Collection Blood was drawn, in the fasting state ( hours), by venipuncture, from the patients with a stroke or TIA on the first or second day after the admission to hospital before the receiving ASA and next after 0 days of the therapy with 50 mg ASA daily. For platelet reactivity tubes with buffered citrate, for coagulation and lipid profiles standard tubes containing 0.09 mol/l trisodium citrate (one part of trisodium citrate and nine parts of the whole blood) were used. Platelet-poor plasma was separated by centrifugation twice at 500 g for 5 min. at +4 C and used for blood coagulation measurements. The whole blood was used within hour after blood withdrawal for platelet function analyzer (PFA-00 TM ) method and for platelet aggregometry assessment. Platelet reactivity was assessed using two methods: platelet function analyzer (PFA-00 TM ) with collagen/epinephrine and collagen/adp cartridges to measure aperture closure time (Dade Behring, Germany). The whole blood platelet aggregometry was assessed with agonists: 0 µm ADP, collagen µg/ml, 0.5 mm arachidonic acid (Chrono-Log,
3 Aspirin Responsiveness, Diabetes and Stroke 595 USA). Aspirin unresponsiveness was defined as the lack of the prolongation of collagen/epinephrine closure time 50 sec. (PFA-00 TM method) and/or the lack of complete inhibition of arachidonic acid-induced whole blood aggregation. The coagulation and lipid profiles were also measured. Aliquots of plasma were stored at 70 C until use (for further measurements). Evaluation of coagulation profile included the routine assays by standard procedures, D-dimer (Dade Behring, Germany) and thrombin antithrombin complex (TAT) (Dade Behring, Germany). Lipid profile was assessed using enzymatic method total cholesterol, triglycerides, high-density lipoprotein phospholipids (HDL-P), high-density lipoprotein triglycerides (HDL-TG) and total phospholipids (biomerieux, France). High-density lipoprotein cholesterol (HDL-C) was measured after precipitation with phosphotungstic acid (biomerieux, France). Low density lipoprotein cholesterol (LDL C) was calculated by the Friedewald formula. Lipoprotein (a) Lp(a) was measured using immunoturbidimetric method (Roche, France). Statistical Analysis Data are expressed as mean ± standard deviation (SD) or median and range (if distribution not normal). For comparisons of means between two groups Student s t test or Mann-Whitney U test (if distribution not normal), Fischer exact test or χ -test for testing of frequency distributions were performed. Comparisons of means in the same group were assessed based on Student s test for dependent data or Wilcoxon test (if distribution not normal). Correlation assessment was performed using Pearson coefficient of correlation or Spearman s coefficient of rank correlation. An α = 0.05 was considered as significance level of the statistical tests. Results Among 64 patients (34.4%) had type diabetes mellitus (5 M; mean age: 57. ± 7.5 years, median of diabetes duration:.5(0.04 0) years, median HbA c: 6.3 ( )%), 4/ (8.%) patients with retinopathy, 5 patients treated with insulin, patients treated with oral blood glucose lowering agents, 4 patients treated with insulin and oral blood glucose lowering agents, patients with diet only). In the other 4 (65.6%) stroke patients diabetes mellitus was not diagnosed (6 M; mean age: 56. ±.3 years). No differences were observed in relation to age, sex, proportion of smokers between these two groups. BMI in diabetic patients was significantly higher than in nondiabetic stroke patients 8.9 ± 4. kg/m vs. 6.6 ± ± 4.6 kg/m, p < 0.05). ASA unresponsiveness was found in 6/ (7.3%) in group A (diabetic stroke patients) and in 7/4 patients (40.5%) in group B (non-diabetic stroke patients); the differences were not significant. In the control group only 3/37 (8.%) persons were ASA-unresponsive. Because of no differences in the prevalence of ASA unresponsiveness in relation to diabetes we considered in the further analysis 3 ASA-unresponsive and 4 ASA-responsive stroke patients. These groups did not differ in relation to age (59.5 ± 9.9 vs. 57 ± 0.7 years), sex (8M/5F vs. 3M/8F) and BMI 9. (0 35.) vs. 5.9 ( ) kg/m. Hyperliporoteinemia (defined as total cholesterol > 6. mmol/l (39 mg/dl) and/or triglycerides >.4 mmol/l ( mg/dl)) was diagnosed in 8/3 (34.8%) ASA unresponsive patients and in /4 (6.8%) ASA responsive patients (no significant difference). We compared in both groups lipid profile (Table ) and coagulation profile (Table ). We found differences in Lp(a) concentration which was significantly higher in the group of ASA-unresponsive compared with ASA-responsive (Table ). Some parameters were significantly different before and after 0 days of ASA treatment Lp(a) (Table ) and D-dimer (table ) in the group of ASA unresponsive and ASA responsive (both parameters were lower after ASA treatment). In the group of ASA responsive fibrinogen concentration and platelet count increased after ASA treatment, while TAT concentration in the same group decreased after ASA treatment (Table ). Discussion The enhanced prevalence of ASA resistance in diabetic patients was reported by some authors [,, 5, 7, 8] but others did not confirm it [0, 9]. Little is known about ASA resistance especially in diabetic stroke patients. In the study of Grau et al., the presence of diabetes mellitus in patients after stroke did not influence platelet response after ASA . In our work, differences in subgroups of diabetic and non diabetic stroke patients were also not significant (7.3% vs. 40.5% respectively). Diabetic patients, enrolled in our study, have relatively good metabolic control according to the range of HbA c. Uchiyama et al. found more frequent incidence of ASA responsiveness in stroke patients with combined risk factors (hypertension, diabetes mellitus, hyperlipidemia), compared to patients with only one or two risk factors . According
4 596 A.B. Sobol et al. Table. Lipid parameters of the ASA-unresponsive and ASA-responsive stroke patients before and after ASA treatment Tabela. Wskaźniki lipidowe u pacjentów nieodpowiadających i odpowiadających na ASA przed i po leczeniu ASA Parameter (Wskaźnik) ASA-unresponsive stroke patients (Pacjenci z udarem mózgu nieodpowiadający n = 3 ASA-responsive stroke patients (Pacjenci z udarem mózgu odpowiadający n = 4 p Cholesterol (mg/dl) (A). ± ± 4.5 ns. Cholesterol (mg/dl) (B).3 ± ± 43.9 ns. Triglycerides (mg/dl) (A) (Triglicerydy) Triglycerides (mg/dl) (B) (Triglicerydy) 46 (68 39) (56 353) ns. 67 (66 7) 46 (56 36) ns. HDL cholesterol (mg/dl) (A) 4. (7 6.3) 38.8 ( ) ns. HDL cholesterol (mg/dl) (B) 39.4 ( ) 40. ( ) ns. LDL cholesterol (mg/dl) (A) 40. ± ± 34.6 ns. LDL cholesterol (mg/dl) (B) 38.7 ± ± 36.9 ns. Phospholipids (mg/dl) (A) (Fosfolipidy) Phospholipids (mg/dl) (B) (Fosfolipidy) HDL triglycerides (mg/dl) (A) (HDL triglicerydy) HDL triglycerides (mg/dl) (B) (HDL triglicerydy) HDL phospholipids (mg/dl) (A) (HDL fosfolipidy) HDL phospholipids (mg/dl) (B) (HDL fosfolipidy) Lipoprotein (a) (mg/dl) (A) (Lipoproteina (a)) Lipoprotein (a) (mg/dl) (B) (Lipoproteina (a)) 94.6 ± ± 38.8 n.s. 04 (96 9) 5 (73 34) ns. 4 ± 5. 4 ± 5.3 ns. 4. ( ) 3. ( ) ns (6. 67) 89. (65.3 4) ns ( ) 89.3 ( ) ns. 43 (4 0) 7 (4 30) (4 94) 7 ( 90) 0.0 n number. p level of statistical significance. ns. not significant. (A) results before 0 days of ASA (acetylsalicylic acid) treatment. (B) results after 0 days of ASA treatment., results statistically significant in relation to before ASA treatment (A) to after ASA treatment (B) p < 0.0. Conversion rates: cholesterol: mg/dl = mmol/l 38.6, mg = 0.03 mmol/l, triglycerides: mg/dl = mmol/l 88.5, mg = 0.0 mmol/l n liczba. p istotność statystyczna. n.s. nieistotne statystycznie. (A) wyniki przed 0-dniowym leczeniem (ASA) kwasem acetylosalicylowym. (B) wyniki po 0-dniowym leczeniu ASA., wyniki istotne statystycznie przed leczeniem ASA (A) w porównaniu z po leczeniu ASA (B), p < 0,0. Współczynniki przeliczeniowe: cholesterol: mg/dl = mmol/l 38,6, mg = 0,03 mmol/l, triglicerydy: mg/dl = mmol/l 88,5, mg = 0,0 mmol/l.
5 Aspirin Responsiveness, Diabetes and Stroke 597 Table. Hemostatic parameters of the ASA-unresponsive and ASA-responsive stroke patients before and after ASA treatment Tabela. Wskaźniki hemostazy u pacjentów z udarem mózgu nieodpowiadających i odpowiadających na leczenie ASA przed i po leczeniu ASA Parameter (Wskaźnik) ASA unresponsive stroke patients (Pacjenci z udarem mózgu nieodpowiadający n = 3 ASA responsive p stroke patients (Pacjenci z udarem mózgu odpowiadający n = 4 APTT (s) (A) 3.8 ± ± 3.9 ns. APTT (s) (B) 3 (0 47) 3 ( 56) ns. Prothrombin time (%) (A) (Czas protrombinowy) Prothrombin time (%) (B) (Czas protrombinowy) Fibrinogen (mg/dl) (A) (Fibrynogen) Fibrinogen (mg/dl) (B) (Fibrynogen) Platelet count (tys./mm 3 ) (A) (Liczba płytek krwi) Platelet count (tys./mm 3 ) (B) (Liczba płytek krwi) 93.5 (70 03) 95.5 (65 06) ns. 94 (78 03) 95 (54 09) ns ± ± 76.5 ns ± ± 0.4 ns. 9 (8 6) 3.5 (04 380) ns. 36 (6 500) 49 (43 50) ns. D dimer (μg/l) (A) 89.6 (7. 88) ( ) 4 ns. D dimer (μg/l) (B) 9.8 ( 8.7) (8 50.6) 4 ns. TAT (μg/ml) (A) (Kompleks trombina antytrombina) TAT (μg /ml) (B) (Kompleks trombina antytrombina).9 ( 5.4).7 ( ) 5 ns..7 (0. 5.4).5 (0. 3.7) 5 ns. n number, p level of statistical significance. ns. not significant. (A) results before 0 days of (ASA) acetylsalicylic acid treatment. (B) results after 0 days of ASA treatment.,, 3, 4, 5 results statistically significant in relation to before ASA treatment (A) to after ASA treatment (B). p = p = APTT activated partial thromboplastin time. TAT thrombin antithrombin complex. n liczba. p istotność statystyczna. n.s. nieistotne statystycznie. (A) wyniki przed 0-dniowym leczeniem (ASA) kwasem acetylosalicylowym. (B) wyniki po 0-dniowym leczeniu ASA.,, 3, 4, 5 wyniki istotne statystycznie przed leczeniem ASA (A) w porównaniu z po leczeniu ASA (B). p = 0, p = 0,03. APTT aktywowany czas częściowej tromboplastyny. TAT kompleks trombina antytrombina.
6 598 A.B. Sobol et al. to results of study published by Singla et al. aspirin resistance in type diabetic patients may be associated with lipid parameters (total cholesterol, LDL-cholesterol and triglycerides) . Karepov et al. suggested the role of increased triglicerydes associated with ASA resistance and probably with diminished platelet membrane fluidity in patients after first ischemic stroke . We analyzed in details lipid profile including not only routine parameters in order to find any association with ASA-unresponsiveness. Lp(a) was the only parameter which significantly increased in ASA-unresponsive compared with ASA-responsive patients. The role of Lp(a) is discussed in the context of atherothrombosis and stroke risk factors [4 6]. Structural homology of Lp(a) with plasminogen may implicate its antithrombolytic properties and lead to thrombosis . Other lipid parameters did not differ in groups of ASAresponsive and ASA- unresponsive patients. Lp(a) was decreased after 0 days of 50 mg ASA treatment. Interestingly, none of hemostatic parameters could be used for discrimination of ASA- responsive from ASA-unresponsive patients. Earlier study suggested the inhibited action of ASA on thrombin generation and coagulation pathways [8 9] and the decrease of this inhibitory effect was caused by high levels of cholesterol and Lp(a) . It may be speculated that higher Lp(a) level in ASA-unresponsive patients may be responsible for a weaker inhibitory effect of ASA on thrombin generation and procoagulant tendency in this group. However, the lack of differences in hemostatic profile between ASA-responsive and ASAunresponsive patients, including fibrinogen, TAT, D-dimer (higher but no significantly in ASA-unresponsive), does not confirm this possibility. The role of Lp(a) in mechanisms of ASA resistance deserves further investigations. The authors concluded that the prevalence of diabetes mellitus seems to be not associated with ASA unresponsiveness in ischemic stroke patients, the elevated Lp(a) before ASA treatment as well as after ASA therapy in ASA-unresponsive patients may indicate the link of Lp(a) with ASA unresponsiveness, the blood coagulation profile was not associated with ASA unresponsiveness in ischemic stroke patients. Acknowledgments. The authors thank Dr hab. Jacek Golanski (Medical University of Lodz, Poland) and Dr Marzenna Galar (Medical University of Bialystok, Poland) for the technical help. References  Kannel WB, McGee DL: Diabetes and cardiovascular risk factors: the Framingham study. Circulation 979, 59, 8 3.  Sobol AB, Watala C: The role of platelets in diabetes-related vascular complications. Diab Res Clin Pract 000, 50, 6.  Final report on the aspirin component of the ongoing Physicians Health Study. Steering Committee of the Physicians Health Study Research Group. N Engl J Med 989, 3,  ETDRS Investigators: Aspirin effects on mortality and morbidity in patients with diabetes mellitus. JAMA 99, 68,  Antiplatelet Trialists Collaboration, Collaborative overview of randomised trial of antiplatelet therapy I; prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 994, 308,  Colwell JA: American Diabetes Association. Aspirin therapy in diabetes [position statement]. Diabetes Care 004, 7, S7 S73.  Haggerty SA, Cerulli J, Zeolla MM, Cottrell JS, Weck MB, Faragon JJ: Community pharmacy Target Intervention Program to improve aspirin use in persons with diabetes. J Am Pharm Assoc 005, 45, 7.  Goldstein LB, Adams R, Alberts MJ Appel LJ, Brass LM, Bushnell CD, Culebras A, DeGraba TJ, Gorelick PB, Guyton JR, Hart RG, Howard G, Kelly-Hayes M, Nixon JV, Sacco RL, American Heart Association, American Stroke Association: Primary prevention of ischemic stroke: a guideline from the American Heart Association/ American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 006, 3, e  Welin L, Wilhelmsen L, Bjoernberg A, Oden A: Aspirin increases mortality in diabetic patients without cardiovascular disease: a Swedish record linkage study. Pharmacoepidemiol Drug Saf 009, 8,  Zimmermann N, Hohlfeld T: Clinical implications of aspirin resistance. Thromb Haemost 008, 00,  Mehta SS, Silver RJ, Aaronson A, Abrahamson M, Goldfine AB: Comparison of aspirin resistance in type versus type diabetes mellitus. Am J Cardiology 006, 97,  Abaci A, Caliskan M, Bayram F, Yilmaz Y, Cetin M, Unal A, Cetin S: A new definition of aspirin non-responsiveness by platelet function analyzer-00 and its predictors. Platelets 006, 7, 7 3.
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