Pobierz PDF - Advances in Clinical and Experimental Medicine

Pobierz PDF - Advances in Clinical and Experimental Medicine

original papers
Adv Clin Exp Med 2010, 19, 5, 593–599
ISSN 1230-025X
© Copyright by Wroclaw Medical University
Anna B. Sobol1, Krzysztof Selmaj2, Alina Mochecka2, Anna Kumor3, Jerzy Loba1
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
1 2 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 (22 with diabetes, 41 men, mean age 57.9 ± 10.4 years) with ischemic stroke
or transient ischemic attack treated with the routine dose of 150 mg acetylsalicylic acid (ASA) daily were included
into this study. Aspirin responsiveness was assessed based on platelet reactivity using platelet function analyzer
(PFA-100TM) with collagen/epinephrine cartridges and whole blood platelet aggregometry with 0.5 mM arachidonic acid on the first day of acute stroke and after 10 days of a 150 mg ASA intake. Lipid and hemostatic profiles
were determined.
Results. The authors observed ASA unresponsiveness in 6/22 (27.3%) of diabetic and in 17/42 (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 (4–102) mg/dl vs. 27 (4–130) mg/dl, p = 0.03 as well after 10 days of ASA
treatment 37 (4–94) mg/dl vs 27 (1–90) mg/dl, p = 0.01.
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 2010, 19, 5, 593–599).
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 (22 chorych na cukrzycę, 41 M, średnia wieku 57,9 ± 10,4 lat)
z niedokrwiennym udarem mózgu lub przejściowym atakiem niedokrwiennym (TIA), leczonych rutynową dawką
150 mg kwasu acetylosalicylowego (ASA) dziennie. Odpowiedź na aspirynę oceniano, badając reaktywność płytek
krwi z wykorzystaniem analizatora czynności płytek krwi (PFA-100TM), 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 10 dniach przyjmowania 150 mg ASA. Oceniano profil lipidowy i wybrane wskaźniki hemostazy.
Wyniki. Brak odpowiedzi na ASA stwierdzono u 6 (27.3%) spośród 22 pacjentów chorych na cukrzycę i u 17 (40,5%)
spośród 42 pacjentów niechorujących na cukrzycę (różnice nieistotne statystycznie). Lipoproteina (a) była wyższa
* This study was supported by the Medical University of Lodz, grant no 502-16-784.
The preliminary results of this study were presented at the 41st European Association for the Study of Diabetes
Annual Meeting, September 2005, Athens, Greece.
594
A.B. Sobol et al.
u pacjentów nieodpowiadających na ASA w porównaniu z pacjentami odpowiadającymi na ASA zarówno przed
leczeniem: 43 (4 – 102) mg/dl vs 27 (4–130) mg/dl, p = 0,03, jak i po 10 dniach leczenia ASA: 37 (4–94) mg/dl vs
27 (1–90) mg/dl, p = 0,01.
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 2010, 19, 5,
593–599).
Słowa kluczowe: odpowiedź na aspirynę, krzepnięcie krwi, cukrzyca, niedokrwienny udar mózgu, lipoproteina (a).
The incidence of stroke in diabetic patients is
2–4 fold higher than in non-diabetic patients [1].
The essential role in atherogenic pathogenesis in
diabetes is played by platelets [2].
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
[9].
Despite therapeutic doses of ASA a group of
patients does not respond to this drug presenting
clinically or laboratory “unresponsiveness” [10].
Among several risk factors for stroke diabetes
was reported as associated with the diminished or
the lack of ASA response [11–13]. However, there
are only few data concerning ASA unresponsiveness in diabetic stroke patients [14–15].
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 [16].
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 (22 with diabetes and
42 without diabetes) hospitalized at the Department of Neurology, Medical University of Lodz,
Poland, with diagnosis of ischemic stroke, with
symptoms lasting < 72 hours or transient ischemic attack (TIA) and with recommended routine
dose of ASA (150 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 10 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
(150 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 (12 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 10 days of the therapy with 150 mg ASA daily.
For platelet reactivity tubes with buffered citrate,
for coagulation and lipid profiles – standard tubes
containing 0.109 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 2500 g for 15 min.
at +4°C and used for blood coagulation measurements. The whole blood was used within 1 hour
after blood withdrawal for platelet function analyzer (PFA-100 TM) method and for platelet aggregometry assessment.
Platelet reactivity was assessed using two methods: platelet function analyzer (PFA-100TM) with
collagen/epinephrine and collagen/ADP cartridges
to measure aperture closure time (Dade Behring,
Germany). The whole blood platelet aggregometry
was assessed with agonists: 20 µM ADP, collagen
2 µg/ml, 0.5 mM arachidonic acid (Chrono-Log,
595
Aspirin Responsiveness, Diabetes and Stroke
USA). Aspirin unresponsiveness was defined as
the lack of the prolongation of collagen/epinephrine closure time ≤ 150 sec. (PFA-100TMmethod)
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
χ2-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 22 (34.4%) had type 2 diabetes mellitus (15 M; mean age: 57.2 ± 7.5 years,
median of diabetes duration: 2.5(0.04–20) years,
median HbA1c: 6.3 (5.5–8.8)%), 4/22 (18.2%) patients with retinopathy, 5 patients treated with insulin, 11 patients treated with oral blood glucose
lowering agents, 4 patients treated with insulin
and oral blood glucose lowering agents, 2 patients
with diet only). In the other 42 (65.6%) stroke patients diabetes mellitus was not diagnosed (26 M;
mean age: 56.2 ± 11.3 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 28.9 ± 4.2 kg/m2 vs. 26.6 ±
± 4.6 kg/m2, p < 0.05).
ASA unresponsiveness was found in 6/22
(27.3%) in group A (diabetic stroke patients) – and
in 17/42 patients (40.5%) in group B (non-diabetic stroke patients); the differences were not
significant. In the control group only 3/37 (8.1%)
persons were ASA-unresponsive. Because of no
differences in the prevalence of ASA unresponsiveness in relation to diabetes we considered in
the further analysis 23 ASA-unresponsive and 41
ASA-responsive stroke patients. These groups did
not differ in relation to age (59.5 ± 9.9 vs. 57 ± 10.7
years), sex (18M/5F vs. 23M/18F) and BMI 29.1
(20–35.2) vs. 25.9 (19.3–38.3) kg/m2. Hyperliporoteinemia (defined as total cholesterol > 6.2 mmol/L
(239 mg/dl) and/or triglycerides > 2.4 mmol/L
(212 mg/dl)) was diagnosed in 8/23 (34.8%) ASA
– unresponsive patients and in 11/41 (26.8%) ASA
– responsive patients (no significant difference).
We compared in both groups lipid profile (Table 1)
and coagulation profile (Table 2). We found differences in Lp(a) concentration which was significantly higher in the group of ASA-unresponsive
compared with ASA-responsive (Table 1). Some
parameters were significantly different before and
after 10 days of ASA treatment – Lp(a) (Table 1)
and D-dimer (table 2) 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 2).
Discussion
The enhanced prevalence of ASA resistance in
diabetic patients was reported by some authors [11,
12, 15, 17, 18] but others did not confirm it [10, 19].
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
[20]. In our work, differences in subgroups of diabetic and non – diabetic stroke patients were also
not significant (27.3% vs. 40.5% respectively). Diabetic patients, enrolled in our study, have relatively
good metabolic control according to the range of
HbA1c. 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 [21]. According
596
A.B. Sobol et al.
Table 1. Lipid parameters of the ASA-unresponsive and ASA-responsive stroke patients before and after ASA treatment
Tabela 1. 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 na ASA)
n = 23
ASA-responsive stroke patients
(Pacjenci z udarem mózgu odpowiadający na ASA)
n = 41
p
Cholesterol (mg/dl) (A)
212.1 ± 35.6
198.8 ± 41.5
ns.
Cholesterol (mg/dl) (B)
212.3 ± 43.7
210 ± 43.9
ns.
Triglycerides (mg/dl) (A)
(Triglicerydy)
146 (68–239)
121 (56–353)
ns.
Triglycerides (mg/dl) (B)
(Triglicerydy)
167 (66–272)
146 (56–326)
ns.
HDL – cholesterol (mg/dl) (A)
41.2 (27–61.3)
38.8 (27.1–85.7)
ns.
HDL – cholesterol (mg/dl) (B)
39.4 (24.9–62.3)
40.2 (29.2–76.7)
ns.
LDL – cholesterol (mg/dl) (A)
140.1 ± 31.8
128.5 ± 34.6
ns.
LDL – cholesterol (mg/dl) (B)
138.7 ± 42.6
135.8 ± 36.9
ns.
Phospholipids (mg/dl) (A)
(Fosfolipidy)
194.6 ± 35.3
216 ± 38.8
n.s.
Phospholipids (mg/dl) (B)
(Fosfolipidy)
204 (96–291)
215 (73–324)
ns.
HDL – triglycerides (mg/dl) (A)
(HDL – triglicerydy)
14 ± 5.1
14 ± 5.3
ns.
HDL – triglycerides (mg/dl) (B)
(HDL – triglicerydy)
14.2 (9.1–43.6)
13.2 (7.5–46.1)
ns.
HDL – phospholipids (mg/dl) (A)
(HDL – fosfolipidy)
84.8 (61.1–167)
89.1 (65.3–141)
ns.
HDL – phospholipids (mg/dl) (B)
(HDL – fosfolipidy)
85.9 (67.3–174)
89.3 (47.8–158)
ns.
Lipoprotein (a) (mg/dl) (A)
(Lipoproteina (a))
43 (4–102)1
27 (4–130)2
0.03
Lipoprotein (a) (mg/dl) (B)
(Lipoproteina (a))
37 (4–94)1
27 (1–90)2
0.01
n – number.
p – level of statistical significance.
ns. – not significant.
(A) – results before 10 days of ASA (acetylsalicylic acid) treatment.
(B) – results after 10 days of ASA treatment.
1, 2 – results statistically significant in relation to “before ASA treatment (A)” to “after ASA treatment (B)”
1
p < 0.01.
2
p < 0.005.
Conversion rates: cholesterol: mg/dl = mmol/L × 38.6, 1 mg = 0.03 mmol/L, triglycerides: mg/dl = mmol/L × 88.5, 1 mg = 0.01 mmol/L
n – liczba.
p – istotność statystyczna.
n.s. – nieistotne statystycznie.
(A) – wyniki przed 10-dniowym leczeniem (ASA) kwasem acetylosalicylowym.
(B) – wyniki po 10-dniowym leczeniu ASA.
1, 2
– wyniki istotne statystycznie „przed leczeniem ASA (A)” w porównaniu z „po leczeniu ASA (B)”,
1
p < 0,01.
2
p < 0,005.
Współczynniki przeliczeniowe: cholesterol: mg/dl = mmol/L × 38,6, 1 mg = 0,03 mmol/L, triglicerydy: mg/dl = mmol/L
× 88,5, 1 mg = 0,01 mmol/L.
597
Aspirin Responsiveness, Diabetes and Stroke
Table 2. Hemostatic parameters of the ASA-unresponsive and ASA-responsive stroke patients before and after ASA
treatment
Tabela 2. 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 na ASA)
n = 23
ASA – responsive p stroke patients
(Pacjenci z udarem mózgu odpowiadający na ASA)
n = 41
APTT (s) (A)
31.8 ± 4.6
31.3 ± 3.9
ns.
APTT (s) (B)
31 (20–47)
32 (22–56)
ns.
Prothrombin time (%) (A)
(Czas protrombinowy)
93.5 (70–103)
95.5 (65–106)
ns.
Prothrombin time (%) (B)
(Czas protrombinowy)
94 (78–103)
95 (54–109)
ns.
Fibrinogen (mg/dl) (A)
(Fibrynogen)
330.8 ± 89.8
332.4 ± 76.51
ns.
Fibrinogen (mg/dl) (B)
(Fibrynogen)
366.2 ± 110.3
375.7 ± 101.41
ns.
Platelet count (tys./mm3) (A)
(Liczba płytek krwi)
229 (118–622)
213.5 (104–380)2
ns.
Platelet count (tys./mm3) (B)
(Liczba płytek krwi)
236 (126–500)
249 (143–510)2
ns.
D – dimer (μg/L) (A)
89.6 (17.2–1288)3
71.6 (14.7–364.8)4
ns.
D – dimer (μg/L) (B)
29.8 (11–182.7)3
24.3 (8–150.6)4
ns.
TAT (μg/ml) (A)
(Kompleks trombina–antytrombina)
1.9 (1–5.4)
1.7 (0.6–6.3)
ns.
TAT (μg /ml) (B)
(Kompleks trombina–antytrombina)
1.7 (0.2–5.4)
1.5 (0.2–23.7)5
5
n – number, p – level of statistical significance.
ns. – not significant.
(A) – results before 10 days of (ASA) acetylsalicylic acid treatment.
(B) – results after 10 days of ASA treatment.
1, 2, 3, 4, 5
– results statistically significant in relation to “before ASA treatment (A)” to “after ASA treatment (B)”.
1
p = 0.03.
2
p < 0.005.
3
p < 0.005.
4
p < 0.005.
5
p = 0.03.
APTT – activated partial thromboplastin time.
TAT – thrombin–antithrombin complex.
n – liczba.
p – istotność statystyczna.
n.s. – nieistotne statystycznie.
(A) – wyniki przed 10-dniowym leczeniem (ASA) kwasem acetylosalicylowym.
(B) – wyniki po 10-dniowym leczeniu ASA.
1, 2, 3, 4, 5
– wyniki istotne statystycznie „przed leczeniem ASA (A)” w porównaniu z „po leczeniu ASA (B)”.
1
p = 0,03.
2
p < 0,005.
3
p < 0,005.
4
p < 0,005.
5
p = 0,03.
APTT – aktywowany czas częściowej tromboplastyny.
TAT – kompleks trombina–antytrombina.
ns.
598
A.B. Sobol et al.
to results of study published by Singla et al. aspirin resistance in type 2 diabetic patients may be
associated with lipid parameters (total cholesterol,
LDL-cholesterol and triglycerides) [22]. 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 [23].
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 [24–26]. Structural homology of Lp(a)
with plasminogen may implicate its antithrombolytic properties and lead to thrombosis [27]. Other
lipid parameters did not differ in groups of ASAresponsive and ASA- unresponsive patients. Lp(a)
was decreased after 10 days of 150 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
[28–29] and the decrease of this inhibitory effect
was caused by high levels of cholesterol and Lp(a)
[30]. 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
[1] Kannel WB, McGee DL: Diabetes and cardiovascular risk factors: the Framingham study. Circulation 1979, 59,
8–13.
[2] Sobol AB, Watala C: The role of platelets in diabetes-related vascular complications. Diab Res Clin Pract 2000, 50,
1–16.
[3] 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 1989, 321, 129–135.
[4] ETDRS Investigators: Aspirin effects on mortality and morbidity in patients with diabetes mellitus. JAMA 1992,
268, 1292–1300.
[5] 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 1994, 308, 81–106.
[6] Colwell JA: American Diabetes Association. Aspirin therapy in diabetes [position statement]. Diabetes Care 2004,
27, S72–S73.
[7] 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 2005, 45, 17–22.
[8] 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 2006, 113, e873–923.
[9] 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 2009, 18, 1143–1149.
[10] Zimmermann N, Hohlfeld T: Clinical implications of aspirin resistance. Thromb Haemost 2008, 100, 379–390.
[11] Mehta SS, Silver RJ, Aaronson A, Abrahamson M, Goldfine AB: Comparison of aspirin resistance in type 1 versus type 2 diabetes mellitus. Am J Cardiology 2006, 97, 567–570.
[12] 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-100 and its predictors. Platelets 2006, 17, 7–13.
Aspirin Responsiveness, Diabetes and Stroke
599
[13] Angiolillo DJ, Suryadevara S: Aspirin and clopidogrel: efficacy and resistance in diabetes mellitus. Best Pract Res
Clin Endocrinol Metab 2009, 23, 375–388.
[14] McCabe DJ, Harrison P, Mackie IJ, Sidhu PS, Lawrie AS, Purdy G, Machin SJ, Brown MM: Assessment of
the antiplatelet effects of low to medium dose aspirin in the early and late phases after ischemic stroke and TIA.
Platelets 2005, 16, 269–280.
[15] Stejskal D, Vaclavik J, Lacnak B, Proskova J: Aspirin resistance measured by cationic propyl gallate platelet
aggregometry and recurrent cardiovascular events during 4 years of follow-up. Eur J Intern Med 2006, 17, 349–
354.
[16] Sobol AB, Mochecka A, Selmaj K, Loba J: Is there a relationship between aspirin responsiveness and clinical
aspects of ischemic stroke? Czy istnieje związek między odpowiedzią na aspirynę a klinicznymi aspektami niedokrwiennego udaru mózgu? Adv Clin Exp Med 2009, 18, 473–479.
[17] Evangelista V, Totani L, Rotondo S, Lorenzet R, Tognoni G, De Berardis G, Nicolucci A: Prevention of cardiovascular disease in type-2 diabetes: how to improve the clinical efficacy of aspirin. Thromb Haemost 2005, 93,
8–16.
[18] De Gaetano G: Aspirin resistance in diabetic patients. Diabetes Care 2004, 27, 1244–1245.
[19] Christiaens L, Macchi L, Herpin D, Coisne D, Duplantier C, Allal J, Mauco G, Brizard A: Resistance to aspirin
in vitro at rest and during exercise in patients with angiographically proven coronary artery disease. Thromb Res
2002, 108, 115–119.
[20] Grau AJ, Reiners S, Lichy C, Buggle F, Ruf A: Platelet function under aspirin, clopidogrel, and both after ischemic stroke: a case-crossover study. Stroke 2003, 34, 849–855.
[21] Uchiyama S, Nakamura T, Yamazaki M, Kimura Y, Iwata M: New modalities and aspects of antiplatelet therapy
for stroke prevention. Cerebrovasc Dis 2006, 21, Suppl. 1, 7–16.
[22] Singla MK, Lahiri P, Mukhopadhyay P, Pandit K, Chaudhuri U, Chowdhury S: A study of aspirin resistance in
type 2 diabetes. J Indian Med Assoc 2008, 106, 720, 722–723, 740.
[23] Karepov V, Tolpina G, Kuliczkowski W, Serebruany V: Plasma triglycerides as predictors of platelet responsiveness to aspirin in patients after first ischemic stroke. Cerebrovasc Dis 2008, 26, 272–276.
[24] Milionis HJ, Winder AF, Mikhailidis DP: Lipoprotein (a) and stroke. J Clin Pathol 2000, 53, 487–496.
[25] Milionis HJ, Filippatos TD, Loukas T, Bairaktari ET, Tselepis AD, Elisaf MS: Serum lipoprotein(a) levels and
apolipoprotein(a) isoform size and risk for first-ever acute ischaemic nonembolic stroke in erderly individuals.
Atherosclerosis 2006, 187, 170–176.
[26] Ohira T, Schreiner PJ, Morrisett JD, Chambless LE, Rosamond WD, Folsom AR: Lipoprotein(a) and incident
ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2006, 37, 1407–1412.
[27] McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM: cDNA sequence
of human lipoprotein(a) is homologous to plasminogen. Nature 1987, 330, 132–137.
[28] Szczeklik A: Inhibition of thrombin generation by aspirin. Thromb Haemost 1994, 72, 988–989.
[29] Undas A, Undas R, Musial J, Szczeklik A: A low dose of aspirin (75 mg/day) lowers thrombin generation to
a similar extent as a high dose of aspirin (300 mg/day). Blood Coagul Fibrinolysis 2000,11, 231–234.
[30] Szczeklik A, Musial J, Undas A, Swadzba J, Duplaga M, Grzywacz M: High levels of cholesterol and lipoprotein
(A) in serum decreases the inhibitory effect of aspirin on generation of thrombin. Pol Arch Med Wewn 1995, 93,
483–489.
Address for correspondence:
Anna B. Sobol
Department of Internal Medicine and Diabetology
Medical University of Lodz
2/4 Jęczmienna Street
94-202 Lodz
Poland
Tel.: +48 426 339 913
E-mail: [email protected]
Conflict of interest: None declared
Received: 11.05.2010
Revised: 19.05.2010
Accepted: 20.09.2010