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Title: Aspirin resistance and its mechanism in pregnant women

Abstract:

A phenomenon termed aspirin (ASA) resistance with a prevalence from 5.5% to 61% of treated subjects is considered to be a potential cause of ASA’s failure in the prevention of atherothrombosis. At present, there is no widely accepted definition of ASA resistance or diagnostic criteria and tests to evaluate this phenomenon. The cause of ASA resistance also remains unclear. Until now ASA resistance has not been investigated in pregnant women taking this drug. The aim of this study was to evaluate the influence of pregnancy on the occurrence of ASA resistance and to determine factors that may increase the risk of this phenomenon, especially antiphospholipid syndrome (APS), inflammation, the presence of PlA2 allele. We also sought to investigate the effect of decreased sensitivity to ASA on the pregnancy, delivery, puerperium and newborn state. A case-control study was performed on 75 pregnant women, aged 20 to 44 years. Forty-three women took 75 mg of ASA daily. The main cause of ASA intake was APS (n=27). The remaining 32 women, who were not treated with ASA, represented 24 healthy women and 8 women with systemic lupus erythematosus (SLE). Venous blood and urine samples were obtained 3 times: between 18 and 22 weeks of gestation (2nd trimester), between 28 and 32 weeks of gestation (3rd trimester) and after puerperium (on average 26 weeks after childbirth). To identify patients resistant to aspirin we determined urinary 11-dehydro-thromboxane B2 (11-dTXB2) concentrations and defined ASA resistance based on the quartile distribution (the highest quartile - women resistant to ASA) and my own parameter, the resistance index (RI), namely, a difference between urinary levels of 11-dTXB2 of each woman treated with ASA and their median value at the same time point measured in the control group. Additionally, C-reactive protein (CRP), interleukin 6 (IL-6), anticardiolipin antibodies IgG (aCL IgG) and IgM (aCL IgM), lupus anticoagulant (LA), soluble CD40 ligand (sCD40L), thrombin-antithrombin complexes (TAT), total homocysteine (tHcy) and the presence of PlA1 and PlA2 alleles of integrin β3 using the PCR-RFLP technique were determined. There were no significant differences between the groups with respect to demographic data or the prevalence of PlA2 allele. However, women treated with ASA had higher mean body mass index (BMI). Women treated with ASA had no significant differences during pregnancy and after puerperium with respect to urinary 11-dTXB2 concentrations. Patients treated with ASA had significantly lower urinary concentration of 11-dTXB2 in comparison with the control group in the 2nd trimester (224.0 ± 257.1 vs 499.6 ± 182.1 pg/μmol creatinine; p<0.0001) and the 3rd trimester (232.6 ± 235.0 vs 678.0 ± 337.0 pg/μmol creatinine; p<0.0001) and after puerperium (170.0 ± 154.0 vs 384.0 ± 185.6 pg/μmol creatinine; p<0.0001). There were no significant differences between the highest and the lowest quartile with respect to the prevalence of PlA2 allele, APS and the concentration of IL-6 and sCD40L but in the 2nd trimester there was a significant difference with regard to CRP (p=0.05), tHcy (p=0.05), aCL IgG (p=0.01) and after puerperium with respect to aCL IgG (p=0.01). In women in the highest quartile the pregnancy was shorter (p=0.03). Intrauterine growth restriction and delivery of small for gestational age newborns (p=0.05) and fetal distress (p=0.05) were also more frequently observed in this subgroup. The 2nd trimester range of the highest quartile classified also 9 women in the 3rd trimester as resistant to ASA and only 3 women after puerperium. The analysis based on the RI value showed that women with a low response to ASA had higher urinary 11-dTXB2 concentrations in the 2nd trimester (64.35 ± 32.36 vs 443.67 ± 273.56 pg/µmol creatinine, p<0.0001) and the 3rd trimester (77.65 ± 25.27 vs 492.62 ± 197.09 pg/µmol creatinine; p<0.0001), tHcy in the 2nd trimester (p=0.05) and sCD40L in the 3rd trimester (p=0. ; 05) compared to women responsive to ASA. In the latter group the effect of ASA seen as a reduction in concentration of 11-dTXB2 during the 2nd trimester was more profound during the 3rd trimester and weaker after puerperium. In women who poorly responded to ASA, urinary 11-dTXB2 concentration increased during the 3rd trimester and during pregnancy. There were no signifficant differences with the median of 11-dTXB2 in the control group but after puerperium 11-dTXB2 concentrations were similar to those in women responsive to ASA. Women responsive and nonresponsive to ASA had a similar prevalence of APS and PlA2 allele. However, these groups differed in the prevalence of SLE (37.5% vs 5.0%, p=0.04), preeclampsia (p=0.02), exacerbations of SLE (p=0.04) and small for gestational age newborns delivery (p=0.01). In women with APS the highest quartile of urinary 11-dTXB2 concentrations was associated in the 2nd trimester with higher concentrations of TAT (p=0.03), tHcy (p=0.01), aCL IgG (p=0.01) and aCL IgM (p=0.05) as well as with higher levels of aCL IgG in the 3rd trimester (p=0.04) and after puerperium (p=0.01) compared with the lowest quartile. Pregnancies in the highest quartile lasted shorter (p=0.008) and showed a tendency to small for gestational age newborns delivery (p=0.07). The method of RI in group with APS showed no statistically significant differences between responsive and nonresponsive to ASA women with respect to markers of inflammation. Nonresponsive to ASA women in the 2nd trimester had higher concentrations of tHcy (p=0.01), 11-dTXB2 (p=0.005), in the 3rd trimester had higher levels of 11-dTXB2 (p<0.0001) and after puerperium higher levels of aCL IgG (p=0.05) and TAT (p=0.02). Low response to ASA was associated with the occurence of SLE (p=0.04), preeclampsia (p=0.01) and small for gestational age newborns delivery (p=0.04). In conclusion, ASA resistance is associated with increased risk of complications during pregnancy, has an adverse effect on the duration of pregnancy and neonatal birthweight. ASA resistance is more pronounced in pregnancy compared to the first year after delivery. In preganant women, ASA resistance is more prevalent in women with higher levels of anticardiolipin antibodies and is associated with inflammation but not with the PlA1/A2 polymorphism.

Level of degree:

2 - studia doktoranckie

Degree discipline:

farmakologia ; ginekologia

Degree grantor:

Wydział Lekarski

Promoter:

Anetta Undas

Date issued:

2007

Format:

application/pdf

Identifier:

oai:dl.cm-uj.krakow.pl:986

Call number:

ZB-107320

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tylko w bibliotece

Location of original object:

Biblioteka Medyczna Uniwersytetu Jagiellońskiego - Collegium Medicum

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Last modified:

Jun 25, 2019

In our library since:

Nov 21, 2012

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http://dl.cm-uj.krakow.pl:8080/publication/986

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ZB-107320 Jun 25, 2019
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