http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2015; 28(6): 643–648 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.927860

ORIGINAL ARTICLE

The impact of platelet functions and inflammatory status on the severity of preeclampsia Sadik Sahin1, Ozlem Bingol Ozakpinar2, Mustafa Eroglu1, Aysin Tulunay3, Enver Ciraci2, Fikriye Uras2, and Sermin Tetik2 1

Division of Perinatology, Department of Obstetrics and Gynecology, Zeynep Kamil Maternity and Children’s Hospital, Istanbul, Turkey, Department of Biochemistry, School of Pharmacy, Marmara University, Istanbul, Turkey, and 3Department of Immunology, School of Medicine, Marmara University, Istanbul, Turkey

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Objective: To find out whether there is a correlation between the extent of platelet activation and inflammation and the severity of preeclampsia (PE) in the third trimester of pregnancy. Methods: Forty-one women with PE (n ¼ 23 severe, n ¼ 18 mild) and 80 normotensive pregnant (NP) women were included in the study. Their blood samples were obtained and interleukin (IL)-8 and IL-10 levels measured by an enzyme-linked immunosorbent assay. Basal CD61 and CD62P expressions on CD41-positive platelets were analyzed with the use of flow-cytometry. Platelet aggregation was induced by adenosine diphosphate and determined by aggregometry. Results: CD62P expression was increased in severely preeclamptic women, and the platelet aggregation was decreased in both mildly and severely preeclamptic women in comparison with NP women. However, CD61 expression was similar among the groups. An enhanced inflammatory response was seen in severely preeclamptic women demonstrated by increased levels of IL-8 and decreased levels of IL-10. However, the intensity of platelet activation did not correlate directly with the change in plasma levels of IL-8 and IL-10 in preeclamptic women. Conclusions: Platelets may have a role in the inflammatory response in PE. However, the severity of inflammation is found to be independent from the intensity of platelet activation in preeclamptic women. This seems to be related to mechanisms causing alterations of cytokine levels such as IL-8 and IL-10, rather than platelet activation.

Aggregometry, inflammation, interleukins, platelet activation, preeclampsia, severity

Introduction Preeclampsia (PE) is a hypertensive disease of pregnancy complicating 2–8% of all pregnancies. Although the exact pathophysiology still remains unknown, abnormal trophoblastic invasion, vascular endothelial dysfunction, platelet activation and immunological maladaptation to pregnancy are thought to be responsible for the pathogenesis of PE [1]. Platelet activation, both in normal pregnancies and PE, has been extensively studied in previous studies, which showed platelets were in an activated state in PE [2–4]. There are numerous markers of platelet activation as follows: cell surface and soluble markers, platelet–monocyte and platelet–neutrophil aggregates [5]. CD61 (fibrinogen receptor) is a surface glycoprotein on platelets, which undergoes conformational change when the platelets are activated. Upon activation, CD61 binds to fibrinogen, which can act as Address for correspondence: Sadik Sahin, MD, Zeynep Kamil Maternity and Children’s Hospital, Op. Dr. Burhanettin Ustunel Cd No:10, 34668 Istanbul, Turkey. Tel: +90 216 391 06 80. Fax: +90 216 391 06 90. E-mail: [email protected]

History Received 10 December 2013 Revised 22 April 2014 Accepted 21 May 2014 Published online 19 June 2014

bridging molecules between platelets to form aggregates [5]. P-selectin or CD62P is an alpha granular membrane protein, which is translocated to the surface of activated platelets. It is well known that CD62P expression on platelet surface increases in preeclamptic women [3]. The interaction of activated platelets with neutrophils and monocytes is mainly mediated through P-selectin [6]. There is a good deal of evidence indicating that platelets have a role in initiating inflammation in vasculature through interactions with leukocytes and endothelial cells and cause the release of pro-inflammatory cytokines [6]. Interleukin (IL)-8 is a secretory product of monocytes, macrophages and endothelial cells, leading mainly to recruitment and activation of neutrophils [7,8]. Therefore, platelets and ILs, particularly IL-8, are interrelated with each other to some extent. Ellis et al. reported that the levels of IL-8 were higher in severe PE compared to mild PE [9]. IL-8 seems to have a pivotal role in the severity of PE. On the other hand, IL-10 is a regulatory cytokine, and its decreased production may contribute to poor placentation and production of vasoactive anti-angiogenic factors, which are involved in the pathogenesis of PE [10].

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Though the roles of inflammation and platelet activation in PE have been documented in many studies [4,11], the interrelationship and severity of platelet activation and inflammation have not been questioned at all in this patient population. The aim of this study was to find out whether there is a correlation between the extent of platelet activation and inflammation and the severity of PE in the third trimester of pregnancy.

Materials and methods Patients and controls Forty-one consecutive patients in their third trimester of pregnancy admitted to the Zeynep Kamil Maternity and Children’s Hospital during one-year period between April 2013 and 2014 with the diagnosis of PE were included in the study. Twenty-three of the 41 PE patients were diagnosed with severe PE and 18 with mild PE. Eighty pregnant women in their third trimester with uncomplicated pregnancies who visited the outpatient clinic of the same hospital served as control cases. All of the control cases were matched according to gestational weeks and age, and they were randomly assigned during the study period. The diagnosis of PE was determined by the criteria of the American College of Obstetricians and Gynaecologists for PE (2002) [12]. Briefly, mild PE was defined as maternal blood pressure  140/90 mmHg, on more than two consecutive occasions six hours apart, and proteinuria 1 + or more on dipstick or  300 mg protein in 24-hr urine collection. Diagnosis of severe PE was defined as follows: sustained systolic blood pressure of  160 mmHg or a sustained diastolic blood pressure of  110 mmHg on more than two consecutive occasions six hours apart; proteinuria measurement of 3 + or more on dipstick or 24-hr urine protein collection with  5 g in specimen. The exclusion criteria were as follows: women in labour, multiple pregnancies, ruptured membranes, medical history of chronic hypertension and diabetes. All of the 80 normotensive pregnant (NP) women were in their third trimester of pregnancy and none of them developed subsequent PE or other pregnancy complications. In these women, blood pressures and urinary protein excretion (assessed by dipstick) were within the normal ranges. All participants gave informed consents, and the Ethics Committee at the Zeynep Kamil Maternity and Children’s Hospital – Istanbul approved the study (Rep No: 05.04.2013/044). Blood samples To determine cytokine levels and platelet activation and aggregation, venous blood samples were collected prospectively into three different vacuum tubes containing 3.8% sodium citrate. The samples taken for cytokine analyses were centrifuged at 1000  g for 15 min at 4  C. Plasma was then collected and kept frozen at 80  C until use. Measurement of platelet aggregation Citrated blood was centrifuged for 10 min at 200  g to obtain platelet-rich plasma (PRP), and then platelet-poor plasma was obtained after centrifugation for 15 min at

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1500  g. The platelet aggregation induced by adenosine diphosphate (ADP) (5 mM) was performed on a four-channel lumi-aggregometer (Chrono-Log, Havertown, PA). For the assessment of platelet aggregation, blood samples rested for at least 30 min at room temperature but no longer than two hours before analysis. Flow-cytometry analysis PRP obtained from PE and NPs was used for the identification of cell surface CD41, CD61 and CD62P expressions of platelets. After obtaining PRP, platelets were washed with phosphate buffered saline (pH 7.4) at 1000  g for five minutes and then were stained with fluorescein isothiocyanate-conjugated CD41a, phycoerythrin (PE)-conjugated CD62P and allophycocyanin-conjugated CD61 monoclonal antibodies (Biolegend, San Diego, CA) and their corresponding isotype controls. The platelet gates were confirmed by the expression of CD41. CD41-positive platelets were gated according to their size (FSC) and granularity (SSC) patterns and CD41 staining. Isotype-matched control of each antibody was used for the measurement of non-specific background signals. Analyses of platelet activation markers were performed in the basal state. Both CD62P and CD61 expressions were used to determine platelet activation. The percentage of CD61 and CD62P expressions on CD41-positive platelets were analyzed according to their isotype-matched controls using FACSCanto flow cytometer with Diva software (BD Biosciences, Franklin Lakes, NJ). Results are expressed as percentage of positive platelets, which defines the negative control (isotype control) to 0%. Determination of cytokine level Cytokine IL-8 and IL-10 levels were measured in duplicates in plasma samples using commercially available enzymelinked immunosorbent assay (Invitrogen, Life Technologies, Carlsbad, CA) following manufacturer’s instructions. Statistical analysis The GraphPad Prism 6.0 software (GraphPad, San Diego, CA) was used for statistical analyses. Descriptive results of continuous variables are expressed as mean ± standard deviation. The Kruskal–Wallis test was used to compare data from women with both severe and mild PE and normal pregnancies. Correlations between platelet activation and inflammation markers were investigated using the Spearman test. p50.05 value was accepted as significant.

Results Demographic and clinical parameters are listed in Table 1. There were no significant differences between women in the two PE groups and the NPs regarding maternal age, gravidity, parity and gestational age at blood sampling except for the body mass index. The blood pressure, proteinuria and intrauterine growth retardation were significantly higher in the PE groups compared with the NPs. The severe PE group had lower mean platelet counts than the NPs.

Platelets and severity of inflammation in preeclampsia

DOI: 10.3109/14767058.2014.927860

Data related to platelet aggregometry are given in Figure 1. The percentages of platelet agonist-induced aggregation were significantly lower in patients with both severe and mild PE than those in healthy pregnant women (severe PE: 36 ± 13%, mild PE: 34 ± 9% and NPs: 54 ± 21%). We could not find a statistically significant difference between mildly and severely preeclamptic patients in regard to platelet aggregation. The percentage of basal CD61 expression did not differ among the NPs and PE groups (NPs: 95.63 ± 4.32, mild PE: 95.86 ± 3.98% and severe PE: 95.09 ± 4.01%, respectively). The expression of basal CD62P is shown in Figure 1. While there was no difference between the mild and severe PE groups, patients with severe PE had a significant increase in the expression of CD62 receptor in comparison with the

Table 1. Demographics and clinical parameters of the study population.

Age (years) Gravida Parity Body mass index (kg/m2) Gestational age at sampling (weeks) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Proteinuria Intrauterine growth retardation (weeks) Platelet count (106/mm3)

NP (n ¼ 80)

Mild preeclampsia (n ¼ 18)

Severe preeclampsia (n ¼ 23)

29.1 ± 0.7 2.6 ± 0.3 1.1 ± 0.3 27.5 ± 0.3

30.44 ± 1.30 2.9 ± 0.4 1.4 ± 0.4 30.4 ± 0.6*

31 ± 1.1 2.9 ± 0.2 1.5 ± 0.2 29.9 ± 0.6y

33.6 ± 0.4

34.7 ± 0.9

33.9 ± 0.5

115 ± 1.5

146.7 ± 3.2*

159.1 ± 3.2yz

72.3 ± 1.4

92.8 ± 1.8*

98.0 ± 1.4yz

1.2 ± 0.1* 1.05 ± 0.29*

2.5 ± 0.14yz 1.35 ± 0.31y

220 ± 19

199 ± 11y

0 0 244 ± 17

*, y and z stand for statistically significant difference between NP – mild PE, NP – severe PE and mild PE – severe PE, respectively.

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NPs (NPs: 9.59 ± 4.33%, mild PE: 11.29 ± 3.5% and severe PE: 12.35 ± 4.55%). Although, there was an increase in the levels of CD62P in mildly preeclamptic women, it was not significant. The levels of IL-8 between NPs and the mild PE were not significant (NPs: 7.49 ± 4.14 pg/ml and mild PE: 7.19 ± 2.85 pg/ml, respectively). On the other hand, the increase in the level of IL-8 in patients with severe PE was very prominent when compared to the normal pregnancies and the mild preeclamptics (12.04 ± 5.8 pg/ml) (Figure 1). The IL-10 levels did not differ among normal pregnancies (11.95 ± 3.7) and the mild preeclamptics (11.04 ± 2.9 pg/ml), while there was a significant difference in the levels of IL-10 in the severely preeclamptics (6.23 ± 3.1 pg/ml) and the normal pregnancies and mildly preeclemptics (Figure 1). Correlation analyses between CD62P, IL-8 and IL-10 levels in PE groups are shown in Figure 2. The alterations in the levels of CD62P did not correlate with IL-8 and 10 levels in both the mildly and severely preeclamptic patients. FACSCanto images of CD62P expressions in each group were given in Figure 3.

Discussion The results of this study have indicated that platelet activation plays an important role in the pathogenesis of PE. Moreover, the major determinant of the severity of PE is found to be the enhanced inflammatory response, which is not directly proportional to the enhanced platelet activation. The findings of this study support these suggestions. First, basal CD62P expression on platelet surfaces was found to be increased in severely preeclamptic women, and platelet aggregation was decreased in both mildly and severely preeclamptic women in comparison with NPs. Second, the inflammatory response in severe PE was enhanced, demonstrated by the increased levels of IL-8 and decreased levels of IL-10 in maternal plasma. Finally, the intensity of platelet activation did not correlate

Figure 1. Percentages of CD62p expressions and platelet aggregation, and the levels of IL-8 and IL-10 in severe, mild preeclamptic and normotensive women. Bars reflect significant difference between the groups.

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Figure 2. Correlation graphs between CD62P and IL-8 and IL-10 in mildly and severely preeclamptic patients. Correlation graph between (a) CD62P and IL-8 in mild PE, (b) CD62P and IL-8 in severe PE, (c) CD62P and IL-10 in mild PE and (d) CD62P and IL-10 in severe PE. Data are Spearman’s correlation coefficient (r) and p value.

Figure 3. FACSCanto images of isotype control and CD62P expressions in study groups.

directly with the changes in plasma levels of IL-8 and IL-10 in preeclamptic women. Platelet count and functions are altered in preeclamptic women [13,14]. This study demonstrated that platelet aggregation ability and count were decreased significantly in patients with severe PE in comparison with NPs. However, we could not find a significant difference between mildly and severely preeclamptic women. The platelet aggregation ability in response to different agonists in PE has been widely studied previously. Most of them have shown that PE was accompanied by a reduction in platelet aggregation in

response to collagen, ADP, adrenalin and arachidonic acid when compared with normal third trimester pregnancies [13–16]. The reduced platelet aggregation response to ADP in this study may suggest increased platelet turnover and platelet exhaustion as a result of on-going activation. These results are consistent with those of other studies [15,16]. CD62P, expressed both in activated platelet and endothelial cell surfaces, mediates interactions of leukocytes with platelets and endothelial cells [6]. In our study, the percentage of basal CD62P expression on platelet surfaces was significantly higher in severely preeclamptic women than in NPs.

DOI: 10.3109/14767058.2014.927860

However, a significant difference between severely and mildly preeclamptic patients regarding CD62P intensity was not found. Although basal CD62P expression was elevated in mild PE, it did not reach a significant level. Consistent with the findings of this study, previous studies have demonstrated that CD62P expression on platelets was increased in preeclamptic patients [2,3,11,17]. CD62P can recruit both platelets and leukocytes to sites of tissue injury and lead to the formation of platelet–leukocyte aggregates [18]. Adhesion of polymorphonuclear leukocytes (PMN) to platelets induces PMN activation followed by neutrophil–endothelial interaction [6]. Based on these findings, increased levels of CD62P in this study might explain the role of platelets in the inflammatory response seen in preeclamptic patients. On the other hand, basal CD61 expression on platelet surfaces was similar between PE and NPs in our study. In contrast with our findings, Holthe et al. reported that basal expression of CD61 was higher in women with PE compared with NP women [17]. Upon activation, platelets release proinflammatory cytokines, which promote endothelial activation and leukocyte–endothelial interactions, thus triggering IL-8 production in PE [19,20]. Our study revealed that higher levels of IL-8 were observed in severely preeclamptic women in comparison with NPs and mildly preeclamptics. Furthermore, IL-8 levels were similar in mild PE and NPs. Consistent with our findings, several studies showed higher IL-8 plasma levels in preeclamptic women [21–23]. Bachawaty et al. reported that infiltration of activated leukocytes in the vasculature of preeclamptic women resulted in increased production of IL-8 and the release of reactive oxygen species, myeloperoxidase, matrix metalloproteinase 8 and thromboxane [24]. These findings suggest that the severity of inflammation might be related to higher levels of IL-8 in severe PE. Therefore, IL-8 seems to have a pivotal role in the severity of inflammation, especially in severely preeclamptic women. Our study has shown that severely preeclamptic patients had significantly lower levels of IL-10 than NPs and mildly preeclamptics. Although there was a slight decrease in IL-10 levels in mild PE, this was not prominent. There were conflicting results of IL-10 levels in PE in previous studies. Maternal serum IL-10 levels were decreased in preeclamptic patients in some studies [21,23], whereas they were elevated or not changed in others [25,26]. In a recent meta-analysis including four studies, IL-10 levels were increased in preeclamptic patients [27]. However, studies investigating the human placental IL-10 production demonstrated that placental IL-10 levels were decreased or not changed in preeclamptic patients [28,29]. Moreover, an animal study including genetically deficient IL-10 model suggested that a single administration of human PE serum in pregnant IL-10/ mice induced PE-like symptoms [30]. In accordance with these findings, increased IL-10 levels were found to lessen the severity of PE in this study. Correlation analysis of platelet activation with both IL-8 and IL-10 levels in preeclamptic patients has not shown any significance in this study. Although a significant increase in IL-8 and a decrease in IL-10 levels were demonstrated in severe PE, this cytokine network disturbance was not influenced by the intensity of basal CD62P expression on

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platelets. In other words, the intensity of platelet activation seems not to be correlated with the severity of inflammation in PE. In agreement with our findings, Pinheiro et al. reported that severely preeclamptic women had higher levels of IL-8 and lower levels of IL-10 in comparison with NPs [21]. In the same study, they found that there was a positive correlation between IL-8 and interferongamma in severely preeclamptic patients and proposed this to be important in the pathogenesis. In our opinion, altered levels of cytokines like IL-8 and IL-10 might have a direct impact on the endothelium of maternal systemic vasculature. In summary, our results revealed that activated platelets and alterations in the levels of cytokines seem to be important in patients with severe PE. Furthermore, the severity of inflammation is found to be independent of the intensity of platelet activation in preeclamptic women. Although platelet activation may play a role in initiating an inflammatory response in PE, the severity of inflammation seems to be related to the mechanisms causing alterations of cytokine levels rather than platelet activation. Therefore, further molecular studies are warranted to explain the pathophysiology of this devastating clinical situation.

Declaration of interest All of the authors state that there is no conflict of interest to disclose.

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The impact of platelet functions and inflammatory status on the severity of preeclampsia.

To find out whether there is a correlation between the extent of platelet activation and inflammation and the severity of preeclampsia (PE) in the thi...
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