Prevalence of circulating procoagulant microparticles in women with recurrent miscarriage: a case-controlled study

Howard Carp1,2,4, Rima Dardik3, Aharon Lubetsky3, Ophira Salomon3, Regina Eskaraev3, Esther Rosenthal3 and Aida Inbal3

1 Department of Obstetrics & Gynecology, 2 Department of Embryology and 3 Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Israel

4 To whom correspondence should be addressed at: Department of Obstetrics & Gynecology, Sheba Medical Center, Tel Hashomer, 52621, Israel. e-mail: carp{at}netvision.net.il


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: Circulating microparticles are markers of cell activation associated with various prothrombotic states. As hypoxia due to uteroplacental thrombosis is considered to be one of the causes of pregnancy loss, microparticles may be associated with pregnancy loss, in addition to, or as part of, other procoagulant states such as antiphospholipid syndrome or hereditary thrombophilias. The objective of this study was to examine the prevalence of circulating microparticles in women with recurrent pregnancy loss. METHODS: A total of 96 women with recurrent pregnancy losses were enrolled in a case–control study and compared with 90 parous women. Microparticles were measured by flow cytometry using fluorescent anti-CD51/CD31 antibodies. RESULTS: Microparticle levels >2 SD above the mean of controls (57 700/ml) were detected in 12 out of 96 women with recurrent miscarriages (12.5%), compared with two of the 90 control women (2.2%), P < 0.008. The titre of microparticles did not correlate with age, number of pregnancy losses, primary secondary or tertiary aborters status, or with pregnancy losses in the 1st or 2nd trimesters. CONCLUSIONS: A proportion of women with pregnancy loss have elevated endothelial microparticles suggesting that endothelial damage or activation might be associated with the pathogenesis of pregnancy loss.

Key words: circulating endothelial microparticles/habitual abortion/recurrent pregnancy loss


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Pregnancy itself is a hypercoaguable state associated with increased levels of coagulant factors (Stirling et al., 1984Go) and decreased levels of naturally occurring anticoagulants such as protein S (Comp et al., 1986Go) and fibrinolysis due to increased plaminogen activator inhibitor-1 (PAI1) (Sattar et al., 1999Go). Thrombosis in decidual vessels is believed to be one possible cause of recurrent miscarriage. Antiphospholipid antibodies (aPL) can cause pregnancy loss (Blank et al., 1991Go; Bakimer et al., 1992Go), and thrombosis has been described as one of the mechanisms whereby aPL may cause pregnancy loss (De Wolf et al., 1982Go). More recently, hereditary thrombophilias have been described as risk factors for pregnancy loss (Preston et al., 1996Go; Rai et al., 1996Go; Brenner et al., 1997Go; Grandone et al., 1997Go; Tal et al., 1999Go; Martinelli et al., 2000Go). Greer (2001Go) has suggested that various complications of pregnancy, including pregnancy loss, may be associated with procoagulant changes in general, rather than congenital or acquired thrombophilias in particular.

Circulating microparticles can be produced from the cell membrane after apoptotic cell death. They are released following cell activation when there is remodelling of the membrane leading to externalization of phospholipids, such as phosphotidylserine. Microparticles in turn lead to increased expression of adhesion molecules (Barry et al., 1997Go; Mesri and Altieri, 1998Go), so amplifying the procoagulant and/or inflammatory response on the endothelial cell surface. Microparticles have been found in increased numbers in normal pregnancy (Bretelle et al., 2003Go), and have been associated with several prothrombotic conditions such as thrombotic thrombocytopenic purpura (Galli et al., 1996Go), myocardial infarction (Mallat et al., 2000Go), sepsis (Joop et al., 2001Go), heparin-induced thrombocytopenia (Hughes et al., 2000Go; Walenga et al., 2000Go) and even pre-eclampsia (Greer, 1999Go; Bretelle et al., 2003Go).

Laude et al. (2001Go) have measured total microparticles in women with a history of recurrent pregnancy loss compared with controls, and found microparticle levels to be above the upper limit of normal in 59% of patients. The purpose of this study was to assess the prevalence of circulating endothelial microparticles in a large group of recurrently miscarrying women, compared with that of parous control women.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients
Between 1998 and 2001, 96 consecutive patients with three or more consecutive miscarriages (cases) were assessed for microparticles. The control group consisted of 90 healthy women, with at least two living children and no miscarriages, no concurrent disease, on no medication, with no previous history of thromboses, and no antinuclear factor, or aPL. Most of the patients and controls were obtained from the cohort included in our previous publication (Carp et al., 2002Go).

The clinical features of each patient and her miscarriages were recorded, paying particular attention to whether the patients were primary, secondary or tertiary aborters (primary aborters were women with no previous live births, secondary if there was a live birth followed by miscarriages, and tertiary if there were miscarriages followed by a live birth and at least three subsequent miscarriages). The following additional features were also noted: whether previous miscarriages occurred in the first or second trimesters, whether they presented as blighted ova, fetal deaths etc., and the presence of hereditary thrombophilias, e.g. Factor V Leiden and prothrombin gene (G20210A) mutations and methyltetrahydrofolate reductase (MTHFR) homozygosity determined as previously described (Carp et al., 2002Go).

Cases or controls were excluded from this study if there was a previous history of thrombosis, pregnancy at the time of investigation, or if using oral contraceptives. Cases were only included after other presumptive aetiological factors were found to be normal: karyotype of both parents, glucose tolerance test, toxoplasmosis serology, hysterosalpingogram, thereby excluding anatomical abnormalities, intrauterine adhesions and cervical incompetence, thyroid function, serum prolactin levels, normal luteal phase of ≥12 days and plasma progesterone >24.8 ng/ml, absence of antinuclear factor, or aPL.

The Human Investigation Review Board of the Sheba Medical Center approved the study. Each patient signed an informed consent form.

Laboratory testing
Circulating endothelial microparticles were measured in platelet-poor plasma (PPP), 3–4 months after the previous miscarriage, according to the method of Combes et al. (1999Go). Briefly, PPP was obtained from nine parts of whole blood drawn into one part of 3.8% sodium citrate, centrifuged for 10 min at 1500 g, followed by centrifugation of PPP for 5 min at 13 000 g, and stored at –35°C. Aliquots of 100 µl of plasma were incubated for 30 min at 4°C with 10 µl of PhycoErythrin-conjugated PECAM monoclonal antibody to CD31 (Immunotech, France) and 10 µl of FITC-conjugated {alpha}v monoclonal antibody to CD51 (Immunotech). 105 beads of 3 µm (Sigma, USA) were added and the number of fluorescence-positive microparticles was quantified by flow cytometry on a Coulter Epics (Coulter, UK). Thrombophilia markers, Factor V Leiden, Factor II G20210A and MTHFR C677T were measured as previously described (Carp et al., 2002Go).

An increased level of endothelial microparticles was defined as a level >2 SD from the mean of control parous women.

Statistical analysis
The data were entered into a computerized database (SPSS, Chicago, USA). The unpaired Student’s t-test was used to compare continuous variables between patients and controls, and {chi}2 with Yates’ correction for categorical variables. Fisher’s exact test was used where the numbers were small. P < 0.05 was taken to be statistically significant. Linear regression analysis was used to assess whether age had an influence on microparticle levels.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The 96 cases were slightly older than the controls (P = 0.001) (Table I). There was no difference in the prevalence of the measured thrombophilia markers between patients and controls (Table I).


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Table I. Prevalence of thrombophilia polymorphisms in women with recurrent pregnancy loss and controls
 
The distribution of microparticles in the peripheral blood of cases and parous control women was parametric, ranging from 0 to 120 000/ml in cases and 0 to 71 000/ml in controls. Levels >2 SD from the mean of control women were considered to be abnormal. The cut-off value was 57 700/ml. Twelve out of 96 patients with recurrent miscarriages had an increased number of circulating endothelial microparticles (12.5%), compared with only two of 90 controls (2.2%) (P < 0.008). Figure 1 shows the distribution of microparticle levels for each patient and control tested. It can be seen that a significantly higher proportion of women with recurrent miscarriage had raised microparticle levels. Linear regression analysis showed no association between age and endothelial microparticles. The odds ratio for recurrent miscarriage in the presence of elevated endothelial microparticles is 6.29 [95% confidence interval (CI) = 1.37–28.93].



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Figure 1. Distribution of microparticles in patients and controls. EMP = endothelial microparticles.

 
Table II shows the clinical features of the patients with normal and increased levels of microparticles. Both groups of patients were similar with regard to the mean number and trimester of previous miscarriages. Although the recurrently miscarrying women were younger than the control women, there was no significant age difference between recurrently miscarrying women with normal or raised microparticle levels. Due to the small number of patients with raised microparticle levels (n = 12), no inferences can be drawn about different prevalences of hereditary thrombophilias in the patients with raised and normal endothelial microparticle levels.


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Table II. Details of cases with raised microparticles compared with normal microparticle levels
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The results showed that a significantly higher number of recurrently miscarrying women had increased levels of circulating endothelial microparticles (12.5% as opposed to 2.2% of parous control women), indicating that endothelial microparticles are associated with pregnancy loss. The odds ratio for recurrent miscarriage was 6.29 (95% CI = 1.37–28.93) in the presence of endothelial microparticles. The presence of endothelial microparticles was independent of maternal age, number of prior miscarriages or hereditary thrombophilias.

None of the patients in this series had any apparent thrombotic phenomena. It is conceivable that other procoagulant features of pregnancy, such as those listed in the introduction, or possibly the activation of Th-1 cytokines such as tumour necrosis factor (TNF)-{alpha} and interleukin-6 (which have been reported to initiate thrombosis, by causing release of tissue factor (Ten Cate et al., 1999Go), may be necessary to effect thrombosis. In other conditions of prothrombotic states leading to pregnancy loss, such as aPL or congenital thrombophilias, the association with second trimester loss has been much greater than the association with first trimester loss (Lockshin, 1992Go; Carp et al., 1993Go; Preston et al., 1996Go; Martinelli et al., 2000Go). However, in this series, there was no significant association between the prevalence of microparticles and the clinical presentation of the pregnancy loss (Table II). In fact, 75% of the women with raised microparticle levels had only experienced first trimester miscarriages.

Microparticles have been shown to be elevated in normal pregnancy (Bretelle et al., 2003Go), indicating an ongoing process of cell activation in pregnancy. Constant deportation of trophoblast also occurs into the maternal circulation. Extrusion of trophoblast may lead to the formation of microparticles. The question arises whether endothelial microparticles may be causative of pregnancy loss or may be a byproduct of embryonic demise. In the case of first trimester miscarriage, 29–60% of recurrent pregnancy losses are due to chromosomal aberrations (Stern et al., 1996Go; Ogasawara et al., 2000Go; Carp et al., 2001Go), which invariably cause abortion, irrespective of the presence of microparticles, or other associations or causes of pregnancy loss. Structural anomalies have been found in 10 of 19 missed abortions examined by transcervical embryoscopy (prior to curettage) (Philipp and Kalousek, 2001Go). Embryonic structural anomalies have been associated with increased cytokines such as transforming growth factor {beta} (Jaskoll et al., 1996Go), TNF{alpha} (Ivnitsky et al., 1998Go), and apoptosis (Torchinsky et al., 1995Go). The above suggest that embryonic death may occur due to genetic or structural anomalies, proinflammatory cytokines or inappropriate apoptosis. All of these mechanisms may trigger subsequent microparticle formation and thrombosis. However, in certain patients, circulating endothelial microparticles may themselves act as a trigger for thrombosis and subsequent loss of a normal pregnancy.

The only other paper to examine microparticles in women with pregnancy losses was that of Laude et al. (2001Go). In their paper, microparticles were found in 59% of patients with recurrent pregnancy losses. The lower prevalence in the current study may be due to assessing endothelial microparticles rather than total microparticles. Endothelial microparticles are only a fraction of the total microparticles. This study concentrated on endothelial microparticles as endothelial activation and pertubation may contribute to placental dysfunction and subsequent miscarriage. The presence of endothelial microparticles in the interval between pregnancies may be a chronic state of blood vessel activation which only becomes apparent in pregnancy.

The obstetric complications in which microparticles have been studied include pre-eclampsia and intrauterine growth restriction. Microparticles have been reported to have a causative role in pre-eclampsia by impairing endothelium-dependent relaxation of isolated myometrial arteries in vitro (Van Wijk et al., 2002aGo), and increasing thrombin generation (Van Wijk et al., 2002bGo). In pre-eclampsia, the number of platelet microparticles has been reported to be decreased (Bretelle et al., 2003Go) which may reflect their consumption in thrombus generation.

If microparticles do cause thrombosis in certain patients with recurrent pregnancy loss, the question arises whether anticoagulants are indicated to prevent subsequent thrombosis, and subsequent pregnancy losses. Although anticoagulants have been reported to have a beneficial effect in antiphospholipid syndrome (Kutteh, 1996Go; Rai et al., 1997Go) and hereditary thrombophilia (Carp et al., 2003Go) they may also have an effect in patients with increased levels of procoagulant microparticles. However, before this question can be answered, it is necessary to have a comparative cohort study comparing the prognosis for the subsequent pregnancy in patients with and without increased circulating microparticles. The results of such a study should be corrected for patients losing genetically or otherwise aberrant embryos, as anticoagulants are administered for maternal conditions which cause the loss of normal embryos.


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Submitted on May 9, 2003; resubmitted on June 24, 2003; accepted on September 16, 2003.





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