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Keywords:

  • endothelium;
  • fibrinolysis;
  • pre-eclampsia;
  • pregnancy;
  • uterine artery Doppler

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References

Summary. Background: Pre-eclampsia (PET) and/or fetal growth restriction (FGR) remain a major cause of maternal and fetal morbidity and mortality. In pregnancy, fibrinolysis is controlled by the maternal endothelium and placenta, both of which are central to the pathogenesis of PET/FGR. Clinically, uterine artery Doppler screening at 23 weeks is used to predict PET/FGR. An abnormal uterine artery Doppler finding is defined as early diastolic bilateral uterine artery notching (BN) in the waveform. However, about 50% of mothers with BN do not develop PET/FGR. Objectives: We investigated fibrinolytic changes and uterine artery Doppler findings in the second trimester, and related them to pregnancy outcome; in particular assessing whether fibrinolytic markers could discriminate between normal and abnormal outcome in mothers with BN. Patients/methods: Plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), plasminogen activator inhibitor-2 (PAI-2), plasmin-α2 antiplasmin (PAP), D-dimers and markers of endothelial dysfunction were measured with Doppler ultrasound at 23 weeks. Results: Those with BN had decreased PAP and D-dimer levels, and raised PAI-1 and thrombomodulin levels. Mothers with BN and PET/FGR had significantly increased t-PA levels and reduced PAI-2 levels. Conclusions: BN at 23 weeks of gestation is associated with increased PAI-1 levels. Within the BN group, mothers who developed PET/FGR had increased t-PA levels and decreased PAI-2 levels, although there was no net change in fibrinolysis as measured by D-dimer levels. No single fibrinolytic marker is helpful in determining pregnancy outcome in those with BN, but t-PA and PAI-2 are worthy of study in a multifactorial algorithm.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References

Pre-eclampsia (PET) is a pregnancy-related multisystem syndrome, of uncertain etiology, that is characterized by hypertension and proteinuria after 20 weeks of gestation, resolving after delivery [1]. PET complicates approximately 2–8% of all pregnancies, and remains a major cause of maternal and fetal morbidity and mortality [2–4]. Worldwide, it is estimated that 50 000 maternal deaths occur annually because of pre-eclampsia/eclampsia. Fetal growth restriction (FGR) [or intrauterine growth restriction (IUGR)] is the failure of fetuses to exercise their full genetically determined growth potential. The incidence of FGR is estimated to be approximately 5% in the general obstetric population. FGR results in significant perinatal complications, including fetal death, prematurity, neonatal death, fetal compromise in labor, neonatal morbidity, induction of labor, and caesarean delivery.

PET is associated with FGR in one-third of cases [1,5]. Premature delivery to prevent the progression of PET is responsible for 15% of all preterm births [1,6]. Infants of women with PET have a five-fold increase in mortality [2]. Screening by maternal history can detect only about 30% of PET cases, with a false-positive rate of 10% [7]. Uterine artery Doppler screening by detecting bilateral uterine artery notching (BN) or raised pulsatility index in the second trimester identifies women at high risk for developing adverse pregnancy outcomes [8–10]. Uterine artery Doppler has particularly high sensitivity for early-onset PET and FGR, identifying about three-quarters of these cases occurring before 34 weeks [10].

Screening performance may be enhanced by combination with maternal characteristics and simultaneous measurement of a blood marker [11]. It is known that, as uterine artery Doppler resistance increases, so does the risk of adverse outcomes, including PET and FGR [12]. However, it is recognized that about 50% of women with BN at 23 weeks have a normal pregnancy outcome. The factors determining pregnancy outcome after BN at 23 weeks are not clear. It would be helpful to discriminate between those women with BN who have normal and abnormal outcomes, to improve care, reassure mothers who are at low risk, and rationalize the use of resources.

The current theory of PET is that it is a two-stage disease, with the first stage due to the reduced placental perfusion, and the second stage due to the increased maternal endothelial activation, as a response to this [1]. Accelerated endothelial dysfunction is a central feature of both PET and FGR, with uteroplacental ischemia and abnormal placental implantation being common findings [1,13]. The two differ in their association with maternal signs of PET: the link between the pathophysiology of abnormal placentation and the development of the maternal syndrome remains unclear. Women with PET also show prothrombotic changes, which contribute to the increased susceptibility of pre-eclamptic women to venous thromboembolism and to the formation of placental fibrin deposits, which can reduce nutrient transport across the placenta [14,15]. A hypofibrinolytic state is recognized as a normal physiologic response to pregnancy, and it has been considered to be more profound in PET.

Plasminogen activator inhibitor-1 (PAI-1) is the physiologic inhibitor of both urokinase and tissue-type plasminogen activator (t-PA) and is a primary regulator of fibrinolysis in vivo [16]. The increased expression of PAI-1, as occurs in endothelial cell activation (ECA), may compromise normal fibrin clearance [17]. In pregnancy, there is increased synthesis of PAI-1 and de  novo synthesis of a further inhibitor, plasminogen activator inhibitor-2 (PAI-2), by the placenta [18]. The maternal plasma concentration of PAI-1 increases with gestational age in normal pregnancy, and levels are even higher in PET, reflecting ECA [19]. PAI-1 expression is increased in pre-eclamptic placentas, and PAI-1 plasma levels have been found to be positively correlated with the severity of placental damage [20]. In contrast, the plasma concentration of PAI-2 increases progressively in normal pregnancy, but decreases with reduced placental function and PET [18,21]. The PAI-1/PAI-2 ratio decreases in normal pregnancy as the placental mass increases, but is increased in patients developing PET, because of maternal ECA and placental insufficiency [18].

The aim of this study was to investigate fibrinolysis in the second trimester of pregnancy, and in particular to assess whether there was any difference in fibrinolysis between mothers with BN who did not develop PET or FGR and those mothers with BN who had PET and/or babies with FGR. For analysis, mothers were allocated to different groups on the basis of uterine artery Doppler ultrasound findings at 22–25 weeks of gestation, and the pregnancy outcome. Their results were investigated by making three prespecified statistical comparisons.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References

Patient details

Consecutively recruiting women attending for antenatal care at an inner city teaching hospital, who undergo routine uterine artery Doppler screening at approximately 23 weeks of gestation, were recruited to this study.

Gestation was based on early ultrasound dating scans or certain menstrual dates. An abnormal uterine artery Doppler finding was defined as the presence of BN, which was present in approximately 5% of the screened population [10,12]. A notch was defined, as in earlier studies, as an early diastolic incisura in the uterine artery Doppler waveform [8–10,12]. Women with normal and abnormal Doppler results were recruited for this study, which had Local Research Ethics Committee approval, and written consent for venesection was obtained. All mothers fulfilled the following criteria: singleton pregnancies without concomitant cardiovascular disease or diabetes; and not being on antihypertensive medication or aspirin.

Women with BN were followed up in a dedicated ‘high-risk’ clinic and monitored with regular growth scans, blood pressure tests, and urinalysis. Pregnancy outcome was recorded from hospital computerized records, and, in the case of PET or FGR, verified in detail from patient notes. PET was defined as blood pressure > 140/90 mmHg, measured on two occasions, with proteinuria of one ‘+’ or more of proteinuria on dipstick testing after 20 weeks in the absence of a pre-existing cardiovascular condition. FGR was defined as birth weight less than the 10th centile for gestation [20].

For the purposes of analysis, women were divided into the following groups:

  • Group 1:
     27 women with normal uterine artery Doppler findings at 23 weeks of gestation and normal pregnancy outcome.
  • Group 2:
     24 women with BN at 23 weeks of gestation and subsequent normal pregnancy outcome.
  • Group 3:
     24 women with BN at 23 weeks of gestation and subsequent PET or FGR.
  • Group 4:
     seven women with BN at 23 weeks of gestation with pre-existing PET and/or ultrasound evidence of FGR.

Blood sampling

At the time of uterine artery Doppler studies (22–25 weeks), 20 mL of venous blood was collected into 0.102 m sodium citrate (ratio 9 : 1) (Becton Dickinson, Oxford, UK) from the antecubital fossa, using flawless venepuncture, and centrifuged within 60 min at 2000 × g for 20 min. Plasma was aliquoted and stored at − 70 °C until the assays were performed.

Assay methods

For each assay, all the samples were measured together to prevent interassay variability. The following enzyme-linked immunosorbent assays were performed.

Fibrinolysis  An ELIZA assay of the physiological activator of fibrinolysis, t-PA, which detected both active and latent forms of t-PA, and the inhibitors of t-PA, PAI-1 (Trinity Biotech UK Ltd, Oxon, UK) and PAI-2, were measured (Axis Shield UK, Cambridge, UK), as were levels of plasmin-α2 antiplasmin (PAP) [Immuno Diagnostic Systems Ltd (IDS) UK, Tyne and Wear, UK]; overall fibrinolytic activity was also assessed by measuring D-dimer levels (Trinity Biotech UK Ltd). The intra-assay (interassay) variables for the assays were: PAI-1, 3.3% (2.9%); t-PA, 5% (4%); PAI-2, 3.7% (3%); D-dimers, 4% (3%); and PAP, 4.2% (7.5%).

Endothelial function  During ECA, adhesion molecules are shed into the plasma, and levels of soluble intercellular adhesion molecule-1 (ICAM-1) were therefore measured (R&D Systems, Oxford, UK). During endothelial cell perturbation or damage, soluble thrombomodulin (TM) is shed from the endothelium, and levels of this were therefore measured (Diagnostica Stago UK Ltd, Reading, UK). The intra-assay (interassay) variables for the assays were: ICAM-1, 4% (7%); and TM, 4.8% (4%).

Coagulation  Activation of coagulation was assessed by measuring thrombin–antithrombin (TAT) levels (Sysmex UK Ltd, Milton Keynes, UK). The intra-assay and interassay variables for TAT were 5% and 8%, respectively.

Statistical analysis

For several plasma markers (TAT, t-PA, PAP, and D-dimers), the distributions were right-skewed. Accordingly, summary statistics are presented as medians and interquartile ranges. A non-parametric Mann–Whitney test was used to test the statistical null hypothesis of no difference in markers of fibrinolysis between women with normal uterine artery Doppler findings and those with BN (regardless of pregnancy outcome). Among women with BN, a non-parametric trend test [21] was used to compare markers of fibrinolysis between women with a normal outcome (baseline group), women with an adverse outcome (intermediate-risk group), and women with established PET/FGR (high-risk group). A Bonferonni correction was used to adjust for the fact that eight different markers of fibrinolysis were used for two comparisons. P-values corrected for multiple testing are shown in parentheses beneath uncorrected P-values in Tables 1 and 2. Statistical analyses were carried out using stata statistical software (version 8.0; Stata Corporation, London, UK).

Table 1.   Maternal basic demographic and outcome characteristics
 Normal Doppler: group 1 (n = 27)Bilateral notch Doppler outcomePET/FGR: group 4 (n = 7)
Normal: group 2 (n = 24)Abnormal: group 3 (n = 24)
  1. FGR, fetal growth restriction; PET, pre-eclampsia.

Maternal age (years)30.5 ± 1.129.0 ± 1.028.9 ± 1.335.7
Gestational age at delivery (weeks)40.4 ± 0.439.1 ± 0.735.1 ± 0.929.0 ± 0.9
Birthweight (g)3394.4 ± 924.03076.0 ± 140.81963.5 ± 165.7822.8 ± 179.1
Birthweight percentile (%)46.1 ± 5.536.1 ± 5.211.5 ± 3.35.6 ± 5.1
Table 2.   Comparisons of fibrinolytic, endothelial and coagulation markers in women with abnormal uterine artery Doppler findings (bilateral uterine artery notching) and those with normal Doppler findings and pregnancy outcome
Assay (normal range)Median (interquartile range)P (Mann–Whitney)
Normal: group 1 (n = 27)BN: Normal + abnormal, group 2 + group 3 (n = 48)Normal vs. BN, 1 vs. (2 + 3)
  1. BN, bilateral notching on uterine artery Doppler at 23 weeks of gestation; t-PA, tissue-type plasminogen activator; PAI-1, plasminogen activator inhibitor-1; PAI-2, plasminogen activator inhibitor-2; PAP, plasminogen–antiplasmin; ICAM-1, soluble intercellular adhesion molecule-1; TM, soluble thrombomodulin; TAT, thrombin–antithrombin; NA, not applicable; Padj, P-value corrected for multiple testing.

 
Fibrinolysis
 t-PA (1–20 ng mL−1)7 (6–9)7 (6–9.5)P = 0.47 (NA)
 PAI-1 (4–43 ng mL−1)39 (31–50)51 (38–62.5)P = 0.01 (Padj = 0.16)
 PAI-2 (0 ng mL−1)92 (71–114)97 (79–122.5)P = 0.52 (NA)
 PAI-1/PAI-2 (NA)0.41 (0.33–0.62)0.50 (0.38–0.63)P = 0.25 (NA)
 PAP (150–800 μg L−1)274 (223–348)210 (151.5–251)P = 0.005 (Padj = 0.08)
 D-dimers (4–78 μg L−1)208 (74–405)79.5 (45–135)P = 0.01 (Padj = 0.16)
Endothelial function
 ICAM-1 (115–306 ng mL−1)228 (198–268)231.5 (148.5–292.5)P = 0.92 (NA)
 TM (12–145 ng mL−1)24 (21–35)30 (26–37)P = 0.02 (Padj = 0.32)
Coagulation
 TAT (0.8–3.8 ng mL−1)10 (4–14)7 (3–13)P = 0.09 (nNA)

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References

The mean gestational age at screening was 23.5 weeks [standard deviation (SD), 0.9; range, 22–25 weeks), the mean maternal age was 29.5 years (SD, 5.4; range, 18–41 years), and the mean birthweight was 2513 g (SD, 936.1; range, 746–3960 g); these data, divided by group, are shown in the Table 1. Table 2 shows the comparisons of fibrinolytic, endothelial and coagulation markers in the different groups. Those with BN had higher levels of PAI-1 and soluble TM, and lower levels of PAP and D-dimers.

The median and range of the hemostatic and endothelial factors in those with BN are shown in Table 3, and by box and whisker plot in Fig. 1. After correcting for multiple testing, there were no significant differences in any assay between group 3 (BN and normal pregnancy outcome) and group 4 (BN and abnormal pregnancy outcome).

Table 3.   Assay results from those mothers with bilateral uterine artery notching
Assay (normal range)Median (interquartile range)Ptrend (adjusted Ptrend)
Bilateral notching
Normal: group 2 (n = 24)Abnormal: group 3 (n = 24)PET/FGR: group 4 (n = 7)
  1. Column 2: BN but with normal pregnancy outcome. Column 3: BN with abnormal pregnancy outcome. Column 4: BN with established PET/FGR at time of scanning. BN, bilateral notching on uterine artery Doppler at 23 weeks of gestation; PET, pre-eclampsia; FGR, fetal growth restriction; t-PA, tissue-type plasminogen activator; PAI-1, plasminogen activator inhibitor-1; PAI-2, plasminogen activator inhibitor-2; PAP, plasminogen–antiplasmin; ICAM-1, soluble intercellular adhesion molecule-1; TM, soluble thrombomodulin; TAT, thrombin–antithrombin; NA, not applicable; Padj, P-value corrected for multiple testing.

 
Fibrinolysis
 t-PA (1–20 ng mL−1)7 (6–7.5)9.5 (6,–13)15 (9–19)P = 0.000009 (Padj = 0.0001)
 PAI-1 (4–43 ng mL−1)51 (35.5–60)50.5 (41–64.5)67 (53–116)P = 0.03 (Padj = 0.48)
 PAI-1/PAI-2 (NA)0.47 (0.38–0.56)0.53 (0.39–0.78)1.73 (1.29–2.58)P = 0.00005 (Padj = 0.0008)
 PAI-2 (0 ng mL−1)104.5 (91.5–135)86 (74.5–110.5)46 (26–69)P = 0.0002 (Padj = 0.003)
 PAP (150–800 μg L−1)212.5 (159.5–261.5)210 (151–234.5)226 (132–304)P = 0.85 (NA)
 D-dimers (4–78 μg L−1)99.5 (25–192)56 (32.5–123)104 (52–145)P = 0.34 (NA)
Endothelial function
 ICAM-1 (115–306 ng mL−1)255 (184–290.5)202.5 (141.5–295.5)296 (256–368)P = 0.19 (NA)
 TM (12–145 ng mL−1)30.5 (25–36.5)30 (26.5–39)40 (31–42)P = 0 .07 (NA)
Coagulation
 TAT (0.8–3.8 ng mL−1)7.5 (3–13)5.5 (2.5–16.5)32 (17–45)P = 0.007 (Padj = 0.11)
image

Figure 1.  Box and whisker plots of the median and range of the hemostatic and endothelial factors in women with bilateral uterine artery notching. TAT, thrombin–antithrombin; BN, bilateral notching on uterine artery Doppler at 23 weeks of gestation; PET, pre-eclampsia; t-PA, tissue-type plasminogen activator; PAI-1, plasminogen activator inhibitor-1; PAI-2, plasminogen activator inhibitor-2; PAP, plasminogen–antiplasmin; IUGR, intrauterine growth restriction.

Download figure to PowerPoint

Fibrinolysis

Plasma levels of PAI-1 were increased in those with BN and adverse pregnancy outcome as compared with those with normal uterine artery Doppler findings and outcome. Plasma levels of t-PA and PAI-1 were highest in those with established PET or FGR at the second trimester. In contrast, PAI-2 levels were lowest in those with established PET/FGR, and those with BN and subsequent adverse outcome also had reduced levels as compared with the control group, although this difference was not significant after accounting for multiple testing. There was no significant effect of the changes in t-PA and its inhibitors PAI-1 and PAI-2 on overall fibrinolytic activity in those with BN and adverse outcome as measured by PAP and D-dimers.

Endothelial cell function

There were slightly lower levels of ICAM-1 in those with BN and adverse outcome, and slightly higher levels in those with established FGR, but neither of these differences was significant. Soluble TM levels showed a trend to being increased in those with established IUGR and higher in those with BN as compared with healthy controls.

Coagulation activity

There was a highly significant difference in the levels of TAT between the women with BN and those with established PET and/or FGR at 23–26 weeks. In women with BN, there was no significant difference between those who had normal or adverse outcomes.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References

In this study, we compared fibrinolytic and other markers between healthy mothers with normal uterine artery Doppler findings at 23 weeks, mothers with BN in whom there was either a normal or an abnormal outcome, and mothers with BN and pre-existing FGR and/or PET. The study design is unique, in that those with healthy pregnancies and BN were recruited to the study at a time when their pregnancy outcome was not known. The relatively small numbers in each group and our statistical correction for multiple analyses do, however, mean that it is possible that we have missed true differences in markers between the groups.

There was significantly less overall fibrinolytic activity as measured by D-dimer levels in those with BN than in healthy controls, reflecting increased levels of PAI-1 in those with BN. Within the groups with BN and normal and abnormal outcomes, there was no difference in overall fibrinolytic activity, but those with abnormal outcomes had decreased PAI-2 levels and increased t-PA levels, suggesting that the latter are responsible for maintaining fibrinolytic activity in those with placental dysfunction. However, there is a substantial overlap in t-PA ranges, suggesting that they, along with PAI-2 levels, are not helpful alone, but may have utility in predicting PET and FGR in an algorithm where multiple factors are used.

The favored model of PET and FGR is a two-stage process, in which the first stage, reduced placental perfusion, is the ‘root cause’ [1]. This translates, in some but not all women, into the second stage, the multisystem maternal syndrome of PET [1]. Normal placental development requires the invasion of cytotrophoblasts into maternal spiral arteries, resulting in remodeling into large-capacitance, low-resistance vessels between 12 and 20 weeks of gestation. In women who develop PET, cytotrophoblast endovascular invasion remains shallow, leading to a defective uteroplacental circulation and subsequent placental ischemia [22]. In the second stage of PET, maternal ECA leads to hypertension, increased glomerular vascular permeability (causing proteinuria), and prothrombotic changes [22].

The endothelium plays a central role in controlling hemostasis in the maternal and placental circulations. Normal pregnancy is associated with a hypofibrinolytic state due to an increase in the fibrinolytic inhibitors PAI-1 and PAI-2. The concentration of PAI-1 increases with gestation in normal pregnancy, and levels are even higher in PET [15,18,23]. Cytotrophoblasts isolated from the placenta and placental bed from FGR pregnancies express significantly higher levels of PAI-1 and reduced levels of t-PA as compared with trophoblasts from normal pregnancy [24].

Women with BN and pre-existing FGR and/or PET had the greatest changes in fibrinolysis as compared with normal pregnancy, as well as being the only group with significantly increased levels of TAT, signifying activation of coagulation. Moreover, PAI-2 levels were the lowest, and PAI-1 levels, PAI-1/PAI-2 ratio, t-PA levels and soluble ICAM-1 levels were significantly greater. PAI-2 is synthesized by the placenta, and its levels increase progressively in normal pregnancy, but decrease with the reduced placental function of FGR and PET [14,18,25]. In normal pregnancy, PAI-1/PAI-2 ratio decreases as placental mass increases. In PET, however, the PAI-1/PAI-2 ratio is increased, presumably because of maternal endothelial cell activation and placental insufficiency [11,18]. Our findings of raised PAI-1 levels in pregnancies with BN and PET/FGR is consistent with the findings of other studies.

t-PA levels increased in those with BN and abnormal outcome, and in those with established FGR and/or PET, as compared with women with BN and normal outcome, consistent with recent data suggesting that t-PA is elevated in PET, and that its level is inversely correlated with birthweight [23]. During endothelial cell activation, there is upregulation of t-PA and PAI-1 production together. The net effect of this in those at risk of PET or with established PET, and in combination with the diminishing PAI-2 levels, is to maintain fibrinolytic activity as measured by plasmin–antiplasmin and D-dimer levels. Previous studies have used the PAI-1/PAI-2 ratio as a marker of possible adverse pregnancy outcome [26]. Our study suggests that t-PA levels may be useful in combination with the PAI-1/PAI-2 ratio in a predictive algorithm at 23 weeks of gestation.

Adhesion molecules are involved in trophoblast invasion of the spiral arteries; normally, cytotrophoblasts increase their expression of vascular cell adhesion molecule-1 (VCAM-1) as they invade the spiral arteries [27–31]. ICAM-1 is not expressed in endovascular cytotrophoblasts of women with normal pregnancy, but is upregulated by PET and/or IUGR [27,30,31], and increased levels of soluble ICAM-1 and soluble VCAM-1 have been reported to appear in pregnancy before clinical signs of PET [28]. In our study, there was a trend for soluble ICAM-1 levels to be increased in those with established FGR and/or PET at 23 weeks as compared with those with normal outcome. In contrast, Airoldi et al. [29] reported decreased soluble ICAM-1 levels in PET at 27–29 weeks of gestation. These findings may reflect the distorted trophoblast expression of adhesion molecules in pregnancies destined to be complicated by PET. In this study, we did not control for variables such as maternal age, parity, body mass index and smoking habits that might affect the levels of ICAM-1.

TM is present on the maternal and fetal endothelium, and measurable soluble TM levels are found in normal plasma. The pathogenic mechanisms involved in the increases in soluble TM are not fully understood [32]. As TM is endocytosed during ECA, and cleaved upon cell injury, increased circulating levels of TM are interpreted as reflecting endothelial injury rather than activation. TM levels remain constant throughout normotensive pregnancy, but, as demonstrated in our study, are elevated in women with established PET [33–35].

In conclusion, those pregnant women with BN at 23 weeks of gestation have altered levels of fibrinolytic activators and their inhibitors, with a net decrease in fibrinolytic activity as measured by decreased PAP and D-dimer values. Despite elevated PAI-1 levels, we suggest that increases in t-PA levels and diminishing PAI-2 levels are responsible for the lack of deterioration in fibrinolysis in those with established or later PET and FGR in the second trimester. The increase in t-PA levels in those with adverse pregnancy outcomes appears to be related to endothelial cell activation/dysfunction, as there are increases in TM and ICAM-1 levels in the same groups. No sole fibrinolytic marker is helpful in determining pregnancy outcome; the relatively small numbers in each group and our statistical correction for multiple analyses do, however, mean that it is possible that we have missed true differences in markers between the groups. It would nevertheless appear that t-PA and PAI-2 are worthy of further study in a multifactorial algorithm applied to an unselected population.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References

The authors state that they have no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References