Fibrinolytic capacity decreases during pregnancy, mainly because endothelial PAI-1 increases in late pregnancy and placental PAI-2 is detectable in plasma during the first trimester and increases substantially throughout pregnancy. In early pregnancy, t-PA activity is close to the normal range observed in non-pregnant women and there is a gradual decrease with gestational age. This decrease in t-PA activity is due to increased levels of the t-PA inhibitors PAI-1 and PAI-2.
The hypercoagulable state in sickle cell disease (SCD) is well documented and is associated with an increased risk of fetal and maternal complications in pregnant patients with SCD. In addition, the biochemical balance in normal pregnancy is biased in favor of coagulation. The rationale for conducting this study was two-fold: (a) the fibrinolytic state in pregnant sickle cell patients has not been adequately studied and (b) PAI-2 levels and its possible genetic links have never been investigated in pregnant SCD patients previously. Therefore, this study aimed to determine antigen levels in plasma and genotypes of PAI-2 in pregnancy associated with homozygous sickle cell anemia (SCA). To examine the separate effects of pregnancy and sickle cell disease on these parameters, the study included three control groups: (a) healthy non-pregnant, (b) healthy pregnant, and (c) non-pregnant SCA.
The study subjects were all Bahraini females in the reproductive age group. The study population included 31 pregnant homozygous SS (SCA) patients. Three control groups were also studied to evaluate the effect of pregnancy and SCA on PAI-2 levels and fibrinolysis: (1) 31 healthy non-pregnant volunteers; (2) 31 cases of normal pregnancy; and (3) 20 non-pregnant SCA patients. Pregnancies were screened in the second (TM2) and third (TM3) trimesters. Global coagulation, fibrinolysis rate (euglobulin clot lysis time, ECLT), PAI-2 antigen (ELISA), and PAI-2 Ser(413)/Cys polymorphism (restriction fragment length polymorphism analysis) were determined.
Fetal and maternal complications were reported in both pregnancy groups. PAI-2 antigen levels were undetectable in the non-pregnant groups but were quantifiable in both pregnant groups. An impaired rate of fibrinolysis and an increase in PAI-2 levels with pregnancy progression were observed in both normal and SCA subjects. These changes were more pronounced in SCA, although the increase in ECLT was less dramatic and PAI-2 antigen levels were not significantly different from normal pregnancies in the third trimester. No correlation was observed between PAI-2 genotypes and plasma antigen levels.
No significant difference in feto-maternal complications was found in normal (n = 25) versus SCA pregnant patients (n = 30). Coagulation tests in pregnant normal and pregnant SCA patients, revealed a mild shortening of PTT and TT in some cases which indicates the presence of a hypercoagulable state in these patients. However, results from the second to third trimester differed between the groups. These observations are consistent with earlier studies and are likely the result of increased coagulation factors VII, VIII, X, XII, XIII, VWF, and fibrinogen that is attributed to increased estrogen levels in pregnancy.
D-dimers are specific degradation products of plasmin fibrin, and elevated levels above normal are observed in conditions such as deep vein thrombosis with or without thromboembolism. Normal pregnancy results in maternal plasma D-dimer concentrations gradually increasing from conception to delivery. The results of the current study showed that the elevated baseline D-dimer level at steady state in SCA was significantly elevated in the second trimester in pregnant SCA subjects with a further increase in the third trimester. These values were significantly different from the other groups, suggesting a higher level of thrombin activation, fibrin formation and subsequent fibrinolysis in these patients, similar to observations in SCA patients in crisis in other studies. Clinically, none of these patients were in crisis at the time of sampling. Furthermore, the incidence of crises also did not increase during pregnancy. Therefore, it is likely that other balancing factors were acting in pregnant SCA patients to prevent the pathological consequences of an overactive coagulation system. Alas, no comparable studies were found in the literature.
The cumulative conclusion of this study showed that PAI-2 antigen levels increased more sharply from the second to the third trimester in pregnant SCA patients in Bahrain compared to their normal peers, although the mean levels were not significantly different. Moreover, a significant activation of the coagulation system with ongoing fibrinolysis in the setting of impaired fibrinolysis was characteristic of pregnant SCA patients. No correlation was observed between PAI-2 genotypes and plasma antigen levels. Despite the increased risk of hypercoagulability in pregnant SCA patients in Bahrain, their pregnancy outcome appears to be significantly better than reported in other populations such as Nigeria and Benin, suggesting a possible role for compensatory anticoagulant mechanisms.