Measurements of Prothrombin Fragment 1.2 In Urine and Blood to Assess Hypercoagulability In Preeclampsia

Pregnancy is an acquired hypercoagulable condition as coagulation is shifted towards a more procoagulant state. Prothrombin fragment 1.2 (F1.2) is a direct measure of thrombin generation and thus of activation of the haemostatic system. We aimed to investigate the relationship between plasma F1.2 and urinary elimination in pregnancies complicated by PE compared to uncomplicated normotensive pregnancies and to establish whether levels of urinary F1.2 reflects thrombin generation de facto or is influenced or a result of proteinuria.

In 62 pregnancies with PE and 10 randomly selected normotensive pregnancies, blood samples were collected at inclusion and at gestational weeks 17, 23, 29, 33, 37, 39 and 41, and urine samples were collected every two weeks from inclusion until delivery or in a subgroup of patients only once before delivery. Levels of plasma and urinary F1.2, albumin and creatinine and plasma D-dimer were measured and standardized data collected on pregnancy, delivery, placenta and neonatal outcome. F1.2 in urine and plasma were analyzed by enzyme immunoassay Enzygnost® F1.2 (Dade Behring Marburg GmbH, Germany). All measurements were performed in duplicate and a reference curve established for each series. Creatinine was analyzed by enzymatic reaction IDMS (Isotope Dilution Mass Spectroscopy) by Ortho Clinical (Johnson & Johnson Nordic AB, Sweden), albumin was analyzed by direct immunoassay by Ortho Clinical (Johnson & Johnson Nordic AB, Sweden), and finally D-dimer analyzed by BCSXP (Siemens 2750-DK, reagens Auto Dimer, Biopool, UK).

In all pregnancies, levels of urinary F1.2 and plasma F1.2 increased throughout pregnancy until delivery especially in pregnancies complicated by PE (Figure 1). This difference between PE and controls was more pronounced at gestational weeks 30 and 37. D-dimer demonstrated a small increase with gestational age in all pregnancies with non-significant higher measurements in the second and third trimesters of women with PE. Creatinine was fairly constant in all pregnancies. In PE, albuminuria was significantly increased at 30 and 37 gestational weeks, coinciding with declining plasma levels. There was no significant association between levels of urinary F1.2 and albuminuria (Figure 2).

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In all pregnancies, levels of uF1.2 increased with gestational age with an even further increase at 37 gestational weeks. The increase in urinary F1.2 was even more pronounced in pregnancies with PE, emphasising the hypercoagulable character of this disease. Furthermore, the levels of uF1.2 reflected plasma generation of F1.2 and thus the amount of thrombin generated. F1.2 was eliminated in urine irrespective of the co-existence of proteinuria and urinary F1.2 may be a more reliable and sensitive parameter for assessing haemostatic activation than plasma levels although the exact role of uF1.2 warrants further studies.

Lassen:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Speakers Bureau; Sanofi Aventis: Consultancy; Astellas Pharma: Consultancy; GSK: Consultancy.