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Effect on Thrombin Generation of the “In Vitro” Addition of Low-Dose LMWH to Plasma of Healthy Pregnant and Nonpregnant Women

An increased risk of venous thromboembolism (VTE) is present during pregnancy and the main reason is the shift of the hemostatic system toward hypercoagulability. An increase in plasma concentration of some coagulation factors (ie, factors V, VII, VIII, IX, X, XII, fibrinogen, and von Willebrand factor) on one hand and a decrease in free protein S as well as acquired activated protein C resistance on the other was reported. Moreover, microparticles derived from endothelial cells, platelets, and trophoblast can represent additional procoagulant stimuli. Hypercoagulability during pregnancy is reflected by an increase in coagulation activation markers (ie, prothrombin fragment 1 þ 2, thrombin–antithrombin complexes, soluble fibrin polymer, and D-dimer). More recently, thrombin generation (TG) in plasma has been used to assess the endogenous thrombin potential (ETP) in platelet-poor and/or platelet-rich plasma. Only few data are available on TG during pregnancy and the results from different observations are conflicting. Low-molecular-weight heparin (LMWH) is the anticoagulant treatment of choice for VTE prophylaxis and treatment during pregnancy. Despite the increased risk of VTE during pregnancy and the postpartum period, only women at very high risk like those with previous thrombotic events, particularly if occurred during hormonal treatments, or those with inherited deficiency of natural anticoagulants need anticoagulant prophylaxis during pregnancy and postpartum. However, the optimal dose of LMWH thromboprophylaxis in pregnancy at risk is still unknown. We performed a preliminary study investigating the in vitro effect of low-dose LMWH (Nadroparin; Italfarmaco, Milan, Italy) on TG after the ‘‘in vitro’’ addition to plasma from healthy pregnant women during the first trimester. The data obtained were compared with those of a control group of healthy women. Of the 19 women in the first trimester of pregnancy, consecutively referred to the University Hospital of Padua, 3 were excluded because of a history of VTE and/or obstetric complications, 2 because of younger than or equal to 18 years, and 2 because of the intake of any antithrombotic therapy. No women enrolled had a previous diagnosis of hypertension and none had preexisting or gestational diabetes. Thus, 12 healthy pregnant women and 12 healthy nonpregnant women of comparable age were included in the study. After informed consent, 9 mL of blood were drawn through a butterfly needle, from an antecubital vein, into a syringe prefilled with 1 mL of sodium citrate 109 mmol/L. Blood was centrifuged at 3000 rpm for 10 minutes to separate cells from platelet-poor plasma (PPP); PPP was dispensed as 500 mL aliquots and was stored at 80 C. For each participant, prothrombin time ([PT], seconds), activated partial thromboplastin time ([aPTT], seconds), and antithrombin activity (AT, %) were determined. Prothrombin time, aPTT, and AT were performed on a BCT-Analyser (Dade Behring, Marburg, Germany), according to standard procedures. Thrombin generation was determined on PPP by means of calibrated automated thrombogram (CAT) method as previously reported. Briefly, coagulation was started with a homemade trigger composed of tissue factor of 5 pmol/L (Innovin; DADE-Behring, Marburg, Germany), a mixture of synthetic phospholipid vesicles of 4 mmol/L (Rossix, Mölndal, Sweden), and CaCl2. Thrombin activity in PPP was monitored continuously with the fluorogenic substrate Z-Gly-Gly-Arg-AMC (BACHEM, Bubendorf, Switzerland). Fluorescence was read in a Fluoroskan Ascent reader (Thermo Labsystems, Helsinki, Finland), and TG curves were calculated using Thrombinoscope software (Thrombinoscope, Maastricht, The Netherlands). Lag time (minutes), ETP (nmol/L min), and