Thrombin Generation and Low Molecular Weight Heparin Prophylaxis In Pregnant Women With Thrombophilia

Abstract

Introduction Pregnancy is associated with an increased risk of venous thromboembolism (VTE) which is even more pronounced in the presence of inherited thrombophilia. Despite the well-established relation between thrombophilic pregnancies and VTE, there is no consensus on the optimal approach for thromboprophylaxis in this population. There is growing evidence that thrombin generation correlates with the overall procoagulant state of the plasma leading to elevated thrombosis risk. The aim of this study was to evaluate thrombin generation over the course of pregnancy in women with inherited thrombophilia compared to healthy pregnant women. We also aimed to investigate the effectiveness of low molecular weight heparin (LMWH) prophylaxis in pregnancy by measuring thrombin generation and anti-Factor-Xa activity. Methods In this cohort study women with severe (n=8) and mild (n=47) thrombophilia were followed throughout their pregnancies. In addition, healthy pregnant women (n=15) were recruited as control subjects. Thrombin generation was evaluated in each trimester as well as 5 days after delivery and 8 weeks postpartum (baseline). In order to assess the effect of LMWH therapy at each stage of the pregnancy, thrombin generation and anti-Factor-Xa activity were measured just before and 4 hours after administration of the drug (peak and trough effect). Thrombin generation was determined using Technothrombin TGA assay system, and the results were evaluated with the provided software. For analysis, the median peak thrombin and endogenous thrombin potential were determined. The anti-Factor-Xa activity was measured by a commercially available chromogenic assay. Results In all the 3 study groups, both peak thrombin and endogenous thrombin potential were increased over the course of pregnancy compared to the non-pregnant state. Peak thrombin and endogenous thrombin potential were higher in the severe thrombophilia group than in the other 2 groups in every trimester and also after delivery. There was no distinct difference in thrombin generation between the mild group and the controls. In women undergoing LMWH prophylaxis a decrease was observed in both the peak thrombin and endogenous thrombin potential after the drug was administered. Over the course of pregnancy the extent of this decrease reduced in a stepwise fashion. The difference between the 2 measurements (before and after LMWH) was smallest in the third trimester and increased again after delivery. Anti-Factor-Xa activity appeared to be enhanced at the peak effect of LMWH. However, the difference between the anti-Factor-Xa activity before and after LMWH administration remained unchanged over the progression of pregnancy. None of the women suffered from VTE or had any bleeding complications during the observation period. Conclusions Our results show that thrombin generation is increased during pregnancy, with higher levels in women with severe thrombophilic defects. In addition, our data demonstrate a decrease in the effect of LMWH with advancing stages of pregnancy. Until now no studies evaluated prospectively the effect of LMWH prophylaxis on thrombin generation over pregnancy. Our findings contribute to the ongoing debate about the necessity and intensity of thromboprophylaxis during pregnancy, providing new information about the coagulable state of mild and severe thrombophilic pregnant women. The decreasing antithrombotic effect of LMWH over pregnancy suggests a need for dose adjustment in late gestational weeks. Furthermore, our results imply that thrombin generation as a global coagulation test may demonstrate more sensitively the effect of LMWH than the anti-Factor-Xa activity assay. Disclosures: No relevant conflicts of interest to declare.

Anti-Xa Monitoring of Low-Molecular-Weight Heparin during Pregnancy: A Systematic Review

“…55 Three studies used either LMWH alone or in combination with warfarin, alternately. 50,53,56 In a prophylaxis setting, LMWH was dosed as a fixed dose, 25,26,28,30,33,34,40,42 weight based, 29,38 or anti-Xa adjusted. 24,27,31,32,35,37,39,41,43 When LMWH was anti-Xa adjusted, the initial dose was a fixed dose, 27,35 a weight based dose, 24,41,43 or based on the preference of the treating physician.…”

“…Varying targets were present in one study, 50 while two studies changed target during the study period. 52,54 Nine studies had no defined anti-Xa target, 25,26,[28][29][30]33,34,38,42 and one study had no target for the prophylaxis part of the study group. 40 Safety and effectiveness were addressed in 28 studies.…”

“…40 Safety and effectiveness were addressed in 28 studies. 24,[26][27][28][29][31][32][33]35,[37][38][39][40][41][42][43][44][45][46][48][49][50][51][52][53][54][55][56] In 12 studies, adverse events were recorded at follow-up appointments, 24,27,38,39,42,44,46,48,49,51,55,56 and in one study adverse events were self-reported and triggered clinical control with echocardiography and obstetric examination. 52 In addition, one study performed a control ultrasound for recurrent deep vein thrombosis 48 and three studies performed regular echocardiography in women with MHV.…”

“…40,53,54 Twelve studies gave no information on method or criteria used for recording thrombosis or bleeding events. 26,28,29,[31][32][33]35,37,41,43,45,50 The characteristics of bleeding episodes were either not defined or defined with different criteria from study to study.…”

“…31 The remaining two studies did not report any excessive bleeding. 28,29 Sarig et al did not report on effectiveness and safety. 30 The majority (89%) of the study population in Sarig et al was also part of the LIVE-ENOX trial.…”