Thrombin generation post elective caesarean section: Effect of low molecular weight heparin

Green

et al. 2012

Blood

503 The optimal dosing strategy of low molecular weight heparins (LMWH) for the treatment of antenatal venous thromboembolism (VTE) is not known. The physiological changes associated with pregnancy alter the pharmacokinetic (PK) profile of LMWH, and this has led to controversy and subsequent variation in practice, when pregnant women are managed with LMWH for VTE [Voke et al., 2009]. The perceived impact of these PK changes has led to the Royal College of Obstetrics and Gynaecologists (RCOG) recommending a twice daily dose of LMWH, whilst the American College of Chest Physicians recommend that either a once or twice daily dose of LMWH can be used in this setting. We conducted a population PK modelling study of enoxaparin during pregnancy in order to address this issue. Women requiring antenatal enoxaparin, all indications and doses, referred to the specialist haematology clinic at King's College Hospital, a London teaching hospital, were eligible to enrol in the study. Recruited women were reviewed monthly in clinic during their pregnancy, and had up to three anti-Xa activities (trough, 1 hour post dose, and 3 hours post dose) drawn at each clinic attendance. This anti-Xa sampling strategy was based on d-optimal design, to ensure gestation related changes in enoxaparin clearance (CL) and volume of distribution (Vd) were captured in the PK model developed [van Hasselt et al., 2012]. Women under 18 years of age, those with impaired renal function and those non-adherent to enoxaparin were excluded. Compartmental PK modelling was conducted using non linear mixed effects modelling (NONMEM version 7.2.2). One hundred and twenty three patients contributed 795 anti-Xa activities (712 antenatal, 83 postnatal), for PK modelling purposes. A one compartment model with exponential between subject variability on CL and Vd, with a combined proportional and additive error model best fitted the data, with both enoxaparin CL and Vd found to have increased during pregnancy (table). Enoxaparin PK parameter CL (L/hr) Vd (L) Non-pregnancy (literature values) 0.5-0.7 3-7 Pregnancy (this study) 1.6 13.2 Time dependent changes during pregnancy were found to be significant covariates on both CL and Vd. A full covariate analysis identified weight to be a significant covariate for enoxaparin CL and gestation and baseline lean body weight to be significant covariates for Vd during pregnancy. The final pregnancy enoxaparin PK models for CL and Vd can be represented mathematically as: where Wt is the women's actual weight, GEST is their gestational stage, and LBW is their baseline lean body weight. Goodness of fit plots, a bootstrap analysis and a visual predictive check revealed that a robust enoxaparin model for use in pregnancy had been developed. Simulations of women injecting enoxaparin once versus twice daily demonstrate that both dosing regimens will reach RCOG target 3 hour plasma concentrations throughout the duration of the pregnancy (Figure 1). This should provide confidence to clinicians who prescribe a once daily dose of enoxaparin for the antenatal population. Perhaps the more important concentration to assess however is the trough anti-Xa activity, due to the historical thinking that during pregnancy CL increases, therefore so should the dose/dosing frequency. When the trough activity is simulated, the majority of women on a once daily dose, will have measurable anti-Xa activity; with both once and twice daily regimes demonstrating an increase in trough anti-Xa activity with the progression of pregnancy. This occurs due to the increase in Vd and demonstrates that enoxaparin never reaches a steady state during pregnancy. The measurable trough activity confirms the appropriateness of a once daily dose of enoxaparin in this setting. Our work provides compelling evidence that a once daily dose of enoxaparin for the treatment of antenatal VTE is appropriate. As a result, the current guidelines should be revised. Figure 1: Simulation of 3 hour (red) and trough (blue) anti-Xa activity of women receiving once daily and twice daily treatment doses of enoxaparin during their pregnancy. The solid line is the median concentration and the dashed lines represent the 5th and the 95th percentile concentrations. Grey horizontal lines represent RCOG 3 hour target anti-Xa concentration. Figure 1:. Simulation of 3 hour (red) and trough (blue) anti-Xa activity of women receiving once daily and twice daily treatment doses of enoxaparin during their pregnancy. The solid line is the median concentration and the dashed lines represent the 5th and the 95th percentile concentrations. Grey horizontal lines represent RCOG 3 hour target anti-Xa concentration. Disclosures: Off Label Use: Enoxaparin use during the antenatal period.

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Green

et al. 2012

Blood

“…In contrast to our findings, Ismail et al reported higher ETP and peak thrombin in women with low VTE risk following VD compared with those following elective CS. 22 There was no significant change in thrombin generation pre-to post-CS and they did not measure predelivery thrombin generation in the VD group. It is therefore unclear whether the changes reported relate to mode of delivery, labour or other patient characteristics.…”

Section: Discussionmentioning

confidence: 88%

Mode of Delivery Does Not Influence Postpartum Hypercoagulability Measured by Thrombin Generation or Thromboelastometry

Guimicheva

Roberts

et al. 2020

TH Open

Introduction Venous thromboembolism (VTE) is a significant cause of maternal mortality with the greatest risk postpartum. Mode of delivery influences VTE risk, with emergency caesarean section (CS) associated with the highest risk (CS). Thromboprophylaxis is recommended for selected women to reduce the risk of VTE.We aimed to investigate the impact of mode of delivery and thromboprophylaxis on hypercoagulability as measured by thromboelastometry (TEM) and thrombin generation (TG) in women at high VTE risk. Materials and Methods Blood was collected from 99 pregnant women with VTE risk factors at up to five time points from pre- (T1) and post (T2)-delivery to 6 weeks postpartum (T5). Multiple linear regression was utilised to compare TG and TEM between those with vaginal delivery (VD) and CS at each time point. Paired sample t-test with post hoc Bonferroni correction was utilised to compare laboratory markers over time. Results Women in both groups had a median of three postpartum VTE risk factors, with higher body mass index and parity post-VD. In both the groups, TG and TEM parameters suggested hypercoagulability at T2 compared with T1, with resolution at T5. There were minimal differences between groups, apart from T2 with shorter clot formation time and higher maximum clot firmness in the VD group. Conclusion TG and TEM illustrate hypercoagulability associated with pregnancy and delivery. The pattern of postpartum hypercoagulability seen in women with VTE risk factors was similar irrespective of mode of delivery. Further research is required to establish the effect of labour on TG/TEM in the absence of low molecular weight heparin use.

Rev Bras Ginecol Obstet

“…Sequential mechanical compression devices, simple graduated compression socks, low molecular weight heparin (LMWH), and fractionated heparin (FH) and unfractionated heparin (UFH) demonstrated to be effective in this issue. 4,6,[10][11][12]20,21,23,[26][27][28][29] In 2011, the American College of Obstetricians and Gynecologists (ACOG) 30 published an opinion supporting the routine use of perioperative pneumatic compression devices during cesarean section. Sequential compression devices reduce the risk of VTE by increasing femoral blood flow through mechanical compression of the lower limbs, as well as by stimulating fibrinolysis through an increase in tissue plasminogen activator concentration and a decrease in inhibitor levels.…”

Section: Prophylaxis Techniquesmentioning

confidence: 99%

“…However, the "Confidential Inquiry into Maternal Deaths" (CEMACH) report showed that risk factors were absent in more than 20% of women who died from venous thromboembolism events. 21 The Norwegian Society of Gynecology and Obstetrics recommends prophylaxis with low-molecular weight heparin for 4 to 8 days after all cesarean sections. On the other hand, the Royal College of Obstetrics and Gynecology (RCOG) classifies women who underwent cesarean section in three degrees, and recommends thromboprophylaxis only for those women classified as having a medium or high risk of thrombosis.…”

Section: Prophylaxis Techniquesmentioning

confidence: 99%

Venous Thromboembolism and Route of Delivery – Review of the Literature

Evangelista

Slompo

Timi

2018

Venous thromboembolism events are important causes of maternal death during pregnancy and the postpartum period worldwide. A review of the literature with the objective of evaluating venous thromboembolism events in the puerperium according to the route of delivery was performed through a bibliographic survey in the Medline, LILACS and Scielo databases. We observed that patients submitted to cesarean sections present a significantly higher risk of developing venous thromboembolism when compared with those who undergo spontaneous vaginal delivery. The pathophysiological bases for this difference were explored and described in this review, as well as the indications of prophylaxis and treatment. Doctors and health professionals must be continuously vigilant regarding this condition, since it is associated with high morbidity and mortality.