Pregnancy is considered a risk factor for venous thromboembolism (VTE), with deep vein
thrombosis and pulmonary embolism the main causes of maternal morbidity and mortality.
studies report a 5-fold increase in risk during pregnancy. The post-partum period is also
at risk of thrombosis, with 24.4 events per 100,000 births observed in the first 6 weeks
after delivery, compared with 2.3 in the same period a year later. During the period 7 to
12 weeks after delivery, the risk is modest but still significant. Pregnant women are
therefore at high risk of thrombosis during the first 6 weeks post-partum. This risk
decreases, but persists for up to 3 months. Although many data suggest that the incidence
of VTE is similar during the 3 trimesters of pregnancy, a recent study actually shows
that the risk increases exponentially throughout gestation.
Treatment with low-molecular-weight heparin (LMWH) is the anticoagulant treatment of
choice for the prevention or cure of VTE during pregnancy, and throughout the 3
trimesters of gestation, due to its ease of administration and monitoring, and the low
incidence of adverse effects.
However, physiological changes during pregnancy may alter the pharmacokinetic properties
of LMWH. The increased volume of distribution and higher glomerular filtration rate may
result in a reduced anticoagulant effect. Nevertheless, the need to adjust doses during
pregnancy remains controversial. Some authors suggest simply increasing the dose
according to weight, especially at therapeutic doses. Others go further, advocating dose
adjustment not only according to weight, but also by monitoring anti-Xa activity to keep
it within defined limits. On the other hand, other authors have shown that few women
require dosage adjustment.
As a result, monitoring of anti-Xa activity is not clearly recommended, and the true
hemostatic profile of women undergoing LMWH treatment is still open to question. This
means that the optimal dose of LMWH in pregnant women, for both preventive and curative
treatment, remains poorly understood. Initiation of treatment with LMWH therefore
requires discussion of the dosage to be administered, in order to avoid over- or
under-dosing and the inherent risks. For prophylaxis, a single daily dose of LMWH (e.g.
enoxaparin 40 mg) is commonly administered throughout pregnancy, without monitoring
anti-Xa activity and without taking into account physiological changes during
pregnancy.Recently, Bistervels et al. recommended the use of low-dose LMWH for the
prevention of deep vein thrombosis. Nevertheless, it appears that intermediate doses
adapted to weight may be justified in women with a body mass index of less than 30, to
prevent pulmonary embolism or in the post-partum period . Anticoagulation assessment
using more precise tools than those currently available on a routine basis could be
useful in this context.
There is a lack of data on the true state of hypercoagulability and the mechanisms
involved during pregnancy. Most studies have focused on the levels of procoagulant and
anticoagulant factors. This type of study gives only a fragmentary view of the
haemostatic balance of pregnant women. More recently, more comprehensive coagulation
tests such as thrombinography have been used in pregnant women.
The purpose of plasma coagulation is to generate a large quantity of thrombin, the key
coagulation enzyme, enabling fibrinogen to be converted into a fibrin network. Routine
coagulation tests (PT, APTT) use supra-physiological doses of coagulation activators, and
report only the first traces of fibrin in plasma, corresponding to less than 5% of the
thrombin formed in vivo. Conventional tests therefore fail to study the kinetics of the
remaining 95% of thrombinoformation. The C.A.T. (Calibrated Automated Thrombography)
method was developed by Hemker and is distributed by Stago®.
Thrombinography thus enables us to monitor thrombin generation kinetics, integrating the
action of procoagulant and anticoagulant factors, unlike standard haemostasis tests (PT
and APTT). As a result, measuring thrombin generation better reflects a subject's
hemostatic potential, especially when the subject presents complex variations in
coagulation molecules, as is the case during pregnancy. Available data on thrombinography
in pregnancy are limited and contradictory. Some authors consider that thrombin
generation increases as early as the first trimester of pregnancy and then remains stable
throughout pregnancy, whereas others find an increase during pregnancy, at least during
the first 2 trimesters. There are few longitudinal studies evaluating thrombin generation
during pregnancy and post-partum in a given pregnant woman. These studies are carried out
on small numbers.
A global coagulation test such as thrombinography could be used to assess the impact of
in vitro addition of different doses of LMWH in pregnant and postpartum women.
Preliminary dose-ranging studies carried out in the laboratory have shown that the in
vitro addition of LMWH corresponding to 0.3 IU/mL anti-Xa activity results in a decrease
in thrombinography parameters. The area under the curve, or AUC, was reduced by 50%.
Comparing thrombin generation profiles with and without in vitro addition of LMWH in
pregnant versus non-pregnant women can help assess the action of LMWH. Indeed, some
authors have studied the effect on thrombin generation of in vitro addition of LMWH to
the plasma of pregnant and non-pregnant women. In vitro addition of LMWH reduces thrombin
generation in pregnant and non-pregnant women, but the percentage of inhibition is
significantly lower in pregnant women, reflecting a "resistance" to the action of LMWH.
Nevertheless, the population studied was small (n=12), and anti-Xa activity was not
determined. What's more, only women in their first trimester of pregnancy were included,
so this study does not allow longitudinal assessment of resistance during pregnancy and
post-partum.
In this pilot study, the investigators propose to evaluate thrombin generation, before
and after in vitro addition of LMWH, in pregnant women longitudinally, during the 3
trimesters of pregnancy, post-partum and post-pregnancy.
This descriptive study could be the indispensable preamble to a larger-scale clinical
study aimed at using thrombinography to optimize anticoagulant therapy in pregnant women.