Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT01394107 |
| Other study ID # |
LMWH_jB |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 2011 |
| Est. completion date |
May 2025 |
Study information
| Verified date |
February 2024 |
| Source |
Charles University, Czech Republic |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The project aims to clarify the effect of the thromboprophylactic LMWH dose on coagulation in
pregnant women just before birth, at the period of maximal physiological hypercoagulable
state and with high risk of thromboembolism, the most common cause of maternal mortality in
developed countries. Although LMWH are now routinely administered as prevention of
thromboembolism, their effect on coagulation in pregnant women was not yet studied. The doses
of LMWH in pregnancy are only derived in terms of coagulation from totally different groups
of patients (surgical, orthopedic). We therefore will map the effect of thromboprophylactic
LMWH dose on coagulation in pregnant women using recently available methods, especially a
complex examination of coagulation within 24 h after LMWH application using
thrombelastography, including examination with heparinase, and monitoring the effect of LMWH
by measuring antiXa and TGT (thrombin generation time) activity. Based on these results we
will also evaluate the possible influence of LMWH prophylaxis on the risk of spinal haematoma
during neuraxial analgesia/anesthesia for delivery/Caesarean section. On the basis of our
pilot results we can presume the current dosage of LMWH in pregnant women is inadequate and
that it would be appropriate to adjust presently used dosage. At the same time we want to
prove that the standard LMWH thromboprophylaxis in pregnant women does not increase the risk
of spinal haematoma during neuraxial blockade. In both situations the targeted outcome is to
increase the safety of pregnant women.
Description:
AIMS OF THE PROJECT:
The aim of this project is to map the effect of the thromboprophylactic dose of LMWH on
coagulation of women at the end of pregnancy, using recently available methods and laboratory
tests, and simultaneously to evaluate the possible influence of LMWH on incidence of spinal
hematoma. The methodology is based primarily on a complex examination of coagulation by
thrombelastography (TEG), including comparative tests with heparinase, and on the monitoring
effect of LMWH by measuring thrombin generation time (TGT) and levels of AntiXa. At the same
time and, in cooperation with the Thrombotic Centre, standard and special laboratory
hematology tests will be performed (INR, APTT, TT, fibrinogen, AT III, D-dimer, protein S,
protein C, APC resistance, PFA, F VII, F VIII, PFA 100, TAT micro, vWf, APA, t-PA, PAI-1,
blood count) together with genetic tests for FV Leiden and prothrombin II mutations.
HYPOTHESIS AND EXPECTED RESULTS:
We assume that with hypercoagulation and other influencing factors in pregnancy, the effect
of LMWH on coagulation, compared to the population of non-pregnant women, will be
significantly lower. Thus significantly lower will be also the effect of TED prophylaxis. For
the same reason we assume that the current thromboprophylactic dosage of LMWH could not
affect coagulation of pregnant women enough to increase the risk of spinal hematoma with
neuraxial analgesia/anaesthesia administration.
SPECIFIC AIMS:
Primary aims: To map the coagulation effect of standard prophylactic dose of LMWH in pregnant
women at the end of pregnancy. Based on these results, to evaluate the possible prophylactic
effect of LMWH on TED prevention in pregnant compared to non-pregnant women and to evaluate
the possible influence of LMWH on the potential risk of spinal hematoma development during
neuraxial blockade in pregnancy.
Secondary aims: To propose a change of the thromboprophylactic regimen in pregnancy. To
suggest a change of the recommended time interval between LMWH application and administration
of neuraxial blockade in pregnant women.
METHODS AND RESEARCH SAMPLE CHARACTERISTICS:
Study design: prospective, monitoring
Size and type of study group: a total of 50 pregnant women with physiological ongoing
pregnancy and undergoing planned caesarean section, without known coagulation disorders, will
be included in to the study
Inclusion criteria: pregnant women undergoing planned caesarean section, 39th-40th week of
pregnancy, age 18-40 years, informed consent.
Exclusion criteria: disapproval or non-cooperation of the mother, allergy to LMWH,
coagulation disorders or the risk of, anticoagulant therapy in the last 3 months, signs of
infection, history of cancer, signs of thrombosis or a history of thrombosis, the ongoing
non-physiological pregnancy, significant obesity, or other severe comorbidity.
Withdrawal criteria: development of obstetric complications in the mother or foetus during
the study following, finding of prothrombotic state.
Control group: 50 healthy women in fertility age (18-40 years) undergoing elective surgery
for other than oncology or inflammatory indication, without known risk factors for
coagulation disorders, not using hormonal contraception, informed consent.
LMWH applications: a standard thromboprophylactic dose of LMWH (4000 IU of enoxaparin
subcutaneously) will be given to pregnant woman/patient in control group.
Monitoring of coagulation: To evaluate coagulation changes after administration of LMWH dose
we will perform thrombelastographic examination (TEG; Haemascope Corp., USA.) of venous blood
(including examination with heparinase) and specific laboratory tests to measure the effect
of LMWH activity - antiXa and TGT (thrombin generation time). Coagulation system will be also
be examined by other available laboratory tests (INR, APTT, TT, fibrinogen, AT III, D-dimer,
protein S, protein C, APC resistance, PFA, F VII, F VIII, PFA 100, TAT micro, vWf, APA, t-PA,
PAI-1, blood count) including genetic testing for FV Leiden and prothrombin II mutation.
Monitoring of coagulation takes place in four phases:
1. Basal level - before LMWH application
2. The maximum effect of LMWH - 4 hours after application
3. Low efficiency of LMWH - 8 hours after application
4. Control level of LMWH effectiveness - 24 hours after application
Samplings for laboratory testing will be performed in the same way as a sample for TEG
examination - venous blood will be in planned times taken by one-time blood draw to prevent
premature coagulation activation and dilution of the sample. Blood samples will be collected
according to standard guidelines (for coagulation tests and TEG in a test tubes with sodium
citrate) - and subsequently processed in Central haematology laboratory.
For TEG examination 1 ml of whole blood will be activated by 1% celite and then 360 μl of
sample (340 μl blood + 20 μl CaCl2) will be analyzed in a standard cuvette and 360 μl of
sample (340 μl blood + 20 μl CaCl2) in the cuvette with heparinase. Following parameters will
be recorded: time r, time K, angle alpha, maximum amplitude MA and LY30 as a factor of
fibrinolysis. From the measured values coagulation index (CI) will be calculated.
DATA COLLECTION:
Demographic, obstetric and clinical data - age, height, weight, BMI, gestational age,
previous pregnancy, associated medical conditions. Standard pre-operative assessment and
pharmacological history. Fluid intake and output during the surveillance. Any bleeding and /
or thromboembolic complications from beginning of the study to the end of hospitalization
after Cesarean section.
DATA PROCESSING:
All data will be stored at electronic database with safety back up. Statistical analysis will
be performed in cooperation with Biomedical Statistics Dept. of the Institute of Biophysics
and Informatics, Charles University in Prague, 1st Faculty of Medicine. Based on preliminary
analysis the overall number of subjects was determined as 50 in both study groups.
DATA EVALUATION:
Based on study results the relationship between the potential risk of spinal hematoma and the
LMWH application will be evaluated by the Expert Committee for Obstetric Anaesthesia of the
Czech Society of Anaesthesiology and Intensive Care Medicine (ČCSARIM). The conclusions and
the resulting recommendations will be submitted to the Executive Committee of ČSARIM.
TIME SCHEDULE:
Based on the feasibility test and pilot study we consider as real inclusion 3 patients into
the study per month. This number is based on the number of anticipated elective caesarean
operations and the possibility of recruiting appropriate subjects satisfying all the
criteria, and also on organizational difficulties when samples at study hour 8 and 24 will be
taken at the place of subject's residence.
1. st year - creating a study database, patient recruitment, inclusion of 15 pregnant women
+ 15 controls; samples processing.
2. nd year - recruiting patients, inclusion of 25 pregnant women + 15 controls, processing
and analysis of samples, evaluation and presentation of preliminary study data.
3. rd year - recruiting patients, inclusion 10 pregnant women + 20 controls, processing and
analysis of samples. The evaluation of all study data, statistical evaluation,
presentation and publication the final results.
DEPARTMENTS INVOLVED, PRINCIPAL INVESTIGATOR´S READINESS:
Department of Anaesthesiology and Intensive Care Institute of Clinical Biochemistry and
Laboratory Diagnostics, Central Hematology Laboratory, Thrombotic Centre Department of
Gynaecology and Obstetrics
EXPECTED RESULTS AND PROJECT IMPORTANCE:
The expected project outcome is the detailed evaluation of the influence of LMWH on
coagulation in pregnant women and suggested modification of dosing schemes for
thromboprophylaxis before Caesarean operation, which would better reflect physiological
hypercoagulation in pregnancy. Due to improved TED prophylaxis the main long-term outcome
then should be the reduction of maternal mortality in connection to thromboembolic diseases.
At the same time we want to prove that the current dosage of LMWH in pregnant women cannot
increase the risk of epidural hematoma during neuraxial blockades and we would recommend
changes of time relationships between administration of LMWH and neuraxial blockade.
COOPERATION ON THE PROJECT:
The project will be performed in cooperation between the Dept. of Anaesthesiology and
Intensive Care, Thrombotic Centre of Institute of Clinical Biochemistry and Laboratory
Diagnostics and Dept. of Gynaecology and Obstetrics.
The relationship between the risk of spinal hematoma and the LMWH applications will be
evaluated by the Expert Committee for Obstetric Anaesthesia and Executive Committee of the
Czech Society of Anaesthesiology and Intensive Care Medicine.
DISCUSSION:
So far, no studies have been published dealing with the influence of thromboprophylactic LMWH
dose on coagulation in pregnant women. The only study, showing a reduced effect of LMWH
during pregnancy, was only evaluating its effect on antiXa activity. Our project differs in
complexity and range of other available methods used such as thrombin generation time and
especially thrombelastography. Thus our project also builds on the results of previous grant
project IGA No. NR8157 "The use of thrombelastography in evaluating coagulation in women with
physiologically and pathologically ongoing pregnancy, during birth and beyond".
EXPECTED PROJECT BENEFITS AND IMPACTS OF THE PROPOSED PROJECT The project aims to clarify the
effect of LMWH on coagulation in pregnant women just before birth, at a period of maximal
physiological hypercoagulable state and with high risk of thromboembolism, the most common
cause of maternal mortality in developed countries. Although LMWH are now routinely
administered as prevention of thromboembolism in all women undergoing Caesarean operation,
their effect on coagulation in pregnant women was not yet studied. Research of
haemocoagulation in pregnant women worldwide is rather difficult, so the results of such a
project are highly awaited and are then a great opportunity to present Czech research on
European and World forums.
The main expected benefit of this project will be the evaluation of the adequacy of current
LMWH thromboprophylaxis in pregnant women (which is recently only derived from surgical
patients). The next important study outcome will be the evaluation of possible influence of
the LMWH thromboprophylaxis on risk of spinal hematoma in connection to neuraxial
anaesthesiology techniques in pregnant women. In both situations the targeted outcome is to
change present recommendations to increase the safety of pregnant women undergoing Caesarean
operation. Just in Czechia this issue affects about 30 000 women/year.
