Clinical trial NCT02579941: Evaluation of the Minimum Concentration of Tranexamic Acid Required to Inhibit Fibrinolysis in a Population of Pregnant Women at Term.
Official title: Evaluation of the Minimum Concentration of Tranexamic Acid Required to Inhibit Fibrinolysis in a Population of Pregnant Women at Term.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hyperfibrinolysis
Keywords: Hyperfibrinolysis
Pregnant women at term
Tranexamic acid
Lead sponsor: Brugmann University Hospital
Sponsor class: OTHER
First posted: 2015-10-20
Enrollment: 40
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: Pregnancy induces a physiological change of hemostasis to a prothrombotic state : protein S decrease and increase of virtually all the clotting factors, in particular fibrinogen, von Willebrand factor and factor VIII. However, a state of hyperfibrinolysis may occur in the immediate postpartum period (especially after placental delivery), thereby promoting postpartum hemorrhage.

This state of hyperfibrinolysis is associated with the use of transfusions of blood products and the realization of hysterectomy.It is currently the most common etiology of maternal mortality in childbirth.There is an imperative to develop an efficient and reliable protocol for the management of this postpartum complication.

Tranexamic acid is an anti-fibrinolytic agent (like lysine) which acts by preventing the conversion of plasminogen to plasmin, by blocking the binding of plasminogen to the heavy chain of fibrin.The optimal dose of tranexamic acid enabling to inhibit fibrinolysis without increasing the complications rate remains to be defined. It is in this context that the investigators aim to evaluate, in an in-vitro model, the minimum dose of tranexamic acid required to inhibit fibrinolysis after activation of the latter by t-PA. The degree of fibrinolysis will be evaluated by thromboelastometry.

Detailed description: Pregnancy induces a physiological change of hemostasis to a prothrombotic state : protein S decrease and increase of virtually all the clotting factors, in particular fibrinogen, von Willebrand factor and factor VIII. However, a state of hyperfibrinolysis may occur in the immediate postpartum period (especially after placental delivery), thereby promoting postpartum hemorrhage.

This state of hyperfibrinolysis is associated with the use of transfusions of blood products and the realization of hysterectomy.It is currently the most common etiology of maternal mortality in childbirth. Although its incidence is low in western countries, it remains very high in the world.There is an imperative to develop an efficient and reliable protocol for the management of this postpartum complication.

Tranexamic acid is an anti-fibrinolytic agent (like lysine) which acts by preventing the conversion of plasminogen to plasmin, by blocking the binding of plasminogen to the heavy chain of fibrin.The use of this agent has spread in recent years in many types of surgery (cardiac, orthopedic, etc.), and in patient polytrauma. However, the number of studies evaluating its efficacy in the management (treatment and / or prevention) of postpartum hemorrhage is limited. In addition, the doses used are extrapolated from studies of a different population (multiple trauma, cardiac surgery, etc).

The tranexamic acid proposed scheme is currently used is not suitable for the population of pregnant women at term. It was established arbitrarily on the basis of the adult population without considering the physiological and metabolic characteristics of the term pregnancy. The optimal dose of tranexamic acid enabling inhibition of fibrinolysis, without increasing the complications rate, remains thus to be defined.

It is in this context that the investigators aim to evaluate, in an in-vitro model, the minimum dose of tranexamic acid required to inhibit fibrinolysis after activation of the latter by t-PA. The degree of fibrinolysis will be evaluated by thromboelastometry.

Eligibility criteria: Inclusion Criteria:

Pregnant women group:

* pregnant women at term (\>37 weeks of gestation)
* patients admitted for delivery or elective cesarian section
* written informed consent

Healthy volunteers group:

- women aged from 18 to 40

Exclusion Criteria:

* Dying patients (ASA 5)
* Jehovah's witnesses
* Patients with pre-eclampsia, HELLP syndrome, placenta previa or placental abruption.
* Multiple pregnancy
* Presence of preoperative coagulation disorders defined as: platelets \<150,000 / mm3; PTT \<70%; aPTT\> 33 sec; fibrinogen \<350 mg / dL.
* Treatment with anticoagulant or antiplatelet agent.

Primary outcomes:
measure: Coagulation (EXTEM)
timeFrame: within 24h of blood collection
measure: Coagulation (NATEM)
timeFrame: within 24h of blood collection
Secondary outcomes:
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: CHU Brugmann
Study officials:
affiliation: CHU Brugmann
name: Philippe Van der Linden, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Brugmann
name: Arnaud Lechien, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cerneca F, Ricci G, Simeone R, Malisano M, Alberico S, Guaschino S. Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis. Eur J Obstet Gynecol Reprod Biol. 1997 May;73(1):31-6. doi: 10.1016/s0301-2115(97)02734-6.
citation: Bonnar J, McNicol GP, Douglas AS. Coagulation and fibrinolytic mechanisms during and after normal childbirth. Br Med J. 1970 Apr 25;2(5703):200-3. doi: 10.1136/bmj.2.5703.200.
citation: Brenner B. Haemostatic changes in pregnancy. Thromb Res. 2004;114(5-6):409-14. doi: 10.1016/j.thromres.2004.08.004.
citation: Faraoni D, Carlier C, Samama CM, Levy JH, Ducloy-Bouthors AS. [Efficacy and safety of tranexamic acid administration for the prevention and/or the treatment of post-partum haemorrhage: a systematic review with meta-analysis]. Ann Fr Anesth Reanim. 2014 Nov;33(11):563-71. doi: 10.1016/j.annfar.2014.07.748. Epub 2014 Oct 18. French.
citation: Sentilhes L, Lasocki S, Ducloy-Bouthors AS, Deruelle P, Dreyfus M, Perrotin F, Goffinet F, Deneux-Tharaux C. Tranexamic acid for the prevention and treatment of postpartum haemorrhage. Br J Anaesth. 2015 Apr;114(4):576-87. doi: 10.1093/bja/aeu448. Epub 2015 Jan 8.
citation: Ronsmans C, Graham WJ; Lancet Maternal Survival Series steering group. Maternal mortality: who, when, where, and why. Lancet. 2006 Sep 30;368(9542):1189-200. doi: 10.1016/S0140-6736(06)69380-X.
citation: Ortmann E, Besser MW, Klein AA. Antifibrinolytic agents in current anaesthetic practice. Br J Anaesth. 2013 Oct;111(4):549-63. doi: 10.1093/bja/aet154. Epub 2013 May 9.
citation: Collis RE, Collins PW. Haemostatic management of obstetric haemorrhage. Anaesthesia. 2015 Jan;70 Suppl 1:78-86, e27-8. doi: 10.1111/anae.12913.