Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): a single-centre, randomised, double-blind, placebo-controlled trial

Shakur-Still, Haleema; Roberts, Ian; Fawole, Bukola; Kuti, Modupe; Olayemi, Oladapo; Bello, Folasade Adenike; Huque, Sumaya; Ogunbode, Olayinka Oladunjoye; Kotila, Taiwo R.; Aimakhu, Chris; Okunade, Olujide; Olutogun, Tolulase; Adetayo, Cecilia Olusade; Dallaku, Kastriot; Mansmann, Ulrich; Hunt, Beverley J.; Pepple, Tracey; Balogun, Eni

doi:10.12688/wellcomeopenres.14722.1

Cited by 30 publications

(38 citation statements)

References 14 publications

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“…Several narratives highlighted the contribution of anaemia to maternal death. Although we did not measure haemoglobin on all women, a sub-study conducted at University College Hospital, Ibadan (Nigeria) [ 31 – 33 ], showed that most (88%) women were anaemic (haemoglobin < 110 g/L) and 40% were severely anaemic (haemoglobin < 70 g/L) at the time of PPH onset [ 31 ]. Women with such low haemoglobin levels have little physiological reserve and even mild to moderate bleeding can have serious consequences.…”

Section: Discussionmentioning

confidence: 99%

The WOMAN trial: clinical and contextual factors surrounding the deaths of 483 women following post-partum haemorrhage in developing countries

Picetti

Miller

Shakur-Still

et al. 2020

BMC Pregnancy Childbirth

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Background: Post-partum haemorrhage (PPH) is a leading cause of maternal death worldwide. The WOMAN trial assessed the effects of tranexamic acid (TXA) on death and surgical morbidity in women with PPH. The trial recorded 483 maternal deaths. We report the circumstances of the women who died. Methods: The WOMAN trial recruited 20,060 women with a clinical diagnosis of PPH after a vaginal birth or caesarean section. We randomly allocated women to receive TXA or placebo. When a woman died, we asked participating clinicians to report the cause of death and to provide a short narrative of the events surrounding the death. We collated and edited for clarity the narrative data. Results: Case fatality rates were 3.0% in Africa and 1.7% in Asia. Nearly three quarters of deaths were within 3 h of delivery and 91% of these deaths were from bleeding. Women who delivered outside a participating hospital (12%) were three times more likely to die (OR = 3.12, 95%CI 2.55-3.81) than those who delivered in hospital. Blood was often unavailable due to shortages or because relatives could not afford to buy it. Clinicians highlighted late presentation, maternal anaemia and poor infrastructure as key contributory factors. Conclusions: Although TXA use reduces bleeding deaths by almost one third, mortality rates similar to those in high income countries will not be achieved without tackling late presentation, maternal anaemia, availability of blood for transfusion and poor infrastructure. Background Post-partum haemorrhage (PPH), the leading cause of maternal death worldwide, accounts for about 19.7% of maternal deaths [1, 2]. There are considerable variations across regions with for instance PPH accounting for about 8.0% of maternal deaths in developed countries compared to 19.7% in the developing countries [1]. Maternal outcomes for obstetric haemorrhages, e.g. PPH, are also more severe in developing countries [3]. This disparity between developed and developing areas may be explained by the limited resources in the latter. Some of the deficiencies in the health systems include insufficient availability of properly formed birth attendants both in hospitals and to assist home births, insufficient emergency transport to a facility with better expertise,

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Section: Discussionmentioning

confidence: 99%

The WOMAN trial: clinical and contextual factors surrounding the deaths of 483 women following post-partum haemorrhage in developing countries

Picetti

Miller

Shakur-Still

et al. 2020

BMC Pregnancy Childbirth

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“…13 TXA also reduces heavy menstrual bleeding, 14 perioperative blood loss following elective vaginal or cesarean delivery, [15][16][17] and death from postpartum hemorrhage. 18,19 However, TXA does not show survival benefit in patients with acute gastrointestinal bleeding 20 or in some studies of trauma. 21 Moreover, many of these situations are also associated with increased risk of thrombotic complications, and TXA has been associated with increased risk of venous thromboembolism.…”

Section: Introductionmentioning

confidence: 99%

Application of a plasmin generation assay to define pharmacodynamic effects of tranexamic acid in women undergoing cesarean delivery

Miszta

Ahmadzia

Luban

et al. 2021

Journal of Thrombosis and Haemostasis

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Tranexamic acid (TXA) is an antifibrinolytic drug used to reduce bleeding. Assaying plasmin generation (PG) in plasma detects clinically relevant TXA levels in vitro and ex vivo. 3.1‐16.2 µg/mL TXA half‐maximally inhibits PG in plasma from women undergoing cesarean delivery. PG velocity shows the strongest dose‐relationship at low TXA concentrations (≤10 µg/mL). Abstract BackgroundTranexamic acid (TXA) is used to reduce bleeding. TXA inhibits plasmin(ogen) binding to fibrin and reduces fibrinolysis. TXA antifibrinolytic activity is typically measured by clot lysis assays; however, effects on plasmin generation (PG) are unclear due to a lack of tools to measure PG in plasma. AimsDevelop an assay to measure PG kinetics in human plasma. Determine effects of TXA on PG and compare with fibrinolysis measured by rotational thromboelastometry (ROTEM). MethodsWe characterized effects of plasminogen, tissue plasminogen activator, fibrinogen, and α2‐antiplasmin on PG in vitro. We also studied effects of TXA on PG in plasma from 30 pregnant women administered intravenous TXA (5, 10, or 15 mg/kg) during cesarean delivery. PG was measured by calibrated fluorescence. PG parameters were compared with TXA measured by mass spectrometry and ROTEM of whole blood. ResultsThe PG assay is specific for plasmin and sensitive to tissue plasminogen activator, fibrin(ogen), and α2‐antiplasmin. Addition of TXA to plasma in vitro dose dependently prolonged the clot lysis time and delayed and reduced PG. For all doses of TXA administered intravenously, the PG assay detected delayed time‐to‐peak (≤3 hours) and reduced the velocity, peak, and endogenous plasmin potential (≤24 hours) in plasma samples obtained after infusion. The PG time‐to‐peak, velocity, and peak correlated significantly with TXA concentration and showed less variability than the ROTEM lysis index at 30 minutes or maximum lysis. ConclusionsThe PG assay detects pharmacologically relevant concentrations of TXA administered in vitro and in vivo, and demonstrates TXA‐mediated inhibition of PG in women undergoing cesarean delivery.

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“…As it’s mechanism of action is to prevent plasmin formation and thus slow down fibrinolysis, it naturally decreases D-Dimer levels. This has been demonstrated in both laboratory and clinical settings [ 26 , 27 ] with time-scales as short as 30 minutes after administration [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Associations of longitudinal D-Dimer and Factor II on early trauma survival risk

et al. 2021

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Background Trauma-induced coagulopathy (TIC) is a disorder that occurs in one-third of severely injured trauma patients, manifesting as increased bleeding and a 4X risk of mortality. Understanding the mechanisms driving TIC, clinical risk factors are essential to mitigating this coagulopathic bleeding and is therefore essential for saving lives. In this retrospective, single hospital study of 891 trauma patients, we investigate and quantify how two prominently described phenotypes of TIC, consumptive coagulopathy and hyperfibrinolysis, affect survival odds in the first 25 h, when deaths from TIC are most prevalent. Methods We employ a joint survival model to estimate the longitudinal trajectories of the protein Factor II (% activity) and the log of the protein fragment D-Dimer ($$\upmu$$ μ g/ml), representative biomarkers of consumptive coagulopathy and hyperfibrinolysis respectively, and tie them together with patient outcomes. Joint models have recently gained popularity in medical studies due to the necessity to simultaneously track continuously measured biomarkers as a disease evolves, as well as to associate them with patient outcomes. In this work, we estimate and analyze our joint model using Bayesian methods to obtain uncertainties and distributions over associations and trajectories. Results We find that a unit increase in log D-Dimer increases the risk of mortality by 2.22 [1.57, 3.28] fold while a unit increase in Factor II only marginally decreases the risk of mortality by 0.94 [0.91,0.96] fold. This suggests that, while managing consumptive coagulopathy and hyperfibrinolysis both seem to affect survival odds, the effect of hyperfibrinolysis is much greater and more sensitive. Furthermore, we find that the longitudinal trajectories, controlling for many fixed covariates, trend differently for different patients. Thus, a more personalized approach is necessary when considering treatment and risk prediction under these phenotypes. Conclusion This study reinforces the finding that hyperfibrinolysis is linked with poor patient outcomes regardless of factor consumption levels. Furthermore, it quantifies the degree to which measured D-Dimer levels correlate with increased risk. The single hospital, retrospective nature can be understood to specify the results to this particular hospital’s patients and protocol in treating trauma patients. Expanding to a multi-hospital setting would result in better estimates about the underlying nature of consumptive coagulopathy and hyperfibrinolysis with survival, regardless of protocol. Individual trajectories obtained with these estimates can be used to provide personalized dynamic risk prediction when making decisions regarding management of blood factors.

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Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): a single-centre, randomised, double-blind, placebo-controlled trial

Cited by 30 publications

References 14 publications

The WOMAN trial: clinical and contextual factors surrounding the deaths of 483 women following post-partum haemorrhage in developing countries

The WOMAN trial: clinical and contextual factors surrounding the deaths of 483 women following post-partum haemorrhage in developing countries

Application of a plasmin generation assay to define pharmacodynamic effects of tranexamic acid in women undergoing cesarean delivery

Associations of longitudinal D-Dimer and Factor II on early trauma survival risk

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