SIMTI Servii Srl - Blood Transfusion · postpartum haemorrhage prevention? A systemic review and...
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321 Blood Transfus 2018; 16: 321-3 DOI 10.2450/2018.0067-18 © SIMTI Servizi Srl Editorial Tranexamic acid to prevent post-partum haemorrhage Riana Van Der Linde 1 , Emmanuel J. Favaloro 1,2 1 Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead Hospital, Westmead, NSW; 2 Sydney Centres for Thrombosis and Haemostasis, Westmead, NSW, Australia "Only Women Bleed" - Alice Cooper, 1975 Whilst the title of the song made famous by Alice Cooper in 1975 does not exactly hold true, it is well recognised in the field of haematology that women represent by far the predominant gender in bleeding investigations, and also within bleeding registries. For example, in our own local Westmead database registry, now totalling over 6,000 entries, the ratio of female:male representation is almost 2:1. Similarly, in the Australian Bleeding Disorders Registry (ABDR) 1 , the female:male ratio in the von Willebrand disease category is 1.6:1.0. It is not so much that bleeding disorders are more prevalent in females than males. Indeed, for haemophilia A and haemophilia B, at least, the reverse is true, since these reflect X-linked disorders. Irrespectively, more women than men will require medical attention because of bleeding challenges 2 . The main reason women are "over-represented" within "bleeding" categories is that they carry a higher risk of haemostatic challenge. The main haemorrhagic risks unique to women are menstruation and child-birth. The World Health Organization (WHO) describes haemorrhage as one of the three biggest causes of obstetric mortality globally, representing 27.1% of all obstetric-related deaths from 2003 to 2009 2 . The classification of massive haemorrhage after delivery varies between different countries, but is most commonly classified as severe post-partum haemorrhage (PPH) if bleeding of more than 1,000 mL after a caesarean section or more than 500 mL after a normal vaginal delivery occurs 3 . The most significant cause of PPH is uterine atony, and this is often associated with coagulation abnormalities 4 . Treatment of PPH relies primarily on uterotonics, but early use of tranexamic acid (TXA) has become part of several recommended algorithms 5 . Tranexamic acid is an antifibrinolytic agent that reduces fibrinolysis by inhibition of plasminogen and plasmin by acting as a lysine analogue and binding to the lysine receptors on these proteins 6,7 . This increased use of TXA is based on the findings of several studies, including the CRASH (Clinical Randomization of Antifibrinolytic in Significant Haemorrhage) 2 trial in trauma, and the recently published results from the WOMAN (women with post-partum haemorrhage) study 5,8,9 . The CRASH 2 trial showed a significant reduction in all cause- mortality and bleeding in trauma patients receiving early TXA if administered over less than three hours 5,9 . The WOMAN study was conducted in women with PPH with the CRASH 2 data findings in mind 8 . The WOMAN trial showed a significant reduction in haemorrhage and need for surgery to treat severe bleeding. There was no evidence of increased thrombotic events, and early administration of TXA was associated with better outcomes 8 . The largest proportion of the study population was derived from developing countries, and so transfer to developed countries may not be ideal 5 . Several other smaller studies reviewing the use of TXA in environments with better resources have been carried out to evaluate the efficacy and safety of this drug in obstetric patients with PPH. Significantly, then, Franchini et al . 10 , within the framework of scientific activities carried out by the Italian National Blood Centre 11-17 with the aim of promoting the nationwide implementation of Patient Blood Management, have performed an updated meta-analysis of the use of TXA in PPH after caesarean section, using the incidence of PPH as a primary outcome. The secondary outcomes evaluated were: mean blood loss volume (mL), need for blood transfusion, and overall severe side effects related to TXA use. The analysis found that the use of TXA significantly reduced the occurrence of severe PPH after caesarean section. This is in keeping with findings of the WOMAN trials and an earlier meta- analysis by Chunbo et al. in 2017 18 . With regards to the secondary findings, Franchini et al. 10 found that the need for transfusion was also reduced when compared to control groups. The amount of blood loss did appear to be reduced by the use of TXA, compared to control groups, but the included studies showed marked heterogeneity. Similar findings were noted in the earlier meta-analysis by Chunbo et al. 18 Bias analysis also showed that patient inclusion in studies reported in the meta-analyses was variable. For example, some studies excluded anaemic women, © SIMTI Servizi Srl All rights reserved - For personal use only No other use without premission
Transcript of SIMTI Servii Srl - Blood Transfusion · postpartum haemorrhage prevention? A systemic review and...
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Blood Transfus 2018; 16: 321-3 DOI 10.2450/2018.0067-18© SIMTI Servizi Srl
Editorial
Tranexamic acid to prevent post-partum haemorrhage
Riana Van Der Linde1, Emmanuel J. Favaloro1,2
1Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead Hospital, Westmead, NSW; 2Sydney Centres for Thrombosis and Haemostasis, Westmead, NSW, Australia
"Only Women Bleed" - Alice Cooper, 1975
Whilst the title of the song made famous by Alice Cooper in 1975 does not exactly hold true, it is well recognised in the field of haematology that women represent by far the predominant gender in bleeding investigations, and also within bleeding registries. For example, in our own local Westmead database registry, now totalling over 6,000 entries, the ratio of female:male representation is almost 2:1. Similarly, in the Australian Bleeding Disorders Registry (ABDR)1, the female:male ratio in the von Willebrand disease category is 1.6:1.0. It is not so much that bleeding disorders are more prevalent in females than males. Indeed, for haemophilia A and haemophilia B, at least, the reverse is true, since these reflect X-linked disorders. Irrespectively, more women than men will require medical attention because of bleeding challenges2. The main reason women are "over-represented" within "bleeding" categories is that they carry a higher risk of haemostatic challenge. The main haemorrhagic risks unique to women are menstruation and child-birth.
The World Health Organization (WHO) describes haemorrhage as one of the three biggest causes of obstetric mortality globally, representing 27.1% of all obstetric-related deaths from 2003 to 20092. The classification of massive haemorrhage after delivery varies between different countries, but is most commonly classified as severe post-partum haemorrhage (PPH) if bleeding of more than 1,000 mL after a caesarean section or more than 500 mL after a normal vaginal delivery occurs3.
The most significant cause of PPH is uterine atony, and this is often associated with coagulation abnormalities4. Treatment of PPH relies primarily on uterotonics, but early use of tranexamic acid (TXA) has become part of several recommended algorithms5. Tranexamic acid is an antifibrinolytic agent that reduces fibrinolysis by inhibition of plasminogen and plasmin by acting as a lysine analogue and binding to the lysine receptors on these proteins6,7. This increased use of TXA is based on the findings of several studies, including the CRASH (Clinical Randomization of Antifibrinolytic in Significant
Haemorrhage) 2 trial in trauma, and the recently published results from the WOMAN (women with post-partum haemorrhage) study5,8,9. The CRASH 2 trial showed a significant reduction in all cause-mortality and bleeding in trauma patients receiving early TXA if administered over less than three hours5,9. The WOMAN study was conducted in women with PPH with the CRASH 2 data findings in mind8. The WOMAN trial showed a significant reduction in haemorrhage and need for surgery to treat severe bleeding. There was no evidence of increased thrombotic events, and early administration of TXA was associated with better outcomes8. The largest proportion of the study population was derived from developing countries, and so transfer to developed countries may not be ideal5. Several other smaller studies reviewing the use of TXA in environments with better resources have been carried out to evaluate the efficacy and safety of this drug in obstetric patients with PPH.
Significantly, then, Franchini et al.10, within the framework of scientific activities carried out by the Italian National Blood Centre11-17 with the aim of promoting the nationwide implementation of Patient Blood Management, have performed an updated meta-analysis of the use of TXA in PPH after caesarean section, using the incidence of PPH as a primary outcome. The secondary outcomes evaluated were: mean blood loss volume (mL), need for blood transfusion, and overall severe side effects related to TXA use. The analysis found that the use of TXA significantly reduced the occurrence of severe PPH after caesarean section. This is in keeping with findings of the WOMAN trials and an earlier meta-analysis by Chunbo et al. in 201718. With regards to the secondary findings, Franchini et al.10 found that the need for transfusion was also reduced when compared to control groups. The amount of blood loss did appear to be reduced by the use of TXA, compared to control groups, but the included studies showed marked heterogeneity. Similar findings were noted in the earlier meta-analysis by Chunbo et al.18 Bias analysis also showed that patient inclusion in studies reported in the meta-analyses was variable. For example, some studies excluded anaemic women,
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Van Der Linde1 R, Favaloro EJ
Blood Transfus 2018; 16: 321-3 DOI 10.2450/2018.0067-18
whilst others consisted only of anaemic women. The timing of PPH measurement also differed significantly between studies. These features may confound meta-analyses results, making evaluation of the effect of TXA on these secondary outcomes difficult.
Potential side-effects when using TXA include an increased risk of thromboembolic events and neurological side-effects. Most studies, including the meta-analyses and the WOMAN trial, showed no significant increase in thromboembolic events in women receiving low-dose TXA treatment6,8-10,18. One article by Frimat et al. describes 18 patients who developed renal cortical necrosis due to either renal artery constriction or obstruction, possibly associated with TXA use19. However, it should be noted that the dose of TXA used in these patients was much higher than the recommended 1 g as an initial bolus followed by 1g after four hours, as supported by most other groups20.
Other case studies describe an increase in seizures associated with TXA use. The development of seizures is likely related to an increase in neuron excitability due to reduced inhibition of neurotransmission secondary to antagonisation of gamma-aminobutyric acid (GABA) by TXA. This is a dose-dependent side-effect, occurring at doses higher than the recommended 1 g. All these cases were described in non-pregnant patients; no cases in obstetric patients have been reported to our knowledge5,6,21.
The meta-analysis by Franchini et al.10 did not evidence an increase in serious side-effects, including thromboembolic events. This is in keeping with the findings from the WOMAN trial. The authors did, however, mention one study that reported severe side-effects in both the control and study group. The meta-analysis by Chunbo et al.18 also did not show an increase in severe side-effects, but did mention minor side-effects including nausea, vomiting, headache, and dizziness.
In conclusion, the currently available information suggests that the use of TXA in a patient with PPH leads to reduced use of blood products, reduced need for surgical intervention, and possibly decreased blood loss. However, performing conclusive meta-analyses of available studies is challenging given the significant heterogeneity between studies, including the definition of PPH, measurement of the amount of blood loss and patient inclusion. Furthermore, evaluation of severe side-effects, including mortality, is also problematic due to the small size of many of the reported studies. Thus, larger studies in well-resourced environments are needed to better evaluate the safety of TXA in obstetric haemorrhage. Lastly, it
should also be noted that studies on the use of TXA in vaginal delivery22 are largely lacking, and this therefore requires more extensive evaluation.
The Authors declare no conflicts of interest.
References1) Australian Bleeding Disorders Registry. Annual reports
available from: https://www.blood.gov.au/data-analysis-reporting. Accessed on 5/04/2018.
2) Hvas AM, Favaloro EJ. Gender related issues in thrombosis and hemostasis. Expert Rev Hematol 2017; 10: 941-9.
3) Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health 2014; 2: e323-33.
4) Sebghati M, Chandraharan E. An update on the risk factors for and management of obstetric haemorrhage. Womens Health (Lond) 2017; 13: 34-40.
5) Sullivan JT. The expanding role of tranexamic acid in the management of obstetric hemorrhage. J Thorac Dis 2017; 9: 2251-4.
6) Pacheco LD, Hankins GDV, Saad AF, et al. Tranexamic acid for the management of obstetric hemorrhage. Obstet Gynecol 2017; 130: 765-9.
7) Hawke L, Grabell J, Sim W, et al. Obstetric bleeding among women with inherited bleeding disorders: a retrospective study. Haemophilia 2016; 22: 906-11.
8) WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet 2017; 389: 2105-16.
9) Lakshmi SD, Abraham R. Role of prophylactic tranexamic acid in reducing blood loss during elective caesarean section: A Randomized Controlled Study. J Clin Diagn Res 2016; 10: QC17-21.
10) Franchini M, Mengoli C, Cruciani M, et al. Safety and efficacy of tranexamic acid for prevention of obstetric hemorrhage: an updated systematic review and meta-analysis. Blood Transfus 2018; 16: 329-37.
11) Franchini M, Muñoz M. Towards the implementation of patient blood management across Europe. Blood Transfus 2017; 15: 292-3.
12) Vaglio S, Gentili S, Marano G, et al. The Italian Regulatory Guidelines for the implementation of Patient Blood Management. Blood Transfus 2017; 15: 325-8.
13) Franchini M, Mengoli C, Cruciani M, et al. The use of viscoelastic haemostatic assays in non-cardiac surgical settings: a systematic review and meta-analysis. Blood Transfus 2018; 16: 235-43.
14) Franchini M, Mengoli C, Marietta M, et al. Safety of intravenous tranexamic acid in patients undergoing major orthopaedic surgery: a meta-analysis of randomised controlled trials. Blood Transfus 2018; 16: 36-43.
15) Mengoli C, Franchini M, Marano G, et al. The use of fibrinogen concentrate for the management of trauma-related bleeding: a systematic review and meta-analysis. Blood Transfus 2017; 15: 318-24.
16) Franchini M, Marano G, Mengoli C, et al. Red blood cell transfusion policy: a critical literature review. Blood Transfus 2017; 15: 307-17.
17) Guerra R, Velati C, Liumbruno GM, Grazzini G. Patient Blood Management in Italy. Blood Transfus 2016; 14: 1-2.
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Blood Transfus 2018; 16: 321-3 DOI 10.2450/2018.0067-18
Tranexamic acid to prevent post-partum haemorrhage
Correspondence: Emmanuel J. Favaloro Department of Haematology Institute of Clinical Pathology and Medical Research (ICPMR) Level 2, ICPMR, Westmead Hospital, Hawkesbury RdWestmead, NSW, 2145, Australia. e-mail: [email protected]
18) Vaglio S, Prisco D, Biancofiore G, et al. Recommendations for the implementation of a Patient Blood Management programme. Application to elective major orthopaedic surgery in adults. Blood Transfus 2016; 14: 23-65.
19) Chunbo L, Gong Y, Dong L, et al. Is prophylactic tranexamic acid administration effective and safe for postpartum haemorrhage prevention? A systemic review and meta-analysis. Medicine (Baltimore) 2017; 96: e5653.
20) Frimat M, Decambron M, Lebas C, et al. Renal cortical necrosis in postpartum hemorrhage: a case series. Am J Kidney Dis 2016; 68: 50-7.
21) Reddi Rani P, Begum J. Recent advances in the management of major postpartum haemorrhage - A Review. J Clin Diagn Res 2017; 11: QE01-5.
22) Bouet PE, Ruiz V, Legendre G, et al. High-dose tranexamic acid for treating postpartum haemorrhage after vaginal delivery. Br J Anaesth 2015; 114: 339-41.
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