Effectiveness and safety of antifibrinolytic agents in the management of pulmonary haemorrhage: A systematic review with narrative synthesis

Table 1 Study-level risk-of-bias assessment with domain-level justification

Study	Tool	Overall judgement	Justification
Wand et al[15]	RoB 2	Low risk	Double-blind, placebo-controlled, adequate randomisation and allocation concealment reported; outcome assessment blinded; low attrition; pre-specified outcomes reported
Gopinath et al[4]	RoB 2	Some concerns	Open-label design means lack of blinding of participants/clinicians could influence co-interventions and subjective outcomes (e.g., decision to embolise); randomisation and outcome data otherwise adequate
Bellam et al[22]	RoB 2	Some concerns	Single-blind pilot design with small sample size; underpowered for the pre-specified intervention-rate outcome, raising risk of bias from imprecision and possible selective emphasis on significant secondary endpoints
Al-Samkari et al[16]	NOS	Moderate risk	Before-after pathway design without concurrent control; patients act as their own historical comparator, so secular trends and regression to the mean cannot be excluded; outcome ascertainment was consistent within the pathway
Kinoshita et al[17]	NOS	Moderate risk	Large propensity-matched administrative cohort with robust ascertainment of mortality and length of stay; however, administrative coding cannot capture bleeding severity, indication for treatment, or unmeasured confounders, so residual confounding by indication remains likely
Bethuel et al[5]	NOS	Serious/critical risk	Retrospective multicentre cohort with strong likely confounding by indication (nebulised tranexamic acid preferentially used in more severely bleeding or deteriorating patients); treatment selection not randomised or adjusted for all relevant severity markers; mortality finding should not be read as a causal estimate
Alkazemi et al[21]	NOS	Moderate/serious risk	Retrospective matched cohort with a small treated group (n = 14), limiting power to detect true differences; matching reduces but does not eliminate confounding by indication
Alabdrabalnabi et al[20]	NOS	Serious/critical risk	Uncontrolled case series of three patients with no comparator; high risk of selective reporting and very limited generalisability
O'Neil et al[18]	NOS	Serious risk	Single-centre retrospective observational study without a comparator group; small sample (n = 19); outcome ascertainment based on clinical record review with no blinding
Singleton et al[19]	NOS	Serious risk	Retrospective ECMO-specific cohort without a comparator group; highly selected, anticoagulated population with multiple competing risks for bleeding outcomes

NOS: Newcastle-Ottawa Scale; RoB 2: Cochrane Risk of Bias tool, version 2; ECMO: Extracorporeal membrane oxygenation.

Table 2 Simplified GRADE-informed certainty of evidence for main outcomes

Outcome	Population/setting	Certainty	Main reasons for rating
Bleeding cessation	Stable non-massive adult haemoptysis, nebulised TXA	Low	Two consistent randomised trials; downgraded for imprecision (small samples)
Mortality	ICU/mixed-acuity adult haemoptysis	Very low	Directly conflicting observational signals; serious risk of bias from confounding by indication; downgraded for inconsistency and risk of bias
Recurrence	Stable non-massive adult and CF haemoptysis	Low	Sparse data from one trial and one uncontrolled pathway study; downgraded for imprecision and indirectness
Need for invasive procedures	Stable non-massive adult haemoptysis, nebulised TXA	Low	Consistent direction across two randomised trials and observational data; downgraded for imprecision
Length of stay	Stable non-massive adult haemoptysis, nebulised TXA	Low	Consistent direction across trial and observational data; downgraded for imprecision and indirectness across settings
Adverse events (thromboembolism, bronchospasm)	All settings	Very low	Most studies not designed or powered to detect these events; inconsistent or absent reporting; serious risk of bias and imprecision
Bleeding cessation, safety, and feasibility	ICU, paediatric, and ECMO populations	Very low	Small, retrospective, uncontrolled studies with serious risk of bias and indirectness; downgraded on all major domains

Certainty ratings are based on a simplified application of GRADE domains (risk of bias, inconsistency, indirectness, imprecision, publication bias) rather than a full formal GRADE assessment with separate domain scoring. CF: Cystic fibrosis; ECMO: Extracorporeal membrane oxygenation; ICU: Intensive care unit; TXA: Tranexamic acid.

Table 3 Characteristics of included studies evaluating antifibrinolytic therapy for haemoptysis and pulmonary haemorrhage

Ref.	Study design	Population and setting	Indication/scenario	Agent	Route	Dose/regimen	Comparator	Outcomes assessed	Key results	Safety and limitations
Al-Samkari et al[16], 2019, United States	Before-after pathway study	Adults with cystic fibrosis; inpatient and outpatient care (n = 21; 72 episodes)	Haemoptysis in cystic fibrosis	Tranexamic acid or epsilon-aminocaproic acid	Systemic (oral/IV)	Pathway-defined; oral or IV according to episode	Pre-enrolment period in the same patients	Bleeding cessation time; haemoptysis-related admissions; adverse events	Median time to bleeding cessation was 2 days; annualised admissions decreased by 50% (2.44 to 1.23 per patient-year; P = 0.0024)	One catheter-associated upper-extremity DVT; otherwise well tolerated. Cystic fibrosis-specific, uncontrolled, small sample
Alabdrabalnabi et al[20], 2020, Saudi Arabia	Case series	Critically ill adults with significant haemoptysis in ICU (n = 3)	Recurrent or persistent haemoptysis	Tranexamic acid	Nebulised	500 mg three times daily	None	Symptom improvement; transfusion requirement	All patients improved, with reduced transfusion need and discharge after symptom resolution	Well tolerated. Very small heterogeneous case series
Alkazemi et al[21], 2023, United States	Retrospective matched cohort	Adult inpatients with haemoptysis, 2018-2021 (n = 14 TXA; 58 controls)	Moderate-to-massive haemoptysis	Tranexamic acid	Nebulised	Per institutional practice	Conventional management without TXA	Need for invasive intervention; resolution; recurrence; LOS	No significant difference in invasive intervention (35.7% vs 56.9%; P = 0.344); similar resolution, recurrence, and LOS	No specific adverse events reported. Small TXA cohort; retrospective; limited power
Bellam et al[22], 2016, India	Single-blind RCT	Adults with sub-massive haemoptysis (n = 66)	Sub-massive haemoptysis	Tranexamic acid	Intravenous	1 g loading dose, then 1 g over 8 hours infusion	IV normal saline placebo	Frequency; quantity; VAS score; intervention; transfusion; LOS	VAS improved (P = 0.001); fewer interventions (16% vs 38%; P = 0.053); lower volume/frequency; shorter LOS, not statistically significant	No adverse events. Pilot size; limited power
Bethuel et al[5], 2025, United States	Retrospective multicentre analysis	Adults hospitalised with haemoptysis across three tertiary hospitals (n = 488; 96 received TXA)	All-cause haemoptysis in critically and non-critically ill patients	Tranexamic acid	Nebulised	Per clinician decision	Supportive care only	ICU/hospital LOS; ventilation; bronchoscopy; mortality	Higher crude mortality; propensity-adjusted OR for death with TXA 2.51 (95%CI: 1.56-4.02)	Possible indication bias and safety signal. Retrospective design; confounding by severity
Gopinath et al[4], 2023, India	Open-label RCT	Adults with active non-massive haemoptysis in the ED (n = 110)	Acute non-massive haemoptysis	Tranexamic acid	Nebulised vs IV	500 mg three times daily	Alternative route: Nebulised vs IV	Cessation at 30 minutes; bleeding amount; BAE; discharge; adverse events	30-minute cessation higher with nebulised TXA (40 vs 28; P = 0.0019); less BAE (13 vs 21; P = 0.024); higher discharge (68% vs 39%; P = 0.005)	Two asymptomatic bronchoconstriction episodes, resolved. Single-centre; non-massive cases only
Kinoshita et al[17], 2019, Japan	Nationwide retrospective propensity-matched cohort	Emergency admissions for haemoptysis, 2010-2017 (n = 28539; 9933 matched pairs)	Haemoptysis requiring emergency admission	Tranexamic acid	Intravenous	On admission day	No TXA	In-hospital mortality; LOS; cost	Mortality 9.0% vs 11.5% (risk difference -2.5%; 95%CI: -3.5 to -1.6); shorter LOS (-2.4 days); lower costs	Adverse events not reported. Administrative database; residual unmeasured confounding
O'Neil et al[18], 2020, United States	Retrospective observational study	Paediatric ICU patients aged 0-18 years with pulmonary haemorrhage (n = 19)	Pulmonary haemorrhage	Tranexamic acid	Inhaled or endotracheal	Varied dosing	None	Cessation of bleeding; adverse events	Bleeding cessation in 18/19 patients (95%)	No major adverse events observed. Small, single-centre study; no comparator
Singleton et al[19], 2023, United States	Retrospective cohort	Paediatric ECMO patients with pulmonary haemorrhage (n = 53)	Pulmonary haemorrhage during ECMO	Tranexamic acid	Inhaled	Per institutional protocol	None	Change in bleeding scale; cessation within 48 hours; adverse events	Bleeding cessation in 48/53 patients (91%) within 48 hours; no adverse events reported	No adverse effects reported. Retrospective; ECMO-specific population
Wand et al[15], 2018, Israel	Double-blind RCT	Adults admitted with non-massive haemoptysis (n = 47)	Non-massive haemoptysis	Tranexamic acid	Nebulised	500 mg three times daily	Placebo (normal saline)	Resolution by day 5; LOS; invasive procedures; recurrence	Resolution 96% vs 50% (P < 0.0005); LOS 5.7 days vs 7.8 days (P = 0.046); invasive procedures 0% vs 18% (P = 0.041); lower 1-year recurrence (P = 0.009)	No side effects. Small sample; excluded massive bleeds

Studies are presented in alphabetical order by first author; the Population and setting column explicitly states whether each study enrolled adult or paediatric patients, and adult and paediatric studies are interpreted separately throughout the Results and Discussion. Baseline demographic detail and severity criteria were reported with varying completeness across the primary studies; where a field was not reported in the source publication, this is reflected by its absence from the corresponding cell rather than by an assumed value. BAE: Bronchial artery embolisation; DVT: Deep vein thrombosis; ECMO: Extracorporeal membrane oxygenation; ED: Emergency department; ICU: Intensive care unit; IV: Intravenous; LOS: Length of stay; OR: Odds ratio; RCT: Randomised controlled trial; TXA: Tranexamic acid; VAS: Visual analogue scale.