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. 2026 Jul 13;10(5):106827. doi: 10.1016/j.rpth.2026.106827

Alpha-1 antitrypsin deficiency associated with increased risk of venous thromboembolism: a nationwide cohort study in Denmark

Sine Voss David 1,∗, Malin Fromme 2, Katharina Remih 2, Børge Grønne Nordestgaard 3,4,5, Pavel Strnad 6, Morten Dahl 1,4,5
PMCID: PMC13499170  PMID: 42633228

Abstract

Background

Mechanistic investigations suggest that alpha-1 antitrypsin may influence hemostatic processes; however, whether alpha-1 antitrypsin deficiency is associated with an elevated risk of venous thromboembolism is unclear.

Objectives

We tested whether alpha-1 antitrypsin deficiency is associated with venous thromboembolisms in 2 large independent cohorts.

Methods

In a nationwide nested cohort of 3046 individuals with alpha-1 antitrypsin deficiency and 29,742 controls without it matched for sex, age, and municipality, we recorded admissions and deaths due to pulmonary embolism and admissions due to deep vein thrombosis and venous thromboembolism during a median follow-up time of up to 61 years. Sixteen thousand seven hundred sixty-eight individuals being heterozygous for alpha-1 antitrypsin deficiency and 415,208 controls from the UK Biobank were used as a confirmatory cohort.

Results

Compared with controls, individuals with alpha-1 antitrypsin deficiency had increased risks of pulmonary embolism (adjusted hazard ratio, 3.28, 95% CI, 2.73-3.94), pulmonary embolism–specific mortality (2.83; 95% CI, 1.65-4.84), deep vein thrombosis (1.85; 95% CI, 1.53-2.25), and venous thromboembolism (2.43; 95% CI, 2.12-2.80). Individuals with vs without alpha-1 antitrypsin deficiency also had an increased use of the direct oral anticoagulants apixaban (1.83; 95% CI, 1.30-2.56) and rivaroxaban (1.49; 95% CI, 1.11-1.99). The association between the heterozygosity of alpha-1 antitrypsin deficiency and pulmonary embolism, deep vein thrombosis, and venous thromboembolism was confirmed in the UK Biobank. Moreover, hospitalization rates for these conditions were higher in individuals heterozygous for alpha-1 antitrypsin deficiency compared with those in controls.

Conclusion

Alpha-1 antitrypsin deficiency was associated with increased risks of pulmonary embolism, deep vein thrombosis, and venous thromboembolism in 2 independent populations.

Keywords: alpha 1-antitrypsin deficiency, cohort studies, epidemiology, serpins, venous thromboembolism

Essentials

  • •

    The risk of venous thromboembolism may be increased with deficient plasma alpha-1 antitrypsin levels.

  • •

    The association was assessed in both a nationwide cohort and a population-based cohort.

  • •

    Pulmonary embolism risk was 3.3-fold higher in individuals with alpha-1 antitrypsin deficiency.

  • •

    Venous thromboembolism risk was 2.4-fold higher in individuals with alpha-1 antitrypsin deficiency.

1. Introduction

Alpha-1 antitrypsin is a glycoprotein synthesized in hepatocytes and secreted into the circulation [1]. Its primary function is to inhibit neutrophil elastase, a proteolytic enzyme released by activated neutrophil leucocytes during inflammation [2], that breaks down elastic fibers in connective tissue and thereby aid the migration of immune cells from the circulation to the sites of inflammation [3]. Alpha-1 antitrypsin deficiency is a genetic disease caused by mutations in the SERPINA1 gene and is best known to be associated with early-onset chronic obstructive pulmonary disease (COPD) and liver cirrhosis, but recent research has suggested that it may affect other organ systems as well [[4], [5], [6], [7], [8]]. The Z-variant (rs28929474) is clinically most relevant and its heterozygous form (MZ genotype) is found in ∼1:30 Caucasians [9].

Beyond elastase inhibition, alpha-1 antitrypsin exhibits weak anticoagulant activity, targeting key proteases within the coagulation cascade, including FXa, FXIa, and thrombin, and it also binds fibrinogen and prothrombin. Consequently, deficient levels of alpha-1 antitrypsin could disturb the balance between coagulation and fibrinolysis, potentially predisposing individuals with alpha-1 antitrypsin deficiency to an increased risk of venous thromboembolism (VTE) [[10], [11], [12], [13], [14]].

VTE, comprising pulmonary embolism (PE) and deep vein thrombosis (DVT), are common causes of morbidity and mortality, with an annual incidence from 0.75 to 2.69 per 1000 individuals worldwide and with risk increasing with age [15]. VTE is thought to be a multicausal disease, with a number of known risk factors—some being strong, such as cancer and major surgery, and others being weak, such as obesity [16]. In most cases of PE and DVT, the recommended treatment is direct oral anticoagulants for a varied period of time depending on the primary cause of thrombosis [17].

Although evidence linking alpha-1 antitrypsin deficiency to VTE remains limited, a few case reports [18,19] and epidemiologic studies have pointed toward an association [[20], [21], [22]]. In this nationwide nested cohort study, we extend previous reports by investigating the association between alpha-1 antitrypsin deficiency and the risk of VTE using Danish national health registries, which allow long-term follow-up and individual-level linkage across multiple nationwide registries, enabling a robust evaluation of the rare exposure of alpha-1 antitrypsin deficiency in relation to VTE risk. These findings were further evaluated in individuals with the MZ genotype from the UK Biobank.

2. Methods

2.1. Nationwide cohort Denmark

Individuals with alpha-1 antitrypsin deficiency were identified by one of the following ways: (1) the ICD-10 code for the disease (E88.0, E88.0A, or E88.0B) obtained from the Danish Patient Registry (n = 1613) [23]; (2) genotype information obtained through the Copenhagen General Population Study, where 102,610 individuals were genotyped for both the Z (rs28929474) and S (rs17580) mutations of the SERPINA1 gene (n = 47) [5]; or (3) genotype or protein isotype defined by electrophoresis, obtained through the Danish Alpha-1 Registry (n = 1386) [5]. In total, 3046 individuals with alpha-1 antitrypsin deficiency were included.

Using the Danish health registries, each individual with alpha-1 antitrypsin deficiency was matched with up to 10 controls according to sex, age, and municipality. A total of 29,742 control subjects were included out of a population of 9,397,363. All individuals were included from birth and followed until outcome, emigration, death, or end of follow-up, which was December 31, 2021. The median follow-up time was 61 years.

2.2. Population-based cohort United Kingdom Biobank

The UK Biobank is a population-based cohort study, which was conducted in the United Kingdom, and recruited volunteers between 2006 and 2010. All participants underwent an initial examination and gave informed consent for genotyping and data linkage to medical reports. Diagnoses were identified using ongoing inpatient hospital records available since 1996 and coded according to the International Classification of Diseases, 10th Revision (ICD-10). These records are continuously collected, with inpatient data last updated on October 31, 2022, and mortality data on December 31, 2023. An MZ cohort of 16,768 subjects and a non–alpha-1 antitrypsin deficiency (MM) cohort of 415,208 individuals were studied. Genotyping for both the Z (rs28929474) and S (rs17580) mutations of SERPINA1 was performed in 487,234 participants. Individuals with heterozygous or homozygous S mutation (n = 43,925) and those with homozygous Z mutation (n = 141) were excluded because statistical power for meaningful analysis was insufficient for ZZ individuals. The diagnosis of alcoholic liver disease, chronic viral hepatitis (ICD-10: B18-B19), primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, hemochromatosis, and hepatocellular carcinoma resulted in the exclusion of 11,394 subjects. All data handling and analyses were performed under the guidelines and regulations approved by the UK Biobank under application number 148742.

2.3. Outcomes and covariates

For outcomes and covariates, only first occurrences were registered. Outcomes and covariates were defined the following way: PE (ICD-8: 450.99, 673.99; ICD-10: I26, O88.2), DVT (ICD-8: 451.00, 451.08, 451.09, 451.90, 451.92; ICD-10: I80.1-3), liver cirrhosis (ICD8: 571.91, 579.92, 571.99; ICD-10: K74), COPD (ICD-8: 491-492; ICD-10: J41-J44), cancer (ICD8: 14.0-9, 15.0-9, 16.0-3, 17.0-4, 18.0-9, 19.0-9, 20.0-7; ICD-10: C00-99), obesity (ICD-8: 277.99; ICD-10: E66.0-9), and VTE (composite outcome of PE and DVT) were defined as hospital admissions with the ICD code as the primary or secondary discharge diagnosis obtained from the Danish National Patient Registry or the UK Biobank, while PE-specific mortality was defined as the diagnosis (ICD-8: 450.99, 673.99; ICD-10: I26, O88.2) given as either a primary or secondary cause of death, obtained from the Danish National Register of Causes of Death in the Danish nationwide cohort only. Information on the use of the DOACs apixaban (ATC code: B01AF02), rivaroxaban (ATC code: B01AF01), endoxaban (ATC code: B01AF03), dabigatran (ATC code: B01AE07), and vitamin K-antagonists (warfarin [ATC code: B01AA03], phenprocoumon [ATC code: B01AA04]) was obtained from the Danish National Prescription Database in the Danish nationwide cohort only [24]. Individuals were defined as users if they withdrew 2 consecutive prescriptions within 2 calendar years.

2.4. Statistical analysis

All statistical analyses were performed using Stata version 18 (StataCorp). Student’s t-test and Pearson’s χ2-test were used for continuous and categorical comparisons. Cumulative incidence curves of PE hospitalization and death, DVT, and VTE were modelled with Kaplan-Meier curves. The log-rank test was used for comparing the cumulative incidence curves between individuals with vs without alpha-1 antitrypsin deficiency. Cox regression models adjusted for sex and age were used to assess the risk of PE, PE-specific mortality, DVT, and VTE in individuals with alpha-1 antitrypsin deficiency compared with that in controls without alpha-1 antitrypsin deficiency in the Danish nationwide cohort. Multivariable adjusted Cox regression models including sex, age, COPD diagnosis, cirrhosis diagnosis, and income were used to assess the risk of PE, DVT, and VTE in individuals with alpha-1 antitrypsin deficiency compared with that in controls without it in the Danish nationwide cohort. Competing risk regression was performed using the Fine & Gray subdistribution hazards model, with death by other causes than the outcome of interest being the competing event. Additionally, age- and sex-adjusted odds ratios for PE, DVT, and VTE were calculated in the UK Biobank cohort using logistic regression models.

3. Results

A total of 3046 and 29,742 individuals with and without alpha-1 antitrypsin deficiency, were matched for sex, age, and municipality, were included in the Danish nationwide cohort study. Fourty-nine percent were women and 51% were men, with mean ages of 45 years (Table). The median follow-up time was 61 years. During follow-up, PE was diagnosed in 146 and 598 individuals with and without alpha-1 antitrypsin deficiency. DVT was correspondingly diagnosed in 124 and 816 individuals.

Table.

Characteristics of individuals with alpha-1 antitrypsin deficiency in the Danish nationwide cohort.

Alpha-1 antitrypsin deficiency Controls
Women/men 1484/1562 14,499/15,243
Age, y 45.43 ± 20.56 45.14 ± 20.58
Marital status
 Single 911 (30.4) 9462 (32.3)
 Married 1555 (51.9) 14,917 (51.0)
 Divorced 348 (11.6) 3184 (10.9)
 Widow/widower 184 (6.1) 1681 (5.8)
Taxable income (in quartiles)
 Low income 943 (32.3) 8542 (30.4)
 Low-medium income 621 (21.3) 5978 (21.3)
 Medium-high income 633 (21.7) 6290 (22.4)
 High income 722 (24.7) 7275 (25.9)
Diagnoses
 COPD 1489 (48.9) 2131 (7.2)
 Liver cirrhosis 174 (5.7) 200 (0.7)
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Data are presented as n (%) or mean ± SD.

COPD, chronic obstructive pulmonary disease.

3.1. Risk of venous thromboembolism in individuals with alpha-1 antitrypsin deficiency in the Danish nationwide cohort

The cumulative incidence of PE, PE-specific mortality, DVT, and VTE was higher in individuals with alpha-1 antitrypsin deficiency compared with that in individuals without it (log rank P values < .001; Figure 1). After adjustment for sex and age, the hazard ratio for PE in individuals with vs without alpha-1 antitrypsin deficiency was 3.28 (95% CI, 2.73-3.94). Equivalent hazard ratios were 2.83 (95% CI, 1.65-4.84) for PE-specific mortality, 1.85 (95% CI, 1.53-2.25) for DVT, and 2.43 (95% CI, 2.12-2.80) for VTE, respectively. In a multivariable adjusted analysis, adjusting for sex, age, COPD, cirrhosis, and income, the effect sizes were similar, but with wider and nonsignificant confidence intervals (Supplementary Figure S1). When stratifying for some of the known risk factors for VTE, the hazards for PE in individuals with alpha-1 antitrypsin deficiency were highest in those without concomitant cancer (4.24; 95% CI, 3.42-5.25; interaction P = 9 × 10−5) and those younger than 57 years (4.16; 95% CI, 3.27-5.29; interaction P = 5 × 10−4; Figure 2). No interactions were seen for DVT (Figure 3). Furthermore, we found that individuals with alpha-1 antitrypsin deficiency had an increased risk of dying from a PE with a HR of 2.83 (95% CI, 1.65-4.84; Figure 1B). The associations remained but were slightly reduced when including death as a competing event in the analyses (Supplementary Figure S2).

Figure 1.

Figure 1

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Cumulative incidence curves for (A) pulmonary embolism, (B) pulmonary embolism–specific mortality, (C) deep vein thrombosis, and (D) venous thromboembolism in individuals with alpha-1 antitrypsin deficiency vs controls without alpha-1 antitrypsin deficiency in the Danish nationwide cohort, modelled with Kaplan-Meier. Cox regression model adjusted for sex and age.

Figure 2.

Figure 2

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Risk of pulmonary embolism according to alpha-1 antitrypsin deficiency in the stratified analyses in the Danish nationwide cohort. Cox regression model adjusted for sex and age. Any diagnosis = COPD, cancer, obesity, or liver cirrhosis. COPD, chronic obstructive pulmonary disease.

Figure 3.

Figure 3

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Risk of deep vein thrombosis according to alpha-1 antitrypsin deficiency in the stratified analyses in the Danish nationwide cohort. Cox regression model adjusted for sex and age. Any diagnosis = COPD, cancer, obesity, or liver cirrhosis. COPD, chronic obstructive pulmonary disease.

3.2. Use of anticoagulant medication in individuals with alpha-1 antitrypsin deficiency in the Danish nationwide cohort

The cumulative use of the twice-a-day factor Xa inhibitor apixaban, which is used to prevent and treat VTE [25], was higher in individuals with alpha-1 antitrypsin deficiency than in controls (log rank P value = .008; Figure 4A). After adjustment for sex and age, the hazard ratio for apixaban use in alpha-1 antitrypsin deficiency vs controls was 1.83 (95% CI, 1.30-2.56). There was also an increased use of the once-a-day factor Xa inhibitor rivaroxaban [26], with a HR of 1.49 (95% CI, 1.11-1.99), once-a-day factor Xa inhibitor edoxaban with a HR of 6.05 (95% CI, 2.52-14.6), and vitamin K antagonists with a HR of 1.97 (95% CI, 1.66-2.34) in individuals with vs without alpha-1 antitrypsin deficiency (Figure 4B, C, E), but not of dabigatran (Figure 4D).

Figure 4.

Figure 4

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Cumulative use of (A) apixaban, (B) rivaroxaban, (C) edoxaban, (D) dabigatran, and (E) vitamin K antagonists in individuals with alpha-1 antitrypsin deficiency vs controls without alpha-1 antitrypsin deficiency in the Danish nationwide cohort, modelled with Kaplan-Meier. Cox regression model adjusted for sex and age.

3.3. Validation in the United Kingdom Biobank

A total of 16,768 individuals with the MZ genotype and 415,208 without alpha-1 antitrypsin deficiency mutation were included in the analyses. For individuals with vs without the MZ genotype, the sex- and age-adjusted OR was 1.14 (95% CI, 1.03-1.26) for PE, 1.15 (95% CI, 1.02-1.30) for DVT, and 1.13 (95% CI, 1.04-1.23) for VTE (Figure 5A). In line with that, MZ individuals were at a higher risk of hospitalization due to PE, DVT, and VTE (as primary or secondary diagnoses) than controls (Figure 5B).

Figure 5.

Figure 5

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Risk of pulmonary embolism, deep vein thrombosis, and venous thromboembolism in individuals with MZ vs MM genotype in the UK Biobank. Logistic regression analysis adjusted for age and sex. (A) Overall risk (both in- and outpatient clinics). (B) Risk of hospitalization. MM, normal (non–alpha-1 antitrypsin deficiency) genotype; MZ, heterozygous Z genotype (SERPINA1); OR, odds ratio.

4. Discussion

In the large Danish nationwide cohort study, we found that alpha-1 antitrypsin deficiency was associated with an increased risk of PE, PE-specific mortality, DVT, and VTE, further supported by an increased use of anticoagulant medications such as apixaban, rivaroxaban, edoxaban, and vitamin K antagonists in individuals with vs without alpha-1 antitrypsin deficiency. Furthermore, analyses of individuals with the MZ genotype in the UK Biobank supported the association, illustrating that the highly prevalent heterozygosity for the Z allele is sufficient to affect VTE risk.

Mechanistically our findings can be explained by the effect of alpha-1 antitrypsin on the coagulation cascade. Specifically, alpha-1 antitrypsin can inhibit thrombin, a central enzyme in the coagulation cascade responsible for the conversion of fibrinogen to fibrin, involved in the formation of fibrin clots [10]. In vivo studies suggest that alpha-1 antitrypsin deficiency is associated with an increased risk of VTE. In mice, infusion with alpha-1 antitrypsin during sepsis reduced sepsis-induced coagulation through the inhibition of neutrophil elastase. It decreased the formation of neutrophil extracellular trap formations, a network of histones, DNA, and proteins, that are part of the defense mechanism against pathogens, but when too extensive, it can result in microvascular thrombi [27]. Furthermore, a large genome-wide association study including more than 2 million individuals found the Z allele to be associated with an increased risk of VTE [28]. Conversely, alpha-1 antitrypsin has been suggested to inhibit urokinase, an enzyme that converts the inactive pro-enzyme plasminogen to plasmin. Plasmin is a fibrinolytic enzyme responsible for degrading fibrin clots once they are no longer needed [11], and alpha-1 antitrypsin deficient subjects with decreased alpha-1 antitrypsin plasma levels may therefore display shortened clot persistence. Furthermore, alpha-1 antitrypsin inhibits protein C, an endogenous anticoagulant, theoretically reducing the risk of blood clot formation in alpha-1 antitrypsin deficiency [12]. Additionally, the predisposition to hepatic involvement in alpha-1 antitrypsin deficient subjects adds extra complexity. Misfolded alpha-1 antitrypsin accumulates in hepatocytes, causing cellular damage and, in severe cases, liver cirrhosis [29]. This may impair the synthesis of secretory proteins from the liver including natural anticoagulants, such as protein C and antithrombin, reinforcing a prothrombotic state [30,31]. Consistent with this, studies previously reported alterations in endogenous triglyceride synthesis among individuals with alpha-1 antitrypsin deficiency [5,32].

Support of our findings come from Tanash et al. [22] who found that individuals with the less common, severe alpha-1 antitrypsin deficiency (ZZ genotype) had an increased risk of VTE compared with that in the Swedish general population with an adjusted HR of 4.2 (95% CI, 2.9-6.2). In another study, the same group found, that individuals with severe alpha-1 antitrypsin deficiency had an increased risk of dying from PE, compared to controls with a standardized mortality ratio of 6.9 (95% CI, 3.3-12.7) [21]. Furthermore, Riis et al. [20] conducted a Danish population-based cohort study including 55 individuals homozygous for the Z allele and 5655 who were heterozygotes. Here, they identified a dose-response relationship for VTE across genotype combinations, with the strongest association in individuals who were homozygous, with a hazard ratio of 2.2 (95% CI, 1.3-3.7). Additionally, in a population-based cohort study, Manderstedt et al. [33] found that individuals who were carrying either the ZZ genotype or were compound heterozygotes for a Z allele and a rare deficiency variant, had an increased risk of VTE with a hazard ratio of 4.5 (95% CI, 2.0-10.0) compared to controls without a Z allele or a rare deficiency variant allele. Our study of 3046 individuals with alpha-1 antitrypsin deficiency and 29,742 controls now extends these findings using a nationwide nested cohort and a matched study design. The analyses show that alpha-1 antitrypsin deficiency is related to higher hazards of PE, DVT, and VTE and this was verified in an independent UK population.

It is well established that COPD is associated with VTE [34] and further that acute exacerbations of COPD are associated with an increased risk of PE, with studies demonstrating a dose-response relationship between the frequency of exacerbations and the hazard ratio for PE [35,36]. Individuals with alpha-1 antitrypsin deficiency have a higher risk of developing emphysema and clinically manifest COPD, which may contribute to the elevated risk of PE observed in this population. However, our stratified analyses indicated that this alone does not fully account for the observed association, nor does it explain the increased risk of DVT in this study, with the elevated risks being persistent when COPD is not present in either cases or controls. When further evaluating the risk of VTE by the presence of alpha-1 antitrypsin deficiency and COPD, we saw an increased risk of VTE in all 3 study groups, but with the association being strongest in individuals with both alpha-1 antitrypsin deficiency and COPD (Supplementary Figure S3). This observation is in line with a potential anticoagulant role of alpha-1 antitrypsin in the coagulation process.

Importantly, we also observed that individuals with alpha-1 antitrypsin deficiency had an increased use of antithrombotic medications, suggesting that appropriate treatment is initiated in these patients following a VTE diagnosis, potentially reducing the risk of subsequent events.

5. Strengths and Limitations

A major strength of our study is the use of comprehensive Danish national health registries, allowing for a long median follow-up period of 61 years with no loss to follow-up. Additionally, inclusion of the large number of individuals with alpha-1 antitrypsin deficiency in the analysis provides a solid validation. The diagnostic accuracy for PE, DVT, and VTE in the Danish registries is high, with positive predictive values ranging from 86% to 90% [37], supporting the validity of our findings. The positive predictive values for the comorbidities stratified for, is likewise robust being 92% for COPD [38], 85% for liver cirrhosis [39], and 95% to 98% for cancer [40]. The obesity diagnosis has not yet been validated. In addition, we were able to confirm the associations of the Z allele on VTE risk in the UK Biobank, further backing the findings in the present study.

Nonetheless, certain limitations should be acknowledged. Identification of alpha-1 antitrypsin deficiency cases in the nationwide cohort was based primarily on ICD-10 codes. Although genotype data might have added precision, we do not believe this significantly impacted our results, as previous studies involving only our genetically confirmed cases have reported similar associations of comparable magnitude [41]. If the analysis of the nationwide cohort was restricted to only those individuals who had information available for severe ZZ or SZ genotype/phenotypes in this study (n = 1433), individuals with alpha-1 antitrypsin deficiency vs control subjects had adjusted hazards of 4.02 (95% CI, 3.26-4.96) for PE, 1.87 (95% CI, 1.47–2.38) for DVT, and 2.73 (95% CI, 2.31–3.22) for VTE. Moreover, the data on use of anticoagulant medication is strongly limited by the reason for the prescription being unknown. Taking into account the large prevalence of atrial fibrillation, we cannot confirm that the increased use of such therapies is directly associated with the increased risk of PE, DVT, and overall VTE.

In conclusion, we found that individuals with alpha-1 antitrypsin deficiency had a 1.8- to 3.3-fold increased risk of PE, PE-specific mortality, DVT, and VTE, which was independent of some of the known risk factors for these outcomes. This finding was supported by analyses of individuals with the MZ vs MM genotype in the UK Biobank identifying increased risks for PE, DVT, and VTE. This underlines the importance of considering PE as a differential diagnosis when evaluating an individual with alpha-1 antitrypsin deficiency who experiences alterations or worsening in dyspnea, as well as considering alpha-1 antitrypsin deficiency as a contributing risk factor when evaluating patients having or at risk of a VTE event.

Acknowledgments

Funding

This work was supported by a research grant from Grifols Nordic AB. The sponsors of the study had no role in the study’s design, conduct, or reporting and could neither approve nor disapprove the submitted manuscript.

Author contributions

S.V.D. and M.D. had full access to all the data in the Danish nationwide study and take responsibility for the integrity of the data and the accuracy of the data analysis in the Danish nationwide study. M.F., K.R., and P.S. had full access to all the data in the UK Biobank and take responsibility for the integrity of the data and the accuracy of the data analysis in the UK Biobank. S.V.D., B.G.N., and M.D. contributed substantially to the study design, and S.V.D., M.F., K.R., B.G.N., P.S., and M.D. contributed to the interpretation of results. S.V.W., M.F., and M.D. wrote the manuscript. All authors critically reviewed and approved the final manuscript.

Relationship Disclosure

MF received consulting fees from Takeda Pharmaceuticals and honoraria from CSL Behring, Grifols Inc, and Takeda Pharmaceuticals. BGN has consultancies with Amarin, Akcea, Amgen, AstraZeneca, Denka Seiken, Kowa, Novartis, Novo Nordisk, and Silence Therapeutics. PS reports receiving grants and honoraria from Arrowhead Pharmaceuticals, CSL Behring, and Grifols Inc; receiving consulting fees or honoraria from AiRNA Pharmaceuticals, BioMarin Pharmaceutical, Dicerna Pharmaceuticals, GSK, Intellia Pharmaceuticals, Takeda Pharmaceuticals, Tessera Pharmaceuticals, and Novo Nordisk; participating in leadership or fiduciary roles in Alpha1-Deutschland and Alpha-1 Global; and receiving material transfer support for Vertex Pharmaceuticals and Dicerna Pharmaceuticals. MD has sponsored talks or consultancies with Grifols, Takeda, and Chiesi. All other authors have no relationships with the industry relevant to the contents of this paper to disclose.

Footnotes

Handling Editor: Professor Michael Makris

The online version contains supplementary material available at https://doi.org/10.1016/j.rpth.2026.106827.

Supplementary material

Supplementary Figurs S1-S3
mmc1.docx (307KB, docx)

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