# Treatment of patients with hereditary angioedema with the c.988A>G (p.Lys330Glu) variant in the plasminogen gene.

- **DOI:** [10.1186/s13023-020-1334-8](https://doi.org/10.1186/s13023-020-1334-8)
- **Rating:** Limited (2.7 out of 5)
- **Verdict:** A valuable rare-disease treatment series that expands clinical evidence for HAE-PLG, but its uncontrolled observational design cannot establish a first-line hierarchy.
- **Framework version:** v5.9
- **Pipeline version:** v0.4
- **Evaluation date:** 2026-09-18
- **Evaluation page:** https://www.nabu.science/paper/10.1186%2Fs13023-020-1334-8

## Key claims

1. our results support the use if icatibant as first line treatment for acute attacks, followed by pdC1-INH concentrate
   - Support: Tentative
   - Type: Primary finding
   - Basis: first-line ranking is not identified by physician-selected, uncontrolled historical comparisons
   - Location: Conclusions
2. The mean duration of the treated attacks (mean 4.3 h; SD 2.6 h) was significantly shorter than that of the previous 149 untreated attacks (mean 44.7 h; SD 28.6 h, p < 0.0001)
   - Support: Supported
   - Type: Secondary
   - Basis: large diary-recorded difference, though historical controls and unmodelled within-patient clustering limit inference
   - Location: Abstract, Icatibant results paragraph; Results, Icatibant; Table 3
3. The mean reduction in attack frequency was 46.3% under progestins (6 patients), 93.9% under tranexamic acid (3 patients) and 83.3% under danazol (3 patients)
   - Support: Tentative
   - Type: Secondary
   - Basis: descriptive before-during reductions rely on very small uncontrolled prophylaxis groups
   - Location: Abstract, Results; Results, Long-Term Prophylaxis; Table 5

## Strengths

- **Meaningful scale in an ultra-rare disease** The cohort includes 111 symptomatic carriers from 22 families, providing a substantial genotype-specific clinical record for HAE-PLG. The study reports both acute-treatment and prophylaxis experience.
  - Dimension: contribution
  - Location: Results, opening paragraph; Tables 2–5
- **Detailed treatment-level outcome reporting** Tables 3 and 4 present attack duration and response information by patient and attack location for icatibant and pdC1-INH. Negative and mixed responses to other treatments are also reported rather than omitted.
  - Dimension: methodological rigour
  - Location: Results, Treatment for Acute Attacks; Tables 3–4; Figures 1–2
- **Clear connection to specialist decisions** The paper addresses acute management and long-term prophylaxis for a condition associated with potentially fatal upper-airway obstruction. The intended clinical pathway and specialist audience are readily identifiable.
  - Dimension: application pathway
  - Location: Background, final paragraph; Discussion, opening paragraph

## Limitations

- **Confounding prevents comparative treatment ranking** Treatment was selected solely at physician discretion, and treated attacks were compared with prior untreated attacks without adjustment for severity, indication, time trends, or regression to the mean. These comparisons cannot establish a first-line hierarchy.
  - Dimension: methodological rigour
  - Location: Methods, Study Design; Conclusions
- **Repeated attacks inflate nominal precision** The reported t-tests and chi-square tests do not describe adjustment for multiple attacks contributed by the same patients. Treating those observations as independent can overstate the precision of per-attack comparisons.
  - Dimension: methodological rigour
  - Location: Methods, Laboratory and Statistical Methods; Tables 3–4
- **Recommendations exceed acknowledged limitations** The Discussion acknowledges retrospective, non-random allocation, but the Conclusions still recommend first-line acute and prophylactic treatments. The TXA recommendation rests on only three patients.
  - Dimension: positioning
  - Location: Discussion, final paragraph; Conclusions; Table 5

## Reliability checks

Caveats (4 of 4 checks).

- **Internal coherence:** Noted. Reported treatment differences remain descriptively visible, but dependence among repeated attacks and heterogeneous outcome ascertainment limit the precision and comparability of the statistical claims. The overlapping response-category patient counts are clarified in Figure 1 but are not self-explanatory in the Abstract.
- **Research conduct:** Clean. Ethics approval and informed consent are declared, and data are offered on reasonable request. The absent conflict-of-interest, registration, and code statements do not establish a conduct concern for this retrospective clinical series.
- **Reference integrity:** Clean. 29 of 29 checkable references verified
  - 29 references in manuscript
  - 1 reference confirmed by manual review
  - References not verified automatically are resolved manually within 24 hours.

## Post-publication record

- **Status:** Clean
- **Summary:** No retraction or expression of concern found in Crossref (includes Retraction Watch).
- **Last checked:** 2026-10-17