Background: Severe high molecular weight kininogen (HK) deficiency is an autosomal recessive defect of the contact system caused by mutations in KNG1. Limited scientific interest in HK deficiency due to the rarity of the seemingly asymptomatic condition may increase, as HK, the precursor of bradykinin, is now discussed as a therapeutic target e.g. in hereditary angioedema. Aims: We provide a comprehensive analysis of the diagnostic, clinical, and genetic features of HK deficiency and estimate its frequency. Methods: We identified a new case of HK deficiency, systematically review the literature, conduct new genetic studies of reported cases, and comprehensively analyze the clinical course and diagnostic criteria. Clotting activity of HK and prekallikrein (PK) (HK:C/PK:C) and antigen (HK:Ag/PK:Ag) were determined and genetic analyses of KNG1 and KLKB1 were performed by Sanger sequencing. Characteristics deduced from the known HK deficiency-causing variants were used to estimate the frequency of HK deficiency from the KNG1 variants aggregated in GnomAD. Results: 677 studies were identified by systematic review of the literature for HK deficiency. 27 of these contained individual cases of HK deficiency including 6 studies not listed in PubMed. Little-noticed cases from the gray literature account for more than one-third (16/39) of the extracted, unrelated cases. We genotyped one newly diagnosed HK-deficient case and 2 cases described in the literature and additionally evaluated all 10 studies reporting genetic data in HK-deficiency (including one case previously misdiagnosed as having PK deficiency). A total of 10 KNG1 variants causing HK deficiency (one new) were found, the most frequent being c.586C>T, p.Arg196* (4 unrelated families). Interestingly, all HK deficiency-causing variants are truncating, whereas two amino acid substitutions with presumed functional consequence, have been described as the cause of hereditary angioedema. Conservative prevalence estimates based on all known and putative HK deficiency-causing variants extracted from GnomAD (truncating variants in KNG1, including indels, nonsense and canonical splice site mutations located in that part of the gene, where relevant mutations have been described) revealed a frequency of 1 case of HK deficiency among 7,925,172 with slight differences in the analyzed ethnicities (see table). In addition, although not to the same extent as seen in PK deficiency, HK deficiency apparently is more prevalent in Africans. While it is already well known that HK deficiency causes decreased PK levels, our data indicate that factor XI levels are also frequently decreased, albeit to a lesser extent. The number of cases detected so far is too low for a more detailed analysis regarding bleeding, thrombotic, and cardiovascular events or immunological abnormalities. Conclusion: HK-deficiency is probably more frequent than previously thought. Suspected cases of contact phase defects should at least be analyzed for HK activity (besides factor XII, XI and PK activity) to facilitate conclusive evaluation of the clinical significance in the future.

Purpose: Thymic involution, a hallmark of immune ageing, is associated with chronic low-grade inflammation (“inflammaging”) and has been implicated in age-associated inflammatory diseases, including atherosclerosis. This study aimed to evaluate the association between persistent thymus and coronary artery calcification based on the Agatston score. Materials and Methods: In an exploratory effort, we retrospectively analyzed 206 patients aged 40–64 years who underwent ECG-triggered thoracic CT between 2019 and 2024. Coronary artery calcifications were quantified on virtual non-contrast reconstructions using the Agatston score. Thymic tissue was graded on a five-point scale based on the extent of fatty replacement, with higher grades indicating greater thymic preservation. Results: The cohort included 126 men and 80 women. Complete fatty replacement of the thymus (Grade 0) was seen more often in men compared to women (51/126 vs. 18/80; p = 0.011). Linear regression analysis revealed a significant inverse association between thymus grade and coronary Agatston score (Beta (B) = −28.8 (95% CI −45.3 to −12.3); p = 0.001). After adjusting for age and sex, higher thymic grades remained significantly associated with lower coronary Agatston scores (B = −22.2 (95% CI: −41.7 to −2.6); p = 0.03). Further analysis with adjustments for cardiovascular risk factors was not performed. Conclusions: Residual thymic tissue was significantly inversely associated with coronary artery calcification, and this association persisted after adjustment for age and sex. These findings support the hypothetical concept that morphologically detectable thymic remnants may reflect interindividual differences in immune ageing and inflammaging that are associated with age-related inflammatory disease phenotypes. The results of this hypothesis-generating study give incentive to further investigate the nature and strength of these associations in prospective studies.

Background: The purpose of this study is the evaluation of imaging findings of acute-phase cardiac CT (cCT) in stroke patients with large vessel occlusion (LVO) to identify potential cardioembolic sources (CES) in patients without intracardiac thrombi and atrial fibrillation (AF). Material and Methods: This retrospective study included 315 patients with LVO who underwent cCT imaging in the acute stroke setting. The images were analysed for 15 imaging findings following the established minor and major cardioembolic risk factors. The final stroke aetiology was determined using the TOAST classification through interdisciplinary consensus following a thorough clinical evaluation. Multivariate regression analysis was performed to identify imaging findings associated with CES. Results: A cardioembolic aetiology was identified on cardiac CT in 211 cases (70%). After adjustment for AF and intracardiac thrombi, the multivariate regression analysis revealed significant associations with left ventricular dilation (adjusted odds-ratio (AOR) 32.4; 95% CI 3.0–349; p = 0.004), visible interatrial right-to-left shunt (AOR 30.8; 95% CI 2.7–341.3; p = 0.006), valve implants (AOR 24.5; 95% CI 2.2–270.9; p = 0.009), aortic arch atheroma grade > II (AOR 6.9; 95% CI 1.5–32.8; p = 0.015) and post-ischaemic myocardial scars (AOR 6.3, 95% CI 1.2–34.1; p = 0.032) as independent risk factors for a cardioembolic aetiology. The combined model achieved an area under the ROC curve of 0.83. Conclusions: In patients with LVO without AF and intracardiac thrombi as a cause, the presence of left ventricular dilatation, interatrial right-to-left shunts, valve implants, post-ischaemic myocardial scarring and advanced aortic arch atheroma (grade > 2) in particular is significantly associated with a cardioembolic cause of stroke and should be add-on evaluated in acute-phase cCT. Further investigations are warranted to confirm these associations.

Background: Large vessel occlusion (LVO) strokes account for a significant proportion of ischemic strokes and are often cardioembolic in origin, particularly following atrial fibrillation (AF) with thrombus formation in the left atrial appendage (LAA). Although direct oral anticoagulation (DOAC) therapy reduces stroke risk in AF, anatomical and flow-related factors may still allow thrombi to form and persist, revealing the limitations of anticoagulation in high-risk patients. Examining structural and hemodynamic factors contributing to thrombus persistence is essential for optimizing patient management. Methods: We retrospectively analyzed 169 AF patients with LVO stroke who underwent cardiac CT (cCT) during acute stroke assessment. Patients were categorized based on the presence or absence of persistent LAA thrombi and further stratified by DOAC status. LAA volume, blood stasis and left ventricular (LV) diameter were measured. Thrombi were assessed using Hounsfield Unit (HU) analysis to evaluate potential differences in thrombus composition. Logistic regression analysis was performed to identify independent predictors of thrombus persistence with adjustment for DOAC therapy. Results: Persistent LAA thrombi were identified in 23 patients (13.6%). Patients with thrombi had significantly higher rates of stasis (p = 0.004), larger left ventricular diameters (p = 0.0019) and higher LAA volumes (p = 0.004). When adjusted for DOAC therapy, larger LAA volume (OR 1.05, p = 0.011), presence of LAA stasis (OR 6.14, p = 0.013) and increased LV diameter (OR 1.06, p = 0.006) were independent predictors of thrombus persistence. Thrombus size and HU values did not differ significantly between DOAC and non-DOAC groups. Notably, 30.4% of patients with persistent thrombi were on adequate DOAC therapy. Conclusions: LAA volume, stasis and LV enlargement predict thrombus persistence in the LAA of AF patients with LVO stroke, even under adequate DOAC therapy. These findings highlight the potential need for alternative antithrombotic strategies, including interventional LAA occlusion, and warrant further investigation into individualized stroke prevention in high-risk AF populations.