Severe plasma prekallikrein deficiency: Clinical characteristics, novel KLKB1 mutations, and estimated prevalence.

Barco, Stefano; Sollfrank, Stefanie; Trinchero, Alice; Adenaeuer, Anke; Abolghasemi, Hassan; Conti, Laura; Häuser, Friederike; Kremer Hovinga, Johanna A.; Lackner, Karl J; Loewecke, Felicia; Miloni, Erwin; Vazifeh Shiran, Nader; Tomao, Luigi; Wuillemin, Walter A; Zieger, Barbara; Lämmle, Bernhard; Rossmann, Heidi (2020). Severe plasma prekallikrein deficiency: Clinical characteristics, novel KLKB1 mutations, and estimated prevalence. Journal of thrombosis and haemostasis, 18(7), pp. 1598-1617. Wiley-Blackwell 10.1111/jth.14805

[img]
Preview
Text
Severe_plasma_jth.14805.pdf - Published Version
Available under License Creative Commons: Attribution-Noncommercial (CC-BY-NC).

Download (1MB) | Preview

BACKGROUND

Severe plasma prekallikrein (PK) deficiency is an autosomal-recessive defect characterized by isolated activated partial thromboplastin time prolongation. To date, no comprehensive methodologically firm analysis has investigated the diagnostic, clinical, and genetic characteristics of PK deficiency, and its prevalence remains unknown.

PATIENTS/METHODS

We described new families with PK deficiency, retrieved clinical and laboratory information of cases systematically searched in the (gray) literature, and collected blood of these cases for complementary analyses. The Genome Aggregation Database (gnomAD) and the population-based Gutenberg Health Study served to study the prevalence of mutations and relevant genetic variants.

RESULTS

We assembled a cohort of 111 cases from 89 families and performed new genetic analyses in eight families (three unpublished). We identified new KLKB1 mutations, excluded the pathogenicity of some of the previously described ones, and estimated a prevalence of severe PK deficiency of 1/155 668 overall and 1/4725 among Africans. One individual reported with PK deficiency had, in fact, congenital kininogen deficiency associated with decreased PK activity. One quarter of individuals had factor XII clotting activity below the reference range. Four major bleeding events were described in 96 individuals, of which 3 were provoked, for a prevalence of 4% and an annualized rate of 0.1%. The prevalence of cardiovascular events was 15% (6% <40 years; 21% 40-65 years; 33% >65 years) for an annualized rate of 0.4%.

CONCLUSIONS

We characterized the genetic background of severe PK deficiency, critically appraised mutations, and provided prevalence estimates. Our data on laboratory characteristics and clinical course of severe PK deficiency may have clinical implications.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory

UniBE Contributor:

Kremer Hovinga, Johanna Anna

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1538-7836

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Pierrette Durand Lüthi

Date Deposited:

06 Jan 2021 16:03

Last Modified:

06 Jan 2021 16:11

Publisher DOI:

10.1111/jth.14805

PubMed ID:

32202057

Uncontrolled Keywords:

KLKB1 mutations bleeding intrinsic pathway prekallikrein deficiency thrombosis

BORIS DOI:

10.48350/149801

URI:

https://boris.unibe.ch/id/eprint/149801

Actions (login required)

Edit item Edit item
Provide Feedback