Stefano Barco1,2, Stefanie Sollfrank3, Alice Trinchero1,4, Anke Adenaeuer1,3, Hassan Abolghasemi5,6, Laura Conti7, Friederike Häuser3, Johanna A Kremer Hovinga8, Karl J Lackner1,3, Felicia Loewecke9, Erwin Miloni10, Nader Vazifeh Shiran11, Luigi Tomao7,12, Walter A Wuillemin13, Barbara Zieger9, Bernhard Lämmle1,8,14, Heidi Rossmann1,3. 1. Center for Thrombosis and Hemostasis, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany. 2. Clinic of Angiology, University Hospital and University of Zurich, Zurich, Switzerland. 3. Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany. 4. Department of Medical Oncology and Hematology, University Hospital and University of Zurich, Zurich, Switzerland. 5. Pediatric Congenital Hematologic Disorders Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 6. Department of Pediatrics, Baqiyatallah University of Medical Sciences, Tehran, Iran. 7. Clinical Pathology, IRCCS Regina Elena National Cancer Institute, Rome, Italy. 8. Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 9. Zentrum für Kinder- und Jugendmedizin, Klinik IV, Universitätsklinikum Freiburg, Freiburg, Germany. 10. Practicing Physician, Bern, Switzerland. 11. Department of Hematology and Blood Banking, Paramedical Faculty, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 12. Department of Pediatric Hematology-Oncology, IRCCS Bambino Gesù Children's Hospital, Roma, Italy. 13. Division of Hematology and Central Hematology Laboratory, Department of Internal Medicine, Kantonsspital Lucerne, Lucerne, Switzerland. 14. Haemostasis Research Unit, University College London, London, UK.
Abstract
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.
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.