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
Center for Thrombosis and Hemostasis, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany.
Clinic of Angiology, University Hospital and University of Zurich, Zurich, Switzerland.
J Thromb Haemost. 2020 Jul;18(7):1598-1617. doi: 10.1111/jth.14805. Epub 2020 May 15.
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.
We assembled a cohort of 111 cases from 89 families and performed new genetic analyses in eight families (three unpublished).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%.
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.
严重血浆前激肽释放酶（PK）缺乏症是一种常染色体隐性缺陷，其特征为活化部分凝血活酶时间单独延长。迄今为止，尚无全面且方法严谨的分析对PK缺乏症的诊断、临床及遗传特征进行研究，其患病率仍不明确。
患者/方法：我们描述了患有PK缺乏症的新家族，检索了在（灰色）文献中系统搜索到的病例的临床和实验室信息，并采集这些病例的血液进行补充分析。基因组聚合数据库（gnomAD）和基于人群的古登堡健康研究用于研究突变和相关基因变异的患病率。
我们从89个家族中收集了111例病例组成队列，并对8个家族（3例未发表）进行了新的基因分析。我们鉴定出了新的KLKB1突变，排除了一些先前描述的突变的致病性，并估计严重PK缺乏症的总体患病率为1/155668，在非洲人中为1/4725。一名报告患有PK缺乏症的个体实际上患有与PK活性降低相关的先天性激肽原缺乏症。四分之一的个体因子Ⅻ凝血活性低于参考范围。96名个体中描述了4次主要出血事件，其中3次为诱发性，患病率为4%，年化率为0.1%。心血管事件的患病率为15%（<40岁为6%；40 - 65岁为21%；>65岁为33%），年化率为
