School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
Aberdeen Cardiovascular and Diabetes Centre, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, UK.
J Thromb Haemost. 2020 Sep;18(9):2209-2214. doi: 10.1111/jth.14990. Epub 2020 Jul 23.
Thrombomodulin-associated coagulopathy (TM-AC) is a rare bleeding disorder in which a single reported p.Cys537* variant in the thrombomodulin gene THBD causes high plasma thrombomodulin (TM) levels. High TM levels attenuate thrombin generation and delay fibrinolysis.
To report the characteristics of pedigree with a novel THBD variant causing TM-AC, and co-inherited deficiency of thrombin-activatable fibrinolysis inhibitor (TAFI).
PATIENTS/METHODS: Identification of pathogenic variants in hemostasis genes by next-generation sequencing and case recall for deep phenotyping.
Pedigree members with a previously reported THBD variant predicting p.Pro496Argfs10 and chain truncation in TM transmembrane domain had abnormal bleeding and greatly increased plasma TM levels. Affected cases had attenuated thrombin generation and delayed fibrinolysis similar to previous reported TM_AC cases with THBD p.Cys537. Coincidentally, some pedigree members also harbored a stop-gain variant in CPB2 encoding TAFI. This reduced plasma TAFI levels but was asymptomatic. Pedigree members with TM-AC caused by the p.Pro496Argfs*10 THBD variant and also TAFI deficiency had a partially attenuated delay in fibrinolysis, but no change in the defective thrombin generation.
These data extend the reported genetic repertoire of TM-AC and establish a common molecular pathogenesis arising from high plasma levels of TM extra-cellular domain. The data further confirm that the delay in fibrinolysis associated with TM-AC is directly linked to increased TAFI activation. The combination of the rare variants in the pedigree members provides a unique genetic model to develop understanding of the thrombin-TM system and its regulation of TAFI.
血栓调节蛋白相关凝血障碍（TM-AC）是一种罕见的出血性疾病，其中 THBD 基因中的单个报道的 p.Cys537*变异导致高血浆血栓调节蛋白（TM）水平。高 TM 水平会减弱凝血酶生成并延迟纤维蛋白溶解。
报道由导致 TM-AC 的新型 THBD 变异和同时合并凝血酶激活的纤溶抑制物（TAFI）缺乏引起的家系特征。
患者/方法：通过下一代测序和病例回顾识别止血基因中的致病性变异，并进行深入表型分析。
具有先前报道的 THBD 变异的家系成员预测 p.Pro496Argfs10 和 TM 跨膜域的链截断，存在异常出血和显著增加的血浆 TM 水平。受影响的病例表现出与先前报道的 THBD p.Cys537所致 TM-AC 相似的凝血酶生成减弱和纤维蛋白溶解延迟。巧合的是，一些家系成员还携带编码 TAFI 的 CPB2 中的无义变异。这降低了血浆 TAFI 水平，但无症状。由 p.Pro496Argfs*10 THBD 变异和 TAFI 缺乏引起的 TM-AC 家系成员的纤维蛋白溶解延迟部分减弱，但凝血酶生成缺陷无变化。
这些数据扩展了 TM-AC 的报告遗传谱，并建立了一种共同的分子发病机制，源自高血浆 TM 细胞外结构域水平。数据进一步证实，与 TM-AC 相关的纤维蛋白溶解延迟与 TAFI 激活增加直接相关。家系成员中的罕见变异组合提供了一个独特的遗传模型，有助于深入了解凝血酶-TM 系统及其对 TAFI 的调节。
