背景:遗传性出血性毛细血管扩张症(HHT)的特点是毛细血管扩张症和动静脉畸形(AVM)。HHT患者经常报告内脏和粘膜皮肤复发性出血,而关于血栓形成患病率的数据仍然有限。本研究旨在描述HHT患者的临床表现和分子生物学特征。
方法:我们在瑞金医院进行了一项回顾性研究,附属于上海交通大学医学院。共有24例HHT患者,包括在2019年1月至2023年12月期间观察到的。我们记录了生物,临床,和治疗事件,特别注意出血和血栓事件。进行基因突变分析和血液成分测量。
结果:所有HHT患者的出血发生率为100%,而在41.70%的病例中发现了血栓事件。在6例患者中发现了肝动静脉畸形(HAVM),5例患者的肺动静脉畸形(PAVMs),一名患者的脑动静脉畸形(CAVMs)。对于血栓形成的患者,由于出血风险增加,抗血小板治疗停药率为23.08%,抗凝治疗停药率为33.33%.16例患者存在与HHT相关的基因突变,ACVRL1(活化素A受体样1型)突变最常见,为41.67%,其次是20.83%的ENG(endoglin)突变,GDF2(生长分化因子2)突变为4.17%。有ENG突变的HHT1患者PAVMs的发生率为75.00%,有ACVRL1突变的HHT2患者为20%,而HAVM发生在这些组中的0%和40.00%,分别。患者分为非AVM和AVM组。与正常对照相比,所有HHT患者的血管性血友病因子(vWF)活性均显着增加(149.10%vs.90.65%,P<0.001)。在非AVM组中,基质细胞衍生因子-1(SDF-1)的中位数水平显着升高(124.31pg/mLvs.2413.57pg/mL,P<0.05),而vWF抗原水平明显高于AVM组(165.30%vs.130.60%,P=0.021)。根据出血和血栓形成表型对HHT患者的进一步分组显示,血栓形成患者的血吸血细胞百分比中位数明显更高(3.50%vs.0%,P=0.002),铁蛋白浓度(318.50μg/Lvs.115.50μg/L,P=0.001),和乳酸脱氢酶(LDH)水平(437U/Lvs.105U/L,P<0.001)。vWF的活性没有显著差异,蛋白C(PC),蛋白质S(PS),两组之间的因子VIII(FVIII)。
结论:本研究强调了HHT患者动静脉畸形与基因突变之间的复杂关系。应全面评估每位HHT患者的出血和血栓形成风险,此外,需要进一步的临床研究来探讨HHT血栓形成和抗凝相关出血的危险因素。
BACKGROUND: Hereditary Hemorrhagic Telangiectasia (HHT) is charactered by telangiectasia and arteriovenous malformations (AVMs). Recurrent visceral and mucocutaneous bleeding is frequently reported among HHT patients, while data on the prevalence of thrombosis remains limited. This study aims to describe the clinical manifestations and molecular biological characteristics of HHT patients.
METHODS: We conducted a retrospective study at Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine. A total of 24 HHT patients, observed between January 2019 and December 2023, were included. We recorded the biological, clinical, and therapeutic events, with particular attention to bleeding and thrombotic events. Gene mutation analysis and blood constituent measurements were performed.
RESULTS: The prevalence of bleeding among all HHT patients was 100 %, while thrombotic events were noted in 41.70 % of cases. Hepatic arteriovenous malformations (HAVMs) were identified in six patients, pulmonary arteriovenous malformations (PAVMs) in five patients, and cerebral arteriovenous malformations (CAVMs) in one patient. For patients with thrombosis, the discontinuation rates were 23.08 % for antiplatelet therapy and 33.33 % for anticoagulant therapy due to the increased risk of bleeding. Genetic mutations related to HHT were present in 16 patients, with ACVRL1 (activin A receptor-like type 1) mutations being the most frequent at 41.67 %, followed by ENG (endoglin) mutations at 20.83 %, and GDF2 (growth differentiation factor 2) mutations at 4.17 %. The incidence of PAVMs was 75.00 % in HHT1 patients with ENG mutations and 20 % in HHT2 patients with ACVRL1 mutations, while HAVMs occurred in 0 % and 40.00 % of these groups, respectively. Patients were divided into non-AVMs and AVMs groups. Compared to normal controls, von Willebrand factor (vWF) activity was significantly increased in all HHT patients (149.10 % vs. 90.65 %, P < 0.001). In the non-AVMs group, the median level of stromal cell-derived factor-1 (SDF-1) was significantly elevated (124.31 pg/mL vs. 2413.57 pg/mL, P < 0.05), while vWF antigen levels were markedly higher in the AVMs group (165.30 % vs. 130.60 %, P = 0.021). Further grouping of HHT patients based on bleeding and thrombosis phenotypes revealed that those with thrombosis had significantly higher median percentages of schistocytes (3.50 % vs. 0 %, P = 0.002), ferritin concentrations (318.50 μg/L vs. 115.50 μg/L, P = 0.001), and lactate dehydrogenase (LDH) levels (437 U/L vs. 105 U/L, P < 0.001). There were no significant differences in the activity of vWF, protein C (PC), protein S (PS), and factor VIII (FVIII) between the two groups.
CONCLUSIONS: This study highlighted the complex relationship between arteriovenous malformations and genetic mutations in HHT patients. A comprehensive assessment of bleeding and thrombosis risks should be conducted for each HHT patient, additionally, further clinical studies are needed to explore the risk factors for thrombosis and anticoagulant-related bleeding in HHT.