原發性雷諾氏症候群與靜脈血栓栓塞症之關聯：一項傾向分數配對世代研究

研究背景：原發性雷諾氏症候群（Raynaud’s syndrome, RS）傳統上被認為是一種良性的周邊血管痙攣性疾病。然而，近年研究顯示，原發性雷諾氏症候群可能反映全身性血管功能異常及促血栓形成狀態。儘管已有部分研究探討原發性雷諾氏症候群與心血管疾病之間的關聯，但目前有關原發性雷諾氏症候群與靜脈血栓栓塞症（venous thromboembolism, VTE）風險之大型流行病學證據仍相當有限。研究方法及資料：本研究利用TriNetX全球電子病歷資料庫進行回溯性世代研究。納入2015年至2024年間診斷為雷諾氏症候群之成年患者，以 ICD-10-CM I73.0 辨識雷諾氏症候群患者，並排除已知可能造成次發性雷諾氏症候群之疾病，以建立較符合原發性雷諾氏症候群特徵之研究族群。並以傾向分數配對（propensity score matching, PSM）依1：1比例與未診斷雷諾氏症候群者進行配對。配對變項包括人口學特徵、共病、醫療利用情形及實驗室檢驗數值。為降低混雜因子影響，排除自體免疫疾病、惡性腫瘤、遺傳性血栓體質、血管疾病、妊娠，以及使用抗凝血藥物或荷爾蒙避孕藥之患者。主要研究終點為新發生之靜脈血栓栓塞症，包括深層靜脈血栓（deep vein thrombosis, DVT）及肺栓塞（pulmonary embolism, PE），並利用Cox比例風險模式評估其發生風險。研究結果：完成傾向分數配對後，每組共納入93,263位受試者。追蹤期間，原發性雷諾氏症候群組共有1,407位患者發生靜脈血栓栓塞症，而非雷諾氏症候群組則有1,179位患者發生靜脈血栓栓塞症。相較於非雷諾氏症候群，原發性雷諾氏症候群患者發生靜脈血栓栓塞症之風險顯著增加（風險比〔hazard ratio, HR〕=1.33；95%信賴區間〔confidence interval, CI〕：1.24–1.44）。進一步分析顯示，原發性雷諾氏症候群與深層靜脈血栓（HR=1.30；95% CI：1.18–1.43）及肺栓塞（HR=1.38；95% CI：1.24–1.54）之風險增加皆具有顯著相關性。次族群分析發現，此關聯在較年輕族群中更為明顯，且男性與女性皆呈現一致的風險增加趨勢。結論與建議：本研究顯示，原發性雷諾氏症候群與靜脈血栓栓塞症風險增加具有顯著相關性，且此關聯在排除多項重要混雜因子後仍然存在。研究結果支持原發性雷諾氏症候群可能不僅是一種局部血管痙攣疾病，更可能代表一種未被充分重視的全身性血栓形成風險指標。未來仍需更多前瞻性研究進一步驗證本研究結果，並釐清其臨床應用價值。

Background: Primary Raynaud’s syndrome (PRS) is traditionally regarded as a benign vasospastic disorder affecting the peripheral circulation. However, accumulating evidence suggests that PRS may reflect systemic endothelial dysfunction, impaired fibrinolysis, and a prothrombotic state rather than an isolated vascular abnormality. Although several studies have demonstrated an association between PRS and cardiovascular diseases, the relationship between PRS and venous thromboembolism (VTE) remains insufficiently investigated in large-scale population-based studies. Therefore, this study aimed to evaluate the association between PRS and the subsequent risk of VTE using a large real-world electronic health record database.Methods and Materials:A retrospective propensity score-matched cohort study was conducted using the TriNetX Research Network, a multinational electronic health record database. Adult patients diagnosed with PRS between January 1, 2015, and December 31, 2024, were identified and matched 1:1 with individuals without PRS using propensity score matching. Matching variables included demographic characteristics, healthcare utilization, comorbidities, body mass index, and coagulation- and inflammation-related laboratory parameters. To minimize potential confounding, patients with autoimmune diseases, malignancies, hereditary thrombophilia, vascular diseases, pregnancy, or exposure to anticoagulants or hormonal contraceptives were excluded. The primary outcome was incident VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models.Results:After propensity score matching, 93,263 patients were included in each cohort. During follow-up, VTE occurred in 1,407 patients in the PRS cohort and 1,179 patients in the matched control cohort. PRS was significantly associated with an increased risk of VTE (HR, 1.33; 95% CI, 1.24–1.44). The risks of both DVT (HR, 1.30; 95% CI, 1.18–1.43) and PE (HR, 1.38; 95% CI, 1.24–1.54) were also significantly increased. Subgroup analyses demonstrated a stronger association among individuals aged 18–64 years, while consistent associations were observed in both men and women. Kaplan–Meier analyses further demonstrated a persistently higher cumulative incidence of VTE in patients with PRS throughout the follow-up period.Conclusion and Suggestion:Primary Raynaud’s syndrome was associated with an increased risk of venous thromboembolism after propensity score matching. These findings suggest that PRS may represent a systemic vascular disorder characterized by endothelial dysfunction and a prothrombotic tendency rather than merely a localized vasospastic condition. Clinicians should be aware of the potential thromboembolic risk in patients with PRS, particularly in younger individuals and other high-risk populations. Further prospective studies are warranted to validate these findings and to clarify the underlying biological mechanisms.