摘""要:糖尿病血管病變是糖尿病常見的慢性并發(fā)癥,血栓形成的風險高,并伴隨著高致死率和致殘率。糖尿病血管病變與血栓形成之間關系復雜,并且目前的抗血栓治療手段雖有一定成效,但面臨藥物出血傾向、作用機制單一及長期用藥可能引發(fā)藥物抵抗等挑戰(zhàn),亟須創(chuàng)新治療策略。糖尿病血管病變與血栓形成之間的關系密切,其發(fā)病機制涉及內皮細胞功能障礙、血小板活化、凝血系統(tǒng)激活、血液流變學改變、炎癥發(fā)生等多個方面。糖尿病血管病變的治療需采取綜合性策略,包括控制血糖、血脂,使用抗血小板與抗凝藥物,以預防和減少相關并發(fā)癥的發(fā)生。本文就糖尿病血管病變與血栓形成之間的關聯(lián)以及抗血栓治療進行探討。
關鍵詞:糖尿病血管病變;血小板活化因子;凝血;血液流變學;炎癥;血栓形成
中圖分類號:R587.2 """文獻標志碼:A """文章編號:1001-5779(2024)08-0833-07
DOI : 10.3969/j.issn.1001-5779.2024.08.016
Research progress of related factors of diabetic angiopathy and thrombosis
XU Rong HE Ming-jie PENG Lu-lu CHEN Fang CHEN Yi-jian
(1.Endocrine Department,"The First Affiliated Hospital of Gannan Medical University;"2.Hematology Department,"The First Affiliated Hospital of Gannan Medical University,"Ganzhou,"Jiangxi 341000)
Abstract ":"Diabetic angiopathies,"a common chronic complication of diabetes,"has a high risk of thrombosis,"accompanied by high mortality and disability rates. There is a complex relationship between diabetes vascular lesions and thrombosis,"and although the current antithrombotic treatment has certain effect. But it will face challenges of bleeding,"drug resistance because of the single action mechanism "and long-term drug use. Innovative treatment strategies are urgently needed. Diabetes vascular lesions and thrombosis are closely related. The pathogenesis involves endothelial dysfunction,"platelet activation and blood coagulation system activation,"blood rheology change,"inflammation,"and many other aspects. The treatment of diabetes vascular lesions should take a comprehensive strategy,"including the control of blood sugar,"blood fat,"the use of antiplatelet and anticoagulant drugs,"to prevent and reduce the related complications. In this paper,"the diabetes vascular lesions associated with thrombosis and antithrombotic treatment were reviewed.
Key words ":""Diabetic angiopathies;"Platelet activation factor;"Coagulation;"Hemorheology;"Inflammation;"Thrombosis
糖尿病是一種由胰島素分泌絕對或相對不足引起的慢性高血糖狀態(tài)疾病,它是全球增長最快的疾病之一,已成為世界流行性疾病。2021年數據顯示,全球范圍內有5.37億成年糖尿病患者,預測到2045年這一數字將達到7.83億[1]。糖尿病血管病變是由糖尿病引發(fā)的并發(fā)癥,嚴重時可導致糖尿病患者死亡或殘疾[2]。該病變涉及大血管和微血管,其中大血管病變包括心血管疾病、腦血管疾病及外周動脈疾病,微血管病變則涵蓋糖尿病視網膜病變、糖尿病腎病和糖尿病神經病變。糖尿病復雜的代謝環(huán)境,如胰島素抵抗、高血糖狀態(tài)和過量高游離脂肪酸水平,以及其他代謝不平衡,均可能損傷血管壁,出現內皮功能障礙、血小板過度活躍、炎癥和氧化應激上調、血液流變學改變和凝血系統(tǒng)激活,導致動脈和靜脈血栓形成[3],其血栓部位可涉及心臟、腎臟、腦部、下肢血管、視網膜等多處,可能引發(fā)腎衰竭、失明等嚴重并發(fā)癥,不僅使患者的死亡率上升,還顯著降低了患者的整體生活質量。本文就糖尿病血管病變和血栓之間的關系進行綜述。
1""糖尿病血管病變與內皮細胞功能障礙
內皮細胞以單細胞層的形式排列在血管內壁,有維持血管完整性、通透性以及血液流動性、調節(jié)細胞黏附、組織生長和代謝等多種功能。內皮細胞通過產生多種血管收縮劑和擴張劑來維持血管張力[4]。內皮細胞可釋放前列環(huán)素I2(Prostaglandin I2,"PGI2)與一氧化氮(Nitric oxide,"NO)在控制血管張力、調節(jié)血管壁穩(wěn)態(tài)中起著至關重要的作用[5-6]。尤其是NO不僅可以舒張血管,還可以降低血管通透性,抑制單核細胞和淋巴細胞黏附分子的合成,這有助于減少組織氧化、炎癥、血小板聚集和促血栓形成因子的激活。糖尿病血管病變的早期即可出現內皮細胞功能障礙,它是糖尿病血管損傷的主要靶點[7]。糖尿病導致的高糖、缺氧狀態(tài)以及腫瘤壞死因子α和氧化修飾低密度脂蛋白水平升高等一系列病理變化會損害內皮細胞功能,使內皮型一氧化氮合酶(Endothelial nitric oxide synthase,"eNOS)的表達降低,NO、PGI2生成減少,抗血栓作用降低或喪失,血小板黏附增加[8]。高糖抑制內皮細胞抗氧化的能力,上調氧化應激水平,增加活性氧(Reactive oxygen species,"ROS)的生成,引起細胞損傷和內皮通透性升高。ROS過量產生與多種分子機制有關,包括線粒體電子傳遞鏈的改變、晚期糖基化終產物的形成[9]。研究發(fā)現,在糖尿病并發(fā)癥中煙酰胺腺嘌呤二核苷酸磷酸(Nicotinamide adenine dinucleotide phosphate,NADPH)氧化酶介導ROS的生成,使用抗氧化治療能夠顯著防止高糖誘導的氧化應激和內皮細胞表型修飾[10]。在高血糖介導的氧化應激期間,高水平的ROS可誘導DNA損傷,減少NO的產生和影響氧化還原敏感轉錄因子Nrf2的調節(jié),導致內皮功能障礙[11]。此外,高糖誘導的氧化應激會激活核轉錄因子NF-κB的易位,從而誘導促炎細胞因子白介素6的產生[12]。同時高血糖引起的氧化還原改變可能會抑制AMP活化蛋白激酶(Adenosine 5'-monophosphate-activated protein kinase,AMPK)信號通路,該通路通過誘導eNOS活性和NO的產生發(fā)揮抗炎作用[13]。
2""糖尿病血管病變與血小板活化
糖尿病患者血小板活化與血管病變的發(fā)生涉及以下機制:晚期糖基化終產物(Advanced glycation end products,AGEs)產生增加;血管性血友病因子(Von willebrand factor,vWF)、膜糖蛋白(Glycoprotein,GP)Ⅰb和Ⅱb/Ⅲa表達增加;血栓烷A2(Thromboxane A2,"TXA2)產生增加;鈣離子調節(jié)紊亂;P2Y12受體激活降低環(huán)磷酸腺苷(Cyclic adenosine monophosphate,"cAMP)表達。
AGEs是糖類與蛋白質或脂質發(fā)生非酶促反應形成的化合物,它可導致進一步的蛋白質修飾和炎癥信號通路的激活,在糖尿病血管并發(fā)癥中具有重要意義。AGEs受體激活后產生活性氧,糖尿病患者血小板抗氧化能力降低,最終導致血小板功能改變、鈣穩(wěn)態(tài)失調及激酶、磷酸酶激活[14]。同時,AGEs誘導血小板活化,釋放超氧陰離子,增強血小板的聚集作用[15]。AGEs還通過血小板膜磷脂酰絲氨酸外化激活凝血因子誘導血栓形成前狀態(tài)[16]。
健康人血小板活化發(fā)生生理性黏附聚集是通過GPⅠb、vWF和GPⅡb/Ⅲa結合纖維蛋白發(fā)揮作用。高血糖環(huán)境下GPⅠb和GPⅡb/Ⅲa的表達增加[17]。此外,糖尿病患者血小板體積指數(Mean platelet volume,MPV)顯著高于非糖尿病患者,提示高水平的MPV與糖尿病血小板活化增強顯著相關[18]。MPV越大的血小板含有更多的GPⅠb和GPⅡb/Ⅲa受體,血小板聚集增加,產生更多的TXA2[19]。TXA2由前列腺素衍生而來,具有強烈的血管收縮和促進血小板聚集的作用。在糖尿病患者中,血小板內的TXA2水平顯著上升,導致血小板內谷胱甘肽和其他抗氧化劑含量降低,進一步促進了TXA2的產生[20]。這表明糖尿病血管病變與血小板活化導致的TXA2增多密切相關。
糖尿病患者體內Ca2+表達增多會導致血小板活性異常[21]。研究表明,糖尿病患者血小板Ca2+穩(wěn)態(tài)發(fā)生改變,可影響血小板形狀,進而促進TXA2的形成和血小板聚集[22]。此外,糖尿病還會引發(fā)血小板中的Na+/Ca2+交換機制出現故障,加劇血小板活化。血小板Ca2+信號傳導增高,可能會顯著增加糖尿病患者動脈粥樣硬化血栓事件的風險[23]。
二磷酸腺苷(Adenosine diphosphate,ADP)促進血小板聚集,同時還以自分泌的方式分泌組胺、血清素、鈣和其他幾種介質強化血小板聚集效應[24]。ADP還可誘導血小板形狀改變、儲存顆粒分泌、Ca2+流入和細胞內動員以及抑制腺苷酸環(huán)化酶(Adenylate cyclase,AC)活性[25]。當血小板ADP受體P2Y12被激活時,AC活性受到抑制,cAMP水平降低,最終促進血小板活化和聚集[26]。有研究[27]表明,P2Y12受體激活產生的血小板微聚集可能在糖尿病患者血小板高反應性中發(fā)揮關鍵作用。噻吩吡啶類藥物就是通過阻斷P2Y12受體來發(fā)揮抗血小板作用。
3""糖尿病血管病變與凝血系統(tǒng)激活
人體凝血系統(tǒng)與纖維蛋白溶解系統(tǒng)相互平衡,以維持血液正常流動。凝血、纖溶功能異常參與了糖尿病血管病變的發(fā)生,出現血栓形成前狀態(tài)[28]。高血糖損傷血管后,血小板黏附于內皮膠原,激活并釋放凝血因子,啟動內外凝血途徑,凝血酶原轉化為凝血酶,促進纖維蛋白生成。高血糖和糖基化改變纖維蛋白結構,導致形成緊密凝塊,阻礙纖維蛋白溶解。循環(huán)凝血酶原增多、纖溶受阻、纖維蛋白結構功能變化及血小板反應改變共同增加血栓形成風險[29]。研究表明,糖尿病患者體內外凝血酶生成均增加,有微血管并發(fā)癥的患者纖維蛋白原濃度較高,纖維蛋白凝塊密度較大且滲透性差[30]。纖溶酶原激活物抑制因子1(Plasminogen activator inhibitor-1,"PAI-1)、α2-抗纖溶酶屬于纖溶抑制物在糖尿病患者中表達升高,導致糖尿病患者纖維蛋白凝塊溶解時間延長,增加了纖維蛋白凝塊裂解抗性[31]。這些聯(lián)合變化導致凝血功能加強和纖溶功能下降,使糖尿病患者形成血栓風險升高。
4""糖尿病血管病變與血液流變學
糖尿病患者在炎癥或感染時,致病因子降低微血管壁彈性,引發(fā)其功能減弱或喪失,導致血流減緩甚至停滯,嚴重影響血液與組織細胞的物質交換。在糖尿病患者急性炎癥早期,出現微血管擴張,毛細血管內壓增強,血流加快。慢性炎癥期或出現微循環(huán)障礙時,血管內皮細胞功能受到影響甚至破壞,導致管壁變得不光滑。此外,紅細胞變形能力降低、血小板黏附性增強以及血液黏稠度升高等,均可能導致血流速度減慢[32]。在多數毛細血管中,持續(xù)的血流緩慢狀態(tài)可能加劇內皮細胞損傷與壞死,導致血管閉塞。隨著糖尿病病情進展,在微血管系統(tǒng)中可檢測到血管基底膜增厚、血管腔減小和周細胞變性等異常。微循環(huán)中靜水壓力和剪切力增加是毛細血管基底膜增厚的初始步驟[33]。在高剪切速率下,vWF局部釋放和構象變化,導致血小板黏附、血小板活化繼而發(fā)生血栓[34]。血管基底膜增厚使小血管基本結構改變,被認為是糖尿病微血管病的組織學標志[35]。在血管擴張基礎上,血管通透性升高,液體外滲,血管內紅細胞濃縮和血液黏稠度增加,出現血流停滯,微血管腔出現部分或全部堵塞,最終導致微血管系統(tǒng)衰竭[36]。
5""糖尿病血管病變與炎癥
糖尿病和炎癥密切相關,高血糖狀態(tài)下,促炎細胞因子的分泌和活性氧的累積會破壞腸道細胞之間的緊密連接,導致機體容易吸收有害化合物[37]。促炎細胞因子能激活參與氨基酸氧化的髓過氧化物酶和NADPH氧化酶,導致AGEs前體分泌增多[38]。高血糖相關的氧化應激、脂代謝紊亂會加速AGEs的產生,AGEs水平升高標志著糖尿病血管并發(fā)癥的發(fā)生[35]。AGEs與其受體相互作用加劇了氧化應激,通過激活NF-κB信號通路,促進炎癥因子分泌,影響血管生成,破壞血管穩(wěn)態(tài)[39]。炎癥和高血糖均可導致動脈粥樣硬化和血栓性疾病風險增加。
6""糖尿病血管病變的抗血栓治療
糖尿病血管病變急性期出現動脈粥樣硬化斑塊破裂,導致血管栓塞,可行手術或介入治療。如不宜手術,可靜脈注射阿替普酶、尿激酶等溶解血栓,同時使用抗血小板藥物和抗凝藥。慢性期為解決糖尿病患者的血管病變問題,目前臨床的治療建議是積極控制血糖、改善微循環(huán)狀況以及使用抗血小板藥物和抗凝藥物進行治療。下面對糖尿病血管病變的抗血栓治療藥物進行闡述。
6.1 降血糖藥物""控制血糖是預防和治療糖尿病血管病變的關鍵所在。二甲雙胍是大多數2型糖尿?。═ype 2 diabetes,"T2DM)患者治療的一線藥物,可以有效減少糖尿病并發(fā)癥的發(fā)生。針對血糖控制不佳的患者,二甲雙胍血管保護作用主要體現在降低組織因子和血管細胞黏附分子1的水平上[40]。二甲雙胍能改善氧化應激,減少線粒體DNA釋放入循環(huán),保護血小板膜免受氧化損傷,從而抑制血小板聚集。此外,它還具有其他抗血栓作用,如降低血小板中整合素aIIbb3、p-選擇素和胞漿鈣的水平以及降低高胰島素血癥患者PAI-1和血管內皮生長因子的濃度[41]。鈉-葡萄糖轉運體2抑制劑(Sodium-glucose transporter 2 inhibitors,"SGLT2i)通過抑制心肌Na+/H+交換劑,降低了硬脂酸對骨髓血管生成細胞的脂毒性,并抑制血小板活化,從而發(fā)揮其心血管保護作用,穩(wěn)定斑塊并抑制血栓形成[42]。SGLT2i通過抑制脂質合成和NADPH氧化酶活性,減少炎癥因子的表達,從而改善糖尿病誘導的內皮細胞功能障礙;同時它還能抑制血管周圍巨噬細胞積累,減少脂肪細胞死亡,緩解血管纖維化,延緩動脈粥樣硬化的進展[43-44]。研究表明,SGLT2i可顯著減少伴/不伴心血管疾病的T2DM患者不良心血管事件、心力衰竭住院和心血管死亡發(fā)生[45]。在二甲雙胍的基礎上使用恩格列凈用于治療T1DM患者,患者動脈硬度和內皮功能顯著改善[46]。胰高血糖素樣肽1受體激動劑(Glucagon-like peptide-1 receptor agonist,"GLP-1RA)通過激活cAMP/PKA和AMPK通路,減少ROS產生和上調抗氧化劑,抑制氧化應激,從而改善內皮功能,減輕糖尿病相關的血管內皮損傷[47-48]。此外,GLP-1RA可抑制巨噬細胞、單核細胞分泌炎性細胞因子黏附于血管內皮,從而抑制炎癥[49]。一項薈萃分析和亞組分析的結果顯示,GLP-1RA可有效降低T2DM患者發(fā)生重大不良心血管事件、心肌梗死、中風的風險,同時降低心血管和全因死亡率[50]。聯(lián)合應用二肽基肽酶-4抑制劑維達列汀與二甲雙胍,展現出了抗動脈粥樣硬化和心臟保護作用,在對T2DM及伴有癥狀的冠狀動脈粥樣硬化性心臟病患者進行為期3個月的聯(lián)合治療后,糖化血紅蛋白、炎癥相關標志物顯著降低,脂聯(lián)素和高密度脂蛋白膽固醇水平升高[51]。
6.2 抗血小板藥物""阿司匹林作為一種環(huán)氧化酶抑制劑,能夠有效抑制血小板生成TXA2,從而展現出抗炎和抗血栓形成的特性,可降低糖尿病引發(fā)的心血管不良事件的風險[52]。2021年美國糖尿病學會推薦有心血管風險的糖尿病患者使用阿司匹林預防心血管疾病的發(fā)生,對已患有動脈粥樣硬化性心血管疾病的糖尿病患者使用阿司匹林可降低心血管事件的風險[53]。在既往無心血管疾病的糖尿病患者中使用阿司匹林的益處大于出血風險[54]。此外,對于超過70歲的老年人,使用低劑量阿司匹林作為一級預防策略有大出血風險,其潛在益處可能不及風險,應謹慎使用阿司匹林進行一級預防,并不推薦常規(guī)使用[55]。阿司匹林更適合具有高心血管風險但出血風險低的糖尿病患者。
磷酸二酯酶抑制劑西洛他唑在預防復發(fā)性缺血性卒中方面表現出更高的有效性。使用西洛他唑的患者顱內出血和其他出血風險較低,顯示出其良好的安全性[56]。與阿司匹林相比,在為期12個月的治療期內,使用西洛他唑的T2DM患者,其冠狀動脈狹窄和非鈣化斑塊成分的情況得到了顯著改善[57]。因此,西洛他唑較阿司匹林更為安全有效,出血發(fā)生率低,可以用于延緩糖尿病患者冠狀動脈粥樣硬化進展,臨床上對阿司匹林產生的胃腸反應不耐受患者可以考慮使用西洛他唑。
P2Y12受體拮抗劑可以減少血小板聚集、構象改變以及影響凝血過程。氯吡格雷可以顯著降低主要復合終點發(fā)生率,對無ST段抬高的急性冠脈綜合征(Acute coronary syndrome,"ACS)患者有益,但會增加患者大出血風險[58]。雙聯(lián)抗血小板治療一直以來是動脈粥樣硬化性心血管疾病,尤其是ACS患者抗栓治療基礎。目前指南推薦無高出血風險的患者可使用P2Y12抑制劑聯(lián)合阿司匹林治療12個月[59]。在經皮冠狀動脈介入治療成功的ACS患者中,雙抗血小板治療12個月的效果優(yōu)于雙抗血小板治療1~2個月后改用氯吡格雷治療的效果,這表明長期的雙抗血小板治療可能對糖尿病所致的慢性冠脈綜合征患者有益[60]。研究顯示,普拉格雷相較于氯吡格雷具有更快的起效速度,并能迅速抑制血小板聚集[61]。普拉格雷可使接受經皮冠狀動脈介入治療的ACS患者缺血事件(包括支架血栓形成)大幅減少,但相應的出血風險增加[62]。與氯吡格雷相比,替格瑞洛在治療ACS時顯著降低血管事件死亡率,大出血風險未增加,但非手術出血率有所上升,這表明使用替格瑞洛雖然出血風險增高,但臨床治療效果優(yōu)于氯吡格雷[63]。對于70歲及以上的非ST段抬高型ACS患者,氯吡格雷可以減少出血事件,且不增加全因死亡、心肌梗死和卒中的綜合風險[64]。在綜合考慮起效速度、抗栓效果、成本、適應證、出血風險及患者年齡后,氯吡格雷仍被廣泛使用。
6.3 抗凝藥物""對于糖尿病血栓性疾病的預防或長期治療,建議使用口服抗凝藥。華法林、雙香豆素通過抑制機體對維生素K的吸收,減少凝血酶原及Ⅶ、Ⅸ和Ⅹ因子而起抗凝作用,由于需要定期監(jiān)測凝血指標,且與抗血小板藥物聯(lián)合使用出血風險高,限制了其廣泛使用。新型抗凝藥物利伐沙班在療效上與維生素K拮抗劑相似,但安全性更佳,低劑量利伐沙班(每日2次,每次2.5 mg)降低了心血管相關的復合終點死亡風險,對ACS患者血栓事件的二級預防有效[65]。因此,使用低劑量的利伐沙班治療糖尿病血管病變相關的血栓可能是一種新的治療方法。
7""總結與展望
糖尿病導致內皮細胞功能障礙、血小板活化、凝血系統(tǒng)激活、血流速度改變、炎癥發(fā)生,繼而出現微血管和大血管病變,增加血栓形成風險。隨著糖尿病血管病變研究不斷深入,未來基于糖尿病血管病變機制的精準醫(yī)療成為必然趨勢,但仍存在許多問題。首先,人們須深刻認識到糖尿病血管病變的嚴重危害,做到早發(fā)現、早診斷、早治療,避免血栓形成。其次,針對糖尿病血管病變的特效藥物非常有限,單一的治療無法解決問題,其治療應是復雜且全面的,通過控制血糖、血脂以及使用抗血小板藥物和抗凝藥物,進一步降低相關血管并發(fā)癥的形成。通過及時有效治療,可以改善糖尿病患者的預后,降低全球醫(yī)療衛(wèi)生系統(tǒng)的負擔,這一過程的實現需要臨床醫(yī)師共同努力。
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(收稿:2024 - 03 - 12)"(修回:2024 - 05 - 27)
(責任編輯:眭榮燕)