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（1）Complement activation in thrombotic microangiopathy（2）Complement activation in diseases presenting with thrombotic microangiopathy

发布于：2013年7月15日    文字：【大】【中】【小】

Hamostaseologie. 2013 May 29;33(2):96-104. doi: 10.5482/HAMO-12-12-0025. Epub 2013 Feb 15.

Complement activation in thrombotic microangiopathy.

Karpman D, Tati R.

Abstract

The endothelium lining the vascular lumen is continuously exposed to complement from the circulation. When erroneously activated on host cells, complement may generate a deleterious effect on the vascular wall leading to endothelial injury, exposure of the subendothelial matrix and platelet activation. In this review the contribution of complement activation to formation and maintenance of the pathological lesion termed thrombotic microangiopathy (TMA) is discussed. TMA is defined by vessel wall thickening affecting mainly arterioles and capillaries, detachment of the endothelial cell from the basement membrane and intraluminal thrombosis resulting in occlusion of the vessel lumen. The TMA lesion occurs in haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). HUS is further sub-classified as associated with Shiga toxin-producing Escherichia coli (STEC-HUS) or with complement dysregulation (atypical HUS) as well as other less common forms. The contribution of dysregulated complement activation to endothelial injury and platelet aggregation is reviewed as well as specific complement involvement in the development of HUS and TTP.

http://www.ncbi.nlm.nih.gov/pubmed/23411690

Eur J Intern Med. 2013 Jun 4. pii: S0953-6205(13)00137-4. doi: 10.1016/j.ejim.2013.05.009. [Epub ahead of print]

Complement activation in diseases presenting with thrombotic microangiopathy.

Meri S.

Abstract

The complement system contains a great deal of biological "energy ". This is demonstrated by the atypical hemolytic uremic syndrome (aHUS), which is a thrombotic microangiopathy (TMA) characterized by endothelial and blood cell damage and thrombotic vascular occlusions. Kidneys and often also other organs (brain, lungs and gastrointestinal tract) are affected. A principal pathophysiological feature in aHUS is a complement attack against endothelial cells and blood cells. This leads to platelet activation and aggregation, hemolysis, prothrombotic and inflammatory changes. The attacks can be triggered by infections, pregnancy, drugs or trauma. Complement-mediated aHUS is distinct from bacterial shiga-toxin (produced e.g. by E. coli O:157 or O:104 serotypes) induced "typical " HUS, thrombotic thrombocytopenic purpura (TTP) associated with ADAMTS13 (an adamalysin enzyme) dysfunction and from a recently described disease related to mutations in intracellular diacylglycerol kinase ε (DGKE). Mutations in proteins that regulate complement (factor H, factor I, MCP/CD46, thrombomodulin) or promote (C3, factor B) amplification of its alternative pathway or anti-factor H antibodies predispose to aHUS. The fundamental defect in aHUS is an excessive complement attack against cellular surfaces. This can be due to 1) an inability to regulate complement on self cell surfaces, 2) hyperactive C3 convertases or 3) complement activation and coagulation promoting changes on cell surfaces. The most common genetic cause is in factor H, where aHUS mutations disrupt its ability to recognize protective polyanions on surfaces where C3b has become attached. Most TMAs are thus characterized by misdirected complement activation affecting endothelial cell and platelet integrity.

http://www.ncbi.nlm.nih.gov/pubmed/23743117

补体旁路在非典型溶血尿毒综合征（aHUS）中的作用目前已比较清楚，补体旁路蛋白H因子、I因子、MCP、THBD、C3或B因子基因突变，或产生抗H因子自身抗体，导致内皮细胞表面补体旁路活化异常增强，C5a对炎症细胞的趋化作用，MAC在内皮细胞膜上形成引起钙离子内流，内皮细胞活化，出现一系列促进凝血过程的表型，血小板和中性粒细胞也受到损伤，继而出现血栓性微血管病（TMA）表现。目前在约40-60% aHUS患者可以发现上述异常；但aHUS的发病是在上述补体调节缺陷的基础上加之诱因（多种补体缺陷异常同时出现、感染、创伤、手术、内分泌异常、药物、妊娠）。

补体在其他TMA也参与致病，在以下TMA中，补体不是引起内皮细胞损伤的原发因素，补体活化为血栓形成后继发、加重因素，补体活化和凝血系统活动往往分不开：

（1）TTP：目前也已经很明确，TTP发病是由于遗传或获得性的ADAMTS-13缺陷，致使血循环中超大分子vWF形成，网罗血小板形成栓子。补体活化在启动TTP中未发挥作用，但目前研究发现补体旁路在恶化、加重TTP损伤中发挥作用，血小板聚集、脱颗粒反应可以激活补体，血栓和内皮细胞损伤也可以激活补体。

（2）D+HUS：志贺样毒素2（Stx-2）与内皮细胞表面受体（Gb3）结合后可降解核糖体RNA、抑制蛋白合成，对内皮细胞产生毒性及促进凋亡作用，启动内皮细胞损伤。目前的研究发现补体旁路活化在D+HUS中也发挥重要作用；Stx-2可以结合H因子从而干扰H因子的功能，引起补体旁路活化，但Stx-2在血浆的浓度很低，上述机制并不足以解释补体的活化；Stx-2抑制的蛋白合成也包括补体调节相关蛋白；Stx-2引起的内皮细胞损伤、细菌的LPS等也可以继发补体活化；但是，在2011年德国发生的O104：H4 D+HUS患者中，eculizumab（抗C5单抗，抑制C5分解未C5a和C5b，从而抑制C5a和MAC的作用）未显示出显著效果。