ISTH-SSC 国际血栓与止血学会科学标准委员会
T. IBA, J . H. LEVY, H. WADA, J . THACHI L § T . E . WARKENTIN, M. LEVI FOR THE SUBCOMMITTEE ON DISSEMINATED INTRAVASCULAR COAGULATION
J Thromb Haemost 2019; https://doi.org/10.1111/jth.14354.
介绍
脓毒症患者出现凝血功能障碍紊乱很常见，并且容易发展为弥散性血管内凝血。因为DIC的死亡率升高，要进行恰当的临床治疗就需要对DIC进行准确诊断。但是，DIC特定的诊断标准并不完善，近年来又出现一些补充诊断标准。国际血栓与止血学会(ISTH)的DIC标准委员会建议要对类似脓毒症性DIC的疾病进行鉴别诊断。例如溶血性尿毒综合征（HUS）、血栓性血小板减少性紫癜（TTP）、HELLP综合征（溶血、肝酶升高和血小板减少）和肝素诱导的血小板减少症（HIT）（表1 ）。
Introduction
Coagulation disorders are common in sepsisand patients may progress to develop disseminated intravascular coagulation(DIC). Because of the increased mortality of DIC and appropriate clinical management, there is a need for accurate diagnosis [1,2]. However, the specific diagnostic criteria for DIC are not sufficient [3] and additional diagnostic criteria have been developed in recent years [4]. The International Society for Thrombosis and Haemostasis (ISTH) DIC Standardization Committee advises discrimination of diseases that mimic sepsis-related DIC [5]. Important examples include hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), HELLP syndrome (hemolysis, elevated liver enzymes and low platelets) and heparin-induced thrombocytopenia (HIT).
血栓性微血管病（TMA）通常继发于特定情况下，如恶性肿瘤、胶原性疾病或者妊娠相关。DIC也可以被认为是继发性TMA的一部分，但是因为DIC以血小板减少、凝血紊乱为特征，并且发生率远高于其他类型的TMA，因此我们建议把DIC作为区别于其他类型TMA的单独一类疾病。与DIC相比，TMA包括HUS、TTP，是导致血小板减少和微血管病性溶血性贫血的病理生理过程。另一方面，HIT也是一种严重的血栓前疾病，需要特殊的非肝素抗凝剂治疗，也需要快速诊断。因为这些疾病都很危重且需要及时治疗，所以我们在此论述鉴别这些疾病与DIC的方法。
Thrombotic microangiopathy (TMA) is termed secondary when associated with a specific context favouring its occurrence.This encompasses TMAs associated with malignancy, collagen diseases orpregnancy. DIC can also be considered as a part of secondary TMA; however, because DIC is characterized by thrombocytopenia with coagulation disorders, and the incidence of DIC is higher than that of other TMAs, we considered DIC as acategory that is independent from other thrombocytopenic microangiopathic diseases in this recommendation. In contrast to DIC, TMA includes both HUS andTTP, and is a broad pathophysiologic process that leads to thrombocytopenia and microangiopathic hemolytic anemia [6]. On the other hand, HIT is also a severe prothrombotic disease that requires specific therapy with an alternative non-heparin anticoagulant, which therefore has to be diagnosed promptly.Because all of these conditions are critical and require specific prompt treatments, we will review methods to discriminate these disease states fromDIC.
脓毒症性DIC
脓毒症性DIC是脓毒症最常见的并发症之一，并需基于特定标准做出诊断（表2）。DIC的发生率是TMA的150倍。患有TMA的病人很容易被诊断为DIC，因为DIC的临床特征与其他血小板减少相关疾病有重叠。脓毒症性DIC以感染和凝血的系统激活为特征，并由炎凝交互最终导致器官功能障碍。DIC是由多种原因导致局部微血管损伤，进而引起广泛的凝血系统激活和器官功能障碍。因此，脓毒症性DIC主要的实验室特点包括纤维蛋白标志物升高以及血小板和凝血因子消耗。所以纤维蛋白标志物接近正常和PT没有出现延长提示DIC诊断不成立（图1）。当血涂片显示红细胞碎片和血小板计数减少时，TTP和HUS通常会因贫血并血小板减少做出诊断。就临床症状而言，器官衰竭通常在DIC和TMA中均可出现，但急性肺损伤和/或休克则在DIC和TMA患者皆常见，肾衰在脓毒症、DIC和TMA中均常见，脑功能障碍在TMA中更常见。值得注意的是，如果脓毒症好转后血小板减少和溶血仍然持续存在，仍需对DIC进行鉴别诊断。
Sepsis-induced DIC
Disseminated intravascular coagulation isone of the most frequent complications in sepsis and the diagnosis can be madebased on specific criteria (Table 2) [7]. The incidence of DIC is 150-foldhigher than that of TMA [8] and patients with TMA can easily be diagnosed ashaving DIC because the clinical characteristics of DIC and other thrombocytopenic conditions significantly overlap. Sepsis-induced DIC is characterized by an infection and systemic activation of coagulation, which can produce organ dysfunction as a consequence of interactions between coagulation and inflammation [9,10]. DIC is defined as ‘an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes that produces damage to the microvasculature,which if sufficiently severe, can produce organ dysfunction’ [11]. Thus, its main laboratory features include elevated fibrin markers and the consumption of platelet and coagulation factors. Therefore, near normal fibrin-related markers and lack of prolongation of the prothrombin time (PT) suggest the absence of DIC (Fig. 1) [12]. With TTP and HUS, the diagnosis can often be made when anemia and thrombocytopenia result in a blood smear being performed, which shows red cell fragments and thrombocytopenia. As for the clinical symptoms,organ failure is frequently observed in DIC as well as TMA, but acute lung injury and/or shock is more frequently seen in patients with DIC, renal failure is commonly seen in sepsis, DIC and TMA, and cerebral dysfunction is more common in TMA [13]. Of note, if thrombocytopenia or hemolysis are sustained after sepsis resolution, other diseases that should be distinguished from DIC must be considered.
非典型HUS
血栓性微血管病包括非典型HUS (aHUS)、产志贺菌素大肠杆菌HUS和TTP，这些疾病均以微血管病性溶血性贫血为特征，具体表现为溶血性贫血（乳酸脱氢酶LDH升高、血红蛋白降低、结合珠蛋白减少或消失和红细胞碎片）、血小板减少和器官功能衰竭。除了以上实验室表现外，临床上考虑aHUS还要基于临床症状，包括急性肾损伤。考虑aHUS时，还要关注患者的年龄、既往史和家族史，这都有助于诊断。aHUS发病是由失控的补体途径激活导致，补体活化同时会激活血小板，诱导溶血并引起血管内皮损伤。2/3的aHUS病例与类似的补体激活有关，同时溶血导致大量的红细胞损伤相关分子模式（DAMPs）也参与其中。其中一个主要的红细胞DAMPs是游离血红素，它会加剧炎症并诱导中性粒细胞胞外诱捕网（NET）形成，从而导致肾小球内纤维蛋白沉积和血栓形成。
需要注意的是，脓毒症性DIC的不典型的临床过程经常会变成aHUS的线索。例如，感染和血液系统疾病的差异提示其他基础疾病可能。血压也是重要的线索，因为HUS通常表现为严重的高血压，而脓毒症性DIC常伴有血管痉挛和低血压。下一代测序技术检测补体和凝血级联基因的编码区域使确诊成为可能。一旦病人确诊为aHUS，抗-C5单克隆抗体（Eculizumab）应是一线疗法。
Atypical HUS
Thrombotic microangiopathies, including atypical HUS (aHUS), Shigatoxin-producing Escherichia coli HUS and TTP, are different types of microangiopathic hemolytic anemia represented by hemolytic anemia (elevated lactate dehydrogenase [LDH], decreased hemoglobin, decreased or absent haptoglobin and red blood fragmentation), thrombocytopenia and organ failure[14]. Beside the afore mentioned laboratory findings, clinical suspicion of aHUS will be based on the clinical symptoms, including acute kidney injury. When suspecting aHUS, additional information, including the patient’s age and medical and family history, is helpful in establishing a diagnosis. Of note,aHUS results from the uncontrolled activation of the alternative complement pathway, which activates platelets, induces hemolysis and causes vascular endothelium injury. Two-thirds of aHUS cases are associated with an identifiable complement-activating condition, and the release of massive redcell damage-associated molecular patterns (DAMPs) from hemolysis may play a role in this [15,16]. One of the major red cell DAMPs is free-heme, which amplifies inflammation and induces neutrophil extracellular trap (NET) formation, thereby leading to fibrin deposition and thrombus formation within glomeruli [17].
Notably, an atypical clinical course for sepsis-induced DIC often becomes a clue for aHUS. For example, the discrepancy between the infectionstatus and hematologic disorder indicates the possibility of other basal diseases. Another clue is the blood pressure, because HUS often presents with severe hypertension, whereas sepsis-induced DIC presents with vasoplegia and hypotension. Next-generation sequencing to interrogate the coding regions of complement and coagulation cascade genes may make it possible to make a definitive diagnosis [18]. Oncethe patient is diagnosed with aHUS, administration of anti-C5 monoclonal antibody (eculizumab) should be the firstline therapy [19].
产志贺毒素大肠杆菌HUS
产志贺毒素大肠杆菌感染引起的HUS比aHUS更常见。通常认为产志贺毒素大肠杆菌HUS发病机制是由于产志贺毒素大肠杆菌特别是O157:H7或O104:H4引起胃肠道感染后导致的。感染后毒素能引起内皮细胞损伤诱发内皮细胞补体沉积并干扰补体分子调节活性。与其他TMA类似，产志贺毒素大肠杆菌HUS的特征是微血管病性溶血性贫血和以肾脏、中枢神经系统为代表的器官功能障碍。检测志贺毒素O157:H7或O104:H4有助于诊断这种类型的HUS。一旦诊断为产志贺毒素大肠杆菌HUS，通常首选支持疗法，而不建议使用抗生素治疗。
Shiga toxin-producing E. coli HUS
Hemolytic uremic syndrome caused by Shigatoxin-producing E. coli infection is more common than aHUS. A general understanding of the pathogenetic mechanisms driving Shiga toxin-producing E.coli HUS is that it follows a gastrointestinal infection with Shigatoxin-producing E. coli, typically O157:H7 or O104:H4. In Shiga toxin-producing E. coli HUS, the toxin triggers endothelial complement deposition through endothelial injury and possibly interferes with the activity of complement regulatory molecules. Similar to the other TMAs, Shiga toxin-producing E. coli HUS is characterized by microangiopathic hemolytic anemia and dysfunction of affected organs represented by the kidney and central nervous system [14]. For diagnosing this type of HUS, detection of Shiga toxin O157:H7 or O104:H4 is extremely helpful. Once diagnosed as Shiga toxin-producing E. coli HUS,aggressive antibiotic use is not usually recommended and supportive therapy is preferred.
血栓性血小板减少性紫癜（TTP）
DIC和TTP都会引起微血管血栓（依次是毛细血管后小静脉和小动脉），但DIC通常因凝血系统激活引起毛细血管后小静脉血栓，TTP通常是血小板/血管性血友病因子微聚集形成引起毛细血管后小动脉血栓。快速准确地诊断TTP是正确治疗的关键。因为获得性TTP是由VWF裂解蛋白酶ADAMTS-13自身免疫反应导致的，所以近来推荐应用快速ADAMTS-13活性试验，该实验耗时约数小时。紧急血浆置换可用于治疗TTP，如不进行血浆置换TTP死亡率可达80%以上。当TTP发生时，英国指南建议应在4h内启动血浆置换治疗，即便疑似TTP不能及时确诊仍应开始血浆置换治疗，随后再明确诊断。相反，血浆输注也能预防预防或者治疗双等位基因突变导致的遗传性ADAMTS-13缺乏。TTP时ADAMTS-13活性通常都<10%，而DIC和其他类型的TMA很少<30%，可以据此进行鉴别诊断。此外，缓解期的TTP病人可以检测到ulVWF多聚体。Caplacizumab作为VWF抗体已在欧洲被批准和血浆置换和免疫抑制用于获得性TTP的治疗。ADAMTS-13浓缩物或ADAMTS-13重组药物已经在进行临床试验，未来有望进入临床。
Thrombotic thrombocytopenic purpura
Both DIC and TTP cause microvascular thrombosis (postcapillary venules and arterioles, respectively), which is caused mainly by the activation of the coagulation system in DIC and by platelet/von Willebrand factor microaggregate formation in TTP. Prompt differentiation of TTP from other causes is crucial for appropriate treatment. Because acquired TTP is caused by autoantibody-induced depletion or inhibition of a disintegrin and metalloproteinase with a thrombospondin type 1 motif,member 13 (ADAMTS-13), the use of a rapid ADAMTS-13 activity assay with aturnaround time of several hours was proposed recently [20]. A plasma exchange is urgently required for TTP, and without this therapeutic intervention there is the potential for over 80% mortality. When TTP occurs, the treatment shouldbe initiated within 4 h as recommended by British guidelines, and if the diagnosis cannot be excluded then plasma exchange should be started and thediagnosis made later. In contrast, plasma infusion suffices for prophylaxis ortreatment of congenital deficiency of ADAMTS-13 resulting from biallelic mutations of the ADAMTS-13 gene. Because the ADAMTS-13 level in TTP is commonly decreased to <10% and ADAMTS-13 levels in DIC or other TMA disorders arerarely <30%, this may help to facilitate differentiation [21]. Additionally, unusually large von Willebrand factor (VWF) multimers can be detected in TTPpatients in remission [22]. As for new treatments, caplacizumab, an anti-VWF, wasrecently approved in Europe for the treatment of acquired TTP, in conjunction with plasma exchange and immunosuppression [23]. ADAMTS-13 factor concentratesare currently in clinical trials and recombinant ADAMS-13 is also expected inthe near future.
HELLP综合征（溶血、肝酶升高和血小板减少）
妊娠时DIC罕见，但可由急性围产期出血、胎盘早剥、先兆子痫和败血症诱发。HELLP综合征在妊娠期先兆子痫的严重并发症，可增加产妇和新生儿发病率和死亡风险。HELLP综合征的病理生理以微血管血小板血栓和内皮细胞激活为特征。ADAMTS-13活性减弱、活化内皮细胞释放VWF多聚体导致大量活化VWF生成。但遗传性TTP也可在妊娠期间首次发生。所以，凝血筛查对于把DIC与TTP和HUS区别开很有帮助。血小板减少、微血管病性贫血和肝脏损伤是HELLP综合征的主要临床表现。及时分娩是HELLP综合征的标准处理措施，但分娩后症状仍持续或恶化必须考虑获得性TTP的可能。
Hemolysis, elevated liver enzymes and lowplatelets
Disseminated intravascular coagulation inpregnancy is rare but can be caused by acute peripartum hemorrhage, placental abruption, pre-eclampsia and sepsis [24]. HELLP syndrome is also a severe complication of pre-eclampsia in pregnancy, leading to the risk of maternal and neonatal morbidity and mortality. The pathophysiology of HELLP is characterized by microvascular platelet thrombi and the activation of endothelium. The release of VWF multimers from the activated endothelial cell and decreasedADAMTS-13 activity result in increased amounts of an active form of VWF [25],but congenital TTP can also present for the first time in pregnancy. Thus,coagulation screening is helpful for discriminating DIC from both TTP and HUS.Thrombocytopenia, microangiopathic hemolytic anemia and hepatic damage are the major clinical symptoms of HELLP syndrome. Timely delivery of the baby is the standard management of HELLP syndrome in pregnancy, but when the symptoms worsen or are sustained after delivery an acquired TTP should be considered[26].
肝素诱导的血小板减少症
HIT是血小板活化抗体诱发的疾病，这种抗体能够识别PF4（阳离子）和肝素（血小板相关阴离子）结合形成的多分子聚合物。HIT患者很容易形成静脉和动脉血栓，但微循环几乎不会从形成血栓。HIT在临床上可采用4T评分法（血小板减少、发生时间、血栓与血小板减少的其他诱因）进行评估。检测PF4的IgG 特异性抗体的ELISA试验强阳性同时洗涤血小板活化抗体试验阳性即可诊断HIT。这样的联合试验是ISTH-SSC对HIT实验室标准化的建议。所谓的自身免疫性HIT并不常见，通常包括肝素停用后数天出现血小板减少，或者停用肝素后HIT仍然持续数周，甚至以前没有肝素暴露史也突然出现血小板减少（自发HIT）。合并脓毒症时HIT容易诊断错误，因为两者都会出现白细胞增多和显性DIC，而且HIT和脓毒症性都会引起缺血性肢体坏死，HIT时容易出现静脉下肢坏疽，DIC更容易引起对称性周围肢体坏疽甚至截肢。对称性外周肢体坏疽常见于休克、休克肝和DIC，往往这种状况下病人需要肝素治疗，这也容易导致HIT误诊。
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia is caused by platelet activating antibodies that recognize multimolecular complexes of(cationic) platelet factor 4 (PF4) bound to heparin (or platelet-associatedpolyanions). Patients have a high frequency of thrombosis that can affect veins, arteries or, rarely, even the microcirculation. The clinical probability of HIT can be evaluated using a clinical 4Ts scoring system (thrombocytopenia,timing of onset, thrombosis, and other causes of thrombocytopenia) [27]. A diagnosis of HIT can be supported by a strong-positive PF4-dependent ELISA(preferably IgG specific) plus a positive test for platelet-activating antibodies using washed platelets. This test combination reinforces theISTH-SSC recommendation for standardization of laboratory testing for HIT [28].So-called ‘autoimmune’ HIT can present in unusual ways, including onset several days after heparin has been stopped, or HIT that persists for several weeksdespite stopping heparin or, rarely, occurs even without prior heparin exposure(spontaneous HIT syndrome). HIT can cause diagnostic confusion with sepsis, asboth can be associated with leukocytosis and overt DIC; moreover, both HIT and septic DIC can cause ischemic limb necrosis, with venous limb gangrenepredominating in HIT, whereas symmetrical peripheral gangrene is characteristic of limb loss causing complications in septic DIC [29]. The combination ofshock, shock liver and DIC is often seen in symmetrical peripheral gangrene,and when such patients receive heparin an erroneous diagnosis of HIT may occur.
小结
早期识别脓毒症性DIC非常重要，其他潜在的原因也需要进行恰当的临床治疗。产志贺毒素的大肠杆菌检测和ADAMTS-13活性检测试验可以诊断产志贺毒素大肠杆菌HUS和TTP。HELLP和HIT从临床病史、实验室检查和概率评分进行诊断。最后，aHUS是罕见的，但诊断时应该考虑。
Summary
Early recognition of sepsis-induced DIC isimportant and other potential causes need to be considered for appropriate clinical management. Shiga toxin-producing E. coli HUS and TTP can be evaluatedthrough testing for Shiga toxin-producing E. coli and ADAMTS-13 activity. HELLPand HIT can be suspected from the clinical history, laboratory testing and probability scoring. Finally, aHUS is rare but should be considered in the diagnosis.
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