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Traumatic brain injury: Advances in coagulopathy (Review)
创伤性脑损伤:凝血病的研究进展(综述)

HONGQIAO HOU*, ZHE QU*, RUPING LIU, BOWEN JIANG, LANLAN WANG and AIQUN LI
侯红桥*、曲哲*、刘汝平、蒋博文、王兰兰和李爱群
Department of Emergency, Yantai Affiliated Hospital of Binzhou Medical College, Yantai, Shandong 264100, P.R. China
滨州医学院烟台附属医院急诊科,山东烟台 264100

Received May 26, 2024; Accepted August 5, 2024
2024 年 5 月 26 日收到;2024 年 8 月 5 日接受
DOI: 10.3892/br.2024.1844

Abstract  摘要

Trauma is a prevalent cause of coagulopathy, with traumatic brain injury (TBI) accompanied by coagulation disorders particularly linked to adverse outcomes. TBI is distinguished by minimal bleeding volume and unique injury sites, which precipitate complex coagulation disturbances. Historically, research into trauma-induced coagulopathy has primarily concentrated on the molecular biology and pathophysiology of endogenous anticoagulation and inflammation. Nonetheless, recognizing that cells are the fundamental units of structure and function in all living organisms, the present review aimed to distill our understanding of coagulopathy post-TBI by elucidating the intricate cellular mechanisms involving endothelial cells, neutrophils and platelets. Additionally, this study evaluates the strengths and weaknesses of various diagnostic tools and discusses the characteristics of pharmacological treatments and potential therapies for patients with TBI and coagulation disorders. The aim of this review is to amalgamate recent updates in mechanistic research and innovative diagnostic and therapeutic methodologies, thereby fostering the progression of precision medicine within this specialized domain.
创伤是导致凝血功能障碍的一个普遍原因,创伤性脑损伤(TBI)伴随的凝血功能障碍尤其与不良后果有关。创伤性脑损伤的特点是出血量极少,受伤部位特殊,从而引发复杂的凝血功能障碍。一直以来,有关创伤诱发凝血病的研究主要集中在内源性抗凝和炎症的分子生物学和病理生理学方面。然而,由于细胞是所有生物体结构和功能的基本单位,本综述旨在通过阐明涉及内皮细胞、中性粒细胞和血小板的复杂细胞机制,提炼我们对创伤后凝血病的理解。此外,本研究还评估了各种诊断工具的优缺点,并讨论了针对创伤后应激障碍和凝血功能障碍患者的药物治疗和潜在疗法的特点。本综述旨在将最新的机理研究成果与创新的诊断和治疗方法相结合,从而促进这一专业领域精准医学的发展。

Contents  目录

  1. Introduction  导言
  2. Cellular mechanisms of coagulopathy following TBI
    创伤后凝血病的细胞机制
  3. Treatment of coagulation disorders following TBI
    创伤性脑损伤后凝血功能障碍的治疗
  4. Complications  并发症
  5. Diagnostic tools for coagulopathy following TBI
    创伤后凝血病诊断工具
  6. Neurocritical care monitoring tools
    神经重症监护监测工具
  7. Summary and perspectives
    总结与展望
Key words: traumatic brain injury, coagulopathy, platelet dysfunction, endotheliopathy, neutrophil extracellular traps
关键词:创伤性脑损伤、凝血功能障碍、血小板功能障碍、内皮细胞病变、中性粒细胞胞外捕获器

1. Introduction  1.导言

Traumatic brain injury (TBI) encompasses a series of complex pathological processes wherein brain tissue structure and function are compromised due to mechanical force applied to the head, stemming from various causes. Of considerable interest is the potential link between genetic modifications and an augmented susceptibility to TBI. Specifically, the polymorphisms within the apolipoprotein E promoter region, the TAU gene (1) and the brain-derived neurotrophic factor gene have been implicated in elevating the risk of concussion and contributing to adverse outcomes subsequent to a TBI episode. Additionally, alterations in the dopamine receptor D 2 D 2 D_(2)\mathrm{D}_{2} gene may potentiate brain injury risk by impacting cognitive functions and behavioral traits in affected individuals. Nevertheless, the precise contribution of NEFH gene mutations to the pathology of concussion remains an area requiring further elucidation through research (2).
创伤性脑损伤(TBI)包括一系列复杂的病理过程,在这些过程中,由于各种原因导致头部受到机械力的作用,脑组织结构和功能受到损害。基因改变与 TBI 易感性增加之间的潜在联系颇受关注。具体来说,载脂蛋白 E 启动子区域、TAU 基因 (1) 和脑源性神经营养因子基因的多态性已被证实会增加脑震荡的风险,并导致创伤性脑损伤后的不良后果。此外,多巴胺受体 D 2 D 2 D_(2)\mathrm{D}_{2} 基因的改变可能会影响受影响个体的认知功能和行为特征,从而加剧脑损伤风险。然而,NEFH 基因突变对脑震荡病理的确切影响仍是一个需要通过研究进一步阐明的领域 (2)。
The incidence and mortality rates of TBI are notably higher in low- and middle-income countries compared with high-income countries (3), affecting an estimated 10 million individuals worldwide annually (4). Falls are the predominant cause of TBI, especially among individuals > 50 > 50 > 50>50 years old (5). This demographic often presents with comorbidities and may be using anticoagulant medications prior to injury, factors that amplify the complexity and mortality risk associated with coagulation abnormalities post-TBI (6). Coagulopathy in patients with TBI typically manifests as abnormalities in conventional coagulation assays. However, the prevalence of early coagulopathy varies widely due to inconsistent definitions and differences in the severity of the injury (7).
与高收入国家相比,中低收入国家的创伤性脑损伤发病率和死亡率明显更高(3),估计全世界每年有 1 000 万人受到影响(4)。跌倒是造成创伤性脑损伤的主要原因,尤其是在 > 50 > 50 > 50>50 岁的人群中(5)。这些因素增加了创伤后凝血异常的复杂性和死亡风险(6)。创伤性脑损伤患者的凝血功能障碍通常表现为常规凝血检测的异常。然而,由于定义的不一致和损伤严重程度的差异,早期凝血病的发病率差别很大(7)。
Most patients with severe TBI demonstrate abnormal coagulation test results shortly after injury, whereas this is less common in those with mild injuries (8). The severity of TBI is generally assessed utilizing the Glasgow Coma Scale, categorizing injuries as mild (14-15 points), moderate ( 9 13 9 13 9-139-13 points) and severe ( 3 8 3 8 3-83-8 points) (9). The mortality rate for severe TBI cases is approximately one-third, and 60 % 60 % ∼60%\sim 60 \% of survivors suffer from enduring physical, mental and social deficits (10). Patients with TBI accompanied by coagulopathy are often closely associated with poor prognosis (11), thus advancing research and treatment for coagulopathy following TBI is of paramount importance.
大多数严重创伤性脑损伤患者在受伤后不久就会出现凝血测试结果异常,而这种情况在轻度创伤患者中较少见(8)。创伤性脑损伤的严重程度一般采用格拉斯哥昏迷量表进行评估,分为轻度(14-15 分)、中度( 9 13 9 13 9-139-13 分)和重度( 3 8 3 8 3-83-8 分)(9)。重度创伤性脑损伤病例的死亡率约为三分之一, 60 % 60 % ∼60%\sim 60 \% 幸存者在身体、精神和社会方面都存在持久的缺陷(10)。伴有凝血功能障碍的创伤性脑损伤患者往往预后不良(11),因此推进创伤性脑损伤后凝血功能障碍的研究和治疗至关重要。
In the human body, cells are the fundamental units of structure, function and biological processes. The present review updated and simplified the series of coagulopathyrelated events occurring after TBI by summarizing the
在人体中,细胞是结构、功能和生物过程的基本单位。本综述更新并简化了创伤后发生的一系列凝血病相关事件,总结了

mechanistic changes and roles of three types of cells [endothelial cells (ECs), neutrophils and platelets] in the coagulation process post-TBI. Additionally, by consolidating the pharmacological treatments and potential therapeutic applications for patients with TBI with coagulation dysfunction, the present study aimed for this review to provide more insights into precision medicine by summarizing updated mechanistic studies and innovative diagnostic and therapeutic techniques. To facilitate a better understanding of the content for the readers, definitions for the specialized terminology mentioned in this article have been provided (Table I).
本综述旨在总结创伤性脑损伤后凝血过程中三种细胞(内皮细胞、中性粒细胞和血小板)的机理变化和作用。此外,通过整合针对创伤性脑损伤凝血功能障碍患者的药物治疗和潜在治疗应用,本研究旨在通过总结最新的机理研究和创新诊断与治疗技术,为精准医学提供更多见解。为便于读者更好地理解内容,本文提供了文中提及的专业术语的定义(表一)。

2. Cellular mechanisms of coagulopathy following TBI
2.创伤后凝血病的细胞机制

The mechanisms underpinning coagulopathy subsequent to TBI are multifaceted, encompassing a broad spectrum of cellular alterations. These primarily include alterations in ECs, neutrophils and platelets (Fig. 1).
造成创伤性脑损伤后凝血病的机制是多方面的,包括广泛的细胞改变。这些改变主要包括心肌细胞、中性粒细胞和血小板的改变(图 1)。
Endothelium and blood-brain barrier (BBB). The endothelium and BBB are pivotal in maintaining hemostatic balance. Under normal conditions, the ECs function as a barrier to prevent the release of procoagulant factors, such as cerebral microvesicles, into the circulation ( 12 , 13 ) ( 12 , 13 ) (12,13)(12,13). However, these cells can sustain rapid damage during the acute phase of trauma, thereby intensifying coagulation disorders ( 14 , 15 ) ( 14 , 15 ) (14,15)(14,15). Research from 2003 demonstrated that systemic coagulopathy can manifest within minutes following TBI (16), characterized by activation of protein C and enhanced fibrinolysis (17). Ordinarily, tissue-type plasminogen activator (tPA) struggles to access fibrin structures shielded by platelet aggregates, thus impeding the efficiency of subsequent enzymatic reactions essential for clot resolution (18). Moreover, the mechanical forces imparted on the brain during TBI mechanically disrupt the BBB in a pattern akin to a Gaussian distribution (19), precipitating secondary ischemic and inflammatory injuries. These injuries enhance the permeability of adjacent BBB segments, exacerbating the condition. Brain-derived microvesicles (BDMVs) enriched with tissue factor (TF) and phosphatidylserine (PS) are implicated in the exacerbation of brain injury, the initiation of early coagulation abnormalities and the promotion of hyperfibrinolysis (12). The elevated presence of TF and PS (12) in brain tissue not only facilitates the expansion of brain injury ( 20 , 21 ) ( 20 , 21 ) (20,21)(20,21) but also instigates platelet dysfunction and depletion, as well as disseminated intravascular coagulation (DIC) ( 22 , 23 ) ( 22 , 23 ) (22,23)(22,23). Lactoferrin, through its interaction with these microvesicles, has shown promise in mitigating coagulation disturbances and enhancing prognosis in a mouse model of TBI (24). Nonetheless, the specific mechanisms through which lactoferrin exerts its effects and the precise operational definitions of these cellular microvesicles continues to be elusive.
内皮和血脑屏障(BBB)。内皮和血脑屏障是维持止血平衡的关键。在正常情况下,内皮细胞发挥屏障作用,防止促凝因子(如脑微囊泡)释放到血液循环中 ( 12 , 13 ) ( 12 , 13 ) (12,13)(12,13) 。 然而,在创伤的急性期,这些细胞会迅速受损,从而加剧凝血障碍 ( 14 , 15 ) ( 14 , 15 ) (14,15)(14,15) 。2003 年的研究表明,全身性凝血功能障碍可在创伤后几分钟内显现出来(16),其特点是蛋白 C 激活和纤维蛋白溶解增强(17)。通常情况下,组织型纤溶酶原激活剂(tPA)很难进入被血小板聚集体遮挡的纤维蛋白结构,从而阻碍了对血凝块溶解至关重要的后续酶反应的效率(18)。此外,创伤性脑损伤期间对大脑施加的机械力以类似高斯分布的模式机械性地破坏了 BBB(19),引发了继发性缺血和炎症损伤。这些损伤会增强邻近 BBB 区段的通透性,使病情恶化。富含组织因子(TF)和磷脂酰丝氨酸(PS)的脑源性微载体(BDMVs)与脑损伤的加重、早期凝血异常的启动和纤溶亢进的促进有关(12)。脑组织中 TF 和 PS(12)的升高不仅有利于脑损伤的扩大 ( 20 , 21 ) ( 20 , 21 ) (20,21)(20,21) ,而且还会导致血小板功能障碍和耗竭,以及弥散性血管内凝血(DIC) ( 22 , 23 ) ( 22 , 23 ) (22,23)(22,23) 。乳铁蛋白通过与这些微囊的相互作用,在创伤性脑损伤小鼠模型中有望减轻凝血障碍并改善预后(24)。 然而,乳铁蛋白发挥其作用的具体机制以及这些细胞微囊的精确操作定义仍然难以捉摸。
Neutrophils. Upon bodily injury, neutrophils are among the first cells to respond (25). Neutrophil extracellular traps (NETs), which are web-like structures released by activated neutrophils under specific conditions into the extracellular space, play a crucial role in entrapping and neutralizing microorganisms. The formation of NETs is a form of the programmed cell death process (26). Allen et al (27) have revealed that in the context of acute TBI, neutrophils are capable of penetrating cerebral vascular ECs and initiating the
中性粒细胞身体受伤后,中性粒细胞是最先做出反应的细胞之一(25)。中性粒细胞胞外捕获物(NET)是活化的中性粒细胞在特定条件下释放到细胞外空间的网状结构,在捕获和中和微生物方面发挥着至关重要的作用。NETs 的形成是一种程序性细胞死亡过程(26)。Allen 等人(27)发现,在急性创伤性脑损伤的情况下,中性粒细胞能够穿透脑血管 EC 并启动

release of extracellular traps. This process triggers the release of procoagulant factors, including brain-derived microparticles and damage-associated molecular patterns (DAMPs) (27). The delayed apoptosis of neutrophils leads to an exacerbation of NETs formation and coagulation dysfunction during the acute phase of TBI (28). Platelet-neutrophil aggregation interactions play a pivotal role in traumatic coagulopathy. In patients with TBI who exhibit coagulation abnormalities, activated platelets enhance the formation of NETs generation through the secretion of high mobility group box 1 protein (HMGB1) ( 29 , 30 ) ( 29 , 30 ) (29,30)(29,30). NETs exacerbate the disruption of the EC barrier by promoting phosphatidylserine exposure and TF expression on ECs ( 28 , 31 , 32 ) ( 28 , 31 , 32 ) (28,31,32)(28,31,32). Moreover, NETs induce a procoagulant phenotype in ECs through the action of interleukin-1 α α alpha\alpha and cathepsin G (33), which contributes to neurological impairment ( 34 , 35 ) ( 34 , 35 ) (34,35)(34,35). Furthermore, inflammation plays a critical role in underlying secondary injury following TBI (36), with NETs significantly mediating the interaction between inflammation and coagulation (37). Given the comprehensive implications of these processes, NETs may offer a novel therapeutic targets for coagulopathy associated with TBI.
释放细胞外陷阱。这一过程会引发促凝因子的释放,包括脑源性微颗粒和损伤相关分子模式(DAMPs)(27)。在创伤性脑损伤的急性期,中性粒细胞的延迟凋亡会加剧 NETs 的形成和凝血功能障碍(28)。血小板-中性粒细胞聚集相互作用在创伤性凝血病中起着关键作用。在出现凝血异常的创伤性脑损伤患者中,活化的血小板通过分泌高迁移率基团框 1 蛋白(HMGB1) ( 29 , 30 ) ( 29 , 30 ) (29,30)(29,30) 促进了 NET 的形成。NET通过促进磷脂酰丝氨酸暴露和TF在EC上的表达,加剧EC屏障的破坏 ( 28 , 31 , 32 ) ( 28 , 31 , 32 ) (28,31,32)(28,31,32) 。此外,NET 通过白细胞介素-1 α α alpha\alpha 和 cathepsin G(33)的作用,在心血管细胞中诱导促凝血表型,从而导致神经损伤 ( 34 , 35 ) ( 34 , 35 ) (34,35)(34,35) 。此外,炎症在创伤性脑损伤后的潜在继发性损伤中起着至关重要的作用(36),NET 在很大程度上介导了炎症与凝血之间的相互作用(37)。鉴于这些过程的综合影响,NET 可为治疗与创伤性脑损伤相关的凝血病提供新的治疗靶点。
Platelets. Low platelet counts and/or functional platelet defects in platelets markedly enhance the risk of bleeding; a platelet count below 175 × 10 9 / 1 175 × 10 9 / 1 175 xx10^(9)//1175 \times 10^{9} / 1 is associated with an elevated risk of progressive intracranial hemorrhage progression, and counts below 100x10% /le are strongly associated with increased mortality ( 38 , 39 ) ( 38 , 39 ) (38,39)(38,39). This clinical presentation contrasts with traumatic coagulopathy (TIC), which is distinct from DIC, the latter typically characterized by thrombocytopenia (40). Firstly, in patients with TBI a reduced level of platelet reactivity is positively associated with improved prognoses ( 41 , 42 ) ( 41 , 42 ) (41,42)(41,42). During TBI, the depletion of von Willebrand factor hampers platelet aggregation in vitro (43). This impairment is exacerbated by diminished platelet responsiveness to agonists such as adenosine diphosphate (ADP) and/or arachidonic acid (AA), leading to a specific defect in aggregation defects due to inhibition of ADP and AA receptors a phenomenon closely linked to TBI severity ( 22 , 44 ) ( 22 , 44 ) (22,44)(22,44). These defects occur independently of hemorrhagic shock or the absolute platelet count ( 22 , 45 ) ( 22 , 45 ) (22,45)(22,45). Additionally, elevated circulating levels of catecholamine platelet agonists, such as epinephrine and norepinephrine, are associated with compromised platelet aggregation function in patients with TBI (46).
血小板。血小板计数低和/或血小板功能缺陷明显增加了出血风险;血小板计数低于 175 × 10 9 / 1 175 × 10 9 / 1 175 xx10^(9)//1175 \times 10^{9} / 1 与颅内出血进展风险升高有关,计数低于 100x10% /le与死亡率升高密切相关 ( 38 , 39 ) ( 38 , 39 ) (38,39)(38,39) 。这种临床表现与创伤性凝血病(TIC)不同,后者以血小板减少为典型特征(40)。首先,创伤性脑损伤患者血小板反应性水平降低与预后改善呈正相关 ( 41 , 42 ) ( 41 , 42 ) (41,42)(41,42) 。在创伤性脑损伤期间,von Willebrand 因子的耗竭阻碍了血小板在体外的聚集(43)。血小板对二磷酸腺苷(ADP)和/或花生四烯酸(AA)等激动剂的反应减弱加剧了这种损伤,导致ADP和AA受体抑制引起的聚集缺陷,这种现象与创伤性脑损伤的严重程度密切相关 ( 22 , 44 ) ( 22 , 44 ) (22,44)(22,44) 。这些缺陷的发生与失血性休克或血小板绝对计数无关 ( 22 , 45 ) ( 22 , 45 ) (22,45)(22,45) 。此外,儿茶酚胺血小板激动剂(如肾上腺素和去甲肾上腺素)循环水平升高与创伤性脑损伤患者血小板聚集功能受损有关(46)。
This observation elucidates why even patients with mild injuries may exhibit suppressed platelet function in vitro (47). Variations in platelet activity may relate to systemic isch-emia-reperfusion and oxidative stress (48), with declining platelet counts closely associated with injury severity and increased mortality risk ( 42 , 49 ) ( 42 , 49 ) (42,49)(42,49). Overactive platelets may lead to secondary thrombocytopenia, heightening the risk of bleeding (22). Patients with TBI often exhibit moderately low platelet counts, with frequent activation of these cells, which generate microvesicles and display procoagulant activity ( 50 , 51 ) ( 50 , 51 ) (50,51)(50,51). Secondly, platelet adhesion dysfunction is recognized as a pivotal factor in trauma response. Studies have revealed that in the aftermath of severe trauma, a notable reduction in in platelet adhesion to collagen is observed ( 52 , 53 ) ( 52 , 53 ) (52,53)(52,53), along with diminished expression of specific receptors on platelets ( 54 , 55 ) ( 54 , 55 ) (54,55)(54,55). These alterations may
这一观察结果解释了为什么即使是轻伤患者也会在体外表现出血小板功能受抑制(47)。血小板活性的变化可能与全身性缺血再灌注和氧化应激有关(48),血小板数量下降与损伤严重程度和死亡风险增加密切相关 ( 42 , 49 ) ( 42 , 49 ) (42,49)(42,49) 。血小板过度活跃可能导致继发性血小板减少,增加出血风险(22)。创伤性脑损伤患者的血小板计数通常较低,这些细胞频繁活化,产生微囊泡并显示促凝活性 ( 50 , 51 ) ( 50 , 51 ) (50,51)(50,51) 。其次,血小板粘附功能障碍被认为是创伤反应的一个关键因素。研究发现,在严重创伤后,血小板对胶原蛋白的粘附力明显下降 ( 52 , 53 ) ( 52 , 53 ) (52,53)(52,53) ,同时血小板上特定受体的表达也减少 ( 54 , 55 ) ( 54 , 55 ) (54,55)(54,55) 。这些改变可能是
Table I. Definitions of specialized terminology.
表 I.专业术语的定义。
Specialized terminology  专业术语
Gaussian distribution pattern
高斯分布模式
Brain-derived cell microvesicles
脑源性细胞微囊
Lactoferrin  乳铁蛋白
Neutrophil extracellular traps
中性粒细胞胞外捕获器
Damage-associated molecular patterns
损伤相关分子模式
Platelet-derived extracellular vesicles
血小板衍生的细胞外囊泡
Multimodality monitoring
多模态监测

Explanation  说明

A pattern of injury where the brain tissue at the center of the trauma experiences the highest and most severe damage, with the severity of the injury diminishing radially outward.
一种损伤模式,位于创伤中心的脑组织受到的损伤最高、最严重,损伤的严重程度呈放射状向外递减。

Small vesicles secreted by brain tissue cells and vascular endothelial cells containing biomolecules such as proteins, DNA and RNA from their cell of origin.
脑组织细胞和血管内皮细胞分泌的小囊泡,内含来自其原生细胞的蛋白质、DNA 和 RNA 等生物大分子。

A member of the transferrin family with antioxidant and anti-inflammatory properties. Web-like structures released extracellularly by activated neutrophils containing components such as DNA and histones that have the ability to trap and kill pathogens among other functions.
转铁蛋白家族中的一员,具有抗氧化和抗炎特性。活化的中性粒细胞在细胞外释放的网状结构,含有 DNA 和组蛋白等成分,具有捕获和杀死病原体等功能。

Endogenous molecules released by host cells upon injury which include high mobility group box 1, DNA and RNA, triggering immune and inflammatory responses.
宿主细胞在受伤时释放的内源性分子,包括高迁移率基团框 1、DNA 和 RNA,引发免疫和炎症反应。

Vesicles released by platelets through budding or exocytosis, participating in processes such as inflammation and immunomodulation. Platelet-derived exosomes represent a specific subset of these extracellular vesicles.
血小板通过出芽或外排释放的囊泡,参与炎症和免疫调节等过程。血小板衍生的外泌体是这些细胞外囊泡的一个特定子集。

A comprehensive monitoring method that combines multiple monitoring technologies and parameters to assess the functional status of the brain. This approach aims to provide an integrated view of cerebral pathophysiology in real-time.
一种综合监测方法,结合多种监测技术和参数来评估大脑的功能状态。这种方法旨在实时提供大脑病理生理学的综合视图。

Figure 1. Schematic illustration of cellular mechanisms following TBI. At the time of brain injury, direct forces and subsequent inflammatory responses cause progressive damage to the endothelium and the blood-brain barrier, extending outward peripherally. Simultaneously, there is a massive accumulation of TF and thrombin, the latter of which participates in the activation of protein C, alongside tPA-mediated hyperfibrinolysis. BDMVs increase under the influence of NETs produced by neutrophils, binding to TF and PS in the circulation; however, lactoferrin can phagocytose and degrade BDMVs. Brain injury promotes platelet activation, which although can enhance NET production, leading to a vicious cycle between NETs and inflammatory responses, further exacerbating tissue damage. However, due to hyporeactivity to various platelet agonists in circulation, it results in impaired platelet aggregation. Moreover, shedding of the GPVI receptor (an important receptor on the surface of platelets that participates in collagen binding) leads to adhesion defects in activated platelets. ‘Swollen morphology’ prothrombotic platelets and PMVs generated by activated platelets also contribute to the occurrence of coagulopathy. TBI, traumatic brain injury; TF, tissue factor; tPA, tissue-type plasminogen activator; BDMV, brain-derived microvesicles; NETs, neutrophil extracellular traps; PS, phosphatidylserine; PMVs, platelet microvesicles; GPVI, platelet glycoprotein VI.
图 1:创伤性脑损伤后的细胞机制示意图创伤性脑损伤后的细胞机制示意图。脑损伤时,直接作用力和随后的炎症反应导致内皮和血脑屏障逐渐受损,并向外周延伸。与此同时,TF 和凝血酶大量积聚,后者与 tPA 介导的纤溶亢进一起参与激活蛋白 C。在中性粒细胞产生的 NETs 影响下,BDMVs 增加,并与血液循环中的 TF 和 PS 结合;然而,乳铁蛋白可以吞噬和降解 BDMVs。脑损伤会促进血小板活化,而血小板活化会增强 NET 的产生,从而导致 NET 与炎症反应之间的恶性循环,进一步加剧组织损伤。然而,由于血小板对血液循环中的各种血小板激动剂反应迟钝,导致血小板聚集功能受损。此外,GPVI 受体(血小板表面参与胶原蛋白结合的重要受体)的脱落会导致活化血小板的粘附缺陷。肿胀形态 "的促血栓形成血小板和活化血小板产生的 PMV 也会导致凝血病的发生。TBI,创伤性脑损伤;TF,组织因子;tPA,组织型纤溶酶原激活剂;BDMV,脑源性微囊泡;NETs,中性粒细胞胞外捕获器;PS,磷脂酰丝氨酸;PMVs,血小板微囊泡;GPVI,血小板糖蛋白 VI。

stem from fibrin-induced shedding of glycoprotein VI (GPVI) receptor (an important receptor on the surface of platelets that participates in collagen binding) (56) and interference with its signaling pathway (57).
这是因为纤维蛋白诱导糖蛋白 VI (GPVI) 受体(血小板表面参与胶原蛋白结合的重要受体)脱落 (56) 并干扰了其信号传导途径 (57)。
Research conducted by Montague et al (58) has illustrated that inhibiting GPVI shedding by obstructing the fibrin-GPVI interaction offers a potential therapeutic avenue. Furthermore, GPVI shedding is predominantly facilitated by
Montague 等人(58)的研究表明,通过阻碍纤维蛋白与 GPVI 的相互作用来抑制 GPVI 的脱落提供了一种潜在的治疗途径。此外,GPVI 的脱落主要是由以下因素促成的

the metalloprotease ADAM10 (59). In the context of trauma, platelets exhibit a distinctive ‘procoagulant’ phenotype, characterized by an unusual ‘swollen morphology’. This phenotype involves the translocation of PS from the inner to the outer leaflet of the cell membrane, thereby exposing PS on the platelet surface and creating a high-affinity substrate interface for thrombin generation (60). The prevalence of this morphological alteration correlates with injury severity, and these procoagulant platelets demonstrate compromised functionality in primary hemostasis (61). This indicates not only a diminished capacity for platelet aggregation in severe cases but also elevated markers of thrombin generation (62).
金属蛋白酶 ADAM10 (59)。在创伤情况下,血小板表现出独特的 "促凝血 "表型,其特征是不寻常的 "肿胀形态"。这种表型涉及 PS 从细胞膜的内叶转移到外叶,从而使 PS 暴露在血小板表面,为凝血酶的生成创造了一个高亲和性底物界面(60)。这种形态改变的发生率与损伤的严重程度相关,这些促凝血小板在初级止血过程中的功能受到损害(61)。这不仅表明严重病例的血小板聚集能力减弱,还表明凝血酶生成标记物升高(62)。
Collagen and thrombin, frequently found at sites of endothelial damage, conjointly stimulate the central mechanism for the development of procoagulant platelets in vitro, amplifying thrombin production (63). This process is accompanied by significant release of extracellular vesicles (EVs) (64). Certain studies have reported increased levels of platelet-derived EVs in plasma following major trauma, suggesting that purified platelet-derived EVs could potentially ameliorate thrombotic events post-trauma (65-68). Consequently, targeting the emergence of procoagulant platelets presents a promising therapeutic strategy for TIC.
胶原蛋白和凝血酶经常出现在内皮损伤部位,它们共同刺激体外促凝血血小板发展的中心机制,扩大凝血酶的产生(63)。这一过程伴随着细胞外囊泡 (EV) 的大量释放(64)。一些研究报告称,重大创伤后血浆中血小板衍生的 EVs 水平升高,这表明纯化的血小板衍生 EVs 有可能改善创伤后的血栓事件(65-68)。因此,针对促凝血血小板的出现,是治疗 TIC 的一种很有前景的策略。

3. Treatment of coagulation disorders following TBI
3.创伤性脑损伤后凝血功能障碍的治疗

The early rectification of coagulopathy in patients with TBI is critically associated with survival rate (69). The predominant strategy for addressing TBI-induced coagulopathy entails the blood components, with a growing emphasis on the administration of clotting factors and related substances. Moreover, hemostatic agents are an essential element of the therapeutic arsenal employed in these cases, as their indispensable role in the management of coagulopathy post-TBI.
创伤性脑损伤患者凝血功能障碍的早期纠正与存活率密切相关(69)。解决创伤性脑损伤引起的凝血病的主要策略是使用血液成分,并越来越重视凝血因子和相关物质的应用。此外,止血剂在治疗创伤后凝血病中发挥着不可或缺的作用,因此也是这些病例所采用的治疗手段的重要组成部分。
Pharmacological interventions. Tranexamic acid (TXA), a synthetic derivative of lysine, has proven effective in reducing active hemorrhage (70) and mortality (71) in trauma patients when administered within 3 h of injury, as demonstrated by the CRASH-2 trial (clinical randomization of an antifibrinolytic in significant hemorrhage) ( 71 , 72 ) ( 71 , 72 ) (71,72)(71,72). Building on this, the CRASH-3 trial revealed that early administration of TXA within the same timeframe significantly reduces mortality risk in patients with mild-to-moderate TBI ( 67 , 73 ) ( 67 , 73 ) (67,73)(67,73), thus endorsing its immediate use in such scenarios, whereas its efficacy diminishes in patients with severe TBI cases. Considering TXA’s ability to enhance platelet function (74), coupled with its cost-effectiveness and proven efficacy in trauma management, it continues to be a dependable therapeutic option for patients with TBI.
药物干预。氨甲环酸(TXA)是赖氨酸的一种合成衍生物,经CRASH-2试验(重大出血时抗纤溶剂的临床随机化) ( 71 , 72 ) ( 71 , 72 ) (71,72)(71,72) 证实,在受伤后3小时内给药可有效减少创伤患者的活动性出血(70)和死亡率(71)。在此基础上,CRASH-3 试验显示,在同一时间内尽早使用 TXA 可显著降低轻度至中度创伤性脑损伤患者的死亡风险 ( 67 , 73 ) ( 67 , 73 ) (67,73)(67,73) ,从而支持在此类情况下立即使用 TXA,而在重度创伤性脑损伤患者中,其疗效则会减弱。考虑到 TXA 具有增强血小板功能的能力(74),加上其成本效益和在创伤治疗中已被证实的疗效,它仍然是创伤性脑损伤患者的可靠治疗选择。
Furthermore, desmopressin, as tested in a rat model of hemorrhagic shock, has been observed to elevate von Willebrand factor and factor VIII levels, as well as augment platelet aggregation (75). Given its short-acting nature and relative safety, desmopressin presents as a suitable alternative (76). Additional pharmacological agents such as progesterone, vitamin K2, Butylphthalide and recombinant interleukin-1 receptor antagonist (77) have demonstrated potential in the treatment of TBI. Conversely, administration of high-dose corticosteroids for 48 h to patients with moderate
此外,在大鼠失血性休克模型中测试发现,去氨加压素可提高冯-威廉因子和因子 VIII 的水平,并增强血小板聚集(75)。鉴于去氨加压素的短效性质和相对安全性,它是一种合适的替代药物(76)。黄体酮、维生素 K2、丁苯酞和重组白细胞介素-1 受体拮抗剂(77)等其他药理制剂也显示出治疗创伤性脑损伤的潜力。相反,给中度创伤性脑损伤患者服用大剂量皮质类固醇 48 小时,也有一定疗效。

to severe brain injury has been associated with an increased mortality rate at two weeks (78). Amantadine may accelerate the rate of functional improvement in delirium-rating scale scores ( 79,80 ); however, due to its heterogeneity when used in patients with TBI (80), the benefits for this patient population requires further robust investigation. Although theoretically cytidine diphosphocholine (CDP-choline) might have positive effects on cell membrane integrity and cellular edema, studies indicate that its impact on cognitive function improvement in brain-injured patients appears to be negligible ( 81 , 82 ) ( 81 , 82 ) (81,82)(81,82). Hemostatic agents can reduce bleeding in trauma patients, but excessive dosing or prolonged use may lead to acquired thrombosis (83). Therefore, when planning treatment, it is important to assess the risk and extent of thrombosis.
严重脑损伤患者两周后的死亡率增加(78)。金刚烷胺可能会加快谵妄评分量表中功能改善的速度(79,80);然而,由于其在创伤性脑损伤患者中使用时的异质性(80),对这一患者群体的益处还需要进一步的深入研究。尽管理论上胞苷二磷酸胆碱(CDP-choline)可能对细胞膜完整性和细胞水肿有积极影响,但研究表明,它对脑损伤患者认知功能改善的影响似乎微乎其微 ( 81 , 82 ) ( 81 , 82 ) (81,82)(81,82) 。 止血剂可减少创伤患者的出血,但剂量过大或长期使用可能导致获得性血栓形成(83)。因此,在计划治疗时,必须评估血栓形成的风险和程度。
Transfusion of blood components following TBI. Post-TBI, blood component transfusions typically refer to the administration of platelets, red blood cells or plasma based on the individual needs of the patient. In scenarios of ongoing hemorrhage, platelet transfusions have not been proven effective in restoring aggregation function (84) nor have they demonstrated improvements in patient outcomes (85). Notably, the administration of refrigerated platelets has shown to confer superior hemostatic benefits compared with those stored at room temperature (86), a protocol now implemented in numerous trauma centers throughout the United States.
创伤性脑损伤后的血液成分输注。创伤性脑损伤后的血液成分输注通常是指根据患者的个人需求输注血小板、红细胞或血浆。在持续出血的情况下,输注血小板并不能有效恢复聚集功能(84),也不能改善患者的预后(85)。值得注意的是,与室温储存的血小板相比,冷藏血小板具有更好的止血效果(86),目前美国许多创伤中心都采用了这一方案。
Furthermore, transfusions of packed red blood cells (pRBCs) have been recognized to enhance cerebral oxygenation; recent investigations into the combined administration of pRBCs with plasma in patients with TBI with coagulopathy have associated this practice with an escalation in adverse reactions and deteriorated prognoses (87). It is particularly noteworthy that establishing higher transfusion thresholds at 10 g / dl 10 g / dl 10g//dl10 \mathrm{~g} / \mathrm{dl} has been correlated with an upsurge in bleeding complications as opposed to a lower threshold of 7 g / dl ( 88 ) 7 g / dl ( 88 ) 7g//dl(88)7 \mathrm{~g} / \mathrm{dl}(88), indicating that transfusion decisions should extend beyond mere adherence to rigid hemoglobin level. Consequently, a restrictive strategy for pRBC transfusion is advocated, except in instances where patients exhibit intolerance to anemia (89). The determination of the optimal timing and volume of transfusions remains a pivotal focus of ongoing research.
此外,输注包装红细胞(pRBCs)已被认为可提高脑氧合;最近对患有凝血功能障碍的创伤性脑损伤患者联合输注包装红细胞和血浆的研究表明,这种做法与不良反应增加和预后恶化有关(87)。尤其值得注意的是,与 7 g / dl ( 88 ) 7 g / dl ( 88 ) 7g//dl(88)7 \mathrm{~g} / \mathrm{dl}(88) 的较低阈值相比, 10 g / dl 10 g / dl 10g//dl10 \mathrm{~g} / \mathrm{dl} 的较高输血阈值与出血并发症的激增相关,这表明输血决策不应仅局限于严格遵守血红蛋白水平。因此,除非患者表现出对贫血的不耐受性(89),否则应采取限制性 pRBC 输血策略。确定最佳输血时间和输血量仍是当前研究的重点。
Hemostatic factors and associated substances. In recent years, advancements in the study of coagulation factors have significantly progressed the treatment of trauma patients. Fujiwara et al (90), employing a rat model of controlled cortical impact, demonstrated that daily intravenous injections of 350 mg / kg 350 mg / kg 350mg//kg350 \mathrm{mg} / \mathrm{kg} of a synthetically derived activated peptide of factor IX (termed F9-AP) significantly mitigated adjacent neuronal loss associated with secondary brain injury, markedly reducing both the volume of brain injury and associated edema. Moreover, recombinant activated factor VII, which exhibits lesser dependence on platelet function, appears to offer distinct advantages for patients with severely compromised platelet function or severe thrombocytopenia, effectively diminishing the risk of intracranial hemorrhage (91). Prothrombin complex concentrate (PCC), an inactivated blend comprising of factors II, IX, VII and X, has been proven to be highly efficacious in managing refractory bleeding to conventional treatment methods and in correcting elevated international normalized
止血因子和相关物质。近年来,凝血因子研究的进步极大地推动了创伤患者的治疗。Fujiwara等人(90)采用大鼠皮层受控撞击模型证明,每天静脉注射合成的活化多肽因子IX(称为F9-AP)可明显减轻继发性脑损伤引起的邻近神经元损失,显著减少脑损伤的体积和相关水肿。此外,重组活化因子 VII 对血小板功能的依赖性较低,似乎为血小板功能严重受损或严重血小板减少的患者提供了独特的优势,有效降低了颅内出血的风险(91)。凝血酶原复合物浓缩物(PCC)是一种由因子 II、IX、VII 和 X 组成的灭活混合物,已被证明在处理常规治疗方法难治性出血和纠正升高的国际标准化血红蛋白(IGF)方面具有很高的疗效。

ratio (INR) levels (92). In TBI, where fibrinogen levels can be depleted, it is imperative to restore these levels to within normal ranges to alleviate inflammation and reduce endothelial permeability (93). The supplementation of factor XIII plays equally a critical role in inhibiting hyperfibrinolysis, stabilizing clot formations and minimizing surgical blood loss ( 94 , 95 ) ( 94 , 95 ) (94,95)(94,95). However, compared with plasma, PCC may reduce hematoma expansion, yet shows no significant difference in 90-day mortality or Glasgow Coma Scale scores (96).
比值 (INR) 水平 (92)。在创伤性脑损伤中,纤维蛋白原水平可能会耗竭,因此必须将这些水平恢复到正常范围内,以减轻炎症和降低内皮通透性(93)。补充 XIII 因子在抑制纤维蛋白溶解亢进、稳定血凝块形成和减少手术失血 ( 94 , 95 ) ( 94 , 95 ) (94,95)(94,95) 方面同样起着至关重要的作用。 不过,与血浆相比,PCC 可减少血肿扩大,但在 90 天死亡率或格拉斯哥昏迷量表评分方面却无明显差异(96)。
Reversal agents for direct oral anticoagulants (DOACs). With an aging population, the number of patients with TBI concurrently taking oral anticoagulants is increasing. To ameliorate adverse outcomes including bleeding in patients undergoing surgery or those suffering from TBI while on these therapies, the development of antidotes for the reversal of DOACs has emerged as a crucial area of research. In 2015, publication of the first study demonstrating the safety and efficacy of idarucizumab, a targeted monoclonal antibody fragment for the acute reversal of dabigatran, a direct thrombin inhibitor, marked a significant advancement in anticoagulation management (97). This was followed by the introduction of Andexanet alfa, an antagonist of the facto Xa inhibitors, into clinical practice (98). Protamine sulfate is employed for the reversal of both unfractionated heparin and low molecular weight heparin (LMWH). However, its routine administration for reversing prophylactic subcutaneous heparin is not recommended unless there is a significantly prolonged activated partial thromboplastin time (aPTT) (99).
直接口服抗凝剂(DOACs)的逆转剂。随着人口老龄化,同时服用口服抗凝血剂的创伤性脑损伤患者人数不断增加。为了改善手术患者或服用这些疗法的创伤性脑损伤患者的出血等不良后果,开发用于逆转 DOACs 的解毒剂已成为一个重要的研究领域。2015 年,第一项证明伊达珠单抗安全性和有效性的研究发表,伊达珠单抗是一种用于急性逆转直接凝血酶抑制剂达比加群的靶向单克隆抗体片段,标志着抗凝管理取得了重大进展(97)。随后,Xa 抑制剂的拮抗剂 Andexanet alfa 被引入临床实践(98)。硫酸原胺可用于逆转非分叶肝素和低分子量肝素(LMWH)。不过,除非活化部分凝血活酶时间(aPTT)明显延长,否则不建议常规使用硫酸原明逆转预防性皮下肝素(99)。
Notably, non-specific hemostatic agents such as PCC and activated prothrombin complex concentrate may also serve to reverse the effects of DOACs. However, FDA-approved reversal agents are not applicable to all DOACs or all clinical scenarios where reversal may be considered. Furthermore, the complexity of clinical use is compounded by factors such as cost, preparation and the lack of standardized protocols (97).
值得注意的是,PCC 和活性凝血酶原复合物浓缩物等非特异性止血剂也可用于逆转 DOACs 的作用。然而,FDA 批准的逆转剂并不适用于所有 DOAC 或所有需要考虑逆转的临床情况。此外,临床使用的复杂性还因成本、准备和缺乏标准化方案等因素而加剧(97)。
Potential therapies. Research underscores the complex and heterogeneous nature of TBI progression, necessitating exploration beyond conventional treatments toward interventions that may confer additional benefit to patients. This section delineates several promising potential therapeutic avenues post-TBI, aiming to foster groundbreaking advancements in the management during process.
潜在疗法。研究强调了创伤性脑损伤进展的复杂性和异质性,因此有必要在常规治疗之外,探索可为患者带来更多益处的干预措施。本节介绍了创伤后应激障碍的几种有前景的潜在治疗方法,旨在促进创伤后应激障碍治疗过程中的突破性进展。
It has been demonstrated that elevated levels of matrix metalloproteinase-9 (MMP-9) following brain injury contributes to the dysfunction of the BBB (100). Encouragingly, administration of MMP inhibitors in rodent models of brain injury has led to improved outcomes (101), indicating that MMP inhibition may represent a viable therapeutic strategy for patients with TBI. Moreover, the integration of medical science and nanotechnology has facilitated the development of platelet-mimicking nanovesicles, which incorporate the biological characteristics of platelet membranes into a lipid-based nanostructure. Through bioengineering manipulations, these particles can partially or fully emulate the hemostatic functions of natural platelets to varying extents (102), thus offering a promising alternative to platelet transfusion therapy. Additionally, novel resuscitative agents, known as platelet-derived extracellular vesicles (103), have
研究表明,脑损伤后基质金属蛋白酶-9(MMP-9)水平升高会导致 BBB 功能障碍(100)。令人鼓舞的是,在啮齿类动物脑损伤模型中施用 MMP 抑制剂可改善疗效(101),这表明抑制 MMP 可能是治疗创伤性脑损伤患者的一种可行策略。此外,医学科学与纳米技术的结合促进了血小板模拟纳米颗粒的开发,这种颗粒将血小板膜的生物特性融入脂质纳米结构中。通过生物工程操作,这些微粒可在不同程度上部分或完全模拟天然血小板的止血功能(102),从而为血小板输注疗法提供了一种前景广阔的替代方法。此外,被称为血小板源性细胞外囊泡 (103) 的新型复苏剂已

surfaced, exhibiting remarkable hemostatic potency in patients with TBI via multiple mechanisms. However, current investigational agents remain in the experimental phase and additional research and data are required before they can advance to clinical application. As research advances and technology evolves, it is anticipated that additional mechanisms will be elucidated and applied to strategies aimed at ameliorating the outcomes for TBI survivors.
这些药物通过多种机制对创伤性脑损伤患者表现出显著的止血功效。然而,目前的研究药物仍处于实验阶段,在进入临床应用之前还需要更多的研究和数据。随着研究的进展和技术的发展,预计更多的机制将被阐明并应用于旨在改善创伤性脑损伤幸存者预后的策略中。

4. Complications  4.并发症

TBI can be accompanied by a wide array of complications, including but not limited to epilepsy, cerebral herniation, hydrocephalus and cerebrocardiac syndrome (104-106). These concomitant complications are intimately associated with a diminished quality of life and heightened mortality rates. Specifically, in the period following the initial day post-TBI, the emergence of multiple organ dysfunction and thrombotic events become the predominant causes of mortality among critically ill patients (107). Besides emphasizing early preventive strategies, it is equally essential to unravel the mechanisms that underlie the initiation and progression of these complications is equally indispensable. This underscores the imperative for a thorough comprehension and the formulation of precise intervention strategies.
创伤性脑损伤可伴有多种并发症,包括但不限于癫痫、脑疝、脑积水和脑心综合征(104-106)。这些并发症与生活质量下降和死亡率升高密切相关。具体而言,在创伤后第一天之后,多器官功能障碍和血栓事件的出现成为危重病人死亡的主要原因(107)。除了强调早期预防策略外,揭示这些并发症的发生和发展机制也同样不可或缺。这就强调了透彻理解和制定精确干预策略的必要性。
Multiple organ dysfunction syndrome (MODS). Posttraumatic MODS is widely recognized as a consequence of deregulated responses to trauma. The primary pathogenic mechanism likely involves the activation of both coagulation and inflammatory cascades ( 108 , 109 ) ( 108 , 109 ) (108,109)(108,109). Furthermore, MODS is intimately associated with extracellular histones, HMGB1 and S100A8/9, among other factors. Notably, elevated levels of HMGB1 contribute to organ injury (109). Additionally, the dynamic interaction between platelets and leukocytes facilitates leukocyte recruitment to sites of injury, facilitating tissue repair (110). Nevertheless, an excessive immune response appears to inflict organ damage (111). Fortunately, proactive management of coagulopathy exhibits promising potential in ameliorating the incidence of organ failure (112).
多器官功能障碍综合征(MODS)。创伤后 MODS 被广泛认为是创伤反应失调的结果。其主要致病机制可能涉及凝血和炎症级联的激活 ( 108 , 109 ) ( 108 , 109 ) (108,109)(108,109) 。此外,MODS还与细胞外组蛋白、HMGB1和S100A8/9等因素密切相关。值得注意的是,HMGB1 水平升高会导致器官损伤(109)。此外,血小板和白细胞之间的动态相互作用有助于白细胞被招募到损伤部位,从而促进组织修复(110)。然而,过度的免疫反应似乎会造成器官损伤(111)。幸运的是,对凝血功能障碍的积极治疗有望改善器官衰竭的发生率(112)。
Thrombosis. Thromboembolic events play a significant cause in increasing morbidity and disability rates among patients, particularly those who have suffered TBI and are severely injured or unable to mobilize independently. Considering TBI as an established independent risk factor for venous thromboembolism (VTE) ( 113 , 114 ) ( 113 , 114 ) (113,114)(113,114). The present discussion predominantly focuses on VTE, extending beyond traditional triggers to explore the pivotal role played by the interaction between platelets and monocytes in the initiation and propagation of VTE (115). Moreover, factors including NETs, platelet-derived microparticles and protein C depletion (38) are intimately associated with VTE development. In intensive care units, the occurrence of VTE among critically ill trauma patients is notably elevated, with an estimated incidence of up to 35 % 35 % 35%35 \% (116). Even with the implementation of mechanical prophylaxis measures for deep vein thrombosis (DVT), residual DVT and pulmonary embolism (PE) rates remain substantial at 31 and 3 % 3 % 3%3 \% (114), respectively. A recent large comprehensive observational
血栓形成。血栓栓塞事件是增加患者发病率和残疾率的重要原因,尤其是那些遭受创伤性脑损伤、严重受伤或无法独立行动的患者。考虑到创伤性脑损伤是静脉血栓栓塞症(VTE) ( 113 , 114 ) ( 113 , 114 ) (113,114)(113,114) 的独立危险因素。目前的讨论主要集中在静脉血栓栓塞,超越了传统的诱发因素,探讨了血小板和单核细胞之间的相互作用在静脉血栓栓塞的启动和传播中所起的关键作用(115)。此外,包括 NETs、血小板衍生微颗粒和蛋白 C 耗竭(38)在内的因素与 VTE 的发生密切相关。在重症监护病房,重症创伤患者的 VTE 发生率明显升高,估计高达 35 % 35 % 35%35 \% (116)。即使对深静脉血栓(DVT)采取了机械预防措施,DVT 和肺栓塞(PE)的残留率仍然很高,分别为 31 和 3 % 3 % 3%3 \% (114)。最近一项大型综合观察性

study emphasized that de novo pulmonary thrombi are more prevalent than PEs originating from DVT, often manifesting early in the clinical course (117). In animal models of TBI, microthrombi are predominantly observed in the pericontusional cortex (118), composed of fibrin, platelets and other components. LMWH has demonstrated superior efficacy in preventing thromboembolism compared to unfractionated heparin (119), indicating that, following a thorough patient evaluation and confirmation of no contraindications, early initiation of LMWH for thromboprophylaxis is recommended. Apart from LMWH, factor XI inhibitors, such as Abelacimab, have shown effectiveness in preventing VTE (120), offering an alternative preventive strategy in managing thrombotic risks.
该研究强调,与深静脉血栓形成引起的 PE 相比,新生肺血栓更为常见,通常在临床病程早期就会出现(117)。在创伤性脑损伤的动物模型中,微血栓主要出现在皮质周围(118),由纤维蛋白、血小板和其他成分组成。LMWH 在预防血栓栓塞方面的疗效优于非分叶肝素(119),这表明在对患者进行全面评估并确认无禁忌症后,建议尽早开始使用 LMWH 进行血栓预防。除 LMWH 外,阿柏西单抗等因子 XI 抑制剂也显示出预防 VTE 的有效性(120),为控制血栓风险提供了另一种预防策略。
Consequently, early detection, prevention and management of MODS and thrombotic events assume paramount importance. Identification and assessment of disease severity, as well as prediction of risks in patients, are facilitated through monitoring vital signs, imaging changes, laboratory parameters and scoring systems such as APACHE II, SOFA and qSOFA ( 121 , 122 ) ( 121 , 122 ) (121,122)(121,122). Management of these patients should be viewed as a dynamic process, necessitating close surveillance and prompt adjustment of therapeutic strategies as needed. Given the unique nature of each patient’s condition, treatment plans should be individualized, with the overarching goals of maximizing organ function recovery, preventing thrombosis and enhancing quality of life.
因此,早期发现、预防和处理 MODS 和血栓事件至关重要。通过监测生命体征、影像学变化、实验室参数和评分系统(如 APACHE II、SOFA 和 qSOFA ( 121 , 122 ) ( 121 , 122 ) (121,122)(121,122) ),有助于识别和评估疾病的严重程度以及预测患者的风险。对这些患者的管理应被视为一个动态过程,需要密切监测并根据需要及时调整治疗策略。鉴于每位患者病情的特殊性,治疗方案应因人而异,以最大限度地恢复器官功能、预防血栓形成和提高生活质量为总体目标。

5. Diagnostic tools for coagulopathy following TBI
5.创伤后凝血病诊断工具

Laboratory assessments aimed at detecting coagulopathy and techniques reflecting brain injury are crucial in diagnosing and managing coagulation disorders that arise following TBI (Table II). Conventional coagulation assays, routinely employed in clinical settings to evaluate hemostatic function, encompass prothrombin time, aPTT and INR ( 123 , 124 ) ( 123 , 124 ) (123,124)(123,124), which aid in prognostication post-cranial injury. Nonetheless, these tests fail to capture the full complexity of coagulation processes and have limitations in accurately representing thrombin generation and precision in hemostatic evaluation ( 125 , 126 ) ( 125 , 126 ) (125,126)(125,126).
旨在检测凝血功能障碍的实验室评估和反映脑损伤的技术对于诊断和处理创伤性脑损伤后出现的凝血功能障碍至关重要(表 II)。临床上常规用于评估止血功能的传统凝血检测包括凝血酶原时间、aPTT 和 INR ( 123 , 124 ) ( 123 , 124 ) (123,124)(123,124) ,它们有助于颅脑损伤后的预后。尽管如此,这些检测方法无法反映凝血过程的全部复杂性,在准确反映凝血酶生成和止血评估的精确性 ( 125 , 126 ) ( 125 , 126 ) (125,126)(125,126) 方面存在局限性。
More advanced global hemostasis assessments, including rotational thromboelastometry (ROTEM), thromboelastography (TEG) and thrombin generation tests, may offer a superior real-time analysis of hemostatic status. These provide swift feedback for therapeutic intervention and enable more precise predictions treatment outcomes (127). These methodologies further facilitate goal-directed transfusion strategies (128) and guide heparin administration for thromboembolism prophylaxis (129), with TEG particularly unaffected by the administration of TXA (130). A fibrinogen level concentration 2.0 g / l 2.0 g / l 2.0g//l2.0 \mathrm{~g} / \mathrm{l} is recognized as a risk factor for coagulopathy and associated complications post-TBI. Both ROTEM and TEG have proven effective in swiftly and precisely measuring fibrinogen levels (127). Moreover, recent research involving bleeding adult and pediatric patients has demonstrated that transfusion strategies guided by viscoelastic tests improve survival rates, decrease blood product usage and reduce the incidence of renal failure when compared with other methods (131). Point-of-care
更先进的全局止血评估,包括旋转血栓弹性测定法(ROTEM)、血栓弹性成像(TEG)和凝血酶生成试验,可对止血状态进行更出色的实时分析。这些方法可为治疗干预提供快速反馈,并能更精确地预测治疗结果(127)。这些方法进一步促进了以目标为导向的输血策略(128),并为预防血栓栓塞的肝素给药提供指导(129),其中 TEG 尤其不受 TXA 给药的影响(130)。纤维蛋白原水平浓度 2.0 g / l 2.0 g / l 2.0g//l2.0 \mathrm{~g} / \mathrm{l} 被认为是创伤后凝血病和相关并发症的危险因素。事实证明,ROTEM 和 TEG 都能快速、精确地测量纤维蛋白原水平(127)。此外,最近涉及成人和儿童出血患者的研究表明,与其他方法相比,以粘弹性测试为指导的输血策略可提高存活率、减少血液制品用量并降低肾功能衰竭的发生率(131)。护理点

platelet function testing (POC-PFT), exemplified by systems including VerifyNow, Plateletworks, PFA-100/200, show promise in identifying platelet dysfunction or guiding antiplatelet therapy ( 6 , 20 ) ( 6 , 20 ) (6,20)(6,20). However, the absence of a gold standard for POC-PFT and substantial variation among available analyzers in terms of implementation technique and platelet agonists utilized hinder widespread acceptance. Consequently, current European guidelines on massive hemorrhage and coagulation management in trauma do not advocate for the routine use of POC-PFT (132).
( 6 , 20 ) ( 6 , 20 ) (6,20)(6,20) 然而,POC-PFT 缺乏金标准,而且现有分析仪在实施技术和使用的血小板激动剂方面存在很大差异,这阻碍了其被广泛接受。因此,目前欧洲的创伤大出血和凝血管理指南并不主张常规使用 POC-PFT(132)。

6. Neurocritical care monitoring tools
6.神经重症监护监测工具

For patients suffering from moderate to severe brain injuries, the mere reliance on conventional blood tests is insufficient, Conventional coagulation tests measure only 4 % 4 % ∼4%\sim 4 \% of total thrombin generation and do not assess the overall hemostatic state. Furthermore, these tests do not reflect the interactions between multiple coagulation pathway mechanisms (133-135). Therefore, the incorporation of cutting-edge neurocritical care monitoring instruments is of utmost importance. In this context, multimodal monitoring (MMM) encompasses a range of techniques, including intracranial pressure (ICP)-monitoring, cerebral microdialysis (CMD), cerebral tissue oxygenation monitoring and continuous electroencephalography (EEG) (3), amongst others. Through the amalgamation of these diverse monitoring modalities, MMM provides a comprehensive, real-time evaluation of the patient’s cerebral pathophysiology. This significantly bolsters the management of brain disorders, elevates patient outcomes and propels clinical research forward.
对于中重度脑损伤患者来说,仅仅依靠传统的血液检测是不够的,因为传统的凝血检测只能测量 4 % 4 % ∼4%\sim 4 \% 凝血酶生成总量,并不能评估整体止血状态。此外,这些测试不能反映多种凝血途径机制之间的相互作用 (133-135)。因此,采用最先进的神经重症监护仪器至关重要。在这种情况下,多模态监测(MMM)包含一系列技术,包括颅内压(ICP)监测、脑微透析(CMD)、脑组织氧合监测和连续脑电图(EEG)(3) 等。通过综合运用这些不同的监测模式,MMM 可对患者的脑病理生理学进行全面、实时的评估。这大大加强了对脑部疾病的管理,提高了患者的治疗效果,并推动了临床研究的发展。
Primarily, ICP monitoring stands as a pivotal component, as elevated ICP can diminish cerebral perfusion [cerebral perfusion pressure = = == mean arterial pressure ( MAP ) ICP ] ( MAP ) ICP ] (MAP)-ICP](\mathrm{MAP})-\mathrm{ICP}], subsequently augmenting the peril of ischemia and herniation ( 136 , 137 ) ( 136 , 137 ) (136,137)(136,137). In accordance with the established guidelines, maintaining ICP at 20 25 mmHg 20 25 mmHg 20-25mmHg20-25 \mathrm{mmHg} (138), with MAP kept at 60 70 mmHg 60 70 mmHg 60-70mmHg60-70 \mathrm{mmHg} in severe patients with TBI, is paramount in effectively mitigating adverse outcomes. Furthermore, CMD emerges as an invasive yet invaluable technique. It involves hourly sampling and analysis of cerebral extracellular fluid metabolites, offering an unprecedented glimpse into the biochemical shifts within the brain (139). Complementing this, cerebral tissue oxygenation monitoring employs near-infrared spectroscopy for a non-invasive, continuous assessment of regional concentrations of oxygenated and deoxygenated hemoglobin in the brain (140). This, in turn, aids in evaluating the risk of cerebral hypoxia and shaping individualized therapeutic strategies. However, it’s worth noting that its application remains primarily confined to superficial areas such as the frontal cortex, owing to technological limitations.
首先,ICP 监测是一个关键环节,因为 ICP 升高会降低脑灌注[脑灌注压 = = == 平均动脉压 ( MAP ) ICP ] ( MAP ) ICP ] (MAP)-ICP](\mathrm{MAP})-\mathrm{ICP}] ,从而增加缺血和脑疝的危险 ( 136 , 137 ) ( 136 , 137 ) (136,137)(136,137) 。根据既定指南,在严重创伤性脑损伤患者中,将 ICP 保持在 20 25 mmHg 20 25 mmHg 20-25mmHg20-25 \mathrm{mmHg} (138),同时将 MAP 保持在 60 70 mmHg 60 70 mmHg 60-70mmHg60-70 \mathrm{mmHg} ,对于有效减轻不良后果至关重要。此外,CMD 是一种侵入性的宝贵技术。它每小时对脑细胞外液代谢物进行采样和分析,为了解大脑内部的生化变化提供了前所未有的视角(139)。作为补充,脑组织氧合监测利用近红外光谱对大脑中氧合血红蛋白和脱氧血红蛋白的区域浓度进行无创、连续的评估(140)。这反过来有助于评估大脑缺氧的风险,并制定个性化的治疗策略。不过,值得注意的是,由于技术限制,该技术的应用仍主要局限于额叶皮层等浅表区域。
In the realm of severe TBI, post-traumatic seizures affect roughly one in ten patients, with asymptomatic seizure activity prevalence potentially escalating to 20-25% (141). Continuous EEG enables the early detection of these cerebral pathologies and guides antiepileptic therapy. As previously reported, the successful management of a 25 -year-old comatose patient following a car accident was achieved through the utilization of the MMM monitoring and management system. This
在严重创伤性脑损伤领域,创伤后癫痫发作影响到大约十分之一的患者,无症状癫痫活动的发生率可能上升到 20-25%(141)。连续脑电图可早期发现这些脑部病变,并指导抗癫痫治疗。如前所述,通过使用 MMM 监测和管理系统,成功救治了一名车祸后昏迷的 25 岁患者。该系统
Table II. Advantages and disadvantages of various diagnostic tools.
表 II.各种诊断工具的优缺点。
Diagnostic tools  诊断工具 Content  内容 Advantages  优势 Disadvantages  缺点 Clinical application  临床应用
CCAs  共同国家评估 Tests such as prothrombin time, activated partial thromboplastin time and international normalized ratio
凝血酶原时间、活化部分凝血活酶时间和国际标准化比率等检测
It can indirectly predict the prognosis of patients with coagulopathy
它可以间接预测凝血功能障碍患者的预后
It is unable to provide real-time information on coagulation changes; it does not assess the levels of thrombin or the extent of clot formation involved in the reaction
它无法提供有关凝血变化的实时信息;它不能评估凝血酶的水平或反应中血凝块形成的程度
Conventional methods  传统方法
ROTEM Detailed kinetics of blood coagulation such as clot initiation time, fibrin formation velocity, clot firmness and fibrinolysis activity
详细的血液凝固动力学,如血块形成时间、纤维蛋白形成速度、血块坚固程度和纤维蛋白溶解活性
It allows for real-time assessment of hemostatic status, rapid feedback on test results and prediction of treatment efficacy; it can quickly and accurately evaluate fibrinogen levels; and it can guide therapeutic interventions
它可以实时评估止血状态、快速反馈检测结果并预测治疗效果;它可以快速准确地评估纤维蛋白原水平;它还可以指导治疗干预措施
It requires stringent technical expertise; interpretation of results still relies heavily on the operator's experience, with lower standardization compared to conventional tests; and it is relatively more costly
它需要严格的专业技术知识;对结果的解释仍然在很大程度上依赖于操作者的经验,与传统测试相比标准化程度较低;成本相对较高
Preferred methods  首选方法
TEG Reaction time; kinetic time; alpha angle; maximum amplitude; lysis at 30 min
反应时间;动力学时间;α角;最大振幅;30 分钟时的溶解度
It allows for real-time assessment of hemostatic status, rapid feedback on test results and prediction of treatment efficacy; it can quickly and accurately evaluate fibrinogen levels; and it can guide therapeutic interventions
它可以实时评估止血状态、快速反馈检测结果并预测治疗效果;它可以快速准确地评估纤维蛋白原水平;它还可以指导治疗干预措施
It demands strict technical requirements; results can be influenced by human factors; and it is time-consuming
它要求严格的技术要求;结果可能受人为因素影响;耗时长
Preferred methods  首选方法
POC-PFT

TEG(TEG 5000/6 s 止血分析仪系统)、ROTEM(ROTEM Delta 系统)、血小板反应性浊度测试(VerifyNow 系统)、多电极血小板聚集仪(多平板分析仪)和 PFA(PFA-100/200)。
TEG (TEG 5000/6 s
Hemostasis Analyzer
System), ROTEM
(ROTEM Delta System),
platelet reactivity
turbidimetry test
(VerifyNow System),
multiple electrode
platelet aggregometry
(Multiplate Analyzer) and
PFA (PFA-100/200)
TEG (TEG 5000/6 s Hemostasis Analyzer System), ROTEM (ROTEM Delta System), platelet reactivity turbidimetry test (VerifyNow System), multiple electrode platelet aggregometry (Multiplate Analyzer) and PFA (PFA-100/200)| TEG (TEG 5000/6 s | | :--- | | Hemostasis Analyzer | | System), ROTEM | | (ROTEM Delta System), | | platelet reactivity | | turbidimetry test | | (VerifyNow System), | | multiple electrode | | platelet aggregometry | | (Multiplate Analyzer) and | | PFA (PFA-100/200) |
It enables real-time monitoring of platelet function: Reducing blood transfusion in cardiac surgery and in predicting the risk of perioperative blood loss in high risk cardiac surgery patients
它能实时监测血小板功能:减少心脏手术中的输血量,预测高危心脏手术患者围术期失血的风险
There is no universally recognized 'gold standard'; it requires stringent technical expertise; and the results can be subject to human-related variables
没有公认的 "黄金标准";需要严格的专业技术知识;结果可能受人为因素的影响
Not routinely utilized  非例行使用
Diagnostic tools Content Advantages Disadvantages Clinical application CCAs Tests such as prothrombin time, activated partial thromboplastin time and international normalized ratio It can indirectly predict the prognosis of patients with coagulopathy It is unable to provide real-time information on coagulation changes; it does not assess the levels of thrombin or the extent of clot formation involved in the reaction Conventional methods ROTEM Detailed kinetics of blood coagulation such as clot initiation time, fibrin formation velocity, clot firmness and fibrinolysis activity It allows for real-time assessment of hemostatic status, rapid feedback on test results and prediction of treatment efficacy; it can quickly and accurately evaluate fibrinogen levels; and it can guide therapeutic interventions It requires stringent technical expertise; interpretation of results still relies heavily on the operator's experience, with lower standardization compared to conventional tests; and it is relatively more costly Preferred methods TEG Reaction time; kinetic time; alpha angle; maximum amplitude; lysis at 30 min It allows for real-time assessment of hemostatic status, rapid feedback on test results and prediction of treatment efficacy; it can quickly and accurately evaluate fibrinogen levels; and it can guide therapeutic interventions It demands strict technical requirements; results can be influenced by human factors; and it is time-consuming Preferred methods POC-PFT "TEG (TEG 5000/6 s Hemostasis Analyzer System), ROTEM (ROTEM Delta System), platelet reactivity turbidimetry test (VerifyNow System), multiple electrode platelet aggregometry (Multiplate Analyzer) and PFA (PFA-100/200)" It enables real-time monitoring of platelet function: Reducing blood transfusion in cardiac surgery and in predicting the risk of perioperative blood loss in high risk cardiac surgery patients There is no universally recognized 'gold standard'; it requires stringent technical expertise; and the results can be subject to human-related variables Not routinely utilized| Diagnostic tools | Content | Advantages | Disadvantages | Clinical application | | :---: | :---: | :---: | :---: | :---: | | CCAs | Tests such as prothrombin time, activated partial thromboplastin time and international normalized ratio | It can indirectly predict the prognosis of patients with coagulopathy | It is unable to provide real-time information on coagulation changes; it does not assess the levels of thrombin or the extent of clot formation involved in the reaction | Conventional methods | | ROTEM | Detailed kinetics of blood coagulation such as clot initiation time, fibrin formation velocity, clot firmness and fibrinolysis activity | It allows for real-time assessment of hemostatic status, rapid feedback on test results and prediction of treatment efficacy; it can quickly and accurately evaluate fibrinogen levels; and it can guide therapeutic interventions | It requires stringent technical expertise; interpretation of results still relies heavily on the operator's experience, with lower standardization compared to conventional tests; and it is relatively more costly | Preferred methods | | TEG | Reaction time; kinetic time; alpha angle; maximum amplitude; lysis at 30 min | It allows for real-time assessment of hemostatic status, rapid feedback on test results and prediction of treatment efficacy; it can quickly and accurately evaluate fibrinogen levels; and it can guide therapeutic interventions | It demands strict technical requirements; results can be influenced by human factors; and it is time-consuming | Preferred methods | | POC-PFT | TEG (TEG 5000/6 s <br> Hemostasis Analyzer <br> System), ROTEM <br> (ROTEM Delta System), <br> platelet reactivity <br> turbidimetry test <br> (VerifyNow System), <br> multiple electrode <br> platelet aggregometry <br> (Multiplate Analyzer) and <br> PFA (PFA-100/200) | It enables real-time monitoring of platelet function: Reducing blood transfusion in cardiac surgery and in predicting the risk of perioperative blood loss in high risk cardiac surgery patients | There is no universally recognized 'gold standard'; it requires stringent technical expertise; and the results can be subject to human-related variables | Not routinely utilized |
ROTEM, rotational thromboelastography; TEG, thromboelastography; PFA, platelet function analyzer.
ROTEM:旋转血栓弹力图;TEG:血栓弹力图;PFA:血小板功能分析仪。

case underscores the practical utility of MMM. The system is capable of providing real-time updates on physiological changes and offering early indications of potential issues before they escalate, thereby guiding preemptive interventions (142). In conclusion, with the progression of technology and the accumulation of clinical experience, the application of MMM is likely to evolve into a more refined and widespread practice. IF so, it would be an indispensable component of modern neurointensive care.
该案例凸显了 MMM 的实用性。该系统能够提供生理变化的实时更新,并在潜在问题升级之前提供早期迹象,从而指导先发制人的干预措施(142)。总之,随着技术的进步和临床经验的积累,MMM 的应用很可能会发展成为一种更加完善和广泛的做法。届时,它将成为现代神经重症监护不可或缺的组成部分。

7. Summary and perspectives
7.总结与展望

TBI triggers swift and substantial modifications in cellular behaviors, thereby amplifying the intricacy of coagulopathy mechanisms and complicating treatment options by altering both intra- and intercellular connections. The diverse changes induced by TBI are still inadequately targeted by current therapeutic approaches. As a result, there is an urgent necessity for deeper investigation to clarify the fundamental mechanisms
创伤性脑损伤会迅速引发细胞行为的重大改变,从而加剧凝血病机制的复杂性,并通过改变细胞内和细胞间的联系使治疗方案复杂化。目前的治疗方法仍未充分针对创伤性脑损伤引起的各种变化。因此,迫切需要进行更深入的研究,以阐明其基本机制

underlying coagulopathy of post-TBI and to refine precision therapies accordingly. This involves establishing diagnostic thresholds and developing targeted therapeutic interventions aimed at effectively managing coagulation disorders. Current research lacks prospective diagnostic modalities that can accurately determine the timepoint of hemostatic failure, making it challenging to define the optimal timing for initiating anticoagulation therapy in patients with coagulopathy. The aging population of patients with TBI, coupled with the widespread use of antiplatelet medications and anticoagulants, poses a considerable challenge in comprehending the distinct impacts of various antiplatelet medications and anticoagulants on post-TBI coagulopathy. Tackling these challenges is paramount for improving clinical outcomes and minimizing the morbidity and mortality associated with this condition. Hence, there is a critical need for more expeditious and efficacious techniques to restore coagulation, thereby limiting the progression of brain injury in patients on anticoagulant and antiplatelet medications, with the ultimate aim of improving outcomes. Moreover, future research focusing on the management of coagulopathies in both critically and non-critically ill patients post-TBI should prioritize not just survival rates, but also enhancements in quality of life for patients.
创伤后凝血功能障碍的根本原因,并据此改进精准疗法。这包括建立诊断阈值和开发有针对性的治疗干预措施,以有效控制凝血功能障碍。目前的研究缺乏能准确确定止血功能衰竭时间点的前瞻性诊断方法,因此确定凝血功能障碍患者开始抗凝治疗的最佳时机具有挑战性。创伤性脑损伤患者的老龄化,加上抗血小板药物和抗凝剂的广泛使用,给理解各种抗血小板药物和抗凝剂对创伤性脑损伤后凝血病的不同影响带来了相当大的挑战。应对这些挑战对于改善临床疗效、最大限度地降低与该病症相关的发病率和死亡率至关重要。因此,亟需更快速、更有效的技术来恢复凝血功能,从而限制服用抗凝药物和抗血小板药物的患者脑损伤的进展,最终达到改善预后的目的。此外,未来针对脑损伤后重症和非重症患者凝血功能障碍管理的研究不仅应优先考虑存活率,还应提高患者的生活质量。

Acknowledgements  致谢

The authors are grateful to Ms. Du Pengchao (Binzhou Medical College, Yantai, China) for her insightful suggestions and constructive feedback on the manuscript.
作者感谢杜鹏超女士(中国烟台滨州医学院)对稿件提出的精辟建议和建设性意见。

Funding  资金筹措

No funding was received.
没有收到任何资金。

Availability of data and materials
数据和材料的可用性

Not applicable.  不适用。

Authors' contributions  作者的贡献

HH and ZQ performed the literature search and co-wrote the manuscript. RL, BJ, LW and AL participated in the literature search and reviewed the literature and the manuscript. HH, ZQ, RL, BJ, LW and AL made substantial contributions to the conception and revision of the manuscript. Data authentication is not applicable. All authors read and approved the final version of the manuscript.
HH和ZQ进行了文献检索并共同撰写了手稿。RL、BJ、LW和AL参与了文献检索,并审阅了文献和手稿。HH、ZQ、RL、BJ、LW 和 AL 对稿件的构思和修改做出了重大贡献。数据认证不适用。所有作者都阅读并批准了手稿的最终版本。
Not applicable.  不适用。
Not applicable.  不适用。

Competing interests  竞争利益

The authors declare that they have no competing interests.
作者声明他们没有利益冲突。

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  1. Correspondence to: Mr. Aiqun Li, Department of Emergency, Yantai Affiliated Hospital of Binzhou Medical College, 717 Jinbu Street, Muping, Yantai, Shandong 264100, P.R. China
    Correspondence to:山东省烟台市牟平区金埠街717号滨州医学院烟台附属医院急诊科 李爱群先生 邮编:264100

    E-mail: a15905356699@163.com
    电子邮件: a15905356699@163.com

    *Contributed equally  *平等贡献