Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure

Summary. Background: It has been well established that hemostatic potential in patients with chronic liver disease is in a rebalanced status due to a concomitant decrease in pro‐ and antihemostatic drivers. The hemostatic changes in patients with acute liver injury/failure (ALI/ALF) are similar but not identical to the changes in patients with chronic liver disease and have not been studied in great detail. Objective: To assess thrombin generation and fibrinolytic potential in patients with ALI/ALF. Methods: We performed thrombin generation tests and clot lysis assays in platelet‐poor plasma from 50 patients with ALI/ALF. Results were compared with values obtained in plasma from 40 healthy volunteers. Results and conclusion: The thrombin generation capacity of plasma from patients with ALI/ALF sampled on the day of admission to hospital was indistinguishable from that of healthy controls, provided thrombomodulin was added to the test mixture. Fibrinolytic capacity was profoundly impaired in patients with ALI/ALF on admission (no lysis in 73.5% of patients, compared with 2.5% of the healthy controls), which was associated with decreased levels of the plasminogen and increased levels of plasminogen activator inhibitor type 1. The intact thrombin generating capacity and the hypofibrinolytic status persisted during the first week of admission. Patients with ALI/ALF have a normal thrombin generating capacity and a decreased capacity to remove fibrin clots. These results contrast with routine laboratory tests such as the PT/INR, which are by definition prolonged in patients with ALI/ALF and suggest a bleeding tendency.     

Blood coagulation in anhepatic pigs: effects of treatment with the AMC-bioartificial liver

Summary. The function of a newly devised bioartificial liver (AMC‐BAL) based on viable, freshly isolated porcine hepatocytes has been evaluated in anhepatic pigs. The aim of this study was to assess the contribution of BAL treatment on blood coagulation parameters. Pigs were anesthetized and a total hepatectomy was performed (n = 15). The infrahepatic caval vein and the portal vein were connected to the subdiaphragmatic caval vein using a three‐way prosthesis. Animals received standard intensive care (control, n= 5), treatment with an empty BAL (device control, n= 5) or with a cell‐loaded BAL (BAL‐treatment, n= 5) for a period of 24 h starting 24 h after hepatectomy. Coagulation parameters studied concerned prothrombin time (PT), platelet count, the procoagulant system (factors (F)II, FV, FVII, FVIII and fibrinogen), anticoagulant system (AT III), fibrinolytic system (t‐PA, PAI‐1) as well as markers of coagulation factor activation (TAT complexes, prothrombin fragment F1 + 2). FII, FV, FVII, AT III and fibrinogen rapidly decreased after total hepatectomy in pigs in accordance with the anhepatic state of the animals. FVIII levels were not influenced by the hepatectomy. A mild drop in platelet count was seen in all groups. Treatment of anhepatic pigs with the cell‐loaded BAL did not restore PT or clotting factor levels. TAT and F1 + 2 complexes, however, were significantly increased in this group. Levels of t‐PA and PAI‐1 were not influenced by cell‐loaded BAL treatment. Treatment of anhepatic pigs with the AMC‐BAL based on freshly isolated porcine hepatocytes does not result in an improved coagulation state due to extensive consumption of clotting factors. However, increased levels of TAT complexes and prothrombin fragments F1 + 2 during treatment of anhepatic pigs indicate synthesis and direct activation of coagulation factors, leading to thrombin generation. This demonstrates that this bioartificial liver is capable of synthesizing coagulation factors.     

慢性肾衰竭患者止凝血功能的变化

目的探讨止血、凝血系统的变化与慢性肾衰竭并发出血的关系。方法检测55例慢性肾衰竭患者血小板聚集率(PAgT)、P-选择素、血管性血友病因子∶抗原(vWF∶Ag)含量;凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、抗凝血酶Ⅲ(AT-Ⅲ)活性、血浆蛋白C(PC)活性,并与40例健康者比较。结果慢性肾衰竭患者PAgT、P-选择素、AT-Ⅲ活性、血浆PC明显降低,与对照组比较,差异有统计学意义(P<0.01);vWF∶Ag含量升高,与对照组比较,差异有统计学意义(P<0.01),PT、APTT与对照组比较,差异无统计学意义(P>0.05)。结论慢性肾衰竭患者存在出血和血栓栓塞两种状态。     

自制静脉压迫器在肝功能衰竭患者股静脉置管拔除后的应用

目的探讨自制静脉压迫器在肝功能衰竭患者股静脉置管拔除后的应用效果。方法将行股静脉置管的200例肝功能衰竭患者患者随机分为观察组和对照组,每组100例。观察组股静脉置管拔管后采用自制静脉压迫器压迫止血;对照组采用压球按压加绷带加压包扎止血。比较两组患者静脉穿刺处并发症发生、压迫止血操作时间、肢体制动时间的差异。结果观察组患者静脉穿刺处并发症发生率低于对照组;压迫止血操作时间、肢体制动时间短于对照组,两组比较,均P〈0．0l,差异具有统计学意义。结论股静脉拔除后采用自制静脉压迫止血器止血,可降低出血并发症发生,止血时间和肢体制动时间缩短,值得临床推广使用。     

Shock,acute disseminated intravascular coagulation,and microvascular thrombosis: is ‘shock liver’ the unrecognized provocateur of ischemic limb necrosis?

For unknown reasons, a small minority of critically ill patients with septic or cardiogenic shock, multiorgan failure, and disseminated intravascular coagulation develop symmetrical acral (distal extremity) limb loss due to microvascular thrombosis (‘limb gangrene with pulses’). Case reports have described preceding ‘shock liver’ in some critically ill patients who developed such a picture of ischemic limb necrosis. This suggests that profoundly disturbed procoagulant–anticoagulant balance featuring uncontrolled generation of thrombin—resulting from failure of the protein C and antithrombin natural anticoagulant systems due to insufficient hepatic synthesis of these crucial proteins—could explain the microvascular thrombosis and associated limb loss. We hypothesize that shock liver is the key predisposing risk factor underlying ischemic limb necrosis in the majority of patients who develop this complication in the setting of acute disseminated intravascular coagulation complicating septic or cardiogenic shock. As shock liver precedes onset of limb ischemia by several days, therapeutic intervention may be possible.     

ACL 8000型凝血分析仪的抗干扰功能

目的 对美国贝克曼库尔特公司生产的ACL8000型凝血分析仪的抗干扰能力作试验研究。方法 重复测定正常外观血浆凝血酶原时间（PT）、部分凝血活酶时间（APTT）、纤维蛋白原（凝血因子I）定量（Fig）和凝血酶时间（TT）各10次；采用日本国际试药株式会社生产的统一标准干扰物（溶血性血红蛋白、直接胆红素、间接胆红素和乳脂蛋白）分别加入到试验血浆中，再测定各种浓度干扰物一试验血浆的PT，APTT，Fig和TT。结果 重复测定PT，APTT，Fig和TT的CV〈1．76％；测定干扰物试验血浆PT，APTT，Fig和TT的影响范围在士4．9％。结论 该仪器对溶血性血红蛋白、直接胆红素、间接胆红素和乳脂蛋白具有强力抗干扰的能力。     

冠心病患者心血管意外和凝血功能的相关性研究

目的深入研究冠心病患者凝血功能与心血管意外的关系,我们对患者血液中的von willebrand因子(vWF)、抗凝血酶原复合物(TAT),D-二聚体(D-dimers),抗纤维蛋白溶酶复合物(PAP)和心血管意外死亡发生率的关系进行了研究。方法 1057名经冠状造影证实有冠状血管粥样硬化的患者,平均随访时间为6.6年,在此期间有135名患者死亡心血管意外,97名患者发生非致死性心血管意外。高浓度的凝血状态和心血管意外死亡有关,但与非死亡性心血管意外无关。在去除与心血管意外发生的传统因素(C反应蛋白)外,vWF,纤维蛋白原,TAT,D-二聚体,PAP与心血管意外发生的相关性P值分别为0.20,0.011,0.026,0.019,和0.01。在多因素COX模型中,D-dimers和纤维蛋白原是独立影响因素,危害比(95%CI)分别为1.27(1.04-1.55)和1.29(1.09-1.53)。结果结论在冠状血管疾病患者中,纤维蛋白原和D-dimer可以作为预测冠心病患者心血管死亡的独立因素,对此类患者有必要进行预防性的抗凝治疗。     

Effects of acute liver injury on blood coagulation

Summary.  The mechanisms leading to the hemostatic changes of acute liver injury are poorly understood. To study these further we have assessed coagulation and immune changes in patients with acute paracetamol overdose and compared the results to patients with chronic cirrhosis and normal healthy controls. The results demonstrate that in paracetamol overdose coagulation factors (F)II, V, VII and X were reduced to a similar degree and were significantly lower than FIX and FXI (mean levels 0.28, 0.16, 0.13, 0.19, 0.51 and 0.72 IU mL⁻¹, respectively). In cirrhosis, by contrast, FII, FV, FVII, FIX and FX were equally reduced whilst FXI was lower than the other factors (mean levels 0.64, 0.69, 0.62, 0.60, 0.66 and 0.40 IU mL⁻¹, respectively). FVIII was raised in paracetamol overdose patients but normal in those with cirrhosis (mean levels 1.95 and 1.01 IU mL⁻¹, respectively). Interleukin-6 and tumor necrosis factor-α levels were raised in both patient groups, but higher levels were found in paracetamol overdose, compared to cirrhosis. Thrombin-antithrombin and soluble tissue factor levels were higher in those with acute liver injury but normal in cirrhosis. Antithrombin levels were reduced in both acute liver injury and cirrhosis. From these data we put forward a novel mechanism for the coagulation changes in acute paracetamol induced liver injury. We propose that immune activation leads to tissue factor-initiated consumption of FII, FV, FVII and FX, but that levels of FIX and FXI are better preserved because antithrombin inhibits the thrombin induced positive feedback loop that activates these latter factors.     

甲胎蛋白含量在慢加急性肝衰竭中的临床意义

目的：探讨甲胎蛋白（AFP）含量与慢加急性肝衰竭预后的关系,进一步了解肝衰竭患者AFP含量的变化。方法：将回顾分析的65例慢加急性肝衰竭患者根据最后治疗结果分为存活组与死亡组,分析对比两组在不同时间AFP含量的差异,同时观察AFP含量与总胆红素（TBil）,凝血酶原活动度（PTA）的关系。结果：65例患者中AFP含量高于正常者53例（81.54%）,存活组不同时期的AFP含量平均值均高于死亡组,有显著差别（P〈0.01）。AFP含量升高（≥300 IU/mL）主要分布在血清总胆红素〈510μmoL/mL,凝血酶原活动度〉30%患者中,随AFP含量升高,病死率下降。结论：慢加急性肝衰竭患者血清AFP含量升高反应了肝细胞再生活跃,提示预后良好。     

凝血指标和血小板参数在肝病进展中的变化规律

目的包括血小板计数(PLT)、平均血小板体积(MPV)、血小板分布宽度(PDW)和血小板容积(PCT),探讨常见凝血指标和血小板参数在慢性病毒性肝炎、肝硬化及肝衰竭患者中的变化规律。方法选取2015年1月至2016年6月于该院治疗的肝病患者共120例,分为慢性病毒性肝炎组(46例)、肝硬化组(Child-Pugh A、B、C级)(44例)、肝衰竭组(30例)及同期健康体检者30例为健康对照组。检测所有受试者的凝血指标包括凝血酶原时间(PT)、凝血酶原活动度(PTA)、活化部分凝血活酶时间(APTT)、凝血酶时间(TT)、纤维蛋白原(Fg)、D-二聚体(D-D),以及血小板参数(PLT、MPV、PDW、PCT)。结果除TT、Fg和D-D在健康对照组与慢性病毒性肝炎组差异无统计学意义(P0.05),慢性病毒性肝炎组、肝硬化组(Child-Pugh A、B、C级)和肝衰竭组的PT、APTT和TT逐渐延长,PTA和Fg下降,D-D值增加,组间两两比较差异具有统计学意义(P0.05)。慢性病毒性肝炎组、肝硬化组(Child-Pugh A、B、C级)和肝衰竭组的PLT值逐渐下降,而MPV、PDW值逐渐增高,差异有统计学意义(P0.05),肝硬化组和肝衰竭组的PCT值低于慢性病毒性肝炎组(P0.05)。结论凝血指标和血小板参数在慢性肝病进展的不同时期发生规律性改变,为临床诊治及预后判断提供一定的参考。     

急性肝功能衰竭急诊肝移植围术期治疗的单中心经验探讨

背景：急性肝衰竭行急诊肝移植患者围手术期治疗的病情复杂,风险大,并发症多,死亡率高,与普通肝脏移植有着明显不同。目的：总结急诊肝移植治疗急性肝功能衰竭的围手术期治疗经验,以提高急性肝功能衰竭的治疗成功率。方法：回顾性分析38例因急性肝功能衰竭行急诊肝移植患者的临床资料,男21例,女17例,年龄15-69岁。其中乙型肝炎病毒性肝炎23例（其中乙型合并丁型肝炎2例）,Wilsons病7例,3例为毒蕈中毒,2例不明原因药物肝脏损害,1例雷公藤多甙中毒,1例为外伤行肝脏部分切除后失代偿,1例尸体肝移植后患者。结果与结论：38例患者生存时间为13-1740d,中位生存时间为634d。患者的围手术期存活率为76%,1年存活率为63%,2年存活率为58%。9例围手术期死亡原因包括脑水肿及颅内高压、肾功能衰竭、严重肺部感染、多脏器功能衰竭、凝血功能障碍（颅内出血、上消化道出血等）、急性成人呼吸窘迫综合征、移植物原发性无功能。目前急诊肝移植仍是治疗急性肝功能衰竭最有效的方法,出血、感染、排异反应是死亡的主要原因,肝移植围手术期间每一环节的处理,对于肝移植的成功和患者长期存活具有重要意义。     

TECAI型生物人工肝支持系统治疗急性肝衰竭犬的实验研究

目的评价经改进的TECAI型生物人工肝脏支持系统（bioartificial liver supportsyst em,BALSS）治疗醋氨酚诱发急性肝衰竭(acute liver failure,ALF)犬的有效性和安全性。方法采用多次皮下注射醋氨酚的方法建立ALF模型犬。分离中国实验用小型猪肝细胞并培养于BALSS中,对ALF犬进行6小时的治疗,观察治疗前后犬生理、生化和组织学的变化,与常规药物治疗组和对照组进行比较。结果注射醋氨酚48小时后,可建立ALF犬模型,模型成功率为63.16%。应用我们改进的酶消化法,平均从每只小型猪的肝脏可得到（0.8～3.0）×10     

输血相关急性肺损伤动物模型研究进展

输血相关性急性肺损伤（transfusion-related acute lung injury,TRALI）是指输入血液或血制品后6小时内出现的以急性非心源性肺水肿和低氧血症为主要表现的临床综合征。TRALI起病急,病情重,病死率高,是输血的严重并发症,并已成为输血导致死亡的主要原因之一。然而迄今为止,TRALI的病理生理学机制尚未完全阐明,诊断和治疗也面临巨大挑战。研究者们主要借助动物实验逐步理解TRALI的发生发展过程,动物模型也正逐步完善,本文旨在概括TRALI的几种主要动物模型,进一步探讨TRALI的发生发展机制,并为研究者们在TRALI的动物模型设计方面提供帮助。     

急性静脉性脑梗死动物模型的建立

【目的】建立一个稳定的静脉性脑梗死（CVI）的动物模型。【方法】新西兰兔35只，随机分为3组（A组，单纯上矢状窦中1／3段结扎组，15只；B组，上矢状窦中1／3段＋桥静脉结扎组15只；C组，假手术组5只），在术后8h、24h、48h分别测定脑水含量，TTC染色测梗死范围并和大体标本、光镜及电镜行对照研究。【结果】A组术后8h和B组术后8h、24h、48h脑组织水肿明显。与A组比较，B组结扎后脑梗死范围明显增加。B组15只兔24h、48h均可见病理证实的不同程度的CVI，而A组中仅5只兔出现了CVI。假手术组5只均未见上述表现。【结果】上矢状窦中1／3段＋桥静脉结扎制备CVI动物模型的方法是可行的。     

磁共振T1rho技术定量诊断大鼠肝纤维化

目的 探讨T1rho技术定量诊断大鼠肝纤维化的价值。方法 选取45只SD大鼠为实验组,以腹腔注射40% CCl₄橄榄油溶液的方法制备肝纤维化模型;另选取12只SD大鼠为对照组,腹腔注射等量生理盐水。于给药后第1、2、4、6、8、10周分别取实验组5~6只大鼠和对照组2只大鼠进行MR T1rho扫描。完成检查后取肝脏进行病理检查,并进行肝纤维化分级。结果 肝纤维化F0~F6级大鼠肝脏的T1rho值分别为（40.68±1.60）ms、（42.80±1.08）ms、（44.98±1.04）ms、（46.47±3.47）ms、（47.73±3.84）ms、（55.38±7.46）ms及（57.08±5.11）ms,总体差异有统计学意义（F=30.72,P<0.01）。大鼠肝脏T1rho测量值与肝纤维化分级呈正相关（r=0.88,P<0.01）;α-SMA表达水平与肝纤维化分级呈正相关（r=0.74,P<0.01）,与T1rho值亦呈正相关（r=0.57,P<0.01）。结论 MR T1rho可用于定量、无创性评估大鼠肝纤维化程度。