Spatiotemporal regulation of coagulation and platelet activation during the hemostatic response in vivo

The hemostatic response requires the tightly regulated interaction of the coagulation system, platelets, other blood cells and components of the vessel wall at a site of vascular injury. The dysregulation of this response may result in excessive bleeding if the response is impaired, and pathologic thrombosis with vessel occlusion and tissue ischemia if the response is overly robust. Extensive studies over the past decade have sought to unravel the regulatory mechanisms that coordinate the multiple biochemical and cellular responses in time and space to ensure that an optimal response to vascular damage is achieved. These studies have relied in part on advances in in vivo imaging techniques in animal models, allowing for the direct visualization of various molecular and cellular events in real time during the hemostatic response. This review summarizes knowledge gained with these in vivo imaging and other approaches that provides new insights into the spatiotemporal regulation of coagulation and platelet activation at a site of vascular injury.     

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.     

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。     

Association between circulating hemostatic measures and dementia or cognitive impairment: systematic review and meta‐analyzes

Summary. Background and objectives: Hemostasis and thrombosis may be important contributors to cognitive decline and dementia. Certain blood markers may assist in diagnosis or management. Objectives: To collate evidence for the association of circulating hemostatic variables and dementia or cognitive impairment. Methods: A systematic review of studies describing blood markers of hemostatic function and cognition/dementia. Abstracts were reviewed by two independent assessors and studies selected based on pre‐specified criteria. We described methodological quality and performed meta‐analyzes where data allowed. Results: From 7103 titles, 485 abstracts and included 21 studies (n = 32 773) were assessed. In two longitudinal studies, the incident of vascular dementia risk was greater for higher D‐dimer [hazard ratio (HR): 1.50, 95% confidence interval (CI): 1.15–1.96]. For case–control data, we calculated standardized mean differences (SMD) and 95% CI. Higher levels of: factor (F)VII (SMD: 0.93; 95% CI: 0.60–1.26), fibrinogen (SMD: 1.53; 95% CI: 1.17–1.87), prothrombin fragment 1 and 2 (SMD: 0.64; 95% CI: 0.32–0.96), plasminogen activator inhibitor (SMD: 0.68; 95% CI: 0.26–1.10), D‐dimer (SMD: 2.00; 95% CI: 1.59–2.40) and von Willebrand factor (VWF) (SMD: 1.68; 95% CI: 1.30–2.06) showed modest but significant associations with vascular dementia. For patients with any dementia diagnosis, associations were with higher D‐dimer (SMD: 0.36; 95% CI: 0.15–0.56) and VWF (SMD: 0.31; 95% CI: 0.11–0.51). For specific cognitive domains, significant (P < 0.001) positive correlations were fibrinogen and speed of processing (0.76; 95% CI: 0.67–0.84), verbal memory (0.69; 95% CI: 0.59–0.79) and non‐verbal reasoning (0.57; 95% CI: 0.49–0.65). Conclusions: The present results suggest a modest association between hemostasis and vascular dementia including increased levels of thrombin generation markers (D‐dimer and prothrombin fragment 1 + 2) and endothelial dysfunction (VWF and plasminogen activator inhibitor). Associations are weaker for specific cognitive tests and when all dementias are combined.     

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.     

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.     

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。     

Successful treatment of drug‐induced acute liver failure with high‐volume plasma exchange

We report two patients with drug‐induced liver injury (DILI)‐related acute liver failure (ALF) who were successfully treated with high‐volume plasma exchange without liver transplantation. The first patient was a 66‐year‐old man admitted because of a perforated duodenal ulcer complicated with peritonitis and septic shock. After treatment with multiple antibiotics, the patient developed DILI and ALF. Grade 3 hepatic encephalopathy and profound jaundice were present. Symptoms and signs of ALF improved dramatically after initiation of plasma exchange. The patient was discharged uneventfully. The second patient was a 94‐year‐old man admitted for treatment of newly diagnosed pulmonary tuberculosis. DILI and ALF developed 5 days after initiation of anti‐tuberculosis treatment. Grade 4 hepatic encephalopathy was present. After plasma exchange, the patient's level of consciousness improved dramatically, and he recovered from ALF. These 2 cases show the potential of plasma exchange in the treatment of DILI despite occurrence acute liver failure. J. Clin. Apheresis, 28:430–434, 2013. © 2013 Wiley Periodicals, Inc.     

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。     

High‐volume plasma exchange in a patient with acute liver failure due to non‐exertional heat stroke in a sauna

Heat stroke is a life‐threatening condition characterized by an increased core body temperature (over 40°C) and a systemic inflammatory response, which may lead to a syndrome of multiple organ dysfunction. Heat stroke may be due to either strenuous exercise or non‐exercise‐induced exposure to a high environmental temperature. Current management of heat stroke is mostly supportive, with an emphasis on cooling the core body temperature and preventing the development of multiple organ dysfunction. Prognosis of heat stroke depends on the severity of organ involvement. Here, we report a rare case of non‐exercise‐induced heat stroke in a 73‐year‐old male patient who was suffering from acute liver failure after prolonged exposure in a hot sauna room. We successfully managed this patient by administering high‐volume plasma exchange, and the patient recovered completely after treatment. J. Clin. Apheresis 29:281–283, 2014. © 2014 Wiley Periodicals, Inc.     

混合型生物人工肝治疗急性肝衰竭动物的实验研究

目的评估混合型生物人工肝对急性肝衰竭动物的治疗效果。方法混合型生物人工肝由血浆置换、血液滤过和猪肝细胞型生物人工肝构成。6只中国实验小型猪采用D-氨基半乳糖静脉注射建立急性肝衰竭动物模型,在给药48h后给予混合型生物人工肝治疗,先进行血浆置换联合血液滤过,再经过猪肝细胞型生物人工肝处理。观察比较实验动物治疗前后的临床表现及各相关指标的变化;并比较血浆置换联合血液滤过后猪肝细胞型生物人工肝处理后血液中相应指标的变化。结果本组实验动物在混合型生物人工肝治疗过程中生命体征平稳,未发生严重不良反应。与治疗前相比,治疗后实验动物血液中总胆红素、氨、丙氨酸转移酶、内毒素、肌酐明显减少(P0.01),纤维蛋白原、凝血酶原活动度和甲胎蛋白明显增加(P0.01);与血浆置换联合血液滤过比较,猪肝细胞型生物人工肝治疗后血液中纤维蛋白原、凝血酶原活动度有所增加(P0.05),血氨、总胆红素明显降低(P0.01)。结论应用混合型生物人工肝治疗急性肝衰竭安全、有效。混合型生物人工肝较非生物型人工肝(血浆置换+血液滤过)效果好。     

Different degradation rates of nanofiber vascular grafts in small and large animal models

Nanofiber vascular grafts have been shown to create neovessels made of autologous tissue, by in vivo scaffold biodegradation over time. However, many studies on graft materials and biodegradation have been conducted in vitro or in small animal models, instead of large animal models, which demonstrate different degradation profiles. In this study, we compared the degradation profiles of nanofiber vascular grafts in a rat model and a sheep model, while controlling for the type of graft material, the duration of implantation, fabrication method, type of circulation (arterial/venous), and type of surgery (interposition graft). We found that there was significantly less remaining scaffold (i.e., faster degradation) in nanofiber vascular grafts implanted in the sheep model compared with the rat model, in both the arterial and the venous circulations, at 6 months postimplantation. In addition, there was more extracellular matrix deposition, more elastin formation, more mature collagen, and no calcification in the sheep model compared with the rat model. In conclusion, studies comparing degradation of vascular grafts in large and small animal models remain limited. For clinical translation of nanofiber vascular grafts, it is important to understand these differences.     

The effect of lithium administration in animal models of depression: a short review

The aim of this short review was to collate the data involving the effects of lithium alone, or in combination, with antidepressant drugs in several animal models of depression. It has been shown that lithium administration reduced immobility in the mouse forced swimming test when given 30 min, but not 45 min, before testing. Further studies indicated that this activity was probably a result of an activity on serotonin (5-HT) 1A and 1B receptor subtypes. Lithium treatment has been shown to reverse helpless behaviour in the learned helplessness model of depression after chronic treatment (30 days), where lithium was administered in the drinking water. Further studies showed that acute (5 days) administration of lithium failed to reverse behavioural deficits. In the olfactory bulbectomised rat model of depression, several immunological and enzymatic functions have been shown to be altered and these changes are regularised by antidepressant treatment as well as lithium administration for 15 days. Hypokinesia (reduced locomotor activity) is a phenomenon observed following immobilisation stress in rats. This behavioural deficit was attenuated by lithium together with a wide range of antidepressant drugs used in the treatment of unipolar depression at non-stimulant doses. In addition, a single administration of lithium slightly inhibited midbrain raphe lesion-induced muricidal behaviour (25%); however, repeated treatment (5 days) significantly attenuated this behavioural deficit. Lithium treatment has also been shown to reverse behavioural and biochemical deficits induced by reserpine together with those induced by acute administration of single intracerebroventricular (i.c.v.) dose of the Na, K-ATPase-inhibiting compound, ouabain. Long-term studies of lithium augmentation have not been performed, so that no clear recommendations for the duration of this therapy can be made. The points raised in this short review endorse the commencement of such studies.     

Paraquat‐induced acute kidney and liver injury: Case report of a survivor from Bangladesh

Despite high fatality following paraquat ingestion, a few percentages of patients survive even after organ damage appears. We need to focus more on careful clinical and laboratory monitoring. Early diagnosis and Supportive therapy are crucial.     

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。