Coagulopathy in liver disease

Opinion statement The liver plays a central role in hemostasis, as it is the site of synthesis of clotting factors, coagulation inhibitors, and fibrinolytic proteins. The most common coagulation disturbances occurring in liver disease include thrombocytopenia and impaired humoral coagulation. Therapy’s overall goal is not to achieve complete correction of laboratory value abnormalities but to gain hemostasis. Therapy with vitamin K may be a useful option in patients with increased prothrombin time due to vitamin K deficiency; in patients with malnutrition; in patients using antibiotics; and in patients with cholestatic liver disease, particularly prior to invasive procedures. Infusion of fresh frozen plasma is more often effective and is recommended in patients with liver disease before invasive procedures or surgery, as such patients require transient correction in their prothrombin time. Therapy with plasma exchange may be considered in patients who cannot be treated with fresh frozen plasma due to volume overload risk. In patients with severe coagulopathy and hypofibrinogenemia, cryoprecipitate therapy is ideal. Therapy with prothrombin-complex concentrate is seldom pursued in patients with liver disease due to high risk of thrombotic complications. Transfusions of platelets are appropriate for patients with thrombocytopenia (< 50,000/mm³) associated with active bleeding or before invasive procedures in which a short-term platelet count increase is noted. Trial with desmopressin may be considered before invasive procedures in patients with liver disease and with refractory and prolonged bleeding time. Recombinant activated factor VIIa administration is suggested for patients with significantly prolonged prothrombin time and contraindications to fresh frozen plasma therapy; however, this is expensive. Thrombopoietin and interleukin-11 are currently investigational for patients with thrombocytopenia of chronic liver disease. Liver transplantation completely restores impaired coagulation abnormalities and is the ultimate intervention that corrects coagulopathy of advanced liver disease and liver failure.     

Coagulopathy in liver disease:Lack of an assessment tool

There is a discrepancy between the information from clotting tests which have routinely been used in clinical practice and evidence regarding thrombotic and bleeding events in patients with liver disease. This discrepancy leads us to rely on other variables which have been shown to be involved in haemostasis in these patients and/or to extrapolate the behaviour of these patients to other settings in order to decide the best clinical approach. The aims of the present review are as follows:(1) to present the information provided by clotting tests in cirrhotic patients;(2) to present the factors that may influence clotting in these patients;(3) to review the clinical evidence; and(4) to put forward a clinical approach based on the first 3 points.     

Coagulopathy and transfusion therapy in pediatric liver transplantation

Bleeding and coagulopathy are critical issues complicating pediatric liver transplantation and contributing to morbidity and mortality in the cirrhotic child. The complexity of coagulopathy in the pediatric patient is illustrated by the interaction between three basic models. The first model, developmental hemostasis, demonstrates how a different balance between pro- and anticoagulation factors leads to a normal hemostatic capacity in the pediatric patient at various ages. The second, the cell based model of coagulation, takes into account the interaction between plasma proteins and cells. In the last, the concept of rebalanced coagulation highlights how the reduction of both pro- and anticoagulation factors leads to a normal, although unstable, coagulation profile. This new concept has led to the development of novel techniques used to analyze the coagulation capacity of whole blood for all patients. For example, viscoelastic methodologies are increasingly used on adult patients to test hemostatic capacity and to guide transfusion protocols. However, results are often confounding or have limited impact on morbidity and mortality. Moreover, data from pediatric patients remain inadequate. In addition, several interventions have been proposed to limit blood loss during transplantation, including the use of antifibrinolytic drugs and surgical techniques, such as the piggyback and lowering the central venous pressure during the hepatic dissection phase. The rationale for the use of these interventions is quite solid and has led to their incorporation into clinical practice; yet few of them have been rigorously tested in adults, let alone in children. Finally, the postoperative period in pediatric cohorts of patients has been characterized by an enhanced risk of hepatic vessel thrombosis. Thrombosis in fact remains the primary cause of early graft failure and re-transplantation within the first 30 d following surgery, and it occurs despite prolongation of standard coagulation assays. Data, however, are currently lacking regarding the use of anti-aggregation/anticoagulation therapies and how to best monitor for thrombosis in the early postoperative period in pediatric patients. Therefore, further studies are necessary to elucidate the interaction between the development of the coagulation system and cirrhosis in children. Moreover, strategies to optimize blood transfusion and anticoagulation must be tested specifically in pediatric patients. In conclusion, data from the adult world can be translated with difficulty into the pediatric field as indication for transplantation, baseline pathologies and levels of pro- and anticoagulation factors are not comparable between the two populations.     

Coagulopathy in prostate cancer

Patients with metastatic hormone-refractory prostate carcinoma may have dramatic and life-threatening coagulation complications from their disease. We report here the case of a man with relapsing disseminated intravascular coagulation, and review the different coagulation disorders that may occur during prostatic carcinoma evolution. We focus mainly on disseminated intravascular coagulation (DIC), the most frequent coagulation complication. Other coagulopathies associated with prostate cancer are thrombocytopenic thrombotic purpura, thrombosis, Trousseau's syndrome and acquired factor VIII inhibitor development.     

Coagulopathy of acute promyelocytic leukemia

Life-threatening bleeding is frequent in acute leukemias, particularly in acute promyelocytic leukemia (APL), a distinct subtype of acute myelogenous leukemia, characterized by the balanced reciprocal translocation between chromosomes 15 and 17. Laboratory assessments show profound hemostatic imbalance compatible with the clinical picture of disseminated intravascular coagulation. Activation of the coagulation system, hyperfibrinolysis and nonspecific proteases activity can be observed in this condition. An important pathogenetic role is attributed to the leukemic cell properties for activating hemostatic mechanisms. This review will summarize what is currently known about the coagulopathy of APL, the principal pathogenetic mechanisms, and the therapeutic tools for the management of this complication. Special attention will be devoted to the new therapy with all-trans retinoic acid, which has completely changed the natural history of APL and APL-related coagulopathy.     

Genetics of alcoholic liver disease and nonalcoholic fatty liver disease

Although the vast majority of heavy drinkers and individuals with obesity, insulin resistance, and the metabolic syndrome have steatosis, only a minority ever develop steatohepatitis, fibrosis, and cirrhosis. Genetic and environmental risk factors for advanced alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) seem likely to include factors that influence the severity of steatosis and oxidative stress, the cytokine milieu, the magnitude of the immune response, and/or the severity of liver fibrosis. For ALD, the dose and pattern of alcohol intake, coffee intake, and dietary and other lifestyle factors leading to obesity are the most important environmental determinants of disease risk. For NAFLD, dietary saturated fat and antioxidant intake, small bowel bacterial overgrowth, and obstructive sleep apnea syndrome may play a role. Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. For ALD, functional polymorphisms in the ADH and ALDH alcohol metabolizing genes play a role in determining susceptibility in Oriental populations. No genetic associations with advanced NAFLD have been replicated in large studies. Preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, tumor necrosis factor alpha, transforming growth factor beta, and angiotensinogen may be associated with steatohepatitis or hepatic fibrosis or both.     

非酒精性脂肪性肝病与酒精性肝病的异同

脂肪性肝病是一种常见病,根据有无大量饮酒史可分为酒精性脂肪性肝病(alcoholic fatty liver,AFL)与非酒精性脂肪肝(NAFLD),前者是酒精性肝病(ALD)的一个类型。ALD是世界范围内发病率和病死率最高的疾病之一,其发生肝硬化和肝癌的机会要远超过NAFLD[1]。在临床工作中,两种疾病因无特异的临床表现,鉴别主要依赖于饮酒史,但一些患者的饮酒量介于两者诊断（指南）标准之间,此外回忆和估计的饮酒史并不可靠,而作为两种不同原因诱导的疾病,还可能存在重叠的情况。现就近年来流行病学、自然转归、发病机制、诊断和治疗等方面的研究结果对两者进行比较鉴别。     

Clinical Considerations of Coagulopathy in Acute Liver Failure

Acute liver failure (ALF) is the rapid onset of severe liver dysfunction, defined by the presence of hepatic encephalopathy and impaired synthetic function (international normalized ratio of ≥1.5) in the absence of underlying liver disease. The elevated international normalized ratio value in ALF is often misinterpreted as an increased hemorrhagic tendency, which can lead to inappropriate, prophylactic transfusions of blood products. However, global assessments of coagulopathy via viscoelastic tests or thrombin generation assay suggest a reestablished hemostatic, or even hypercoagulable, status in patients with ALF. Although the current versions of global assays are not perfect, they can provide more nuanced insights into the hemostatic system in ALF than the conventional measures of coagulopathy.     

酒精性肝病

酒精性肝病 (ＡｌｃｏｈｏｌｉｃＬｉｖｅｒＤｉｓｅａｓｅ ,ＡＬＤ)是由于长期大量饮酒导致的中毒性肝损伤 ,最初为肝细胞脂肪变性 ,进而发展为肝炎、肝纤维化 ,最终导致肝硬化。酗酒是西方国家肝硬化的主要原因。近来随着我国经济水平的发展 ,酒精的消耗量增加 ,酒精性肝病明显增多 ,本文就有关这方面的研究作一综述。发生酒精性肝病可能与列因素有关 :①每日酒精摄入量及累积时间 ;②性别 ;③遗传因素 ;④饮酒方式 (空腹饮酒及短时间大量饮酒 )。酒精摄入的安全量尚有争议 ,英国皇家医学院推荐量为 :男性 <2 10 ｇ/周 ,女性 <14 0 ｇ/周…     

Drug-induced liver disease

Drug-induced liver injury (DILI), also known as hepatotoxicity, refers to liver injury caused by drugs or other chemical agents, and represents a special type of adverse drug reaction. It has been estimated that more than 600 drugs and chemicals have been associated with significant liver injury. Many previous reviews have focused on DILI pathogenesis or have outlined the clinical features of liver injury linked to different drugs. This article briefly touches on several areas that are potentially vexing for both the novice and cognoscenti, with the goal of guiding the consultant through one of the most challenging areas of hepatology.     

Metabolic liver disease

Diagnosis of metabolic liver disease requires a high level of diagnostic suspicion. Diet is usually the primary treatment for metabolic liver disease. Where indicated, liver transplantation provides lifelong functional correction of liver-based metabolic defects. Liver cell therapy warrants further study for the future treatment of metabolic liver disease. All families should receive genetic advice and pre-emptive management of future affected siblings.