Management of coagulation abnormalities in liver disease

Liver disease is characterized by changes in all phases of hemostasis. These hemostatic alterations were long considered to predispose patients with liver disease towards a bleeding tendency, as they are associated with prolonged conventional coagulation tests. However, these patients may also suffer from thrombotic complications, and we now know that the hemostatic system in patient with liver disease is, in fact, in a rebalanced state. In this review we discuss the concept of rebalanced hemostasis and its implications for clinical management of patients with liver disease. For instance, there is no evidence that the use of prophylactic blood product transfusion prior to invasive procedures reduces bleeding risk. Clinicians should also be aware of the possibility of thrombosis occurring in patients with a liver disease, and regular thrombosis prophylaxis should not be withheld in these patients.     

凝血异常在HBV相关慢加急性肝衰竭患者血栓形成中的作用

目的观察传统凝血功能和血小板相关指标对HBV相关慢加急性肝衰竭(HBV-ACLF)患者血栓形成事件的作用。方法选取2015年1月—2019年12月在苏州大学附属第一医院住院的HBV-ACLF患者56例,分为发生血栓组(n=24)与未发生血栓组(n=32)。回顾性分析两组患者入院时的一般临床资料,观察入院后第1~7天的凝血功能,血小板计数和血小板功能相关指标平均血小板体积(MPV)的变化。符合正态分布的计量资料两组间比较采用t检验,不符合正态分布的计量资料两组间比较采用Mann-Whitney U秩和检验;计数资料两组间比较采用χ2检验。采用重复测量资料方差分析比较组内及组间不同时间凝血指标的差异。结果HBV-ACLF患者在入院时,发生血栓组年龄31.5(29.0~34.0)岁,较未发生血栓组年龄48.5(36.0~50.7)岁小,差异有统计学意义(Z=-2.637,P=0.008);在入院当天,MPV在发生血栓组与未发生血栓组间差异无统计学意义(P>0.05)。在入院后第2~7天,MPV值发生血栓组与未发生血栓组间差异均有统计学意义(t值分别为-2.696、-2.742、-2.894、-4.174、-3.945、-4.716,P值均<0.01)。发生血栓组MPV的峰值为入院第5天,均值为(13.90±1.12)fl,高于正常值范围。所有纳入患者在入院时,PT均值为(28.8±7.2)s、APTT均值(50.5±8.7)s、INR均值(2.6±0.7),均高于正常值;Fb均值为(1.16±0.3)g/L、血小板计数均值为(107.7±26.5)×109/L,均低于正常值。而PT、APTT、Fbg、INR及血小板计数在发生血栓组与未发生血栓组间差异均无统计学意义(P值均>0.05)。结论肝衰竭患者凝血功能障碍,更多是一种低平衡状态,是复杂与异质性的,需要个体化处理。HBV-ACLF患者中,易发生血栓事件者可能与血小板的功能有关,而与血小板计数及凝血常规指标关系不大。     

Splenomegaly, hypersplenism and coagulation abnormalities in liver disease

Splenomegaly is a frequent finding in patients with liver disease. It is usually asymptomatic but may cause hypersplenism. Thrombocytopenia is the most frequent manifestation of hypersplenism and may contribute to portal hypertension related bleeding. A number of therapies are available for treating thrombocytopenia due to hypersplenism including splenectomy, partial splenectomy, partial splenic embolization, TIPS etc. None is entirely satisfactory. Hypersplenism usually improves following liver transplantation. Therapy with cytokines such as thrombopoietin may offer hope for the future. Patients with liver disease also have abnormalities in coagulation. This is not surprising as all coagulation proteins (except for von willebrand factor vWF) and most inhibitors of coagulation are synthesized in the liver. Genetic or acquired abnormalities of coagulation may predispose to thrombosis of the hepatic or portal veins with significant clinical sequelae. An understanding of the mechanisms involved in coagulation and thrombosis is valuable in choosing from the increasing treatment options available. These include clotting factors, haemeostatic drugs and newer therapies such as recombinant factor VIIa. Splenic artery aneurysms are the most common visceral artery aneurysms in man. Rupture is frequently catastrophic. These aneurysms are being increasingly recognized in liver transplant patients and require treatment before or during transplant surgery.     

Intravascular coagulation in acute liver failure in rats and its treatment with antithrombin III.

Liver damage was induced in rats by injection of dimethylnitrosamine (DMN) or carbon tetrachloride (CCl4). Fibrin clots were observed in the hepatic sinusoids at 12 hours and soluble fibrin monomer complexes were markedly detected at 24 hours only in the rats given DMN. When antithrombin III concentrate was infused at 12 hours there was a dose dependent improvement of the values of serum total bilirubin, SGPT, prothrombin time, peripheral platelet count, and plasma fibrinogen and coagulation factor VIIIC and of the histological degree of liver injury at 24 hours in the DMN group. The CCl4-group showed no such improvement. Intravascular coagulation may complicate the course of certain types of acute liver injury and contribute to its aggravation in rats. Under such circumstances, treatment with antithrombin III concentrate would be beneficial.     

Renal failure in acute liver failure.

Renal failure develops in approximately 55% of all patients referred to specialized centres with acute liver failure. The renal failure may be secondary to the liver failure itself (and is termed the hepatorenal syndrome) or the renal failure may be a secondary insult that directly affects both liver and kidney alike (for example paracetamol overdose). The pathogenesis of the hepatorenal syndrome involves the development of a hyperdynamic circulation, with a lowering of renal perfusion pressure, the activation of the sympathetic nervous system, which renders the kidneys more susceptible to modest decreases in perfusion pressure, and increased synthesis of a variety of vasoactive mediators. These mediators can cause renal vasoconstriction, but more importantly they can also decrease the glomerular capillary ultrafiltration coefficient (Kf), thus causing a decline of glomerular filtration rate over and above that caused by renal vasoconstriction alone. The treatment of the renal failure in acute liver failure involves the optimization of renal haemodynamics and haemofiltration. Renal failure will always recover when there is recovery of liver function, and in the absence of a spontaneous hepatic recovery, liver transplantation will reverse the hepatorenal syndrome.     

Thrombopoietin in acute liver failure

Thrombopoietin (TPO) is the primary regulator of platelet production. TPO is produced in the liver and levels are low in patients with cirrhosis. Because thrombocytopenia is common in patients with acute liver failure (ALF), we measured TPO concentrations (normal TPO range, 31 to 136 pg/mL) in 51 patients with ALF to determine if low levels were associated with thrombocytopenia. TPO levels from hospital day 2 were elevated in 43% of patients, normal in 47%, and decreased in 10% of patients. Levels were higher in acetaminophen-induced than in non-acetaminophen-induced ALF, 160 (12 to 549) pg/mL versus 73 (18 to 563) pg/mL, respectively, P =.031. TPO levels did not correlate with platelet count and were not related with survival or infection. We analyzed daily TPO levels for the first week of hospitalization in 12 patients with acetaminophen-induced ALF and observed a gradual increase from a median admission level of 50 (5 to 339) pg/mL to a median peak level of 406 (125 to 1,081) pg/mL occurring on day 5 (3 to 6). Platelets were reduced in 11 of the 12 patients with a nadir platelet count of 52 (19 to 156) x 10(9) cells/L occurring on day 5.5 (1 to 6). The peak TPO level did not correlate with the nadir platelet count (P =.43). In conclusion, the normal inverse relationship between platelet count and TPO levels was not observed in ALF. Despite severe hepatic dysfunction, serum TPO levels were initially normal and increased during hospitalization in acetaminophen-induced ALF, but did not prevent the development of thrombocytopenia.     

Role of liver transplantation in acute liver failure

Orthotopic liver transplantation is employed as salvage therapy for individuals who are unable to recover from acute liver failure. Prognostic models are helpful but not entirely accurate in predicting those who will eventually require liver transplantation. There are specific criteria for United Network for Organ Sharing category 1a (urgent) listing of these patients. Unfortunately, clinical deterioration develops rapidly and many require removal from the waiting list prior to transplantation. With advances in critical care management and surgical technique, 1-year post-transplant survival rates have improved to 60 to 80%. Alternatives to conventional orthotopic liver transplantation include living donor liver transplantation, ABO-incompatible grafts, and auxiliary liver transplantation. There are many ethical and psychosocial issues inherent to transplanting these sick patients due to the urgent nature of acute liver failure. Fortunately, the long-term survival and quality of life in these transplant recipients is good.     

儿童急性肝衰竭

儿童急性肝衰竭是一种以肝性脑病、黄疸、凝血障碍和腹水为主要表现的临床综合征,常导致多器官功能障碍,病死率较高,是重症医学面临的救治难题。由于儿童这个群体的特殊性,儿童急性肝衰竭和成人相比在定义、病因以及诊治过程中均有其独特性。近年来随着医学技术的发展,尤其是重症医学的发展使得急性肝衰竭的预后有所改善。儿童肝移植的发展也为儿童急性肝衰竭的治疗提供了更多的机会。     

Drug-induced acute liver failure

Acute liver failure is the most severe expression and represents the first cause of fatalities related to drugs. As a consequence, it is also the first cause of drug withdrawal from the pharmaceutical market. The incidence of drug-induced hepatotoxicity in the general population has been recently estimated to be around 14/100,000 inhabitants in a Western country. Drugs appear to be responsible for 10-52% of all causes of acute liver failure. In Western countries, paracetamol (acetaminophen) represents the first cause of all liver failures. The contribution of non-paracetamol drugs given at normal doses is equivalent to that of combined viral hepatitis A and B. The natural prognosis varies between drugs. The spontaneous mortality rate ranges from 32% to 50% for paracetamol intoxication and more than 75% for other drugs. The preventive occurrence of drug hepatotoxicity and the course to acute liver failure is rather limited. It is recommended to stop the administration of a suspected drug when alanine aminotransferase levels increase to more than 3-5 times the upper limit of normal. In paracetamol intoxication, the rapid administration of N-acetylcysteine is a classical antidote. At the stage of liver failure, treatment is mostly supportive. Since irreversible damage is unpredictable, early transfer to a transplantation centre should be considered.     

Flutamide-associated acute liver failure

The nonsteroidal antiandrogenic drug flutamide [4'-nitro-3'-(trifluoromethyl)isobutyranilide] is a safe and generally well-tolerated drug used for the treatment of prostate cancer. We describe the case of a 74-year-old male who developed life-threatening acute liver failure during flutamide therapy. Other causes of acute liver failure were appropriately ruled out and there was no evidence of active prostate cancer or liver metastases. The use of the Naranjo probability scale indicated a highly probable relationship between the development of acute liver failure and flutamide therapy. Severe liver dysfunction has been rarely documented in patients treated with flutamide, even though cases of fulminant liver failure have been described. A few cases have been reported also among patients with hirsutism being treated with flutamide. The mechanisms responsible for the occurrence of hepatotoxicity during treatment with flutamide are unknown. Mitochondrial dysfunction seems to be implicated. The potential of flutamide to act as a potent hepatotoxin should be borne in mind when treatment with this drug is being planned.     

Epidemiology of acute liver failure

Acute liver failure (ALF) is an uncommon disorder that leads to jaundice, coagulopathy, and multisystem organ failure. Its definition is based on the timing from onset of jaundice to encephalopathy. In 2005, ALF accounted for 6% of liver-related deaths and 7% of orthotopic liver transplants (OLT) in the United States. Several classification systems have been developed for ALF, with the King's College criteria most widely used for prediction of OLT. Specific diagnostic tests should be implemented to identify the cause of ALF, which will help to determine its treatment and prognosis. Viral hepatitis was previously reported to be the most common cause of ALF in the United States, but acetaminophen overdose and idiosyncratic drug reactions have emerged as the most frequent causes in recent studies. Malignancy is an uncommon cause of ALF, and thus imaging studies may not be useful in this setting, but liver biopsy may be beneficial in selected cases. An overall strategy for ALF should start with identifying the cause, assessing the prognosis, and early transfer to a transplantation center for suitable candidates. OLT has emerged as a life-saving procedure leading to marked improvement in survival rates. Improved surgical techniques, immunosuppression, and comprehensive care have led to an overall survival rate of approximately 65% with OLT. N-acetylcysteine is effective in ALF caused by acetaminophen overdose, with results strongly related to how soon it is given rather than the route of administration. Liver support systems show potential for the treatment of ALF, but their role needs validation in large multicenter randomized trials.     

Artificial liver support in acute liver failure.

The concept that a bioartificial device could compensate for the loss of hepatic function and thus improve the outcome of acute liver failure (ALF) was first suggested more than three decades ago. Currently, and reflecting renewed interest in this possibility, three such devices are undergoing clinical evaluation. Each has been shown to perform metabolic functions normally performed by the liver, thus affecting the serum biochemistry of patients with ALF. However, despite potential merit, these devices have not yet been shown to improve the outcome of patients with ALF. Also, some major safety issues remain to be resolved, in particular the risk of transmission of unknown zoonoses to man.     

Autoimmune acute liver failure: an emerging etiology for intractable acute liver failure

Diagnosis of acute onset autoimmune hepatitis (AIH) is the most challenging task because of atypical clinicopathological features. We examined the nature of acute onset AIH consisting of nonsevere, severe, and fulminant AIH based on our published data and other published papers, and propose how to diagnose and treat this intractable hepatitis. We analyzed clinical, biochemical, immunological, radiological, and histological features of acute onset AIH. Thirty percent of fulminant hepatitis was due to AIH and autoimmune acute liver failure (ALF) was not rare. The important characteristic of acute onset AIH is its histological, radiological, and clinical heterogeneity. Sometimes acute onset AIH develops into ALF in a sub-acute clinical course without appropriate diagnosis and treatment, and becomes resistant to immunosuppressive therapy and has poor prognosis. Unenhanced computed tomography (CT) often shows heterogeneous hypoattenuation in autoimmune ALF. The revised original scoring system (1999) performed better in patients with acute onset AIH than the simplified scoring system (2008). Liver regeneration from periportal progenitor cells to mature hepatocytes was impaired in ALF, resulting in resistance to immunosuppressive therapy. Precise histological evaluation (the presence of centrilobular necrosis/collapse) along with the revised original scoring system and CT findings of heterogeneous hypoattenuation after systematic exclusion of other causes 36 plays an important role in the diagnosis. The most important strategy for autoimmune ALF is to diagnose and treat acute onset AIH before its development into ALF. Liver transplantation should be considered before the occurrence of infectious complications in the case of fulminant liver failure.