Thrombotic risk factors in patients with liver cirrhosis: Correlation with MELD scoring system and portal vein thrombosis development☆
Introduction
The liver has many haemostatic functions, including the synthesis of most coagulation factors and inhibitors as well as fibrinolytic factors [1], [2]. The balance between procoagulant and anticoagulant factors is essential to avoid excessive thrombin generation under physiological conditions [3]. Therefore, it is not surprising that advanced liver disease results in a complex pattern of defects in haemostatic functions in the form of reduced synthesis of coagulation factors, inhibitors, and abnormal clotting factors, abnormalities of fibrinolytic activity, disseminated intravascular coagulation and platelet function defects [4], [5], [6], [7].
Moreover, thrombosis of the intrahepatic veins is frequently observed in cirrhosis and has been associated with its progression [8], while occlusion of small sized intrahepatic veins and sinusoids has been considered a potential triggering factor of liver tissue remodelling [9].
Recently, the prevalence of several genetic and acquired thrombotic risk factors in patients with chronic hepatitis B or C as well as their possible association with necroinflammatory activity and extent of fibrosis has been evaluated [10], [11]. It is well known that protein C, protein S and antithrombin (AT) serum levels are decreased in patients with liver disease [12], [13] but, to date, few reports are available about the association between the above mentioned and other natural anticoagulant factors produced by the liver and different stages of liver cirrhosis.
Portal vein thrombosis (PVT) is an important complication of cirrhosis, and is mostly associated with the occurrence of hepatocellular carcinoma [14]. The incidence of non-neoplastic PVT in cirrhotic patients is unknown, while its prevalence ranges from 0.6% to 16% [15], [16], [17]. Since PVT can be an important source of morbidity and mortality, early detection and treatment for de novo thrombosis is an important issue, especially in patients on the waiting list for liver transplantation [18]. Over the last few years the etiology of PVT has been better defined and large case series have improved our understanding of the natural history of this condition [19]. Male sex, previous abdominal surgery including splenectomy and portocaval shunts, encephalopathy, ascites, past history of bleeding varices, low platelet count, and Child–Pugh class C have been considered predisposing factors to PVT in liver cirrhosis [18], [20], [21]. Previous sclerotherapy of varices has been shown to be a risk factor in some studies [22], [23]; other authors did not confirm this datum [16], [24] or have shown that sclerotherapy may only be a trigger factor for PVT in patients with genetic thrombophilia [25], [26]. Two studies found antiphospholipid antibodies (APA) in more than half of cirrhotic patients with PVT [27], [28] but no relationship was found between anticardiolipin antibodies and PVT in another study [29]. Moreover, inherited (such as the factor V Leiden 1691 G–A mutation and the prothrombin 20210 G–A mutation), or acquired (such as the reduced levels of natural inhibitors of coagulation like protein C, protein S and antithrombin) coagulative defects leading to a hypercoagulable state, have been found in cirrhotic patients with PVT [16], [30], [31], [32], [33], [34].
On the whole, the occurrence of PVT in liver cirrhosis appears to be a multifactorial complication, in which the involvement of inherited and acquired thrombotic risk factors as well as local anatomical and hemodynamic factors may be involved.
This study was designed to determine whether acquired systemic thrombogenic factors and local factors related to hepatic haemodynamics and portal hypertension might be related to liver disease progression and to the development of PVT.
Section snippets
Patient population and study design
One hundred consecutive adult patients with cirrhosis (76 men, 24 women) with a median age of 60 years (range 31–81 yrs) were enrolled in the study, which conformed to the ethical standards of the Declaration of Helsinki and was approved by the local ethics committee. Liver cirrhosis was diagnosed by histological examination of liver biopsy or by unequivocal hematochemical, ultrasound (US) or endoscopic findings suggesting advanced liver disease with portal hypertension. The severity of liver
TRFs and liver dysfunction
Levels of the natural anticoagulant proteins, AT and protein C were low in the entire group of cirrhotic patients (mean values 52.4% and 42.1%, respectively; normal values: AT, 70–120% and protein C, 70–140%) (Table 1).
Associations of high MELD (defined as ⩾13) or low MELD (<13) with levels or presence of TRFs are presented in Table 2. Patients with advanced staging had lower protein C and AT levels (32.1% vs. 54.6%, p < 0.001 and 42.6% vs. 63.4%, p < 0.001, respectively) and higher D-dimers levels
Discussion
The concern that liver function failure is related to the development of severe coagulopathy is firmly established among hepatologists. This condition is mainly reflected by the prothrombin time (PT) and by APTT prolongation. PT is an excellent marker of liver failure and a strong independent prognostic factor of survival in patients with chronic liver disease. For this reason, new and old models of prognosis for patients with advanced liver disease include PT (or INR) as one of its components
Acknowledgements
This work has been supported by an unrestricted grant provided by Fondazione Ricerca in Medicina, Bologna, Italy.
References (49)
Coagulation abnormalities in liver disease
Haemotol Oncol Clin North Am
(1992)Coagulation defects in liver disease
Med Clin North Am
(1994)- et al.
Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension
Hepatology
(1995) - et al.
Role of thrombosis in the pathogenesis of congestive hepatic fibrosis (cardiac cirrhosis)
Hepatology
(1995) - et al.
Hemostasis activation in patients with liver cirrhosis
Thromb Res
(1995) - et al.
Incidence of portal vein thrombosis in liver cirrhosis. An angiographic study in 708 patients
Gastroenterology
(1985) - et al.
Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis
J Hepatol
(2004) - et al.
Endoscopic variceal sclerosis does not increase the risk of portal venous thrombosis
Gastroenterology
(1992) - et al.
Anticardiolipin antibodies in chronic hepatitis C: implications of hepatitis C virus as the cause of the antiphospholipid syndrome
Hepatology
(1996) - et al.
Anticardiolipin antibodies in patients with liver disease
Am J Gastroenterol
(1999)
A model for end-stage liver disease
Hepatology
Automated Lowry method for microgram protein determination
Analyt Biochem
Interobserver and interequipment variability of echo-Doppler examination of the portal vein: effect of cooperative training program
Hepatology
A model to predict survival in patients with end-stage liver disease
Hepatology
Coagulation inhibitors in alcoholic liver cirrhosis
Alcohol
A high incidence of native portal vein thrombosis in veterans undergoing liver transplantation
J Surg Res
Portal vein thrombosis: a concise review
Am J Gastroenterol.
A shortened activated partial thromboplastin time is associated with the risk of venous thromboembolism
Blood
Liver transplantation in patients with portal vein thrombosis
Liver Transpl
Prevalence of spontaneous hepatofugal portal flow in liver cirrhosis. Clinical and endoscopic correlation in 228 patients
Gastroenterology
Value of measurement of mean portal flow velocity by Doppler flowmetry in the diagnosis of portal hypertension
J Hepatol
Prognostic significance of portal hemodynamics in patients with compensated cirrhosis
J Hepatol
Coagulopathy of fulminant hepatic failure
Semin Liver Dis
Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests
Hepatology
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The authors who have taken part in this study declared that they do not have anything to disclose regarding funding from industry or conflict of interest with respect to this manuscript.