Coagulation Inhibitors In Liver Disease

Abstract

Summary Background: Haemostasis is intimately related to liver function since almost all of the haemostatic factors are synthesized by the liver. Derangements in the haemostatic system invariably occur in liver disease and can be associated with life threatening complications, particularly bleeding. Conventional coagulation tests, in the form of PT and APTT, are part of numerous tests used to assess liver function and eventually to reflect the severity of liver disease as well as the risk of bleeding. However, these tests are not sensitive since they become abnormal late in the course of liver disease. Recent evidence suggests that changes in the levels of natural anticoagulants, specifically protein S and protein C, are more sensitive to hepatocyte dysfunction than the PT and APTT. Depressed levels of protein S and protein C were found even in the mildest forms of liver disease when the other coagulation tests and other routine liver function tests were normal. This drop in the protein C and protein S levels in liver disease is mainly attributed to impaired synthesis by the diseased liver. Cytokines, especially the proinflammatory cytokines IL-6 and TNF-á, have been implicated in the pathogenesis of various forms of liver ailments, and were also shown to affect the synthesis of protein S and C4BP by the hepatocytes. Thus, the fluctuations in the levels of protein S and C4BP seen in liver disease may be attributed to changes in the levels of the proinflammatory cytokines, IL-6 and TNF-á. The liver requires vitamin K for the synthesis of functionally active forms of several hamostatic factors including: prothrombin, factors VII, IX, and X, protein C and protein S. Vitamin K deficiency occurs frequently in liver disease and is thought to contribute to its associated coagulopathy. Vitamin K is currently administered to patients with liver disease in an attempt to improve their defective coagulation system. Careful search in the literature failed to uncover detailed studies on the efficacy of vitamin K administration in correcting the coagulation defects seen in liver disease. Objectives. The objectives of the current research were (i) To document the levels of coagulation inhibitors, mainly PS and PC, in various degrees of liver dysfunction (hepatitis B carriers, chronic hepatitis, liver cirrhosis, and HCC). (ii) To evaluate the potential use of these natural coagulation inhibitors as tests of liver function. (iii) To assess the possible role of cytokines, particularly IL-6 and TNF-á in the changes seen in coagulation inhibitors in patients with liver disease. (iv) To see whether the administration of vitamin K to patients with liver disease would affect the levels of vitamin K-dependent coagulation inhibitors, PS and PC. Materials and methods. Two groups were included in the study (i) the liver disease group (n=89), and (ii) the control group (n=50). The liver disease group included four categories of patients with various degrees of hepatocyte dysfunction; HB carriers (n=26), chronic hepatitis (n=23), liver cirrhosis (n=20), and HCC (n=20). The patients were recruited from King Khalid University Hospital and Riyadh Military Hospital, Riyadh. The control group comprised healthy subjects recruited randomly from blood donors, academic staff, and volunteers from the general public. Vitamin K (10mg vitamin K1) was administered subcutaneously as a single dose to all liver disease patients. Blood samples were collected on two occasions from each patient; the first before vitamin K administration, and the second on the third day following vitamin K administration. The following assays were carried out: (i) The coagulation screening tests: prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT), (ii) Coagulation factor assays including: fibrinogen and factor VII, (iii) Coagulation inhibitors (protein C, total and free protein S), (iv) C4b-binding protein, (v) PIVKA-II (des-gammacarboxy prothrombin), (vi) Cytokines: Interleukin-6 (IL-6) and tumor necrosis factor-á (TNF-á). Results. Haemostatic parameters and cytokines before vitamin K administration: coagulation screening tests: the PT was significantly prolonged in liver cirrhosis and HCC groups, while the APTT was significantly prolonged only in the liver cirrhosis group. On the other hand, TT was significantly prolonged in all liver disease groups. Coagulation factors: there was a significant drop in the fibrinogen level only in the liver cirrhosis group, while a statistically significant reduction in FVII levels was observed in both liver cirrhosis and HCC groups. Coagulation inhibitors: the level of PC dropped significantly in all liver disease groups. The reduction in PC levels was greater with the progression of liver disease. Total and free protein S showed statistically significant reduction only in liver cirrhosis and HCC groups. Despite the noticeable reduction in the level of total PS in both HB carriers and chronic hepatitis groups when compared to controls, Duncan's multiple range test failed to give statistical support to this difference. However, when t-test was applied a statistically significant difference in total PS levels was noted for both HB carriers and chronic hepatitis when compared to controls. C4BP levels showed a statistically significant reduction in all liver disease groups except HB carriers. Cytokines: No significant difference was noted in the levels of TNF-á between liver disease groups and controls. On the other hand, a significant elevation in IL-6 levels was seen in both liver cirrhosis and HCC groups. PIVKAII levels showed a highly significant elevation only in the HCC group. Comparison of the measured parameters before and after vitamin K administration among the different liver disease groups: No difference was detected in any of the above measured parameters after vitamin K administration when compared to its level before vitamin K administration. Correlations between the different parameters: (a) Between the measured coagulation inhibitors and C4BP: a significant positive correlation was found between C4BP and both PC and total and free PS. A significant positive correlation was also seen between PC and total and free PS. (b) Between cytokines and coagulation inhibitors: a significant negative correlation was detected only between IL-6 and PC. (c) PIVKA-II levels did not correlate with any of the measured vitamin K-dependent factors (FVII, PC, and PS). Comments and conclusions: It is clear that liver disease is associated with derangements in the haemostatic system. Coagulation inhibitors and TT appear to be more sensitive to hepatocyte dysfunction than the PT and APTT. Impaired synthetic function of the liver, as depicted by the reduction in the levels of these coagulation inhibitors is a major feature of chronic liver disease. Cytokines, especially IL-6, may contribute to the reduction in the coagulation inhibitors seen in liver disease, specifically those affecting PC. The administration of vitamin K failed to correct the coagulation abnormalities of chronic liver disease and had no effect on the levels of the measured coagulation factors and inhibitors. In conclusion, the results of the current study further support the use of coagulation inhibitors (PS and PC) as markers for liver function. In addition, these results do not lend any support to the haemostatic benefits of vitamin K administration to patients with chronic liver disease, particularly liver cirrhosis.