Pro-coagulant imbalance in patients with chronic liver disease
Authors: Armando Tripodi, Massimo Primignani, Veena Chantarangkul, Pier Mannuccio Mannucci
Journal: Journal of Hepatology (2010)

We saw with interest the paper by Lisman et al. [[1]Lisman T. Bakhtiari K. Pereboom I.T.A. Hendriks H.G.D. Meijers J.C.M. Porte R.J. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests.J Hepatol. 2010; 52: 355-361Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar], published in a recent issue of the Journal of Hepatology reporting normal or even increased thrombin generation in patients undergoing liver transplantation (LT) as compared to healthy subjects. This has been interpreted as an in vitro “resistance” to the anti-coagulant action of thrombomodulin [the physiological activator of protein C (PC)]. This resistance is apparently due to the pro-coagulant imbalance consequent to decreased levels of the anti-coagulant drivers PC and antithrombin combined with increased levels of the pro-coagulant driver factor (F)VIII. This is an interesting issue and deserves comments. We have already shown that patients with stable cirrhosis possess a pro-coagulant imbalance detectable by thrombin generation assays performed with/without thrombomodulin [[2]Tripodi A. Primignani M. Chantarangkul V. Dell’Era A. Clerici M. de Franchis R. et al.An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis.Gastroenterology. 2009; 137: 2105-2111Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar]. The pro-coagulant imbalance observed in our cohort was mainly due to decreased levels of PC and antithrombin combined with increased levels of FVIII [[2]Tripodi A. Primignani M. Chantarangkul V. Dell’Era A. Clerici M. de Franchis R. et al.An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis.Gastroenterology. 2009; 137: 2105-2111Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar], which are typical features in cirrhosis. Furthermore, we also showed that the pro-coagulant imbalance increases with the severity of the disease, as patients classified as Child C had a more pronounced pro-coagulant imbalance than patients classified as Child A–B [[2]Tripodi A. Primignani M. Chantarangkul V. Dell’Era A. Clerici M. de Franchis R. et al.An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis.Gastroenterology. 2009; 137: 2105-2111Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar]. Finally, we showed that the extent of the imbalance observed in the Child C class was slightly greater than that observed in plasma from patients who were carriers of congenital-PC deficiency [[2]Tripodi A. Primignani M. Chantarangkul V. Dell’Era A. Clerici M. de Franchis R. et al.An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis.Gastroenterology. 2009; 137: 2105-2111Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar], a condition associated with an increased risk of venous thromboembolism. It can, therefore, be concluded that the pro-coagulant imbalance is a general and typical feature of patients with cirrhosis, and not only of patients undergoing LT. Concerning the cohort of patients investigated by Lisman et al. [[1]Lisman T. Bakhtiari K. Pereboom I.T.A. Hendriks H.G.D. Meijers J.C.M. Porte R.J. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests.J Hepatol. 2010; 52: 355-361Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar], it is intriguing that they were still “pro-coagulant” even 5–10 days after LT when PC was normalized. The authors surmise that the pro-coagulant imbalance persists because of the persisting increased levels of FVIII observed after LT. This requires further comments. While PC levels are reduced pre-transplant because of the impaired synthetic liver capacity, the increased levels of FVIII are not explained by increased synthesis, but probably by decreased clearance from circulation (reviewed in Ref. [[3]Hollestelle M.J. Geertzen H.G. Straatsburg I.H. van Gulik T.M. van mourik J.A. Factor VIII expression in liver disease.Thromb Haemost. 2004; 91: 267-275PubMed Google Scholar]). This is apparently mediated by two mechanisms involving the von Willebrand factor (VWF) and the low density lipoprotein receptor-related protein (LRP) [[3]Hollestelle M.J. Geertzen H.G. Straatsburg I.H. van Gulik T.M. van mourik J.A. Factor VIII expression in liver disease.Thromb Haemost. 2004; 91: 267-275PubMed Google Scholar]. VWF binds FVIII in vivo and protects it from cleavage by plasma proteases and premature clearance. Increased levels of VWF are typical features of patients with cirrhosis and, therefore, they may be causally involved in maintaining elevated circulating levels of FVIII in this condition [[3]Hollestelle M.J. Geertzen H.G. Straatsburg I.H. van Gulik T.M. van mourik J.A. Factor VIII expression in liver disease.Thromb Haemost. 2004; 91: 267-275PubMed Google Scholar]. LRP, on the other hand, is a multi-functional ligand that mediates the cellular up-take and degradation of plasma FVIII. LRP is poorly expressed in cirrhosis and in conjunction with high VWF might sustain the increased circulating levels of FVIII [[3]Hollestelle M.J. Geertzen H.G. Straatsburg I.H. van Gulik T.M. van mourik J.A. Factor VIII expression in liver disease.Thromb Haemost. 2004; 91: 267-275PubMed Google Scholar]. If the above mechanisms hold true one would expect that, after transplantation, patients have normal levels of PC as well as FVIII. The reason why FVIII is persistently high after LT is of interest. One reason could be that as FVIII is an acute phase reactant, it persists to be high solely because of the pro-inflammatory effect mediated by surgery [4Hawkey C.J. Stirling Y. Chakrabarti R. Brozovic M. Cox A.G. Meade T.W. Haemostatic changes following surgery.Thromb Res. 1983; 32: 223-227Abstract Full Text PDF PubMed Scopus (29) Google Scholar, 5Bezeaud A. Denninger M.H. Dondero F. Saada V. Venisse L. Huisse M.G. et al.Hypercoagulability after partial liver resection.Thromb Haemost. 2007; 98: 1252-1256PubMed Google Scholar]. We agree with Lisman et al. [[1]Lisman T. Bakhtiari K. Pereboom I.T.A. Hendriks H.G.D. Meijers J.C.M. Porte R.J. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests.J Hepatol. 2010; 52: 355-361Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar] that the pro-coagulant imbalance observed in cirrhotics [[2]Tripodi A. Primignani M. Chantarangkul V. Dell’Era A. Clerici M. de Franchis R. et al.An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis.Gastroenterology. 2009; 137: 2105-2111Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar] supports the restrictive use of plasma infusion in patients undergoing LT, but the restriction should be extended also to stable patients when they undergo invasive procedures, where plasma infusion is still common practice. We also agree that a more extensive use of anti-coagulant drugs should be explored to reduce the incidence of post-transplant thromboses, but again this should also be extended to pre-transplant patients who develop portal- or peripheral-vein thromboses. In this respect, we surmise that if the mechanism of the pro-coagulant imbalance (i.e., decreased levels of PC combined with increased levels of FVIII) holds true, thromboprophylaxis with vitamin-K antagonists (VKA), as it is currently done for other categories of patients, could prove (at least in principle) less suitable for patients with cirrhosis. VKA work, in fact, by decreasing the activity of vitamin-K-dependent coagulation factors including PC [[6]Kearon C. Kahn S.R. Agnelli G. Goldhaber S. Raskob G.E. Comerota A.J. American College of Chest Physicians. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition).Chest. 2008; 133: 454S-545SCrossref PubMed Scopus (1869) Google Scholar], which is already considerably reduced because of impaired liver synthesis capacity. Therefore, one might speculate that VKA in cirrhosis might (paradoxically) exacerbate the pro-coagulant imbalance leading to a much higher, increased FVIII-to-PC ratio than that observed in patients with cirrhosis not on VKA [[2]Tripodi A. Primignani M. Chantarangkul V. Dell’Era A. Clerici M. de Franchis R. et al.An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis.Gastroenterology. 2009; 137: 2105-2111Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar], especially if high initial doses of VKA are used. Perhaps, the new oral antithrombotic drugs, which act directly by inhibiting FXa or thrombin [[7]Bauer K.A. New anticoagulants.Hematology Am Soc Hematol Educ Program. 2006; : 450-456Crossref PubMed Scopus (66) Google Scholar] might be more effective than VKA in preventing recurrences in patients with cirrhosis after a first episode of venous thromboembolism. Furthermore, at variance with VKA, the new drugs do not require laboratory monitoring to adjust their dosage [[8]Tripodi A. van den Besselaar A.M.H.P. Laboratory monitoring of anticoagulation: where do we stand?.Semin Thromb Hemost. 2009; 35: 34-41Crossref PubMed Scopus (30) Google Scholar], thus also circumventing the problem of standardization of the INR, whose validity, as a laboratory tool to monitor anticoagulation in patients with cirrhosis, has been questioned and not yet resolved [[9]Tripodi A. Monitoring oral anticoagulant therapy.in: Kitchen S. Olson J.D. Preston F.E. Quality in laboratory hemostasis and thrombosis. Wiley–Blackwell, Oxford2009: 179-189Crossref Scopus (5) Google Scholar]. However, the efficacy and safety of the new antithrombotic drugs in the setting of cirrhosis require investigation by appropriate clinical trials. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.