Detection of the imbalance of procoagulant versus anticoagulant factors in cirrhosis by a simple laboratory method

Abstract

Patients with cirrhosis possess an imbalance in procoagulant versus anticoagulant activity due to increased factor VIII and decreased protein C. This imbalance can be detected by thrombin-generation assays performed in the presence/absence of thrombomodulin (predicate assay) that are not readily available in clinical laboratories. We sought to assess this hypercoagulability with a simpler thrombin-generation assay performed in the presence/ absence of Protac, a snake venom that activates protein C in a manner similar to thrombomodulin (new assay). We analyzed blood from 105 patients with cirrhosis and 105 healthy subjects (controls). Results for the predicate-assay or the new-assay were expressed as ratio (with:without thrombomodulin) or as Protac-induced coagulation inhibition (PICI%). By definition, high ratios or low PICI% translate into hypercoagulability. The median(range) PICI% was lower in patients (74% [31%-97%]) than controls (93% [72%-99%]; P < 0.001), indicating that patients with cirrhosis are resistant to the action of Protac. This resistance resulted in greater plasma hypercoagulability in patients who were Child class C than those who were A or B. The hypercoagulability of Child C cirrhosis (63% [31%-92%]) was similar to that observed for patients with factor V Leiden (69% [15%-80%]; P 5 0.59). The PICI% values were correlated with the levels of protein C (rho 5 0.728, P < 0.001) or factor VIII (rho 5 20.517, P < 0.001). Finally, the PICI% values were correlated with the predicate assay (rho 5 20.580, P < 0.001). Conclusion: The hypercoagulability of plasma from patients with cirrhosis can be detected with the new assay, which compares favorably with the other markers of hypercoagulability (i.e., high factor VIII and low protein C) and with the predicate-assay based on thrombin-generation with/without thrombomodulin. Advantages of the new assay over the predicate assay are easy performance and standardized results. Prospective trials are needed to ascertain whether it is useful to predict thrombosis in patients with cirrhosis. (HEPATOLOGY 2010;52:249-255)

Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference

“…These results were confirmed when, instead of thrombomodulin, Protac (a non-physiologic protein C activator) was used for testing [37]. Resistance to anti-coagulant action of thrombomodulin or Protac is recognized as a risk factor for venous thromboembolism in patients without cirrhosis.…”

Efficacy and Safety of Non–Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients With Impaired Liver Function: A Retrospective Cohort Study

“…The coagulation system in patients with ILF is perceived to be unstable compared with healthy individuals, who have both sufficient and properly functioning procoagulants and anticoagulants. Studies of coagulation factors in patients with cirrhosis have revealed decreased amounts and disturbed procoagulant and anticoagulant activity 21, 22. The relative deficiency of both procoagulants and anticoagulants may cause increased thrombosis or bleeding depending on the prevailing circumstantial conditions 23…”

Anticoagulation in chronic liver disease

“…Furthermore, the limitation of the use of a prolonged INR as a marker of bleeding risk in those with chronic liver disease is now increasingly-understood (Tripodi et al, 2010). He had had his varices appropriately treated, minimising the risk of bleeding from this route.…”

“…This defect is demonstrated by prolongation of the prothrombin time (PT) and the activated partial thromboplastin time (APTT), tests which both represent the status of procoagulant proteins synthesised by the liver. However, the use of these conventional tests of haemostasis on peripheral blood correlates poorly with the risk of bleeding in chronic liver disease (Tripodi et al, 2010), reflecting the inability of these tests to take into account an imbalance in endogenous anticoagulants and procoagulants. Patients with advanced fibrosis have significantly lower levels of protein C and 4 antithrombin (Tripodi et al, 2005).…”