Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests

Abstract

The role played by coagulation defects in the occurrence of bleeding in cirrhosis is still unclear. This is partly due to the lack of tests that truly reflect the balance of procoagulant and anticoagulant factors in vivo. Conventional coagulation tests such as prothrombin time and activated partial thromboplastin time are inadequate to explore the physiological mechanism regulating thrombin, because they do not allow full activation of the main anticoagulant factor, protein C, whose levels are considerably reduced in cirrhosis. We used a thrombin generation test to investigate the coagulation function in patients with cirrhosis. Thrombin generation measured without thrombomodulin was impaired, which is consistent with the reduced levels of procoagulant factors typically found in cirrhosis. However, when the test was modified by adding thrombomodulin (i.e., the protein C activator operating in vivo), patients generated as much thrombin as controls. Hence, the reduction of procoagulant factors in patients with cirrhosis is compensated by the reduction of anticoagulant factors, thus leaving the coagulation balance unaltered. These findings help clarify the pathophysiology of hemostasis in cirrhosis, suggesting that bleeding is mainly due to the presence of hemodynamic alterations and that conventional coagulation tests are unlikely to reflect the coagulation status of these patients. In conclusion, generation of thrombin is normal in cirrhosis.

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

“…Because of their design, TGA approximate the in vivo coagulation balance better than conventional coagulation tests (PT/activated partial thromboplastin time [APTT]). When evaluated by TGA, patients with cirrhosis have the potential to generate as much thrombin as healthy subjects after thrombomodulin addition [1,4]. Patients with cirrhosis and relatively high levels of thrombin generation present with a hypercoagulable state in vitro [29] and may be at risk of thrombotic events.…”

“…The net effect of these changes is a rebalanced hemostasis. However, this hemostatic profile is unstable, and patients can be tipped toward both bleeding and thrombosis under certain conditions [1][2][3][4][5]. Thus, there is growing evidence that proper understanding of the hemostatic pathways in liver disease requires a global perspective which account for the complexity of hemostasis, with dynamic interactions between pro-coagulant and anti-coagulant factors.…”

Portal Vein Thrombosis in Cirrhosis

“…In cirrhosis, there is a relatively balanced reduction in both pro-and anticoagulant proteins, and therefore the net result is that there is very little change in the ability of the system to generate hemostatic levels of thrombin under ordinary circumstances. 15,20 In patients with stable cirrhosis, thrombin generation was found to be normal in in-vitro studies, when the natural anticoagulant pathway was activated by the addition of thrombomodulin. 20,21 However, when the coagulation system in cirrhotic patients is stressed, for example by infection the system has limited buffer capacity and gets tipped out of balance into either a state of hemorrhage or thrombosis.…”

“…15,20 In patients with stable cirrhosis, thrombin generation was found to be normal in in-vitro studies, when the natural anticoagulant pathway was activated by the addition of thrombomodulin. 20,21 However, when the coagulation system in cirrhotic patients is stressed, for example by infection the system has limited buffer capacity and gets tipped out of balance into either a state of hemorrhage or thrombosis. 22 Patients with cirrhosis also suffer from defects of platelet function and number that can contribute to a bleeding tendency.…”

“…These tests do not reflect the in vivo physiological state since they do not account for naturally occurring anticoagulants such as protein C and antithrombin, levels of which are also substantially reduced in cirrhotics. 20,40 A test for coagulation that can assess thrombin generation in the presence of thrombomodulin is more appropriate in cirrhotics. The thrombin generation test is one such test in which physiological coagulation is activated with small amounts of tissue factor as a trigger and phospholipids that act as platelet substitutes.…”