Patients with cirrhosis show a relative increase in thrombin generation that is correlated with lower antithrombin levels

Abstract

Predicting the risk of bleeding or thrombosis in cirrhotic patients is difficult due to reduced levels and dysregulation of both procoagulant and anticoagulant factors. We utilized thrombin generation and microvesicle analysis to better understand the regulation of haemostasis in cirrhotic patients. We studied 24 patients with cirrhosis vs. 21 healthy controls. Cirrhotic patients had reduced prothrombin activity (40 ± 9 vs. 112 ± 15), protein C activity (36 ± 10 vs. 114 ± 19) and antithrombin activity (43 ± 14 vs. 109 ± 10). Peak thrombin generation was reduced in cirrhotic patients (165 ± 47 vs. 232 ± 101), but the ratio of peak thrombin generation to prothrombin activity was increased in cirrhotic patients (4.2 ± 1.0 vs. 2.1 ± 0.9) indicating a relative increase in thrombin generation in cirrhosis. The termination time ratio was increased in cirrhotic patients (7.2 ± 1.9 vs. 3.1 ± 0.7) and correlated with reduced antithrombin levels, indicating that cirrhotic patients took longer to stop thrombin generation than controls. Cirrhotic patients showed reduced procoagulant microvesicles from platelets (39 500 ± 24 800 vs. 107 700 ± 74 200) and other cells, but levels overlapped with controls. Cirrhotic patients showed a wide range of procoagulant and anticoagulant levels leading to variability in the regulation of thrombin generation. In conclusion, compared with healthy controls, patients with cirrhosis have lower antithrombin levels that lead to slower downregulation of thrombin generation and more overall thrombin being produced for a given procoagulant level in blood, but also low normal levels of procoagulant microvesicles that would slow initiation of thrombin generation. Whether an individual cirrhosis patient is at a greater risk of bleeding vs. thrombosis may depend on their specific imbalance in procoagulants vs. anticoagulants.

Phosphatidylserine on blood cells and endothelial cells contributes to the hypercoagulable state in cirrhosis

“…Although many studies have investigated the role of cirrhotic plasma in PCA , relatively little is known about the contribution of activated blood cells, especially erythrocytes and leucocytes. Our results showed that PS exposure on BCs progressively increased with Child–Pugh category.…”

“…Many studies have demonstrated that cirrhotic patients have a higher risk of venous thromboembolism than healthy subjects . Other studies have shown that resistance to thrombomodulin, increased factor VIII to protein C ratio, and lower level of antithrombin in cirrhosis may lead to increased thrombosis risk . However, excess exogenous phospholipid was added during the course of these studies.…”

How do we transfuse blood components in cirrhotic patients undergoing gastrointestinal procedures?

“…23 Concentrations of AT decline in cirrhosis with measured activities of 43 6 14% relative to 109 6 10% in healthy controls. 24 This concomitant decline in anticoagulant proteins, specifically AT, accompanied by elevated levels of FVIII may explain the ability of cirrhotic patients to generate thrombin concentrations equivalent to healthy persons. 25,26 Dysfibrinogenemia is common in cirrhosis, occurring in up to 70% of patients secondary to the addition of excess sialic acid residues to fibrinogen, impairing its ability to assemble properly.…”

Thrombin Generation Assay: Are We Ready for Prime Time?

“…The prothrombin time (PT) 3 and partial thromboplastin time (PTT) are useful assays for evaluation of coagulation factor levels and for monitoring anticoagulant therapy with warfarin and heparin, but they are of less value for predicting risk of thrombosis or bleeding in patients with acquired hemostatic defects. As new anticoagulant drugs become available and pathophysiologic mechanisms of abnormal hemostasis are unveiled, it is clear that new laboratory tests are needed to support drug monitoring, establish diagnosis, and develop therapeutic strategies.…”

“…Altered TGA results have been described in several clinical situations, including cirrhosis, trauma, cardiopulmonary bypass surgery, stroke, sepsis, and the use of oral anticoagulants (3)(4)(5)(6)(7)(8). There is some evidence suggesting that TGA is a better indicator of overall hemostatic capability and could provide information for transfusion support in patients with cirrhosis and coagulation factor replacement in patients with hemophilia with and without inhibitors (9)(10)(11).…”