Abstract
Background & AimsPatients with liver disease may acquire substantial changes in their hemostatic system, which are most pronounced in patients who are critically ill. Changes in the quality of the fibrin clot in critically ill patients have not been studied in detail. Here we assessed markers of fibrin clot quality and effects of coagulation factor concentrates in patients with acutely decompensated (AD) cirrhosis and acute on chronic liver failure (ACLF).MethodsWe measured plasma levels of fibrinogen, factor XIII, prothrombin and performed thrombin generation assays in 52 AD patients, 58 ACLF patients and 40 controls. In addition, we examined the effects of coagulation factor concentrates on functional assays of fibrin quality.ResultsWe found increased thrombin generating capacity in both AD and ACLF in comparison with healthy controls. Plasma levels of prothrombin, fibrinogen, and factor XIII were lower in patients compared to controls, appeared lower in ACLF compared to AD patients, and were related to clinical outcomes. Fibrinogen concentrate, but not factor XIII or prothrombin complex concentrate, improved clot quality in vitro. Prothrombin complex concentrate increased the resistance of the clot to break down.ConclusionsWe have demonstrated elevated thrombin generation but decreased plasma levels of prothrombin, fibrinogen and FXIII in acutely ill patients with cirrhosis. In addition, we showed that fibrinogen concentrate and PCCs, but not factor XIII concentrate, improve clot properties in patient plasma. Whether there is true clinical benefit from coagulation factor concentrates in prevention or treatment of bleeding requires further study.Lay summaryPatients with liver diseases are at risk of bleeding, but mechanisms involved in this bleeding risk are incompletely understood. We studied components that determine the stability of the blood clot and found that concentrations of certain proteins involved in clot stability are present in low levels in acutely ill patients with liver disease. We furthermore demonstrated that some clinically available drugs improve the stability of blood clots from these patients in a test tube.
Highlights
Liver diseases are frequently associated with profound hemostatic changes
We have previously shown that prothrombin complex concentrate (PCC) substantially increase thrombin generation in patients and controls,[10] and enhancement of thrombin generation leads to increased resistance to fibrinolysis due to enhanced activation of thrombin-activatable fibrinolysis inhibitor (TAFI).[32]
Plasma levels of prothrombin, fibrinogen, and FXIII were markedly lower in sicker patients, with much lower levels in those who died within 30 days
Summary
Liver diseases are frequently associated with profound hemostatic changes. As these changes concern both pro- and antihemostatic pathways, the net effect is a rebalanced hemostatic system.[1,2] This hemostatic rebalance appears even maintained in the sickest patients, including those with acutely decompensated (AD) cirrhosis and acute-on-chronic liver failure (ACLF).[3]. A recent retrospective study of critically ill patients with cirrhosis showed no independent association of low fibrinogen levels with mortality or bleeding events and concluded that low fibrinogen levels were a reflection of disease severity rather than being causally related to bleeding.[15] That study showed no reduction in bleeding with cryoprecipitate transfusion administered either prophylactically or in actively bleeding patients It is largely unknown whether factor concentrates lead to functional improvement of the fibrin clot, as clinically used laboratory tests do not take important physiological aspects of clot stability into account. As we found markers of fibrin clot quality (fibrinogen and factor XIII levels), but not thrombin generating capacity to be associated with disease stage, severity and outcome, we subsequently assessed effects of in vitro addition of clinically available factor concentrates on functional markers of clot stability
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