Fibrin clot quality in acutely ill cirrhosis patients: Relation with outcome and improvement with coagulation factor concentrates

Abstract

Background & Aims Patients 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). Methods We 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. Results We 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. Conclusions We 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 summary Patients 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.

Review article: Emerging and current management of acute‐on‐chronic liver failure

“…Patients with ACLF have reduced plasma levels of fibrinogen which can be enhanced by fibrinogen concentrate, but not factor XIII or prothrombin complex concentrate (factor II, VII, IX, X), to improve clot quality in vitro 52 . Whether hypofibrinogenemia is independently associated with increased mortality and bleeding events is still hotly contested in the literature 53,54 .…”

Fibrin clot properties and thrombus composition in cirrhosis

“…For example, normal clot lysis times and decreased clot permeability (a function of clot pore size) were measured in in vitro –formed clots from acutely ill cirrhosis patients, suggesting that factors other than plasma fibrinogen concentration also determine these clot properties. [ 15 ] Only when fibrinogen levels were very low (<0.5 U/dL, for example, during liver transplant surgery), and clot stability parameters in ex vivo experiments were severely impaired. [ 16 ]…”

“…Thereby, it defines structure, stability, and effector functions of fibrin. [ 32 ] Patients with cirrhosis have decreased levels of FXIII, [ 15 ] which would theoretically lead to less stable fibrin networks. In vitro experiments of fibrin clot structure with plasma from healthy controls and patients with AD and ACLF showed very minor effects on clot parameters after the addition of exogenous FXIII concentrate, despite markedly decreased FXIII levels and reduced clot permeability in patients compared to controls.…”

“…In vitro experiments of fibrin clot structure with plasma from healthy controls and patients with AD and ACLF showed very minor effects on clot parameters after the addition of exogenous FXIII concentrate, despite markedly decreased FXIII levels and reduced clot permeability in patients compared to controls. [ 15 ] Nevertheless, it was shown that FXIII does contribute to clot stability in these assays because complete inhibition of FXIIIa activity by T101 (a transglutaminase inhibitor) shortened clot lysis time and lowered permeability in pooled normal plasma. In addition, results of a clot retraction assay (in which isolated platelets and red blood cells [RBCs] from a healthy donor are mixed with patient plasma, coagulation is subsequently initiated with tissue factor and calcium, and the red cell extrusion is measured after 2 hours of clot formation [ 33 ]) showed a slightly increased clot weight and a reduced percentage of extruded RBCs in patients compared to controls, despite lower FXIII and fibrinogen levels.…”

“…[ 34 ] It could be that only very small amounts of FXIII are necessary for clot protective effects in the assays performed in this study. [ 15 ]…”