Thromboelastometry Identified Alteration of Clot Stabilization and Factor XIII Supplementation Need in a Patient with Decompensated Liver Disease Undergoing Liver Biopsy

Liver disease has been considered the prototype of hemorrhagic disease. Disorder in any component of coagulation system can lead to hemorrhage. Deficiency of factor XIII may impair clot strength and clot stabilization and can be accessed by thromboelastometry. We report a case of a patient with a rapid evolution of liver disease who underwent a liver biopsy. Thromboelastometry was performed, evidencing impairment of clot stability. This clotting disorder was corrected with factor XIII concentrate after unsuccessful administration of antifibrinolytic drugs and hepatic biopsy was performed without hemorrhagic complications. Case Presentation. We report the case of a previously healthy 38-year-old man, who presented to our emergency department with clinical signs of rapid progression of acute liver failure. The laboratory tests revealed platelets of 142x103/mm3, plasma fibrinogen concentration of 221 mg/dl, increased international nationalized ratio (INR 1.9), total bilirubin of 3.9mg/dl, direct bilirubin of 2.3mg/dl, ALT 751U/l, and AST 540U/l without acute bleeding. A liver biopsy was indicated. Based on the results of the thromboelastometry, Tranexamic Acid was administered to correct hyperfibrinolysis followed by factor XIII concentrate to correct factor XIII deficiency. Thromboelastometry was normal despite conventional coagulation tests were still altered. So, liver biopsy was performed with no signs of bleeding and without need of further transfusion. Conclusion. Thromboelastometry may be considered a useful, feasible, and safe tool to monitor and manage coagulopathy in patients with liver disease, with the potential advantage of helping avoid unnecessary transfusion in such patients.


Introduction
Coagulopathy in liver disease has been considered as one of the major challenges in the area of thrombosis and hemostasis [1]. In recent years liver disease has been proven to be no longer an exclusively hemorrhagic disease; otherwise, clinical signs of thrombosis can be found [2]. The clinical manifestation depends on imbalance between pro-and anticoagulant drivers as well as pro-and antifibrinolytic components [1].
Traditionally, patients with decompensated liver disease who exhibit abnormal results of conventional coagulation tests (CCT) have been subjected to prophylactic transfusion of blood components before undergoing an invasive procedure. However, CCT are poor predictors of bleeding, and allogeneic blood components transfusion is associated with poor outcome.
Studies in patients with liver disease have suggested that thromboelastometry (ROTEM5) may be a better test in predicting risk of bleeding than coagulation conventional tests and platelet count [3]. Thromboelastometry accesses the entire process of clot formation including the initiation, maximum firmness, and stabilization of the clot [4]. Specific coagulation disorder as dysfibrinogenemia, hyperfibrinolysis, and factor XIII deficiency can be identified early [5].
Therefore, thromboelastometry used for identifying coagulopathy and guided hemostatic therapy could be considered in cases of patients with liver disease with risk of bleeding and need to undergo an invasive procedure such as liver biopsy. Consequently, our objective was to describe a case of a patient with fast onset liver disease with unknown cause whose hepatic biopsy procedure was successfully guided by thromboelastometry. Coagulopathy was corrected 2 Case Reports in Gastrointestinal Medicine  with coagulation factor concentrate and hemostatic drugs without transfusion of allogeneic blood component.

Case Presentation
We report the case of a previously healthy 38-year-old man, Afro-Brazilian, with no previous medical records. He presented to our emergency department with an acute onset of abdominal pain, jaundice, fever, nausea, weakness, and malaise. His arterial blood pressure was 90/50mmHg, heart rate was 90 bpm, axillary temperature was 35 ∘ C, and he was dehydrated. The laboratory examinations revealed serum creatinine of 0. 8 Figures  1(j), 1(k), and 1(l)). Thromboelastometry was normal despite CCT were still altered. So, liver biopsy was performed which succeeded with no signs of bleeding and without need of further transfusion. He was discharged from the hospital 5 days after admission.

Discussion
Liver disease is often associated with coagulation disorders. CCT are usually quite altered and therefore transfusion of blood components has been a frequent practice. Transfusion of allogeneic blood products is associated with a higher risk of infection, pulmonary failure, and mortality [6,7]. However, CCT present late results and are punctual since they access only 5% of thrombin generation [8]. Thus, CCT are limited to predict bleeding or guide transfusion therapy with blood components.
In 2001, the concept of the cell-based coagulation model described by Monroe and Hoffman pointed out the role of the surface of cell membrane for the generation of thrombin. This complex process of clot formation is triggered from the release of the tissue factor by the endothelium. In this cellular model, the clot formation process goes through 3 stages: thrombin generation including initiation and amplification phases; maximum clot firmness or propagation phase; and last phase the clot stabilization [9]. Both the fibrinolytic system and factor XIII are considered the determinants of clot stabilization.
Rotational thromboelastometry is a laboratory method performed at the bedside that accesses the entire process of clot formation. First ROTEM identifies the initial process involving the coagulation factors of both the extrinsic and intrinsic pathway to generate thrombin. Subsequent phase consists in a fibrin clot formation from fibrinogen, platelets, and also factor XIII when clot reaches maximum firmness [4]. The final phase of stabilization involves the fibrinolytic system as well as factor XIII activated responsible for cross-linking of fibrin [10].
Discovered in 1940s, blood coagulation factor XIII (F XIII) is a transglutaminase that is present in plasma, activated by the combined action of thrombin and Ca2+. Its function includes cross-linking of fibrin monomers between themselves to generate a stable fibrin strand, but also crosslinking of fibrinogen with 2 antiplasmin, a potent plasmin inhibitor, to protect the fibrin clot from fibrinolysis [11,12]. Thus, factor XIII acts on the clot firmness but mainly on clot stabilization. FXIII deficiency is not detected by routine coagulation assays and needs to be searched by measuring FXIII levels with quantitative assay [4,5]. Inherited FXIII deficiency with undetectable FXIII activity is associated with a severe bleeding tendency. FXIII levels below 50% are associated with a smaller 2AP incorporation and enhanced clot lysis [10,13].
Thromboelastometry allows the evaluation of factor XIII deficiency in two different ways. First, factor XIII deficiency can be thought of if the maximum clot firmness (MCF) in FIBTEM remains reduced even after adequate replacement of fibrinogen. The other possibility is when the maximum lysis found in EXTEM is above 15%; however, the maximum lysis remains above 15% to APTEM, even after the administration of antifibrinolytic drugs [14]. In both situations, the quantitative measurement of factor XIII is not mandatory, since thromboelastometry accesses the quality of formation and stabilization of the clot. Sudden quantitative reduction in the measurement of factor XIII may compromise the stabilization of the clot, without critically low levels of factor XIII being detected necessarily.
In this reported case, traditionally the patient with acute liver disease and INR 1.9 would probably be transfused with fresh frozen plasma because of the high risk of bleeding during liver biopsy. However, thromboelastometry performed identified impairment in clot stabilization. According to the first ROTEM test, Tranexamic Acid 1 g was administered to correct hyperfibrinolysis defined by ML EXTEM > 15% (Figures 1(a), 1(b), and 1(c)). There was partial improvement in the second test that still showed hyperfibrinolysis parameters 8 h after the first test (Figures 1(d), 1(e), and 1(f)). An additional dose of 1 g Tranexamic Acid was administered, but without changing the ML in both EXTEM and APTEM. At this time, the third ROTEM test showed ML EXTEM above 15%; then 1500U of factor XIII concentrated was administered ( Figures  1(g), 1(h), and 1(i)). The control ROTEM was normal and liver biopsy was undergone without any bleeding complication, confirming the usefulness of factor XIII infusion to increase clot stability confirmed by thromboelastometry in a situation where acquired factor XIII deficiency is expected ( Figures  1(j), 1(k), and 1(l)).

Conclusion
This case reports the use of thromboelastometry for diagnosis of specific coagulation disorder in patients with liver disease with high risk of bleeding and need to undergo an invasive procedure such as liver biopsy.
Thromboelastometry identified factor XIII deficiency and guided the therapy with factor XIII concentrate correcting clotting disorder. Factor XIII replacement improved the clot stabilization and liver biopsy was performed without bleeding complications. No transfusion of allogeneic blood component was needed. Nevertheless, additional studies are needed to define the ability of thromboelastometry to identify factor XIII deficiency in liver disease patients, but also to define the role of factor XIII concentrate to improve clot stabilization.

Consent
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.