Thromboelastography and Utility in Hepatology Practice

Watch a video presentation of this article

Watch an interview with the author

Abbreviations

ALF

acute liver failure

FFP

fresh frozen plasma

GPIIb/IIIa

glycoprotein IIb/IIIa

INR

international normalized ratio

MA

maximum amplitude (maximum diameter of clot)

ROTEM

rotational thromboelastometry

TEG

thromboelastography

VET

viscoelastic test

The coagulation system in liver disease is complex, and traditional coagulation tests, such as international normalized ratio (INR), do not predict bleeding risk. ¹ , ² , ³ Thromboelastography (TEG) is a viscoelastic test (VET) that rapidly analyzes both the rate and strength of blood clot formation and the rate of dissolution in whole blood. Through use of whole blood, TEG more closely reflects in vivo hemostasis when compared with traditional coagulation plasma‐based tests such as INR, activated partial thromboplastin time, and prothrombin time. Due to well‐established shortcomings of traditional coagulation tests in cirrhosis, VETs are now increasingly studied and used in patients with cirrhosis. Given the broadly accepted shift in our understanding of hemostasis as “rebalanced” in liver disease, VETs (TEG and rotational thromboelastometry [ROTEM]) offer attractive features to both investigators and clinicians alike. ⁴ Consequently, investigation and clinical use of VETs are expanding with aims of broader clinical applications. ⁴ , ⁵ , ⁶

How is it Performed?

Conventional TEG is performed by adding a sample of blood into a cup that is then slowly rotated. A wire sensor is placed into the blood sample, and a clot is then formed between the sensor and the cup. A computer then analyzes the integrity and kinetics of clot formation, producing corresponding graphics and results in real time. ⁷ ROTEM differs as the blood sample is placed in a stationary cup and a central rotating pin measures clot formation through an optical detection system, rather than a tracing wire affixed to a suspended pin in TEG. ⁴ Separate TEG and ROTEM channels and assay types exist within VETs (Table 1), which allow simultaneous assessment of different components of hemostasis. Tracings and their associated changes are determined qualitatively and assist in determining a patient’s hemostasis and coagulopathy (Fig. 1).

Table 1.

Viscoelastic test properties

	Interpretation	Activator
TEG Channel
Native TEG	Sensitive channel for subtle changes in coagulopathy and hyperfibrinolysis	None
Rapid TEG	Assays extrinsic pathway and common pathway	Tissue factor + kaolin
Conventional/Standard TEG	Intrinsic/Extrinsic pathways activated with an “R” value corresponding to factor activity	Kaolin
Heparinase TEG	Determines whether patient is coagulopathic due to presence of heparin, combined with standard TEG	Heparinase
Functional fibrinogen TEG	Platelet inhibition and assesses fibrinogen contribution to clot strength	GPIIb/IIIa inhibitor
ROTEM Channel
INTEM	Intrinsic pathway activated	Ellagic acid
EXTEM	Extrinsic pathway activated	Tissue factor
FIBTEM	Isolates contribution of fibrinogen through platelet inhibition	Cytochalasin D
APTEM	Fibrinolysis inhibition and may assist in confirming hyperfibrinolysis	Aprotinin/Tranexamic acid
HEPTEM	Heparin inhibition and assists in confirming presence of heparin	Heparinase

Fig. 1.

(A) Fibrinolysis: normal R value with a continuous decreased MA. (B) Normal coagulation. (C) Hypercoagulable: decreased R and k values with increased alpha (α) angle and MA. α angle: rate of fibrin clot formation; k value: time to reach 20‐mm diameter; R value: time to clot formation.

There are few studies that correlate TEG parameters well with traditional coagulation testing and subsequent bleeding or thrombotic events in patients with liver disease. The maximum amplitude (MA) in millimeters in TEG, shown in Fig. 1, is a measure of overall clot stiffness and an important tool that evaluates primary and secondary hemostasis, and helps guide platelet transfusion. ⁴ An MA <50 to 55 mm signifies defective platelet contribution to coagulation and is a signal for platelet transfusion. Lower MA values indicate lower platelet number and platelet dysfunction, as well as factor deficiency. Higher R times correlate with decreased clotting factors and indicate the need for factor replacement (e.g., fresh frozen plasma [FFP] transfusion or cryoprecipitate). Consistent with the majority of TEG studies, an R time cutoff of 8 to 10 minutes or longer signifies the need for factor replacement. An alpha angle less than 45 degrees may signify low or dysfunctional fibrinogen, necessitating fibrinogen replacement (e.g., fibrinogen or cryoprecipitate). Lysis time is a measure of how quickly the clot is broken down and if significantly elevated, it may be a sign of hyperfibrinolysis or rapid clot lysis that can be treated with antifibrinolytic agents.

TEG Prior to Invasive Procedures in Cirrhosis

TEG may be a useful tool in measuring the severity of coagulopathy prior to invasive procedures in patients with cirrhosis. De Pietri et al. ⁶ compared TEG‐guided blood product use with standard traditional measures in a randomized prospective trial. TEG‐guided transfusion resulted in significantly lower transfusions without an increase in bleeding complications. ⁶ Given the conflicting literature on correcting platelet count and INR prior to invasive procedures, a TEG‐guided transfusion protocol may offer advantages. Currently, however, it is unclear what standard baseline VET parameters should be used to guide prophylactic strategies because studies lack control arms without use of prophylaxis and have not been based on bleeding outcomes. ⁸

TEG in Gastrointestinal Bleeding

Patients with cirrhosis commonly experience gastrointestinal bleeding from portal hypertension and nonportal hypertension causative factors. In a randomized controlled trial, Kumar et al. ⁹ evaluated a cohort of 96 patients with cirrhosis with nonvariceal bleeding. Patients were stratified into TEG‐guided transfusion strategy or standard‐of‐care coagulation‐based transfusion. The group in the TEG arm received significantly fewer blood product transfusions and had fewer adverse events related to transfusions. It should be noted that thresholds for transfusion were somewhat arbitrary, and elevated INR was used to guide prophylactic FFP transfusion. In addition, the amount of FFP transfused was the chosen primary outcome rather than a clinical‐based bleeding outcome.

Rout et al. ¹⁰ evaluated TEG‐directed blood product transfusion in variceal bleeding. In the TEG group, 13.3% of patients received transfusions versus 100% of subjects in the standard‐of‐care arm. Rebleeding was significantly less in the TEG group at 42 days. Similarly, this study lacked a clinical‐based primary outcome and also assessed amount of FFP transfused. In addition, variceal bleeding is a complication of portal hypertension and is primarily driven by an increase in portal pressure and not hemostatic failure. Therefore, the practice of prophylactic transfusion is questionable in this setting irrespective of TEG or INR parameters and may even worsen portal hypertension.

TEG in Patients With Cirrhosis Undergoing Liver Transplantation

Introduced in 1985, TEG is now commonly used during liver transplantation to guide transfusions and coagulation management, and aid in distinguishing surgical bleeding from coagulopathy. ¹¹ , ¹² Since this time, several studies have been conducted that analyze the use of both TEG and ROTEM during liver transplantation. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ A randomized controlled trial of 28 patients over a 2‐year period undergoing liver transplantation compared TEG‐based transfusion protocol with standard of care using conventional parameters. ¹⁶ TEG‐guided transfusion decreased total FFP transfusion but did not affect survival. Use of VET (TEG and ROTEM) is now common at liver transplant centers, and use of VET to guide hemostatic support is recommended by the International Society of Haemostasis and Thrombosis rather than reliance on conventional parameters. ¹⁷

VETs are valuable for use during liver transplantation and postoperatively secondary to the rapid availability of results and the subsequent ability to simultaneously assess distinct components of clot formation and hemostasis. Although VETs can distinguish between the contributions of thrombocytopenia and hypofibrinogenemia to bleeding, they can also provide assessment of clot breakdown (fibrinolysis) and heparin‐like effect seen during liver transplant. In particular, preoperative values of TEG (low MA) have been shown to predict need for massive transfusion during liver transplantation. ¹⁸ Significant postperfusion bleeding from hyperfibrinolysis may occur during liver transplantation, and both ROTEM and TEG can assist in recognition and management of this challenging physiology. ¹⁹ , ²⁰ , ²¹

Hypercoagulability is also of concern during liver transplantation, and thrombotic events can be catastrophic. This is particularly relevant in the context of our current understanding of the rebalanced coagulation system in decompensated cirrhosis because patients are at risk for bleeding and thrombosis. TEG has been shown to predict recipients at risk for development of hepatic artery stenosis postoperatively. ²² , ²³ Further study is needed to better understand the value and role of VET in prediction of hypercoagulability in the perioperative setting of liver transplantation.

TEG in Acute Liver Failure

Traditional measures of coagulation do not accurately reflect bleeding risk in acute liver failure (ALF). ²⁴ , ²⁵ Patients with ALF often present with extremely elevated INR, yet rarely bleed. ²⁵ Stravitz et al. ²⁴ assessed hemostasis in patients with acute liver injury/ALF using TEG. Patients presented with significantly elevated INR, yet retained normal hemostasis demonstrated by TEG. These data help clarify the dissonance experienced by clinicians caring for patients with ALF with extremely abnormal traditional coagulation tests, yet lacking clinically evident hemostatic failure (e.g., spontaneous bleeding).

Conclusions

In summary, the utility of TEG in patients within hepatology is promising. VETs are now more widely available, yet studies are still needed to demonstrate overall utility to predict bleeding or thrombosis. Although more closely approximating coagulation and fibrinolysis in principle, VET has yet to demonstrate reliably accurate prediction of clotting or bleeding events in cirrhosis. The coagulation system in cirrhosis is extraordinarily complex, and all ex vivo testing is limited by loss of important mechanisms of vascular endothelial interaction and blood flow. Future high‐quality, prospective studies are now needed to assess bleeding risk using TEG in patients with acute and chronic liver disease to establish parameters that can predict actual clinical events so they may be prevented with intervention.