Monitoring and Treatment of Coagulation Disorders in End-Stage Liver Disease

Abstract

Background: Patients with end-stage liver disease (ESLD) are assumed to be at high risk of bleeding when undergoing any kind of invasive intervention (any kind of operation, including transplantation or minimally invasive interventions). Both bleeding and thrombosis are associated with a poor outcome.

Methods: A selective literature research was conducted with the following key words: 'cirrhosis', 'coagulation', 'bleeding', 'INR' (international normalized ratio), 'aPTT' (activated partial thromboplastin time), and 'thrombocytopenia'. PubMed was used as the basic database.

Results: Pathological values of standard laboratory tests (SLT) and thrombocytopenia have traditionally been regarded as indicators of a high risk for bleeding in all patients, and especially in those with ESLD. However, this approach has been challenged in recent years. The conventional approach in assessing a bleeding risk was based on pathological values of SLT. A 1.5-fold increase of INR or aPTT or platelets < 50/nl is assumed as pathological. The traditional approach of reducing the risk of excessive bleeding during an invasive procedure was to transfuse fresh frozen plasma (FFP) or platelet concentrates in order to improve hemostasis and to avoid bleeding complications. In the recent 20 years, several studies have provided us with a basis for questioning this approach. Their results indicated that SLT were not able to predict hypocoagulation and bleeding complications. Moreover, transfusion of various blood products has been associated with an increased risk for acute lung injury, transfusion-associated circulation overload, bacterial infections, and modulation of the immune system with increased numbers of nosocomial infections. Furthermore, a high volume overload, which is required to correct a hemostasis disorder if FFP are being used in ESLD patients, may increase portal venous pressure. This might significantly increase bleeding in these ESLD patients. Although the first publication about the successful use of a viscoelastic test (VET) in liver transplantation dates back to 1985, physicians are still very reluctant to use VETs (Thrombelastography™ and/or ROTEM™) for the perioperative optimization of hemostasis. However, some very recent studies demonstrated that the use of VETs for assessing the risk of bleeding avoids futile transfusion with a similar safety profile. The implementation of ROTEM-based coagulation management and the use of coagulation factors (prothrombin complex, fibrinogen concentrate) have led to a highly significant reduction of FFP and red blood cell transfusions, without an increased incidence of thrombosis or bleeding.

Conclusion: Patients with ESLD often show pathological values of conventional parameters used to analyze coagulation hemostasis. Without overt signs of excessive bleeding, however, they do not require coagulation treatment. The use of FFP, which is associated with fluid overload and increase in portal venous pressure, should be avoided. The preferable coagulation treatment should be based on VET-guided administration of coagulation factor concentrates.

Keywords: Bleeding; Coagulation management; ESLD; End-stage liver disease.

Fig. 1

On the left side, the ROTEM device is depicted. The coagulation assessment is performed in the whole blood in which an oscillating (4.75°) pin is submerged. A mirror which reflects a beam of the light is mounted on the upper part of the pin. The reflected light is processed by a computer and a graphic according to the coagulation status is printed. When there is no coagulation (the pin can oscillate freely), there is a flat line. When clot formation occurs, the oscillation is impaired and the shape of the graphic changes, i.e. the higher the amplitude of the graph, the higher the clot strength.

Fig. 2

Normal clot: EXTEM CT: 43-82 s; EXTEM MCF: 52-70 mm; EXTEM ML: <15%; FIBTEM MCF: 7-24 mm; INTEM CT: 122-208 s; INTEM MCF: 51-72 mm. There are 4 different channels, with 4 different activators. The EXTEM channel reflects the extrinsic pathway. The assay contains tissue factor and calcium chloride. The INTEM channel reflects the intrinsic pathway. Beside calcium chloride, the activator contains ellagic acid as a surface activator. The FIBTEM channel has the same activator like EXTEM but additionally includes cytochalasin D, which enables all platelets for coagulation. The assessment of the EXTEM and the FIBTEM channel enables stratification if platelets or fibrinogen concentrate is needed. If the MCF in EXTEM as well as MCF in FIBTEM is low, fibrinogen concentrate needs to be replaced. If FIBTEM is normal and MCF in EXTEM is low, platelets should be replaced in a bleeding patient. APTEM is activated with the same activator like EXTEM but contains additional aprotinin. If a clot breaks down in EXTEM and clot firmness is normal in APTEM, the patient suffers from fibrinolysis and should be treated with antifibrinolytic drugs.

Fig. 3

The new hypothesis of the coagulation cascade stratifies the coagulation process into initiation, propagation, and amplification. Fibrin formation will occur at the end of the process. The initiation process reflects only the very early beginning of coagulation and correlates with the first 5-10% of thrombin generation. The SLT assess only these 5-10%; further clot development and clot strength will not be assessed. In contrast to the SLT, the VETs assess the initiation of the coagulation, the acceleration, the clot strength, and finally, if it occurs, also the fibrinolysis.

Fig. 4

a Fibrinolysis after reperfusion. The EXTEM shows a very slight clot forming with immediate breakdown. The FIBTEM channel indicates that no fibrinogen is available (flat line). The APTEM channel indicates that adding aprotinin is able to maintain a weak clot building only from the platelets. After replacement of TXA and fibrinogen bleeding could be stopped. b Example of platelet requirement. MCF in EXTEM is decreased, while it is normal in FIBTEM. c In all 3 channels, i.e. EXTEM, INTEM, and FIBTEM, the clot is broken down. After 30 min a flat line is detected in all channels, which indicates no clotting. ML shows 100% which means that the whole clot undergoes lysis. The APTEM channel contains aprotinin, an antifibrinolytic drug, and indicates that lysis is stopped by antifibrinolytic treatment in vivo. In a bleeding patient, the indication for antifibrinolytic therapy, e.g. with TXA, is given.