Hemostatic Balance in Pediatric Acute Liver Failure: Epidemiology of Bleeding and Thrombosis, Physiology, and Current Strategies

Abstract

Pediatric Acute Liver Failure (PALF) is a rapidly progressive clinical syndrome encountered in the pediatric ICU which may rapidly progress to multi-organ dysfunction, and on occasion to life threatening cerebral edema and hemorrhage. Pediatric Acute Liver Failure is defined as severe acute hepatic dysfunction accompanied by encephalopathy and liver-based coagulopathy defined as prolongation of International Normalized Ratio (INR) >1.5. However, coagulopathy in PALF is complex and warrants a deeper understanding of the hemostatic balance in acute liver failure. Although an INR value of >1.5 is accepted as the evidence of coagulopathy and has historically been viewed as a prognostic factor of PALF, it may not accurately reflect the bleeding risk in PALF since it only measures procoagulant factors. Paradoxically, despite the prolongation of INR, bleeding risk is lower than expected (around 5%). This is due to “rebalanced hemostasis” due to concurrent changes in procoagulant, anticoagulant and fibrinolytic systems. Since the liver is involved in both procoagulant (Factors II, V, IX, XI, and fibrinogen) and anticoagulant (Protein C, Protein S, and antithrombin) protein synthesis, PALF results in “rebalanced hemostasis” or even may shift toward a hypercoagulable state. In addition to rebalanced coagulation there is altered platelet production due to decreased thrombopoietin production by liver, increased von Willebrand factor from low grade endothelial cell activation, and hyperfibrinolysis and dysfibrinogenemia from altered synthetic liver dysfunction. All these alterations contribute to the multifactorial nature of coagulopathy in PALF. Over exuberant use of prophylactic blood products in patients with PALF may contribute to morbidities such as fluid overload, transfusion-associated lung injury, and increased thrombosis risk. It is essential to use caution when using INR values for plasma and factor administration. In this review we will summarize the complexity of coagulation in PALF, explore “rebalanced hemostasis,” and discuss the limitations of current coagulation tests. We will also review strategies to accurately diagnose the coagulopathy of PALF and targeted therapies.

A look into hemostatic characteristics during pediatric liver transplantation using the thromboelastometry (ROTEM ® ) test

“…All coagulation factors are markedly decreased during the synthetic functional deficiency of the liver parenchyma during fulminant liver failure. [26] Our results also showed that all parameters of the conventional coagulation tests in the ALF group were abnormally reduced or prolonged. Most measurements of ROTEM ® in the ALF group were out of the reference range [20] (55% for increased INTEM CT, 85% for increased INTEM CFT, and 63% for decreased EXTEM MCF).…”

Establishment of a risk assessment score for deep vein thrombosis after artificial liver support system treatment

“…Liver failure leads to a decrease in hepatic synthetic coagulation factors, hyperfibrinolysis, and thrombocytopenia caused by hypersplenism[ 27 , 28 ]. Therefore, patients with liver failure have always been considered to be in a low coagulation state [ 29 , 30 ].…”

Diagnosis, treatment, and prevention of severe acute hepatitis of unknown etiology in children

“…If acute liver failure (ALF) occurs, various factors, such as decreased coagulation factor synthesis, decreased hepatic thrombopoietin, and secondary bacterial infection, may lead to coagulation disorders [ 26 ]. Prothrombin activity (PTA) and INR can be used to evaluate coagulation function in clinical practice.…”