My name is Yonca Bulut. I'm a professor of Pediatric Critical Care at UCLA Mattel Children's Hospital at Los Angeles. One of my clinical interest is Pediatric Acute Liver Failure Management in the Pediatric ICU. Our session is Liver Failure in Pediatric ICU, Current Controversies. I will focus on coagulation and acute liver failure, bleeding versus proteomotic state. I do not have any disclosures. Objectives of today's talk are coagulopathy in pediatric acute liver failure, pitfalls of common coagulation assays in pediatric acute liver failure, how to monitor coagulopathy, when to treat coagulopathy. When we look at the definition of pediatric acute liver failure, it is an acute onset catastrophic disease. And coagulopathy, not corrected by vitamin K, is at the center of the definition. Actually, specific levels of INR greater than 1.5 with encephalopathy or greater than two without encephalopathy determines the pediatric acute liver failure definition. Etiology in acute liver failure is important because it may determine the outcome. But almost 50% of the time, we cannot determine the etiology. And etiology changes by age groups and geography as well. While drugs, toxins, and autoimmune reasons are more common in older children, HLH, HSV may be more common in neonates. Why etiology is so important? Because it determines likelihood of spontaneous recovery. Close to 75% of children survive with native liver, especially if they are greater than three months of age. If the liver failure is due to paracetamol toxicity, ischemic event, hepatitis A, they are more likely to recover. If the etiology is mitochondrial disease, HSV, HLH, and the children are younger, then the hope for recovery becomes slim. Other than age, INR is also an important prognostic factor that we follow. Why? That's why it is important not to use plasma factors to correct INR. If it's not necessary, since it is an important prognostic marker. Acute liver failure is a catastrophic disease. These patients can rapidly progress to multi-organ dysfunction with hemodynamic collapse, septic shock, cerebral edema, and herniation. Since there is decreased metabolic function, liver failure also leads to hypoglycemia, lactic acidosis, high ammonia, and coagulopathy. Today, I will focus on the coagulopathy in acute liver failure. How is this coagulopathy different than the others? Coagulopathy in liver disease is multifactorial. And in acute liver failure, all three arms of hemostasis are affected. Primary hemostasis involves formation of the primary platelet plug on the injured vascular endothelium. Secondary hemostasis involves a cascade of coagulation factors leading to formation of the fibrin clot. Fruvinalysis removes the fibrin clot and prevents uncontrolled thrombosis. All these three arms are affected in acute liver failure. Also, if there is bacterial infections, this may also potentiate the risk of bleeding. Renal failure and uremia may further hinder primary hemostasis due to platelet dysfunction. Hysterically acute liver failure believed to be auto-anticoagulated and protected from thrombosis. But in acute liver failure, there is a parallel reduction of both anticoagulant factors and procoagulant factors. And this leaves the patient in a rebalanced coagulation state. Spontaneous bleeding is rare. It is less than 5%. Spontaneous intracranial bleed is also less than 1%. This is due to the absence of esophageal varices in portal hypertension, which are the major risk factors for bleeding in chronic liver failure. And the risk does not correlate with INR values. Since liver is involved in both procoagulant synthesis, such as factors 2, 5, 9, 11, and fibrinogen, and anticoagulant factors, such as protein C, protein S, and antithrombin, when there's acute liver failure, both set of factors decrease, and this leads to a rebalanced hemostasis. Let's look at the primary hemostasis, which is primary platelet plug formation on damaged endothelium. Platelets adhere to the damaged blood vessels and promote aggregation and clot formation with the help of endothelial-derived protein von Willebrand factor. They also facilitate tissue factor and factor VII complex formation, which catalyzes the activation of factor X, and this reaction primes the thrombin formation. In acute liver failure, both platelet numbers and function are reduced. In addition, thrombopoietin is also reduced. Thrombopoietin is a hormone produced in the liver that regulates the platelet production in bone marrow by stimulating megakaryocytes. An increased consumption of platelets further contributes to thrombocytopenia. But this thrombocytopenia is compensated by elevated levels of von Willebrand factor and decreased levels of ADAMS-13. ADAMS-13 is also synthesized in the liver and its job is to cleave large von Willebrand multimers in the smaller, less procoagulant forms. End result, in acute liver failure, von Willebrand factor levels are elevated and ADAMS-13 are reduced. These opposing effects promote platelet adhesion with the net result of rebalanced hemostasis. Secondary hemostasis is characterized by the formation of an insoluble fibrin clot by activated coagulation factors and thrombin. Fibrin in turn stabilize the primary platelet plug to stop the hemorrhage. In acute liver failure, there's reduced production of both procoagulant factors 5, 7, 9, 10, 11, 13 and prothrombin and anticoagulant factors such as antithrombin, protein C and protein S. Factor VIII is the only coagulation factor that is increased in acute liver failure since factor VIII is synthesized both in liver and in the endothelial cells and is an acute phase reactant. Again, all these simultaneous opposing pro- and anticoagulant protein deficiencies result in a net rebalanced hemostasis. During the third arm of hemostasis, fibrinolysis, body breaks down the fibrin clot, limits the thrombosis and maintains vascular patency. Fibrinolysis starts with conversion of plasminogen to plasmin by tissue plasminogen activator, TPA. At the same time, profibrinolytic drivers are opposed by antifibrinolytic drivers such as plasminogen activator inhibitor, plasmin inhibitor and thrombin activatable fibrinolysis inhibitor, TAFI. In liver disease, increased levels of TPA and reduced levels of plasminogen inhibitor and TAFI favors hyperfibrinolysis and bleeding. On the other hand, reduced levels of plasminogen and increased levels of PA1 favors hypofibrinolysis and clot formation. These competing factors result in rebalanced pro- and antifibrinolytic activity in liver failure. If you put it all together, this picture summarizes the effect of liver failure on coagulation factors. Here, the yellow highlighted factors decrease during the liver failure, but there's a compensatory increase in the blue highlighted factors. In summary, contrary to common belief that in acute liver failure, patients are auto-anticoagulated, actually they may be more prone to thrombosis rather than bleeding. There's a combination of a thrombocytopenia compared with elevated levels of onglobulin factor, factor VIII and reduced ADAMS-13. A hypofibrinolytic state due to elevated PAI1 and low plasminogen and elevated levels of pro-coagulant microparticles that may all lead to an increased risk of thrombosis and worsen outcome. What are the limitations of standard hemoaesthetic tests, specifically INR and prothrombin time? Although INR value is followed as a prognostic tool, it has limitations for evaluating the coagulability of liver disease. INR measures pro-coagulant factors and do not take into consideration change in anticoagulant factors, platelets and other hemoaesthetic changes. It is a poor predictor of bleeding and there's significant laboratory-to-laboratory variation in the INR tests in acute liver failure patients. While standard assays of hemoaesthesis are limited and misleading, viscoelastic assays can accurately evaluate the rebalanced hemoaesthesis. Global assays of coagulation such as thromboelastography, TIG, rotational thromboelastometry, ROTEM, and thrombin generation assays provide better estimate of hemoaesthesis. These measure clot formation, ultimate clot strength, and the stability of the clot by integrating the contribution of platelets as well. Unfortunately, we don't have any pediatric data on the use of viscoelastic tests in acute liver failure. There are no current pediatric cutoff values for the use of prophylactic transfusions of plasma or platelets in acute liver failure. If you look at the recent Transfusion and Anemia Expertise Initiative Control taxicab studies and recommendations, they are in agreement that prophylactic FFP and platelets may not be beneficial in the absence of bleeding. They also recommend restrictive plasma and platelet transfusion strategies, including not treating a laboratory number alone because INR trend is useful for prognostication and it will be obscured with FFP transfusion. And also pediatric acute liver failure patients are more prone to thrombosis rather than bleeding. When should we correct coagulopathy in acute liver failure in children? Of course, when there's active bleeding, we should correct coagulopathy. But spontaneous bleeding is not common in acute liver failure. Although it is mild, thrombocytopenia is the most significant contributor to bleeding. There are also no cutoff values for preprocedural correction. In a recent survey among the clinicians of the Coagulation and Liver Disease Symposium, 50% of respondents suggest a cutoff value of INR greater than 1.5 and platelets of greater than 30,000 for liver biopsy and INR of greater than 1.5 and a platelet count of greater than 50,000 for intracranial pressure monitor placement. Coagulopathy can be corrected with fresh frozen plasma. But if the volume is an issue, you can also use factor VII NOVA7 or PCC protein complex concentrate. We give all acute liver failure patients, they will all receive a vitamin K as a single dose. In summary, there is rebalanced hemostasis in pediatric acute liver failure. Spontaneous bleeding is rare and current coagulation tests INR and PT are not predictive of acute bleeding. Arbitrary plasma and blood product transfusion may harm the patient with risks of fluid overload, cerebral edema and thrombosis. Unnecessary plasma transfusions will obscure the INR trend as a prognostic marker. Utilization of viscoelastic tests may provide an accurate assessment of bleeding and prevent overuse of plasma. Further studies are necessary to characterize the coagulopathy in children with acute liver failure and develop treatment guidelines. Thank you for your time.

Pediatric Acute Liver Failure

Management

Pediatric ICU

Coagulopathy

Viscoelastic assays