The Misunderstood Coagulopathy of Liver Disease

A Review for the Acute Setting

Michael F. Harrison, MD, PhD

Disclosures

Western J Emerg Med. 2018;19(5):863-871. 

In This Article

Abstract and Introduction

Abstract

The international normalized ratio (INR) represents a clinical tool to assess the effectiveness of vitamin-K antagonist therapy. However, it is often used in the acute setting to assess the degree of coagulopathy in patients with hepatic cirrhosis or acute liver failure. This often influences therapeutic decisions about invasive procedures or the need for potentially harmful and unnecessary transfusions of blood product. This may not represent a best-practice or evidence-based approach to patient care. The author performed a review of the literature related to the utility of INR in cirrhotic patients using several scientific search engines. Despite the commonly accepted dogma that an elevated INR in a cirrhotic patient corresponds with an increased hemorrhagic risk during the performance of invasive procedures, the literature does not support this belief. Furthermore, the need for blood-product transfusion prior to an invasive intervention is not supported by the literature, as this practice increases the risk of complications associated with a patient's hospital course. Many publications ranging from case studies to meta-analyses refute this evidence and provide examples of thrombotic events despite elevated INR values. Alternative methods, such as thromboelastogram, represent alternate means of assessing in vivo risk of hemorrhage in patients with acute or chronic liver disease in real-time in the acute setting.

Introduction

Liver disease presents a major burden on healthcare systems in both North America[1,2] and Europe[3] and can result in more than 70,000 annual visits to the emergency department (ED).[4] Liver disease in the setting of acute liver failure (ALF)[5] or trauma in a patient with cirrhosis[6–8] are predictors of increased mortality and poor patient outcome. One of the challenges these patients pose to healthcare providers in acute settings, such as sepsis and trauma, relates to the coagulopathy of liver disease – specifically, is an individual patient at an increased risk of a spontaneous hemorrhagic event or hemorrhagic procedural complication? The commonly accepted paradigm - increased risk of hemorrhagic events in the setting of elevated international normalized ratio (INR) - is being challenged though it still widely influences day-to-day practice.[9,10]

The most commonly used tests for identifying and monitoring coagulopathy include partial thromboplastin time (PTT), prothrombin time (PT), and INR. INR, a ratio of the patient's PT as compared to a laboratory normative PT value, was designed as a method of monitoring individual patient responses to anticoagulation therapy with a vitamin-K antagonist such as warfarin.[11] Despite this, tests including INR are often incorrectly applied clinically as a general indication of a patient's overall bleeding risk due to the ease with which the results are obtained and interpreted. This is particularly true in patients with chronic liver disease and cirrhosis.[12] However, the utility of INR with respect to predicting risk of hemorrhagic event in chronic liver patients has been refuted[13–15] and warrants further review. An early study concluded that isolated evaluation of bleeding or clotting time is of little prognostic value in patients with liver disease during pre-operative screening.[16] Given that this study is nearly a half-century old, why are many clinicians still making important clinical decisions based on the interpretation of an INR value in patients who are not being anticoagulated with a vitamin-K antagonist? More specifically, how did the medical community arrive at the commonly accepted "INR less than 1.5" as a safe threshold for invasive procedures?

The liver is responsible for the synthesis of many of the procoagulant and anticoagulant proteins responsible for maintaining hemostasis.[17] Liver dysfunction is often assumed to be associated with increased bleeding risk, but evidence suggests that other factors such as sepsis, hepatorenal syndrome, hypotension, and endothelial dysfunction contribute to this bleeding tendency rather than isolated cirrhosis and liver disease.[10,18] In most cases, a "rebalancing" occurs and the vast majority of chronic liver disease patients achieve a hemostatic equilibrium.[10,15,19–21] In cases of traumatic injury or prior to surgical procedures, the measured coagulopathy as assessed by INR is often reversed with pharmaceutical agents (e.g., vitamin K, prothrombin complex concentrate) or transfused blood products (e.g., plasma or platelets). However, this practice of prophylactic transfusion to minimize the risk of hemorrhagic complications is not evidence based despite its wide acceptance.[15,19,21]

Prophylactic transfusions may expose the patient to increased risk of adverse events (e.g., transfusion reactions including transfusion-related acute lung injury [TRALI] and exacerbation of portal hypertension) as a result of the transfusion, while providing no protective effects.[19,22,23] PT and INR analyses assess isolated clotting pathways in vitro despite our knowledge that in vivo clotting pathways do not function in isolation.[24] As a result, significantly different INR results can be obtained from the analysis of a sample of blood from a cirrhotic patient based on the commercially available thromboplastin used in performing the analysis.[25] This review intends to address these issues as they pertain to practice in the acute setting such as an ED, a trauma surgeon's operating room, or an intensive care unit (ICU).

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