Treatment of Coagulopathy Related to Hepatic Insufficiency

Concise Definitive Review Jonathan E. Sevransky, MD, Series Editor Treatment of Coagulopathy Related to Hepatic Insufficiency Cassie A. Barton, PharmD, BCPS, BCCCP Objectives: To provide a concise review of the medical man- sary and should consider patient specific factors. (Crit Care agement of coagulopathy related to hepatic insufficiency. This Med 2016; 44:1927–1933) review will focus on prevention and management of bleeding Key Words: blood coagulation factors; coagulopathy; hepatic episodes in patients with hepatic insufficiency. The treatment insufficiency; liver failure; prothrombin complex concentrate and prevention of thromboembolic complications will also be addressed. Data Sources: Electronic search of PubMed database using relevant search terms, including hepatic coagulopathy, hemorrhage, anagement of hepatic coagulopathy has tradition- liver diseases, blood coagulation disorders, blood transfusion, ally been addressed dogmatically, but new methods disseminated intravascular coagulation, and liver failure. Subse- Mto evaluate the risk of bleeding and new strategies to quent searches were done on specific issues. address acute bleeding episodes are challenging the status quo. Study Selection: Articles considered include original articles, It is now recognized that hepatic insufficiency results in a myr- review articles, guidelines, consensus statements, and confer- iad of profound changes in the hemostatic system. Concomi- ence proceedings. tant reductions in both pro- and anticoagulant factors create a Data Extraction: A detailed review of scientific, peer-reviewed dynamic rebalancing of hemostasis, but the balance can be easily data was performed. Relevant publications were included and disrupted (1–3). Routine tests of hemostasis, such as activated summarized. partial thromboplastin time (aPTT) and prothrombin time/ Data Synthesis: Available evidence is used to describe and international normalized ratio (PT/INR), are unable to fully summarize currently available tests of hemostasis, utilization of characterize this rebalanced coagulopathy. Using the normaliza- prohemostatic agents, transfusion strategies, use of prophylac- tion of aPTT and PT/INR as an endpoint of prophylactic and tic anticoagulation and treatment of thromboembolic events in resuscitative strategies should be avoided. Advances in trans- patients with hepatic insufficiency. fusion protocols, notably with lower transfusion triggers, have Conclusions: Dynamic changes to hemostasis occur in been shown to reduce rebleeding risk and transfusion-associ- patients with hepatic insufficiency. Routine laboratory tests ated complications. Thrombotic complications are also com- of hemostasis are unable to reflect these changes and should monly seen in patients with hepatic coagulopathy. Prophylaxis not be used exclusively to evaluate coagulopathy. Newer against and treatment of these complications are necessary (4). testing methods are available to provide data on the entire spectrum of clotting but are not validated in acute bleeding. PATHOPHYSIOLOGY Prohemostatic agents utilized to prevent bleeding should only Changes in all phases of hemostasis are seen in liver disease be considered when the risk of bleeding outweighs the risk (Table 1). Due to the liver’s role in the synthesis of most coagula- of thrombotic complications. Restrictive transfusion strate- tion factors, reductions in procoagulant and anticoagulant factors, gies may avoid exacerbation of acute bleeding. Prophylaxis fibrinolytic factors, and antifibrinolytic proteins are seen (5). against and treatment of thromboembolic events are neces- Production of all procoagulant factors, with the exception of factor VIII, occurs in the liver. Consequently, levels of pro- Department of Pharmacy, Oregon Health & Science University, Portland, OR coagulant factors, including prothrombin, V, VII, IX, and X, are Dr. Barton disclosed off-label product use (the use of recombinant factor reduced in hepatic insufficiency (6). Production of anticoagu- VIIa, prothrombin complex concentrates, desmopressin, eltrombopag, lant factors, including antithrombin, protein C, and protein S, and tranexamic acid are all off-label uses for indications discussed in this article). are also decreased (6). Factor VIII levels are frequently elevated For information regarding this article, E-mail: [email protected] in liver failure, possibly due to extrahepatic synthesis, up-regula- Copyright © 2016 by the Society of Critical Care Medicine and Wolters tion of alternate production pathways, or reduced clearance (7). Kluwer Health, Inc. All Rights Reserved. Thrombocytopenia is common in both acute and chronic DOI: 10.1097/CCM.0000000000001998 liver disease, and it has multiple underlying etiologies. Liver Critical Care Medicine www.ccmjournal.org 1927 Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. Barton TABLE 1. Changes to Hemostasis Seen With Hepatic Insufficiency Change to Hemostatic System Proteins Affected Pathophysiology of Change Decreases in procoagulant ↓ Prothrombin Decreased hepatic production proteins ↓ Factor V ↓ Factor VII ↓ Factor IX ↓ Factor X Decreases in anticoagulant ↓ Antithrombin Decreased hepatic production proteins ↓ Protein C ↓ Protein S Increases in procoagulant ↑ Factor VIII Extra-hepatic synthesis protein Up-regulation of alternate production pathways Reduced clearance Thrombocytopenia, functional ↓ Platelets Decreased thrombopoietin production platelet defects Increased platelet consumption Congestive splenomegaly in cirrhosis pooling platelets in spleen Increases in platelet adhesive ↑ von Willebrand factor Increased production protein Reduced hepatic clearance Changes in fibrinogen ↔ Fibrinogen Increased fibrinolysis in acute liver failure Hyperfibrinolysis in advanced liver disease Often normal in stable chronic disease failure results in decreased thrombopoietin production, which, The coagulopathy associated with acute and chronic in turn, leads to decreased platelet production (8). Increased liver failure differ significantly. Changes to liver structure in platelet consumption, possibly from chronic, low level dissem- chronic liver failure lead to portal hypertension, hypersplen- inated intravascular coagulation (DIC), may also be a contrib- ism, thrombocytopenia, and gastroesophageal varices, each of uting factor (9). Thrombocytopenia can be further potentiated which is associated with increased bleeding risk. Acute liver by continued alcohol use and its toxic effects on the bone mar- failure is not associated with significant portal hypertension, row, folic acid deficiency, or myelosuppression from hepatitis and the thrombocytopenia seen is typically modest. Therefore viruses (10, 11). In patients with cirrhosis, portal hypertension less significant bleeding after an invasive procedure is expected can cause congestive splenomegaly, which results in pooling of as compared to bleeding in chronic disease states (21, 22). platelets in the spleen (12). Further complicating this picture Concomitant disease states alter the hemostatic balance in are the platelet function defects found in liver disease patients. liver failure. Bacterial infections in these patients are linked to Defects are seen in both platelet aggregation and platelet vessel an increased risk of and an inability to control bleeding, most wall interaction necessary for primary hemostasis (5, 13). prominently acute variceal bleeding (23–25). While the exact The thrombocytopenia of liver disease is balanced by the con- mechanism of infection inducing or potentiating bleeding is comitant, substantial increase in the concentration of platelet still debated, endotoxins and cytokines are implicated (25). adhesive protein von Willebrand factor (VWF), which is produced Endotoxins and cytokines produced in the presence of bacte- by endothelial cells and megakaryocytes (7, 14). High plasma rial infection can induce DIC, inhibit platelet function, and levels of VWF likely result from increased production, reduced enhance the effects of nitric oxide (25, 26). Adequate treat- hepatic clearance, and increased endothelial activation seen in ment of known infection and prophylaxis against potential portal hypertension and bacterial infection (15–17). Although it infection is required (27). Renal insufficiency is also a common has been shown that the VWF in liver patients has reduced func- complication of liver dysfunction, leading to increased risk of tionality, the elevated levels are still able to partially compensate bleeding through acquired uremic platelet dysfunction and for platelet defects and contribute to primary hemostasis (15). impaired platelet vessel wall interactions (28). Fibrinogen levels are often decreased in acute liver failure and advanced disease, but frequently remain normal in CURRENT COAGULATION TESTING METHODS chronic stable disease (18). The fibrinolytic system is under the Laboratory values are routinely used to assess bleeding and throm- strict control of activators, including tissue plasminogen acti- botic risk in patients with hepatic insufficiency. Unfortunately, vator (tPA) and urokinase plasminogen activator, and inhibi- currently available laboratory tests are unable to provide a com- tors of tPA and thrombin activatable fibrinolysis inhibitor. In prehensive view of hemostatic changes in these patients (Table 2). liver disease, reductions in both the activators and inhibitors of Basic laboratory coagulation tests, including PT/INR and the fibrinolytic system are seen (5,

Load more