Assessment of Bleeding Risk in Patients with Cirrhosis | SpringerLink

Curr Hepatology Rep (2015) 14:9–18 DOI 10.1007/s11901-015-0250-1

MANAGEMENT OF THE CIRRHOTIC PATIENT (NS REAU AND A CARDENAS, SECTION EDITORS)

Assessment of Bleeding Risk in Patients with Cirrhosis Alberto Zanetto & Marco Senzolo & Alberto Ferrarese & Paolo Simioni & Patrizia Burra & Kryssia I. Rodríguez-Castro

Published online: 15 March 2015 # Springer Science+Business Media New York 2015

Abstract Cirrhosis is characterized by varying degrees of alterations of the different components of hemostasis, including thrombocytopenia, reduction of procoagulant factors, overactivation of the fibrinolytic system, and a precarious hemostatic equilibrium that can easily tilt towards bleeding. Predicting the risk of spontaneous bleeding from nonvariceal sites, variceal bleeding, and hemorrhagic complications associated with surgery or invasive procedures is a formidable challenge faced by clinicians caring for cirrhosis patients, and standard assays have demonstrated a poor correlation with episodes of bleeding. While new tests evaluating different components of coagulation as well as global assays are increasingly available and used to guide therapeutic approaches, there is still no optimal method to assess bleeding risk, and a combination between severity of liver disease, the presence of ongoing infection or renal insufficiency, as well as This article is part of the Topical Collection on Management of the Cirrhotic Patient A. Zanetto : M. Senzolo (*) : A. Ferrarese : P. Burra : K. I. Rodríguez-Castro Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani, 2, 35128 Padua, Padua, Italy e-mail: [email protected] A. Zanetto e-mail: [email protected] A. Ferrarese e-mail: [email protected] P. Burra e-mail: [email protected]

the type of bleeding itself seems to still be very important in evaluating the individual patient’s risk. Keywords Bleeding . Cirrhosis . Coagulation . Thromboelastography . Rotation thromboelastography

Introduction While in classical coagulation disorders such as hemophilia A or B or von Willebrand disease, a specific coagulation factor (namely, factor VIII, factor IX, or von Willebrand factor, respectively) is missing or defective and bleeding is predictable based on the absent factor, cirrhosis represents a far more complex scenario, where multiple aspects of hemostasis are profoundly altered, rendering the prediction of bleeding a much more challenging endeavor. Progressively worsening of end-stage liver disease is characterized by varying degrees of alterations of the different components of hemostasis, but in general, cirrhosis entails both modifications in the prothrombotic as well as in the prohemorrhagic components. Although it is becoming clear that standard assays of hemostasis are inadequate to evaluate the rebalanced hemostatic status in cirrhosis and are poor predictors of bleeding, they are still of widespread use and may furnish misleading information regarding the risk of bleeding. Clinicians might be increasingly aware that they can be thus led into administering unneeded or even nocuous prohemostatic factors.

K. I. Rodríguez-Castro e-mail: [email protected] P. Simioni Clinica Medica V, Department of Internal Medicine, Padua University Hospital, Via Giustiniani, 2, 35128 Padua, Padua, Italy e-mail: [email protected]

Hemostatic Alterations in Cirrhosis As far as primary hemostasis is concerned, thrombocytopenia, defined as 3 and platelet count 2.5-s prolongation being associated with 47 and 87 % mortality, respectively) [98]. Moreover, platelet count below 50×103/dL determines an increased risk of bleeding during surgery. Another predictor of bleeding associated with surgery in cirrhosis patients is severity of liver disease itself: recently, severity of liver disease has been shown to be correlated with the risk of bleeding complications during brain surgery, with mortality reaching 63 % in Child C patients [99]. In a study in which outcomes of open-heart surgery (including emergency and elective surgery) in 24 patients with cirrhosis, most postoperative complications were related to bleeding: mediastinal bleeding occurred in 25 % of patients, while cardiac tamponade occurred in 17 %. Moreover, the principal causes of death in Child B patients 4/6 were hemorrhage and infection, while the cause of death in Child A and C patients (1/17 and 1/1, respectively) were infection. In this study, platelet count was not different in survivors vs. nonsurvivors, and other parameters related to coagulation and hemostasis were not explored in relation to survival or to frequency of complications [100]. In another study reporting on outcomes after open-heart surgery in 12 patients with cirrhosis, 6 of whom were in Child A and 6 in Child B classes, major complications including hemorrhage and hepatic

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decompensation were associated with platelet count, while mortality (5/12) was associated with bleeding complications in 3 cases [101]. In yet another study, Hayashida and colleagues reported that open-heart surgery in cirrhosis patients was associated with infection in 33 % and major bleeding in 17 % of patients [102]. As far as cardiac catheterization is concerned, INR does not predict catheterization-related bleeding complications, as was shown in a study in which, however, no patient had an INR greater than 2.35 [103].

Laboratory Methods for the Assessment of Hemostatic Status and Bleeding Risk The net result of dichotomous alterations (pro- vs. anticoagulant) seems to settle a new hemostatic equilibrium that is, however, much more fragile considering the limited buffering capacity, with factors such as infection, renal dysfunction, and other decompensating circumstances determining the tipping of this balance towards bleeding or towards thrombotic complications [59••]. Moreover, establishing adequate laboratory parameters to characterize the dynamic hemostatic process, and, more so, using these values as predictors of bleeding, is certainly challenging. The latter is especially important in decision making, whereas risks of a surgical intervention are concerned, or whether preventive measures before a procedure are enacted, parameters that actually guide such practices are still approximate and partial at best. The inaccuracy and inadequacy of traditional coagulation tests such as INR and PTT as predictors of bleeding in cirrhosis patients have been widely demonstrated, and neither does their correction have an apparent impact on bleeding risk reduction, while this practice may result in documented deleterious effects [104]. Conventional tests such as INR, aPTT, bleeding time, and platelet count do not reflect the pathophysiological changes in cirrhosis and the complete hemostatic status and are inadequate in predicting both spontaneous as well as procedural/ surgical bleeding [77]. They are insensitive for decreased natural anticoagulants antithrombin, protein C and protein S, and do not account for other prothrombotic changes such as elevation of von Willebrand factor. In fact, although PT/INR and PTT are often elevated in cirrhosis, there is no correlation with the risk of bleeding, and this might be particularly true when INR is only mildly to modestly elevated (INR between 1.5 and 2.5) [60]. Moreover, the hemostatic status cannot be satisfactorily assessed by measuring levels of individual components, because the entire system strongly depends on the balance of pro- and antifibrinolytic factors. Traditional tests measure only a fraction of whole blood’s components and only the initial 5 % thrombin burst, without analyzing other clotting aspects that determine bleeding risk, such as clot formation, firmness, and degradation.

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Bleeding time is prolonged in up to 40 % of patients with liver disease, but the clinical relevance of this prolongation is not firmly established [14], and this test is a poor predictor of the risk of bleeding in cirrhosis. A weak but significant correlation exists between platelet count and bleeding time [85], and no prospective studies have analyzed its possible ability to predict both spontaneous and procedural bleeding in cirrhosis. The thrombin generation test, in which platelet-poor or platelet-free plasma is incubated with small amounts of tissue factor as the trigger of coagulation and phospholipids are employed as substitutes for platelet surface [105], has been increasingly used to study coagulation in cirrhosis. Although this test yields more information on the entire amount of thrombin generated (endogenous thrombin potential) and its degradation, this in vitro technique, apart from being impractical and complex, has the drawback of excluding platelets, which not only serve as a scaffold for coagulation but also play an active role in the process. Point-of-care coagulation-monitoring devices assessing the viscoelastic properties of whole blood, that is, thromboelastography (TEG, Haemonetics Corporation, Braintree, MA, USA), rotation thromboelastometry (ROTEM, Pentapharm GmbH, Munich, Germany), and the Sonoclot coagulation and platelet function analyzer or Sonoclot (Sienco Inc., Arvada, CO, USA), have the advantage of being able to characterize the entire clotting process, starting with fibrin formation to clot retraction and fibrinolysis at the patient’s bedside. Furthermore, the coagulation status of patients is assessed in whole blood, allowing the plasmatic coagulation system to interact with platelets and red cells, and thereby providing useful additional information on platelet function [106]. Thus, such global tests are able to better characterize anticoagulation as well as procoagulation components of hemostasis [107] since they provide a composite analysis that reflects function of plasma, blood cells, and platelets. Whereas the Sonoclot and ROTEM measure changes in impedance to movement of a vibrating probe immersed in a blood sample, TEG utilizes an oscillating cup with a fixed probe or piston. The probe is a torsion wire in TEG technology, whereas an optical detector is used by the ROTEM, and all three instruments measure the rate of fibrin formation, clot strength, and clot lysis [108, 109]. Moreover, thromboelastography provides a more adequate characterization of hypofibrinogenemia and hyperfibrinolysis [110] than the clot lysis time and global fibrinolysis capacity [21•]. At present, ROTEM™ or TEG™ may be useful in guiding direct therapeutic interventions in the actual case of bleeding [111••]; TEG is in fact used to guide therapy during liver transplantation in many centers [112–114] and is gaining importance in the assessment of liver-disease associated hemostasis alterations [115, 116], with a possible role in predicting variceal rebleeding [32] and guiding preprocedural

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transfusions [117]. However, although most studies suggest that TEG provides a better assessment of bleeding risk than standard tests of hemostasis in patients with liver disease, it should be emphasized that no studies have directly tested this possibility. Thus, these tests are not yet standardized, validated, or used outside the research scenario, making it still premature to propose them as routine alternatives to the unquestionably inadequate traditional tests. Prospective randomized trials using global assays are needed to assess bleeding risk after invasive procedures [118], since at present, actual prediction or estimation of bleeding risk is not yet feasible. Sonoclot, useful in diagnosing systemic fibrinolysis although it may not reflect localized clot breakdown by plasmin, has shown promising results in cirrhosis, but still needs to be extensively studied [119]. A novel technique, sonorheometry, unlike existing methods, is able to assess mechanical properties of coagulation with minimal disturbance to the delicate structure of a forming thrombus, using acoustic radiation force to produce small, localized displacements within the sample [120, 121]. This whole blood assay seems to adequately reflect thrombotic tendency [120], whereas bleeding tendency, especially in cirrhosis patients, has not yet been studied.

15 Compliance with Ethics Guidelines Conflict of Interest Alberto Zanetto, Marco Senzolo, Alberto Ferrarese, Paolo Simioni, Patrizia Burra, and Kryssia I. Rodríguez-Castro declare that they have no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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Conclusions Routine laboratory tests do not reliably predict the risk of bleeding, and there is yet no optimal management strategy to foretell potential bleeding complications. Moreover, it is clear that the assessment of bleeding risk must be performed based not only on laboratory tests (which can be more or less complex and/or closer to the actual in vivo status) but also on clinical parameters, including severity of liver disease as described by the Child score, the presence of portal hypertension (especially for abdominal surgical procedures), but even more importantly, the presence of ongoing infection, endotoxemia, and uremia. The prediction of bleeding risk in the context of cirrhosis is therefore more theoretical—with the present state of knowledge; thus, preventive measures such as repletion of coagulation factors should be abandoned. Rather, the adequate approach is probably to direct hemostatic interventions to the bleeding patient, rather than to Btreating^ altered coagulation parameters [122]. In conclusion, assessing bleeding risk in patients with cirrhosis is not a straightforward matter. Many local as well as systemic factors interact dynamically, most of which are determined by the severity of the underlying liver disease, but which are also modulated by factors such as concomitant infections and intravascular pressure. The lack of a single test which can adequately characterize the actual hemostatic status, and even less so the associated bleeding risk, illustrates the complex, multifactorial, and dynamic aspects of hemostasis in cirrhosis.

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