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Management of Bleeding and Thrombosis in Critically Ill Patients with Liver Disease Lara N. Roberts, MBBS, MD (Res), FRCPath1

William Bernal, MD, FRCP, FFICM2

1 Department of Haematological Medicine, Kings College Hospital,

London, United Kingdom 2 Liver Intensive Therapy Unit, Institute of Liver Studies, Kings College Hospital, London, United Kingdom

Address for correspondence William Bernal, MD, FRCP, FFICM, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom (e-mail: [email protected]).

Abstract

Keywords

► ► ► ► ►

bleeding thrombosis liver failure procedures coagulation support

Bleeding frequently complicates end-stage chronic liver disease, and may follow procedures which are required for effective care of patients with liver failure. Thrombosis is increasingly recognized as common, important, and potentially preventable. Standard laboratory tests may not be useful in predicting bleeding or thrombotic risk or guiding therapy, and functional testing serves a more useful role. A state of rebalanced hemostasis exists in many patients, with hypocoagulability present only in a minority. Approaches to management are poorly supported by high-quality evidence; in this review, a practical pragmatic approach to care and minimization of procedure-related risk is discussed. General measures include the correction of systemic factors that may affect coagulation status, prevention and treatment of infection, and individualized coagulation support therapies for specific clinical situations and procedures.

Patients with liver disease frequently develop complications requiring critical care support, of which effective management of their coagulation status is a key element. Interventions seek to prevent or control hemorrhage, minimizing the risks of invasive procedures required for monitoring, therapy, and to advance diagnosis and avoid thrombotic complications. Despite the ubiquity of coagulation disturbance in critically ill patients with both acute liver injury and failure (ALI/F) and chronic liver disease (CLD), there is a lack of highquality evidence to guide practice. In this review, we will briefly discuss evidence informing current practice and describe our pragmatic approach to the practical management of this aspect of care of critically ill patients with liver disease.

Laboratory Assessment of Bleeding Risk Standard coagulation assays, such as prothrombin time (PT) or international normalized ratio (INR), are poorly predictive of bleeding complications in patients with liver disease.1–5 As discussed in detail in this issue of the journal, there is increasing evidence that hemostasis in both ALI/F and CLD

published online June 16, 2015

Issue Theme Hemostatic Dysfunction in Liver Diseases; Guest Editors: Ton Lisman, PhD, and Hau C. Kwaan, MD, FRCP.

is rebalanced when measured by global assays, such as thrombin generation and thromboelastometry/thromboelastography (TEM/TEG). It may well be that these dynamic functional assays may provide a better assessment of risk of complications and guide to therapy than standard laboratory assays, such as PT or INR. Laboratory studies of thrombin generation, when measured in the presence of a protein C activator (e.g., thrombomodulin), have demonstrated normo- to hypercoagulable profiles in patients with CLD and ALI/F compared with normal controls.6–11 Of note, there were a few patients with decompensated CLD who were included in these studies. Studies of TEG/TEM also suggest that a majority of patients with ALI/F have normo- or hypercoagulable profile, though up to 20% of the patients had a hypocoagulable profile, with an association between increased R-time (time to detection of first 2 mm fibrin formation) and bleeding outcomes reported.10,12 Studies of thrombin generation in platelet-rich plasma from patients with CLD suggest hypocoagulability with a platelet count < 100  109/L.13 This is supported by a study of TEG in which patients with ALI/F and platelets > 126  109/L had a

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DOI http://dx.doi.org/ 10.1055/s-0035-1550431. ISSN 0094-6176.

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Semin Thromb Hemost 2015;41:520–526.

Bleeding and Thrombosis in Critically Ill Patients with Liver Disease

Prevention of Bleeding General Measures As with all critically ill patients, altered coagulation status with enhanced bleeding risk may result from the effects of systemic homeostatic disturbance, for example, from acidosis, uremia, hypocalcemia, hypothermia, or sepsis. Addressing these systemic issues forms a key initial element of the management of active hemorrhage and prevention of procedure-related bleeding complications (►Table 1).

Subclinical Vitamin K deficiency has been reported in patients with ALI/F, and admission to critical care is a recognized risk factor for Vitamin K deficiency because of inadequate dietary intake. Therefore, all patients with liver disease admitted to critical care should receive parenteral Vitamin K.20–22 Recognition of high mortality associated with in-hospital upper gastrointestinal (UGI) bleeding, particularly in the critically ill, has focused attention on prevention of gastric/ duodenal ulceration. Primary prophylaxis with H2 antagonists and proton pump inhibitors has been demonstrated to reduce the risk of bleeding and blood transfusion requirements and should thus be considered for all patients admitted to intensive therapy units, including patients with liver disease.21,23

Fresh Frozen Plasma Fresh frozen plasma (FFP) is not recommended for empirical correction of prolongation of clotting times in liver disease.21,22 In ALI/F, the risk of spontaneous major bleeding is low7,10 and the INR represents an important prognostic marker, trends of which are obscured by plasma administration.21 Furthermore, plasma transfusion is associated with adverse effects, including volume overload, increased portal pressure, and transfusion reactions.22,24 However, American Association for the Study of Liver Diseases (AASLD) suggests considering administration of FFP and/or FVIIa before “high-risk” invasive procedures in ALI/F.21 In contrast, British Committee for Standards in Haematology (BCSH) recommends against the use of FFP before procedures in liver disease but suggests that if it is given, confirmation of correction of PT should be sought before proceeding with the planned procedure.22

Prothrombin Complex Concentrates Prothrombin complex concentrates (PCCs) may be considered an attractive alternative to FFP due to low infusion volumes. PCC contains vitamin-K dependent factors II, VII, IX, and X and proteins C and S and is recommended for reversal of anticoagulation with Vitamin K antagonists in the context of major bleeding.25 There is minimal evidence for its use in patients with liver disease.26 Of note, PCC does not contain antithrombin and its use could, therefore, induce further hypercoagulability in this patient cohort. Given the lack of association between prolongation of the PT and bleeding, the role of PCC in correction of liver disease-associated coagulopathy is likely to be limited and requires further investigation.

Platelets Fig. 1 Comparison of thromboelastographic variables and routine coagulation tests in patients with cirrhosis admitted with variceal bleeding according to whether they had early rebleeding. Note: Tests were performed on the day of rebleeding. p < 0.001 for comparison of rebleeding (n ¼ 6) with non-rebleeding (n ¼ 14) patients. Other tests are nonsignificant. Data from reference. 18 aPTT, activated partial thromboplastin time; MA, maximum amplitude; PT, prothrombin time.

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In general, empirical correction of thrombocytopenia with platelet transfusion is recommended at a threshold of < 10  109/L, or < 20  109/L in those with additional risk factors for bleeding, such as sepsis.27 There is limited evidence to define the optimal platelet count to enable procedural intervention in patients with liver disease. BCSH recommends raising the platelet count to > 50  109/L before procedures such as central line insertion, liver Seminars in Thrombosis & Hemostasis

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normal maximum amplitude (MA, a measure of clot strength) compared with significantly reduced MA in those with platelets < 83  109/L.12 In CLD, studies of TEM suggest a hypocoagulable profile with prolonged clot formation time (CFT) and reduced maximum clot firmness (MCF, equivalent to MA in TEG), with changes being more pronounced with increasing severity of liver disease.11,14 The reduction in MCF was attributed to thrombocytopenia,14 consistent with previous thrombingeneration studies. However, fibrinogen levels were near normal in this cohort and their role in this setting is not well characterized. Of note, these assays cannot measure the effect of von Willebrand factor (VWF) on platelet adhesion. VWF is increased in both ALI/F and CLD with laboratory studies demonstrating enhanced platelet adhesion in patients with liver disease.15,16 Thrombocytopenia may, therefore, not represent a bleeding risk in these patients because of concomitant high circulating levels of VWF. TEM/TEG has been demonstrated to reduce transfusion requirements when utilized in liver transplantation to evaluate bleeding and guide the use of blood products.17 Small studies in CLD suggest a potential role for TEG in evaluating rebleeding risk following variceal hemorrhage18,19 (►Fig. 1).

Roberts, Bernal

Bleeding and Thrombosis in Critically Ill Patients with Liver Disease Table 1 Basic prevention of bleeding in critically ill patients with liver disease General measures Correct hypocalcemia, acidosis Optimize renal function Avoid hypothermia Treat concomitant infection Parenteral Vitamin K on admission Prophylactic H2 antagonist/proton pump inhibitor Avoid empirical correction of coagulopathy/ thrombocytopenia Functional coagulation testing where available Procedural Use of experienced operators and ultrasound guidance Correct platelets to > 50  109/L for elective procedures Correct fibrinogen to > 1 g/dL for elective procedures

biopsy, or laparotomy. They advocate a higher threshold of > 100  109/L for procedures involving critical sites, such as the brain.27 AASLD suggests a platelet count of 50 to 70  109/L for patients with ALI/F before invasive procedures.21

Fibrinogen BCSH guidance suggests correction of acquired hypofibrinogenemia when fibrinogen is < 1 g/L but acknowledges the lack of clearly defined threshold for clinical significance.22 Options for correction include FFP, cryoprecipitate, and fibrinogen concentrate. FFP administration is associated with limitations outlined above and, in addition, contains low concentrations of fibrinogen (typically 2.5 g/L).22 Fibrinogen content of cryoprecipitate is variable by country of preparation and has limitations in common with FFP, including potential transfusion reaction and delays in availability due to the need for ABO compatibility and thawing, in addition to limited availability in Europe outside of the United Kingdom.28,29 Fibrinogen concentrates have the advantage of standardized fibrinogen content, low infusion volumes, rapid availability (following reconstitution with sterile water), and additional viral inactivation methodology.28 There are published clinical studies supporting the use of fibrinogen concentrate in acquired hypofibrinogenemia associated with trauma, surgery, and massive blood loss but limited observational reports of its specific use in liver disease.28,30–32

Management of Bleeding Risk Associated with Specific Invasive Procedures Central Venous Access Central venous catheterization is frequently required in critically ill patients with liver failure and is performed in many centers as a matter of routine. Complication rates are low even when laboratory tests suggest significant Seminars in Thrombosis & Hemostasis

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coagulation disturbance. Large series suggest minor complications in  5% of the insertions with more significant hemorrhage seen in less than 0.2% of the cases.33–35 Risk factors for procedure-related complications from different series are relatively consistent, with low operator experience, lack of use of ultrasound guidance, and failure of initial cannulation all associated with increased complication rate.33–35 Associations with laboratory measures of coagulation are less consistent, with increased rates seen only with thrombocytopenia and in some but not all studies.33,34 Our approach is to follow established general guidelines for central venous catheterization, with experienced operators and the routine use of ultrasound guidance for insertion.36 Thresholds for administration of platelets or fibrinogen are pragmatically tempered by urgency for insertion; in an elective setting, a platelet threshold of > 50 109/ L is acceptable with > 30  109/L in an emergent procedure. Few, if any, studies have evaluated the clinical relevance of fibrinogen level in this setting; our approach is to view it in the context of other coagulation disturbance but aim for a level of 1 to 1.5 g/L.

Paracentesis Paracentesis is frequently required in hospitalized patients with CLD but is generally well tolerated, with low rates of hemorrhagic complications and bleeding rates do not appear to correlate with the degree of coagulopathy. In a single series of 4,729 paracentesis procedures, the risk of bleeding was low at 0.19% with associated mortality of 0.02%. Bleeding was not predicted by abnormal coagulation parameters or thrombocytopenia and was more frequent in those with more severe liver disease and/or renal impairment.37 In another series of 608 paracenteses and thoracocenteses, bleeding complications were seen in 0.2% of the cases and were not seen in cases with a platelet count > 50  109/L or PT of up to twice normal, but were more common in patients with significant renal dysfunction. 38 Weak association between complications and a platelet count of < 50  109 /L was seen in a further study of 515 procedures.39 Our pragmatic approach is to minimize procedure-related risk in critically ill patients with liver failure by the use of realtime ultrasound guidance for catheter insertion, but without routine use of platelet transfusion or FFP, unless renal dysfunction is present or when platelet count is < 50  109/L or INR is > 2.4,40

Liver Biopsy Liver biopsy is infrequently indicated in critically ill patients with liver disease, but when required presents significant practical challenges. The primary complication of the procedure is intraperitoneal bleeding which complicates 0.16 to 0.59% of the liver biopsies for CLD with an associated mortality rate of 0 to 0.4%.3,41,42 Bleeding may be more common in the critically ill with an increased incidence seen in patients with renal failure, hepatic malignancy, or acute hepatic complications of sickle cell disease.43,44

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Intracranial Pressure Monitoring Elevated intracranial pressure (ICP) is a feared complication of cerebral edema (CE) that may develop in patients with ALF and severe encephalopathy, and was a common cause of death. Its prevalence has fallen in recent years, reflecting earlier recognition and treatment of the condition and the use of liver transplantation in those at greatest risk of its development.48 In some patients, direct monitoring of ICP through intracranial pressure transducers may be utilized to guide treatment, though its role remains controversial. Casecontrol studies suggest it to be associated with a higher level of intervention but without a survival benefit.49 Its use is associated with a risk of intracranial hemorrhage, which can occur in 5 to 7% of the patients and may be fatal.49,50 Minimizing the risk of monitor insertion-related bleeding is a major clinical concern as patients at risk of CE commonly have very significant liver dysfunction, abnormal laboratory coagulation tests, and renal failure, but again there is little evidence to guide practice. AASLD guidelines suggest “treatment of the bleeding diathesis” before insertion but practice varies; in the recent case-control study, FFP was used in 74% of the cases, 19% received platelets, and 4% received FVIIa. The utility of the latter therapy is unclear, though case series do not indicate a high risk of thrombotic complications.51 We insert monitors only when there is evidence of CE from noninvasive assessment or a high clinical suspicion,

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particularly in younger patients undergoing transplantation. We utilize epidural catheters, which may have a lower rate of bleeding complications.50 Coagulation support is individualized and, where possible, we use TEG/TEM to assess functional coagulation status and guide correction, and classifying this as a very high-risk procedure support fibrinogen to > 1.5 g/L and platelets to > 100  109/L, often with the concurrent use of FFP.

Prevention of Thrombosis Deep Vein Thrombosis/Pulmonary Embolism Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is recognized as a significant, preventable complication of hospitalization.52 Critical care admission is a known predisposing factor for VTE, with CLD also recently reported as an additional independent risk factor.53,54 The American College of Chest Physicians and the UK National Institute for Health and Clinical Excellence recommend all patients admitted to hospital are risk assessed for VTE and bleeding risk to guide appropriate thromboprophylaxis.52,55 Liver disease with prolonged PT is considered a contraindication to anticoagulant thromboprophylaxis, despite the evidence that this is a poor predictor of bleeding. However, these patients for mechanical thromboprophylaxis, such as antiembolism stockings and for postoperative patients, intermittent pneumatic compression devices should be considered.55 To our knowledge, there are no studies specifically examining the role of thromboprophylaxis in reducing the risk of VTE in patients with liver disease. There is a single small study investigating the role of prophylactic enoxaparin in preventing portal vein thrombosis (PVT) in outpatients with cirrhosis demonstrating a significant reduction in PVT, decompensation, and improved survival, with no difference in bleeding events.56 This and separate metaanalysis suggest prophylactic anticoagulation to be safe, even in those with relatively advanced CLD.57 Further investigation of efficacy and safety in in-patient and critical care settings is still required. In our practice, early pharmacological prophylaxis is not initiated for most critically ill patients with liver disease, who frequently have coexistent additional bleeding risk factors early in the illness course. Later in in-hospital stay, with resolution or stabilization of these factors, we use prophylaxis with unfractionated or low-molecular-weight heparins. Considerations change when managing patients with an established prothrombotic state or after acute thrombotic events, where clinical judgment is key.

Extracorporeal Circuits Continuous venovenous hemofiltration, extracorporeal liver assist devices, and plasma exchange separators require diversion of blood through an external artificial circuit to perform their functions. Blood exposure to the artificial circuit results in clotting activation and can result in thrombosis, and even in advanced liver disease preventative treatment is required.58,59 Options to minimize circuit thrombosis include Seminars in Thrombosis & Hemostasis

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The optimal management of preprocedure coagulation abnormalities remains controversial and there is no randomized controlled trial (RCT) data for guidance. A review of nine studies of liver biopsy (including percutaneous, transjugular, and laparoscopic routes) in patients with CLD confirmed a lack of association between abnormal laboratory coagulation parameters and risk of bleeding.5 A study of 1,500 patients in the United Kingdom found bleeding after percutaneous biopsy to be more common in those with an INR > 1.7; however, 90% of the bleeds occurred in patients with INR < 1.3.45 There is also some evidence to suggest an increased rate of bleeding complications after liver biopsy in association with platelet count < 60  109/L.42,46 Given the lack of high-level evidence, there are diverging views on correction of coagulopathy for percutaneous biopsy. The British Society of Gastroenterology recommends FFP administration to all patients with PT prolonged > 6 seconds and a platelet count threshold to trigger support of > 60  109/L, while AASLD does not specify a threshold for either accepting “there is no specific PT-INR and or platelet count at or above which potentially adverse bleeding can be predicted.”44,47 Both authorities recognize the importance of renal dysfunction as a risk factor for bleeding complications and that of platelet functional status and the need for discontinuation of medication affecting platelet function. In the critically ill, the cumulative bleeding risk resulting from liver failure and coagulation disorder, renal dysfunction, and sepsis may preclude use of the percutaneous route for liver biopsy. When biopsy is indicated, we most commonly adopt the transjugular route with support of platelets to > 50  109/L and fibrinogen to > 1.5 g/L.

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Bleeding and Thrombosis in Critically Ill Patients with Liver Disease systemic anticoagulation (heparin or prostacyclin) and regional anticoagulation with heparin or citrate. Our preferred method is prostacyclin or regional heparin depending on bleeding risk, utilizing prostacyclin in all patients with active or recent hemorrhage or in whom platelet counts are < 50  109/L. The use of circuits without anticoagulation of any kind is uncommon.

Management of Hemorrhage Variceal Bleeding Variceal bleeding is a frequent indication for critical care support in patients with CLD. Current overall mortality rates for variceal bleeding are now less than 20%, having decreased markedly over the past two decades, reflecting the development of a strong evidence base for therapy.60,61 Acute decompensation of liver function following variceal bleeding now usually only develops in patients with advanced stages of cirrhosis (CPC grade C) and mortality in earlier stage disease (CPC grade A) is less than 5%.60,62 In part, these improvements result from improved initial care and early endoscopy and management of basic principles of airway, breathing, and circulation to prevent procedure-related aspiration and pneumonia.62 Blood volume restoration is conservative, aiming for a hemoglobin of  8 g/dL.63 Infection is closely associated with bleeding due to portal hypertension, with potential mechanisms including increases in portal pressure, impairment of liver function, and hemostatic derangement.64,65 Antibiotic prophylaxis reduces the likelihood of early rebleeding, improves survival, and is given routinely to patients presenting with acute variceal hemorrhage.66,67 However, best practice for the management of coagulopathy in patients with variceal bleeding is unclear. It is likely that the development and later rupture of varices is primarily a consequence of portal hypertension and local vascular abnormalities, with poor correlation between bleeding and standard laboratory markers of coagulation.68–70 There is little data on functional coagulation status in acute variceal bleeding: endogenous heparinoids and fibrinolysis are increased, but whether this influences bleeding is not known.65 Visco-elastic tests of coagulation need to be evaluated in this setting as they may provide a basis to plan therapeutic trials of coagulation factors, platelet transfusions, and/or anti-fibrinolytics.66 To date, RCTs of rFVIIa in patients with variceal bleeding have failed to show significant benefit in respect to mortality or rebleeding rates; functional testing might enable the targeting of this and other specific agents to those most likely to benefit from their use.71,72 Where possible, we perform TEM in all patients with variceal bleeding to guide coagulation support. Pragmatically, we do not routinely administer FFP but we do administer platelets to maintain a count of > 50  109/L and cryoprecipitate for fibrinogen > 1.0 g/L. Meta-analysis of the use of tranexamic acid in UGI bleeding suggests a beneficial effect upon mortality, though only small numbers of patients with variceal bleeding were studied.73 We restrict its use to where there is TEM evidence of fibrinolysis or bleeding from endoscopic band-induced ulceration rather than variceal rupture. Seminars in Thrombosis & Hemostasis

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Management of Thrombosis Hepatic vein thrombosis (Budd Chiari syndrome [BCS]) and portosplenomesenteric vein thrombosis (PSMVT) are discussed in detail elsewhere in this issue of the journal. As BCS can manifest acutely with ALI/F, and PSVMT can lead to intestinal ischemia and infarction with risk of perforation, peritonitis, and multiorgan failure necessitating critical care, we briefly discuss relevant management issues here. Those presenting with BCS or PSVMT in the absence of a local predisposing factor (cirrhosis, intra-abdominal infection, or malignancy) should be further investigated for an underlying prothrombotic state.74,75 Anticoagulation is the mainstay of therapy to prevent thrombus extension and facilitate recanalization in both BCS and acute PSVMT.74,75 There is a lack of high-quality evidence to support this strategy, which is based on the established efficacy of anticoagulation in DVT/PE. Anticoagulation of acute PSVMT in the presence of underlying CLD is tempered by the risk of variceal bleeding. In this scenario, an individualized approach is taken, with anticoagulation frequently avoided or deferred until after variceal banding. Our preferred agent for anticoagulation in the critical care setting is infusional unfractionated heparin because of its short halflife, reversibility, nonrenal/hepatic clearance, and ease of monitoring with activated partial thromboplastin time. Once the patient’s condition has stabilized (and particularly before ward transfer), we switch to therapeutic low-molecular-weight heparin while oral anticoagulation with Vitamin K antagonists is initiated. Anecdotally, heparin-induced thrombocytopenia appears to be disproportionally common in patients with BCS and its detection mandates the use of other anticoagulant agents.

Conclusion Bleeding is a frequent complication of end-stage CLD, and may complicate procedures required for effective care of patients with liver failure. Thrombosis is increasingly recognized as an important and preventable clinical issue. Laboratory and clinical evidence suggests that a state of rebalanced hemostasis exists in many of these patients, with hypocoagulability present only in a minority. This balance is fragile and may be disturbed by superimposed insults, including sepsis and renal failure. Standard laboratory tests may not be useful in predicting bleeding or thrombotic risk, or in guiding the timing and nature of coagulation therapies where functional testing, including TEG/TEM, may serve a useful role. Approaches to management are poorly supported by high-quality evidence and there is a pressing need for trial data to guide treatment.

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Management of Bleeding and Thrombosis in Critically Ill Patients with Liver Disease.

Bleeding frequently complicates end-stage chronic liver disease, and may follow procedures which are required for effective care of patients with live...
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