Chapter 128: Hemostatic Alterations in Liver Disease and Liver Transplantation

Frank W.G. Leebeek; Ton Lisman

INTRODUCTION

SUMMARY

In patients with acute liver failure or chronic liver disease, many changes in the hemostatic system occur. The liver is the site of synthesis of nearly all coagulation factors, both pro- and anticoagulant proteins. A reduced synthesis function of the liver will lead to reduced levels of these factors in circulation. In addition, the liver is involved in the clearance of many activated coagulation factors and protein-inhibitor complexes from the circulation, which, in turn, can lead to activation of the coagulation system if liver function is impaired. Furthermore, the liver is involved in the synthesis and clearance of pro- and antifibrinolytic proteins, which may lead to a shift in the balance of the fibrinolytic system. Also primary hemostasis might be affected in liver disease because of thrombocytopenia and impaired platelet function, which is frequently encountered in these patients. It is evident that patients with liver disease have frequent bleeding episodes, mainly in the gastrointestinal tract, such as variceal bleeding. It has been a longstanding dogma that patients with liver disease are at a high risk of bleeding caused by the above mentioned hemostatic changes. However, in recent years this cause of the bleeding tendency has been questioned because of the concomitant reductions of pro- and anticoagulant factors and pro- and antifibrinolytic factors. More recent studies using more sophisticated coagulation tests showed that thrombin generation is normal in patients with chronic liver failure and that some may even have a prothrombotic phenotype. This led to the development of a model of a rebalanced hemostatic system in these patients, which may have immediate implications for treatment. Hematologists and other clinicians taking care of patients with acute liver failure of chronic liver disease, such as cirrhosis, are still faced with the questions whether these patients need correction of the changes in hemostasis before interventions such as paracentesis, biopsies, dental care, and surgery. It was generally believed that replacement therapy with frozen plasma or prothrombin complex concentrate was indicated. However, based on these new findings, physicians should now be more restrictive in the use of hemostatic agents and blood products in these patients both in liver disease and during liver transplantation.

Acronyms and Abbreviations

ADAMTS13, a disintegrin-like and metalloprotease with thrombospondin domain 13; aPTT, activated partial thromboplastin time; DDAVP, 1-deamino-8-d-arginine vasopressin; DIC, disseminated intravascular coagulation; FFP, fresh-frozen plasma; HAT, hepatic artery thrombosis; INR, international normalized ratio; ISI, international sensitivity index; MELD, model of end-stage liver disease; PAI-1, plasminogen activator inhibitor 1; PFA, platelet function analyzer; PT, prothrombin time; PVT, portal vein thrombosis; TAFI, thrombin-activatable fibrinolysis inhibitor; t-PA, tissue-type plasminogen activator; VWF, von Willebrand factor.

The liver plays a central role in the hemostatic system. Liver parenchymal cells are the site of synthesis of most coagulation factors (except factor VIII), the natural inhibitors of coagulation, including protein C, protein S, and antithrombin, and essential components of the fibrinolytic system, such as plasminogen, α₂-antiplasmin, and thrombin activatable fibrinolysis inhibitor (TAFI). The liver also regulates hemostasis and fibrinolysis by clearing activated coagulation factors and coagulation factor-inhibitor complexes from the circulation. In addition, changes in primary hemostasis mediated by platelets, von Willebrand factor (VWF) and ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats) may occur. Therefore, when acute or chronic liver dysfunction is present in patients with liver disease, complicated hemostatic derangement may occur, which can lead to bleeding, thrombosis, or neither bleeding nor thrombosis.

HEMOSTATIC ALTERATIONS IN CHRONIC LIVER DISEASE

Listen

PRIMARY HEMOSTASIS

More than 75 percent of patients with chronic liver disease, especially in moderate to severe cirrhosis (Child B and C) have reduced levels of platelets (<150,000/μL) and 13 percent have platelet counts between 50,000 and 75,000/μL.¹ This may be caused by splenomegaly resulting in sequestration of platelets in the spleen, reduced synthesis of thrombopoietin by the diseased liver, or consumption coagulopathy.^2,3,4,5 In addition, it has been suggested that autoantibodies against platelets may reduce the half-life of platelets in cirrhosis.⁶ Primary hemostasis may also be defective by a reduced platelet function. In vitro platelet aggregation studies in response to various agonists is frequently diminished in patients with liver disease. Defective platelet function may result from impaired signal transduction, acquired storage pool deficiency, proteolysis of platelet membrane proteins, and increased production of the endothelial-derived platelet inhibitors, nitric oxide and prostacyclin. (reviewed in Ref. 7). A reduced hematocrit may contribute to defective platelet–vessel wall interaction. Platelet adhesion defects were also found under conditions of flow, but were in some studies attributed to thrombocytopenia and a low hematocrit.^8,9,10 Platelet procoagulant activity measured by a thrombin generation assay using platelet-rich plasma was similar in patients and healthy controls, which casts additional doubt on the extent of the functional defects of platelets in patients with liver disease.¹¹

VWF antigen levels are strongly elevated in patients with liver disease. It has been suggested that this is the result from endothelial damage possibly mediated by endotoxemia (bacterial infection).^12,13 VWF mRNA and protein expression in the liver itself are substantially increased in cirrhosis, but VWF ristocetin cofactor activity is variable.^10,14,15,16 The high levels of VWF may ameliorate the hemostatic defect caused by thrombocytopenia and platelet function defects.¹³ In a flow-based model, platelet adhesion to collagen was normalized in thrombocytopenia because of the high levels of VWF in cirrhotic plasma. In patients with liver disease the regulation of VWF multimer size and activity can be impaired because of reduced synthesis of the VWF-cleaving protease ADAMTS13 by stellate cells in the liver.¹⁷ Several studies showed, however, that the most active high-molecular-weight multimers of VWF are diminished in plasma of patients with cirrhosis, which may be mediated by plasmin or other proteases.^18,19 Classical tests of primary hemostasis, such as bleeding time, which is becoming obsolete as a result of its assay-variability and inability to predict bleeding, may still be abnormal in patients with liver disease. Also newer global tests of primary hemostasis, such as platelet function analyzer (PFA), show prolonged closure times with various agonists, but its value in prediction of bleeding in liver disease is unknown.²⁰

SECONDARY HEMOSTASIS: COAGULATION AND ANTICOAGULATION

The liver is the site of synthesis of most procoagulant proteins. As a result, decreased levels of coagulation factors II, V, VII, IX, X, and XI are commonly observed in patients with liver failure.²¹ In contrast, factor VIII levels are increased, which may be related to the elevated level of its carrier protein VWF and to decreased clearance of factor VIII from the circulation by the liver low-density lipoprotein-related receptor.¹⁴ Factor VIII is synthesized primarily in hepatic sinusoidal endothelial cells, whose function is preserved in liver disease.^14,22 Acquired vitamin K–dependent carboxylation deficiency may lead qualitative defects in coagulation factors. Because of vitamin K deficiency or decreased production of gamma-glutamyl carboxylase, circulating vitamin K–dependent coagulation factors II, VII, IX, and X may be deficient in γ-carboxylated glutamic acid residues in their GLA domains, giving rise to impaired function of these factors.²³ On the other hand, levels of anticoagulant protein C, protein S, antithrombin, heparin cofactor II, and α₂-macroglobulin are also decreased in patients with liver disease.²⁴ Fibrinogen levels are frequently in the normal range in patients with chronic liver disease, but may be decreased in patients with decompensated cirrhosis or acute liver failure.²⁵ A qualitative defect in fibrinogen may be found in patients with liver disease.²⁶ Screening tests of coagulation, such as the prothrombin time (PT) or activated partial thromboplastin time (aPTT), are frequently prolonged in patients with chronic liver disease. These results have been traditionally interpreted to reflect a hypocoagulable state. The PT and aPTT are sensitive to levels of procoagulant proteins in plasma, but not to the natural anticoagulants, proteins C, protein S, and antithrombin. The use of a more sophisticated test of coagulation, such as total thrombin generation test, illustrates the limitation of the PT and aPTT. In a thrombin-generation test measuring the total amount of thrombin generated during coagulation, decreased total thrombin generation is measured in patients with cirrhosis compared to controls.^11,27,28 Yet, when measured in the presence of thrombomodulin to enable protein C activation and thereby also taking into account the contribution of the main inhibitor of coagulation protein C, thrombin generation was indistinguishable from controls, despite abnormal conventional coagulation tests. Others found normal thrombin generation without addition of thrombomodulin and even increased thrombin generation with addition of thrombomodulin.^29,30 These results suggest that thrombin generation in vivo can be normal in patients with liver failure, and that a prolonged PT does not per se indicate a bleeding risk. These findings indicate that a concomitant decrease of pro-and anticoagulant factors result in a rebalanced hemostatic system.³¹

Despite the limitations of the use of the PT in patients with liver disease the international normalized ratio (INR), which is a derivative of the PT, is still used in prognostic scores for patients with acute or chronic liver disease. The model of end-stage liver disease (MELD) score is used to prioritize patients for liver transplantation. The INR was originally developed and validated only to monitor anticoagulant therapy with vitamin K antagonists. The interlaboratory variation of the INR in patients with liver disease is substantial, and its use results in significant differences in MELD scores when a single patient sample is tested in different laboratories using various PT reagents.^32,33 The use of alternative international sensitivity index (ISI) values obtained by calibration against plasma samples from patients with liver disease was shown to decrease this variability.^34,35

FIBRINOLYSIS

Except for tissue-type plasminogen activator (t-PA) and plasminogen-activator inhibitor (PAI)-1, all proteins involved in fibrinolysis, both pro- and antifibrinolytic, are synthesized by the liver.³⁶ Therefore, chronic liver disease leads to decreased plasma levels of plasminogen, α₂-antiplasmin, TAFI, and factor XIII. Plasma levels of t-PA are elevated as a result of increased secretion from endothelial cells and/or reduced clearance by the diseased liver. Plasma levels of PAI-1 also are increased but not to the same extent as t-PA, which may lead to a shift in balance in the fibrinolytic system.³⁷ It has long been assumed that most patients with chronic liver disease had accelerated fibrinolysis. This was based on in vitro assays, including various clot lysis assays and on measurements of increased fibrin(ogen) degradation products, D-dimer and plasmin–antiplasmin complexes (reviewed in Ref. 36). However, more recent studies found no evidence of hyperfibrinolysis in the majority of patients with cirrhosis despite decreased levels of TAFI and elevated D-dimer levels.^38,39 This conclusion was recently challenged by a study that used two assays to detect fibrinolysis in patients with various degrees of severity of cirrhosis. In both tests approximately 40 percent of patients had evidence of hyperfibrinolysis, and in 60 percent of the patients, one of the tests revealed an increased fibrinolytic capacity, especially in those with severe liver dysfunction.⁴⁰ Hyperfibrinolysis in patients with cirrhosis may also occur secondary to low-grade disseminated intravascular coagulation (DIC) induced by endotoxemia and is manifested by concomitant increased levels of prothrombin fragment 1+2, fibrinopeptide A, D-dimer, thrombin–antithrombin complex, and plasmin–antiplasmin complex.⁴¹ However, it has been argued that the increased levels of these markers may result from their decreased clearance by the liver rather than from DIC. In patients with liver disease who presented with gastrointestinal bleeding or soft-tissue bleeding after trauma, in vitro signs of increased fibrinolysis have been reported.^42,43

A REBALANCED HEMOSTATIC SYSTEM IN CHRONIC LIVER DISEASE

Listen

It has been a longstanding dogma that patients with liver disease are at a high risk of bleeding due to reduction of synthesis of coagulation factors and other changes in hemostasis. More recent studies using more sophisticated coagulation tests have shown that thrombin generation is normal in patients with chronic liver failure and that some may even have a prothrombotic phenotype.^24,27,44 Because both procoagulant and anticoagulant proteins decline in patients with chronic liver diseases, it has been postulated that the hemostatic system is rebalanced (Table 128–1).^24,31,45 In addition reductions of platelet number and impairment of platelet function is counteracted by high levels of VWF and in many patients the decline in profibrinolytic factors is balanced by the reduction of inhibitors of fibrinolysis.^13,38 This led to the model of a rebalanced hemostatic system in these patients, which has important implications for treatment.^24,31 This model also explains why most patients with liver disease usually do not exhibit severe bleeding manifestations—neither during minor invasive procedures, such as biopsies and paracentesis, nor during major surgeries, including liver transplantation.^46,47 Furthermore, patients with liver disease may even have increased risk of venous thromboembolism, not only liver-specific thrombosis, but also deep vein thrombosis.^48,49,50 The hemostatic balance in patients with liver disease is, however, quite delicate and vulnerable to be tipped toward bleeding or thrombosis. So far it is impossible to identify which patients are more prone to bleeding or to thrombosis based on current laboratory assays. The complex changes in hemostasis encountered in patients with liver disease are depicted in Table 128-1. The delicate hemostatic balance in patients with liver disease may be changed by comorbidities, such as bacterial infections and renal failure frequently observed in these patients. It is of major importance to treat these comorbidities so as to reduce the risk of bleeding and thrombosis.⁵¹

Table 128–1.Changes in the Hemostatic System in Patients with Liver Disease That Contribute to Bleeding (Left) or Contribute to Thrombosis (Right)

View Table||Download (.pdf)

Table 128–1. Changes in the Hemostatic System in Patients with Liver Disease That Contribute to Bleeding (Left) or Contribute to Thrombosis (Right)

Changes That Impair Hemostasis

Changes That Promote Hemostasis

PRIMARY HEMOSTASIS

Thrombocytopenia

Elevated levels of VWF

Platelet function defects

Decreased levels of ADAMTS13

Enhanced production of nitric oxide and prostacyclin

SECONDARY HEMOSTASIS

Low levels of factors II, V, VII, IX, X, and XI

Elevated levels of factor VIII

Vitamin K Deficiency

Decreased levels of protein C, protein S, antithrombin, α₂-macroglobulin, and heparin cofactor II

Dysfibrinogenemia

FIBRINOLYSIS

Low levels of α₂-antiplasmin, factor XIII, and TAFI

Low levels of plasminogen

Increase in PAI-1 levels

Elevated t-PA levels

ADAMTS13, a disintegrin-like and metalloprotease with thrombospondin domain 13; PAI-I, plasminogen activator inhibitor 1; TAFI, thrombin-activatable fibrinolysis inhibitor; t-PA, tissue-type plasminogen activator; VWF, von Willebrand factor.

HEMOSTATIC ALTERATIONS IN ACUTE LIVER FAILURE

Listen

Patients presenting with acute liver failure, for instance in acetaminophen intoxication, have profound changes in the hemostatic system. A severe decrease of coagulation factors is observed, with strongly increased INR.⁵² However, an intact thrombin generation has been observed in acute liver failure patients and hardly any changes were observed using thromboelastography.^53,54 In contrast to chronic liver disease, patients with acute liver failure frequently have normal platelet counts. Highly elevated levels of VWF are observed and strongly decreased levels of ADAMTS13. This imbalance may lead to a prothrombotic state.⁵⁵ In patients with acute liver failure, there is an increased level of PAI-1, and reduced levels of plasminogen which is consistent with a hypofibrinolytic state.^53,56 A strong increase of procoagulant microparticles has been observed in acute liver failure.⁵⁷ Spontaneous bleeding is not frequently encountered in patients with acute liver failure.⁵⁸

HEMOSTATIC ALTERATIONS DURING LIVER TRANSPLANTATION

Listen

Liver transplantation performed in patients in acute or chronic liver failure has always been complicated by significant and sometimes life-threatening bleeding problems requiring massive use of coagulation factors and erythrocyte transfusion.⁵⁹ Therefore blood products were also transfused before and during transplantation to correct the hemostatic dysfunction. Improved surgical techniques and anesthesiologic care have led to a remarkable reduction of blood loss during liver transplantation. Currently, no blood transfusion is given in up to 50 to 80 percent of patients undergoing a liver transplantation, depending on the center.^60,61 This improvement is also because of a better understanding of the coagulation profile during the various stages of the surgical intervention. During the first stage of liver transplantation, the removal of the diseased liver, no significant worsening of the preoperative hemostatic status occurs.⁶² After removal of the diseased liver, the so-called anhepatic stage, significant hemostatic changes occur. Because activated coagulation factors are not cleared from the circulation, DIC can develop, with consumption of platelets and coagulation factors and secondary hyperfibrinolysis. Moreover, hyperfibrinolysis may also occur as a result of defective clearance of t-PA.⁶³ The most severe hemostatic changes during liver transplantation occur immediately after reperfusion of the donor liver. Platelets are trapped in the graft, giving rise to an aggravation of thrombocytopenia and causing damage to the graft by induction of endothelial cell apoptosis.⁶⁴ Release of tissue factor and t-PA from the reperfused graft causes DIC with primary or secondary fibrinolysis.⁶³ Moreover, the graft also releases heparin-like substances that can inhibit coagulation.⁶⁵ In addition, other factors such as hypothermia, metabolic acidosis, and hemodilution adversely affect hemostasis during this phase.

During transplantation, the balance between VWF and ADAMTS13 changes because levels of VWF remain high, the functional properties of VWF improve, and the levels of ADAMTS13 decline, which may partially compensate for the hemostatic dysfunction.⁶⁶ The platelet count and hemostatic proteins are at their nadir after reperfusion and rise gradually during the early postoperative period. However, the levels of procoagulant factors rise more rapidly than the levels of anticoagulant factors, which results in a temporary hypercoagulable state.⁶⁷ A transiently increased level of PAI-1 immediately after surgery can result in a hypofibrinolytic state that may aggravate the hypercoagulable status.

CLINICAL PROBLEMS ENCOUNTERED IN PATIENTS WITH LIVER DISEASE

Listen

BLEEDING IN PATIENTS WITH LIVER DISEASE

Although sophisticated hemostatic tests have now shown that disorders of primary hemostasis, a hypocoagulable status, and hyperfibrinolysis are generally not encountered or are only seen in a minority of patients with chronic liver disease, bleeding still may occur in these patients.²⁴ This is because individual patients still may have a compromised hemostatic function or because patients bleed for nonhemostatic reasons.⁶⁸ The most severe bleeding manifestation in patients with liver disease is bleeding from ruptured esophageal varices. This results from local vascular abnormalities and portal hypertension and not from deranged hemostasis. Occasionally, impaired hemostasis does cause easy bruising, purpura, epistaxis, gingival bleeding, menorrhagia and gastrointestinal bleeding. Also in acute liver failure bleeding has frequently been reported in the past, but more recent studies clearly indicate that spontaneous bleeding occurs rarely.⁵⁸

HEMOSTATIC MANAGEMENT OF PATIENTS WITH LIVER DISEASE

Hemostatic Management of Bleeding Episodes

Variceal bleeding in patients with liver disease should be immediately managed by local interventions, such as endoscopy and rubber band ligation or even shunt (transjugulair intrahepatic portosystemic shunt [TIPS]) placement.⁶⁹ Fluid resuscitation should be given in case of hypotension and restricted blood transfusion in case of severe drop of hemoglobin level.⁷⁰ Because there is no evidence that changes in hemostasis are associated with the risk of variceal bleeding, treatment with coagulation factor concentrates is not indicated. Infusion of plasma may even lead to more bleeding as a result of an increase of portal pressure.^71,72 Upper gastrointestinal bleeding from peptic ulcer disease also occurs frequently in patients with liver disease. Infusion of recombinant factor VIIa did not result in reduction of blood loss or mortality in randomized clinical studies in patients with upper gastrointestinal bleeding and is not indicated.⁷² Recently the use of hemostatic powder was used in patients who did not respond to other measures and was successfully used in some cases, but its value should be tested in larger randomized studies before it will be registered and can be recommended in this setting.^73,74 The most important intervention is to prevent variceal bleeding by prophylactic measures, such as rubber band ligation.

Minor bleeding, including bruising, purpura and gingival bleeding occur more frequently in patients with liver disease, but do not always need treatment, or can be managed by local measures. Mucocutaneous bleeding, such as epistaxis, can be treated with fibrinolysis inhibitors, for instance tranexamic acid, and menorrhagia by oral contraceptives. In case of bleeding in patients with severe thrombocytopenia (<50,000/μL) platelet transfusion should be given, as would also be indicated in patients without underlying liver disease.

Hemostatic Management Before Interventions and Surgical Procedures

Traditional guidelines have advised not to perform invasive procedures in patients with liver disease when routine hemostatic tests are abnormal unless they are corrected by blood products or pharmacologic prohemostatic agents. The rationale for such a prophylactic approach has been questioned for several reasons. First and most important because abnormal coagulation tests in patients with liver disease are not necessarily associated with a bleeding risk.²⁴ As mentioned before, these results have been traditionally interpreted to reflect a hypocoagulable state, but appeared to have no impact on the bleeding risk after invasive procedures.^75,76,77 For instance, in a large prospective study there was no evidence that prolongation of the INR was associated with bleeding after large-volume paracentesis in patients with liver disease and ascites.⁷⁵ Furthermore normalization of traditional coagulation tests is rarely achieved by infusion of plasma products and the efficacy of prophylactic treatment has not been proven.^78,79 In addition, transfusion of blood products carry a substantial risk of allergic reactions, volume overload and potential transmission of pathogens.⁸⁰ Consequently, the current guideline of the American Association for the Study of Liver Diseases (AASLD) do not recommend the routine use of fresh-frozen plasma (FFP) transfusion for prophylactic correction of an abnormal PT before interventions, such as liver biopsy,⁸¹ whereas other guidelines advise the use of FFP with low grade of evidence.⁸² Vitamin K is generally recommended in patients with liver disease and prolonged INR, however its clinical benefit has been questioned.⁸³

Thrombocytopenia in patients with cirrhosis is often mild and does not cause spontaneous bleeding or bleeding following minimally invasive procedures. There is little evidence that tests showing platelet dysfunction, including prolonged bleeding time or closure time measured with the PFA-100 predict bleeding in patients with cirrhosis. Nevertheless, an early study showed that a prolonged bleeding time was associated with a fivefold increase in the risk of bleeding after liver biopsy.⁸⁴ Although shortening of the bleeding time was achieved by administration of 1-deamino-8-d-arginine vasopressin (DDAVP) in patients with liver disease,⁸⁵ no effect of DDAVP was observed in patients with bleeding from esophageal varices or on the blood loss in patients undergoing hepatectomy⁸⁶ or liver transplantation.⁸⁷ Although this has not been addressed in many studies yet, it has been shown that bleeding complications during interventional procedures are associated with a low preprocedural platelet count.^88,89 If platelet counts are below 50 × 10⁹/L, platelet transfusion is recommended before any intervention, as in other patients without underlying liver disease.⁹⁰ In case of neurosurgical interventions platelets should be transfused up to a level of 100 × 10⁹/L.⁹¹ A novel strategy to improve primary hemostasis in patients with hepatitis C is the administration of a thrombopoietin analogue (Eltrombopag). In the ELEVATE study, a short course of Eltrombopag was used to elevate the platelet count prior to invasive procedures. Use of Eltrombopag was associated with a higher rate of thrombosis, but no difference in bleeding was observed in this study, which may be related to the highly elevated VWF levels in patients with liver disease.^92,93 Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease before surgical interventions.

In individuals with generalized mucosal bleeding symptoms, which may be indicative of disorders of primary hemostasis or hyperfibrinolysis, treatment with fibrinolysis inhibitors such as tranexamic acid after the procedure should be considered.^68,89 Tranexamic acid is also advised in case of dental extractions because of the high fibrinolytic activity in the oral mucosa.

The use of fibrin sealant has been studied to reduce blood loss in patient undergoing liver surgery. Although these products reduce the time to hemostasis when applied on the transected liver surface, no improvement in postoperative complications was observed. Therefore its value in these settings has not yet been established.⁹⁴

Hemostatic Management During Liver Transplantation

For many years excessive blood loss during liver transplantation has been recognized as an important cause of morbidity and mortality; consequently, transfusion of a combination of blood products has been advocated for correction of the hemostatic derangements.⁵⁹ Experiments in experimental animal models have shown that the quality of the graft determines the extent of hemostatic changes following reperfusion.^59a Indeed, blood loss following graft reperfusion is substantially increased in recipients of “extended criteria” donor livers (i.e., grafts with poorer quality because of, e.g., elevated donor age or prolonged cold ischemia times).^59b

Because prophylactic transfusion of blood products may be associated with serious side effects, many centers have discontinued to attempt to improve hemostatic functions by administration of blood products prior to liver transplantation.⁶⁰ Liver transplantation procedures can now be performed without a requirement for transfusion of blood products in a substantial proportion of patients. One study reported that 79 percent of patients could be transplanted without the use of any blood product, provided the patient’s central venous pressure was controlled through restriction of volume replacement, and by using intraoperative phlebotomy during the transplantation.⁶¹ Increased experience and improvements in surgical technique, anesthesiologic care, and better graft preservation methods have contributed to a steady decrease in blood transfusion requirements. When uncontrolled bleeding does occur, packed red cells, platelets, FFP, or fibrinogen concentrate can be transfused guided by laboratory values or thromboelastography.⁹⁵ Hyperfibrinolysis is thought to contribute significantly to impaired hemostasis during the anhepatic and reperfusion phases.⁶³ Use of synthetic antifibrinolytic agents, such as tranexamic acid (a lysine analogue) and aprotinin (a serine protease inhibitor) have reduced red cell and plasma transfusion.^96,97 Aprotinin was taken off the market in 2008 because of severe adverse events and mortality in patients undergoing cardiac surgery.⁹⁸

THROMBOSIS IN PATIENTS WITH LIVER DISEASE

Deep Vein Thrombosis and Pulmonary Embolism

The reappraisal of changes in the hemostatic system in patients with liver disease has indicated that the coagulopathy of liver disease may not only reflect a reduced bleeding risk, but may even lead to a prothrombotic state.⁹⁹ Studies indicate that deep vein thrombosis and pulmonary embolism can occur in patients with cirrhosis.^48,100 A large nationwide population-based case-control study in Denmark indicated that patients with liver disease have a substantially increased risk for venous thromboembolism compared to controls with an odds ratio of 1.7 for patients with cirrhosis, and an odds ratio of 1.9 for patients with other liver diseases.⁴⁸ Between 0.5 and 1.8 percent of all hospitalized patients with cirrhosis developed venous thrombosis. Therefore liver disease should not be considered a contraindication for thromboprophylaxis with low-molecular-weight heparin (LMWH). Thromboprophylaxis is warranted in patients that are immobilized or undergo surgery and in hospitalized patients with active cancer. Treatment of venous thromboembolism in patients with liver disease is difficult, because of a higher risk of bleeding associated with anticoagulant treatment than in healthy individuals, although recent data suggest that therapeutic dose LMWH is safe.^{101,102,103,104} This, again, indicates that the balanced hemostatic system in patients with cirrhosis involves a narrow safety margin. Furthermore, the choice of anticoagulant may be difficult. LMWH or unfractionated heparin may be difficult to monitor as a result of low levels of antithrombin. Anti–factor Xa measurement seems to be unreliable in patients with liver disease because of analytical problems.^102,105 Also monitoring of treatment with vitamin K antagonists is difficult and may not be reliable based on the preexistent prolongation of the PT as a result of the underlying disease.⁴⁴ Considering the lack of studies, it is advised however to maintain the INR between 2.0 and 3.0.²⁴

Portal Vein Thrombosis

Patients with advanced liver disease may develop thrombosis in the portal and mesenteric veins. These complications are not only related to decreased levels of the natural inhibitors of coagulation, antithrombin, protein C, and protein S, but occur also more often in individuals carrying common inherited thrombophilia’s such as factor V Leiden mutation and prothrombin G20210A variant.^106,107 A decreased blood flow in the splanchnic venous circulation because of portal hypertension has also been indicated as a risk factor for portal vein thrombosis (PVT). The prevalence of PVT in patients with cirrhosis increases with the progression of the disease, being less than 1 percent in patients with compensated cirrhosis, and 8 to 25 percent in liver transplantation candidates.^44,108 Prophylactic treatment of patients with cirrhosis with low-dose of LMWH reduced the risk of PVT and even increased survival.¹⁰¹ The optimal treatment of PVT in cirrhosis patients remains to be established. Although randomized trials are still lacking, treatment with anticoagulants, such as LMWH of vitamin K antagonists may prevent progression of thrombosis and may achieve recanalization in patients with PVT with or without cirrhosis.^109,110 However not all patients with cirrhosis and PVT will benefit and an individualized approach seems warranted.¹¹¹ Recently the new direct oral anticoagulants have been approved for use in patients with venous thrombosis. Their use is not yet recommended in patients with liver disease, but recently some case reports have been published in patients with splanchnic vein thrombosis.¹¹²

Thrombosis Following Liver Transplantation

Following liver transplantation, both immediate and delayed thrombotic complications frequently occur.¹¹³ Hepatic artery thrombosis (HAT) occurs in 1.6 to 8.9 percent of patients and may lead to graft failure, requiring retransplantation.^114,115 Thrombosis of the portal vein or inferior caval vein are much less common.¹¹⁶ Although HAT has been considered a surgical complication, recent evidence suggests that excessive coagulation activation or inherited thrombophilia also may contribute to HAT.¹¹⁷ Postoperative use of anticoagulants has been limited in liver transplant recipients as a result of the perceived bleeding risk. However, thrombotic complications do occur, and liver-related thrombosis in particular, such as HAT and PVT, are of concern as they often lead to graft loss. A single, uncontrolled retrospective study showed aspirin to substantially reduce the risk of posttransplantation HAT, without increase of bleeding.¹¹⁸ Pulmonary emboli and intracardiac thrombosis may occur during liver transplantation, indicating that the hemostatic system may also tip toward thrombus formation during this procedure.¹¹⁹ Whether or not other anticoagulants will prevent postoperative thrombosis remains to be established.

Role of Coagulation in Fibrosis of the Liver

Thrombin, the key mediator of coagulation, also has several cellular effects mediated by protease-activated receptors (PARs). These PARs are expressed on hepatic stellate cells (HSCs), which are mediators of liver fibrosis. Thrombin generation leads to activation of HSCs and fibrogenesis.¹²⁰ Indeed, patients with prothrombotic phenotypes, such as carriers of the factor V Leiden mutation of antithrombin-deficient individuals were shown to have enhanced progression of liver fibrosis in viral hepatitis.^121,122 In line with these observations, fibrogenesis may be reduced by using anticoagulant treatment, however this has to be established in clinical studies.⁴⁴

REFERENCES

Listen

Afdhal N, McHutchison J, Brown R et al.: Thrombocytopenia associated with chronic liver disease. J Hepatol 48(6):1000–1007, 2008. [PubMed: 18433919]

Aster RH: Pooling of platelets in the spleen: Role in the pathogenesis of “hypersplenic” thrombocytopenia. J Clin Invest 45(5):645–657, 1966. [PubMed: 5327481]

Schmidt KG, Rasmussen JW, Bekker C, Madsen PE: Kinetics and in vivo distribution of 111-In-labelled autologous platelets in chronic hepatic disease: Mechanisms of thrombocytopenia. Scand J Haematol 34(1):39–46, 1985. [PubMed: 3918341]

Goulis J, Chau TN, Jordan S et al.: Thrombopoietin concentrations are low in patients with cirrhosis and thrombocytopenia and are restored after orthotopic liver transplantation. Gut 44(5):754–758, 1999. [PubMed: 10205219]

Ben-Ari Z, Osman E, Hutton RA, Burroughs AK: Disseminated intravascular coagulation in liver cirrhosis: Fact or fiction? Am J Gastroenterol 94(10):2977–2982, 1999. [PubMed: 10520855]

Kajihara M, Kato S, Okazaki Y et al.: A role of autoantibody-mediated platelet destruction in thrombocytopenia in patients with cirrhosis. Hepatology 37(6):1267–1276, 2003. [PubMed: 12774004]

Witters P, Freson K, Verslype C et al.: Review article: Blood platelet number and function in chronic liver disease and cirrhosis. Aliment Pharmacol Ther 27(11):1017–1029, 2008. [PubMed: 18331464]

Ordinas A, Escolar G, Cirera I et al.: Existence of a platelet-adhesion defect in patients with cirrhosis independent of hematocrit: Studies under flow conditions. Hepatology 24(5):1137–1142, 1996. [PubMed: 8903388]

Lisman T, Adelmeijer J, de Groot PG et al.: No evidence for an intrinsic platelet defect in patients with liver cirrhosis—Studies under flow conditions. J Thromb Haemost 4(9):2070–2072, 2006. [PubMed: 16836657]

10.

Escolar G, Cases A, Vinas M et al.: Evaluation of acquired platelet dysfunctions in uremic and cirrhotic patients using the platelet function analyzer (PFA-100): Influence of hematocrit elevation. Haematologica 84(7):614–619, 1999. [PubMed: 10406903]

11.

Tripodi A, Primignani M, Chantarangkul V et al.: Thrombin generation in patients with cirrhosis: The role of platelets. Hepatology 44(2):440–445, 2006. [PubMed: 16871542]

12.

Ferro D, Quintarelli C, Lattuada A et al.: High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: Relationship to endotoxemia. Hepatology. 23(6):1377–1383, 1996. [PubMed: 8675154]

13.

Lisman T, Bongers TN, Adelmeijer J et al.: Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology. 44(1):53–61, 2006. [PubMed: 16799972]

14.

Hollestelle MJ, Thinnes T, Crain K et al.: Tissue distribution of factor VIII gene expression in vivo—A closer look. Thromb Haemost 86(3):855–861, 2001. [PubMed: 11583319]

15.

Beer JH, Clerici N, Baillod P et al.: Quantitative and qualitative analysis of platelet GPIb and von Willebrand factor in liver cirrhosis. Thromb Haemost 73(4):601–609, 1995. [PubMed: 7495066]

16.

Hollestelle MJ, Geertzen HG, Straatsburg IH et al.: Factor VIII expression in liver disease. Thromb Haemost 91(2):267–275, 2004. [PubMed: 14961153]

17.

Mannucci PM, Canciani MT, Forza I et al.: Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 98(9):2730–2735, 2001. [PubMed: 11675345]

18.

Federici AB, Berkowitz SD, Lattuada A, Mannucci PM: Degradation of von Willebrand factor in patients with acquired clinical conditions in which there is heightened proteolysis. Blood 81(3):720–725, 1993. [PubMed: 8427964]

19.

Tersteeg C, de Maat S, De Meyer SF et al.: Plasmin cleavage of von Willebrand factor as an emergency bypass for ADAMTS13 deficiency in thrombotic microangiopathy. Circulation 129(12):1320–1331, 2014. [PubMed: 24449821]

20.

Hugenholtz GG, Porte RJ, Lisman T: The platelet and platelet function testing in liver disease. Clin Liver Dis 13(1):11–20, 2009. [PubMed: 19150305]

21.

Kerr R, Newsome P, Germain L et al.: Effects of acute liver injury on blood coagulation. J Thromb Haemost 1(4):754–759, 2003. [PubMed: 12871412]

22.

Fahs SA, Hille MT, Shi Q, Weiler H, Montgomery RR: A conditional knockout mouse model reveals endothelial cells as the principal and possibly exclusive source of plasma factor VIII. Blood 123(24):3706–3713, 2014. [PubMed: 24705491]

23.

Blanchard RA, Furie BC, Jorgensen M et al.: Acquired vitamin K-dependent carboxylation deficiency in liver disease. N Engl J Med 305(5):242–248, 1981. [PubMed: 6165889]

24.

Tripodi A, Mannucci PM: The coagulopathy of chronic liver disease. N Engl J Med 365(2):147–156, 2011. [PubMed: 21751907]

25.

de Maat MP, Nieuwenhuizen W, Knot EA et al.: Measuring plasma fibrinogen levels in patients with liver cirrhosis. The occurrence of proteolytic fibrin(ogen) degradation products and their influence on several fibrinogen assays. Thromb Res 78(4):353–362, 1995. [PubMed: 7631315]

26.

Francis JL, Armstrong DJ: Acquired dysfibrinogenaemia in liver disease. J Clin Pathol 35(6):667–672, 1982. [PubMed: 7085917]

27.

Tripodi A, Salerno F, Chantarangkul V et al.: Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 41(3):553–558, 2005. [PubMed: 15726661]

28.

Lisman T, Bakhtiari K, Pereboom IT et al.: Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests. J Hepatol 52(3):355–361, 2010. [PubMed: 20132999]

29.

Gatt A, Riddell A, Calvaruso V et al.: Enhanced thrombin generation in patients with cirrhosis-induced coagulopathy. J Thromb Haemost 8(9):1994–2000, 2010. [PubMed: 20546119]

30.

Potze W, Arshad F, Adelmeijer J et al.: Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis. PloS One 9(2):e88390, 2014. [PubMed: 24505487]

31.

Lisman T, Porte RJ: Rebalanced hemostasis in patients with liver disease: Evidence and clinical consequences. Blood 116(6):878–885, 2010. [PubMed: 20400681]

32.

Trotter JF, Brimhall B, Arjal R, Phillips C: Specific laboratory methodologies achieve higher model for endstage liver disease (MELD) scores for patients listed for liver transplantation. Liver Transpl 10(8):995–1000, 2004. [PubMed: 15390325]

33.

Lisman T, van Leeuwen Y, Adelmeijer J et al.: Interlaboratory variability in assessment of the model of end-stage liver disease score. Liver Int 28(10):1344–1351, 2008. [PubMed: 18482269]

34.

Tripodi A, Chantarangkul V, Primignani M et al.: The international normalized ratio calibrated for cirrhosis (INR[liver]) normalizes prothrombin time results for model for end-stage liver disease calculation. Hepatology 46(2):520–527, 2007. [PubMed: 17659574]

35.

Bellest L, Eschwege V, Poupon R et al.: A modified international normalized ratio as an effective way of prothrombin time standardization in hepatology. Hepatology 46(2):528–534, 2007. [PubMed: 17654598]

36.

Leebeek FW: Hyperfibrinolysis in Liver Disease. CRC Press, Boca Raton, FL, 1996.

37.

Leebeek FW, Kluft C, Knot EA et al.: A shift in balance between profibrinolytic and antifibrinolytic factors causes enhanced fibrinolysis in cirrhosis. Gastroenterology 101(5):1382–1390, 1991. [PubMed: 1718809]

38.

Lisman T, Leebeek FW, Mosnier LO et al.: Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology 121(1):131–139, 2001. [PubMed: 11438502]

39.

Stravitz RT: Potential applications of thromboelastography in patients with acute and chronic liver disease. Nat Rev Gastroenterol Hepatol 8(8):513–520, 2012.

40.

Rijken DC, Kock EL, Guimaraes AH et al.: Evidence for an enhanced fibrinolytic capacity in cirrhosis as measured with two different global fibrinolysis tests. J Thromb Haemost 10(10):2116–2122, 2012. [PubMed: 22906184]

41.

Violi F, Ferro D, Basili S et al.: Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis. Gastroenterology 109(2):531–539, 1995. [PubMed: 7615203]

42.

Francis RB Jr, Feinstein DI: Clinical significance of accelerated fibrinolysis in liver disease. Haemostasis 14(6):460–465, 1984. [PubMed: 6534818]

43.

Violi F, Ferro D, Basili S et al.: Hyperfibrinolysis increases the risk of gastrointestinal hemorrhage in patients with advanced cirrhosis. Hepatology 15(4):672–676, 1992. [PubMed: 1551645]

44.

Tripodi A, Anstee QM, Sogaard KK et al.: Hypercoagulability in cirrhosis: Causes and consequences. J Thromb Haemost 9(9):1713–1723, 2011. [PubMed: 21729237]

45.

Lisman T, Caldwell SH, Leebeek FW, Porte RJ: Is chronic liver disease associated with a bleeding diathesis? J Thromb Haemost 4(9):2059–2060, 2006. [PubMed: 16961613]

46.

Massicotte L, Lenis S, Thibeault L et al.: Effect of low central venous pressure and phlebotomy on blood product transfusion requirements during liver transplantations. Liver Transpl 12(1):117–123, 2006. [PubMed: 16382461]

47.

De Gottardi A, Thevenot T, Spahr L et al.: Risk of complications after abdominal paracentesis in cirrhotic patients: A prospective study. Clin Gastroenterol Hepatol 7(8):906–909, 2009. [PubMed: 19447197]

48.

Sogaard KK, Horvath-Puho E, Gronbaek H et al.: Risk of venous thromboembolism in patients with liver disease: A nationwide population-based case-control study. Am J Gastroenterol 104(1):96–101, 2009. [PubMed: 19098856]

49.

Northup PG, McMahon MM, Ruhl AP et al.: Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol 101(7):1524–1528; quiz 1680, 2006. [PubMed: 16863556]

50.

Gulley D, Teal E, Suvannasankha A et al.: Deep vein thrombosis and pulmonary embolism in cirrhosis patients. Dig Dis Sci 53(11):3012–3017, 2008. [PubMed: 18443906]

51.

Vivas S, Rodriguez M, Palacio MA et al.: Presence of bacterial infection in bleeding cirrhotic patients is independently associated with early mortality and failure to control bleeding. Dig Dis Sci 46(12):2752–2757, 2001. [PubMed: 11768269]

52.

Munoz SJ, Rajender Reddy K, Lee W; Acute Liver Failure Study Group: The coagulopathy of acute liver failure and implications for intracranial pressure monitoring. Neurocrit Care 9(1):103–107, 2008. [PubMed: 18379899]

53.

Lisman T, Bakhtiari K, Adelmeijer J et al.: Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure. J Thromb Haemost 10(7):1312–1319, 2012. [PubMed: 22568491]

54.

Stravitz RT, Lisman T, Luketic VA et al.: Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography. J Hepatol 56(1):129–136, 2012. [PubMed: 21703173]

55.

Hugenholtz GC, Adelmeijer J, Meijers JC et al.: An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: Implications for hemostasis and clinical outcome. Hepatology 58(2):752–761, 2013. [PubMed: 23468040]

56.

Pernambuco JR, Langley PG, Hughes RD et al.: Activation of the fibrinolytic system in patients with fulminant liver failure. Hepatology 18(6):1350–1356, 1993. [PubMed: 8244260]

57.

Stravitz RT, Bowling R, Bradford RL et al.: Role of procoagulant microparticles in mediating complications and outcome of acute liver injury/acute liver failure. Hepatology 58(1):304–313, 2013. [PubMed: 23389887]

58.

Munoz SJ, Stravitz RT, Gabriel DA: Coagulopathy of acute liver failure. Clin Liver Dis 13(1):95–107, 2009. [PubMed: 19150314]

59.

Porte RJ, Knot EA, Bontempo FA: Hemostasis in liver transplantation. Gastroenterology 97(2):488–501, 1989. [PubMed: 2663615]

59a.

Bakker CM, Blankensteijn JD, Schlejen P et al.: The effects of long-term graft preservation on intraoperative hemostatic changes in liver transplantation. A comparison between orthotopic and heterotopic transplantation in the pig. HPB Surg 7(4):265–80, 1994. [PubMed: 8204546]

59b.

de Boer MT, Westerkamp A, van den Berg AP et al.: Impact of extended criteria donor grafts on post-reperfusion transfusion requirements in liver transplantation; abstract Liver Transpl 15(7):S128–S129,2009.

60.

de Boer MT, Molenaar IQ, Hendriks HG et al.: Minimizing blood loss in liver transplantation: Progress through research and evolution of techniques. Dig Surg 22(4):265–275, 2005. [PubMed: 16174983]

61.

Massicotte L, Denault AY, Beaulieu D et al.: Transfusion rate for 500 consecutive liver transplantations: Experience of one liver transplantation center. Transplantation 93(12):1276–1281, 2012. [PubMed: 22617090]

62.

Kang YG, Martin DJ, Marquez J et al.: Intraoperative changes in blood coagulation and thrombelastographic monitoring in liver transplantation. Anesth Analg 64(9):888–896, 1985. [PubMed: 3896028]

63.

Porte RJ, Bontempo FA, Knot EA et al.: Systemic effects of tissue plasminogen activator-associated fibrinolysis and its relation to thrombin generation in orthotopic liver transplantation. Transplantation 47(6):978–984, 1989. [PubMed: 2499962]

64.

Sindram D, Porte RJ, Hoffman MR et al.: Platelets induce sinusoidal endothelial cell apoptosis upon reperfusion of the cold ischemic rat liver. Gastroenterology 118(1):183–191, 2000. [PubMed: 10611167]

65.

Agarwal S, Senzolo M, Melikian C et al.: The prevalence of a heparin-like effect shown on the thromboelastograph in patients undergoing liver transplantation. Liver Transpl 14(6):855–860, 2008. [PubMed: 18508379]

66.

Pereboom IT, Adelmeijer J, van Leeuwen Y et al.: Development of a severe von Willebrand factor/ADAMTS13 dysbalance during orthotopic liver transplantation. Am J Transplant 9(5):1189–1196, 2009. [PubMed: 19422343]

67.

Stahl RL, Duncan A, Hooks MA et al.: A hypercoagulable state follows orthotopic liver transplantation. Hepatology 12(3 Pt 1):553–558, 1990. [PubMed: 2401460]

68.

Boks AL, Brommer EJ, Schalm SW, Van Vliet HH: Hemostasis and fibrinolysis in severe liver failure and their relation to hemorrhage. Hepatology 6(1):79–86, 1986. [PubMed: 3943792]

69.

Garcia-Tsao G, Bosch J: Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 362(9):823–832, 2010. [PubMed: 20200386]

70.

Villanueva C, Colomo A, Bosch A et al.: Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 368(1):11–21, 2013. [PubMed: 23281973]

71.

Castaneda B, Debernardi-Venon W, Bandi JC et al.: The role of portal pressure in the severity of bleeding in portal hypertensive rats. Hepatology 31(3):581–586, 2000. [PubMed: 10706546]

72.

Marti-Carvajal AJ, Karakitsiou DE, Salanti G: Human recombinant activated factor VII for upper gastrointestinal bleeding in patients with liver diseases. Cochrane Database Syst Rev 3:CD004887, 2012. [PubMed: 22419301]

73.

Holster IL, Poley JW, Kuipers EJ, Tjwa ET: Controlling gastric variceal bleeding with endoscopically applied hemostatic powder (Hemospray). J Hepatol 57(6):1397–1398, 2012. [PubMed: 22864337]

74.

Sung JJ, Luo D, Wu JC et al.: Early clinical experience of the safety and effectiveness of Hemospray in achieving hemostasis in patients with acute peptic ulcer bleeding. Endoscopy 43(4):291–295, 2011. [PubMed: 21455870]

75.

76.

Piccinino F, Sagnelli E, Pasquale G, Giusti G: Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol 2(2):165–173, 1986. [PubMed: 3958472]

77.

Segal JB, Dzik WH, Transfusion Medicine/Hemostasis Clinical Trials Network: Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: An evidence-based review. Transfusion 45(9):1413–1425, 2005. [PubMed: 16131373]

78.

Youssef WI, Salazar F, Dasarathy S et al.: Role of fresh frozen plasma infusion in correction of coagulopathy of chronic liver disease: A dual phase study. Am J Gastroenterol 98(6):1391–1394, 2003. [PubMed: 12818286]

79.

Gazzard BG, Henderson JM, Williams R: The use of fresh frozen plasma or a concentrate of factor IX as replacement therapy before liver biopsy. Gut 16(8):621–625, 1975. [PubMed: 1102399]

80.

Alter HJ, Klein HG: The hazards of blood transfusion in historical perspective. Blood 112(7):2617–2626, 2008. [PubMed: 18809775]

81.

Rockey DC, Caldwell SH, Goodman ZD et al.: American Association for the Study of Liver Diseases: Liver biopsy. Hepatology 49(3):1017–1044, 2009. [PubMed: 19243014]

82.

Liumbruno G, Bennardello F, Lattanzio A et al.: Recommendations for the transfusion of plasma and platelets. Blood Transfus 7(2):132–150, 2009. [PubMed: 19503635]

83.

Saja MF, Abdo AA, Sanai FM et al.: The coagulopathy of liver disease: Does vitamin K help? Blood Coagul Fibrinolysis 24(1):10–17, 2013. [PubMed: 23080365]

84.

Boberg KM, Brosstad F, Egeland T et al.: Is a prolonged bleeding time associated with an increased risk of hemorrhage after liver biopsy? Thromb Haemost 81(3):378–381, 1999. [PubMed: 10102464]

85.

Agnelli G, Parise P, Levi M et al.: Effects of desmopressin on hemostasis in patients with liver cirrhosis. Haemostasis 25(5):241–247, 1995. [PubMed: 7489963]

86.

Wong AY, Irwin MG, Hui TW et al.: Desmopressin does not decrease blood loss and transfusion requirements in patients undergoing hepatectomy. Can J Anaesth 50(1):14–20, 2003. [PubMed: 12514144]

87.

de Franchis R, Arcidiacono PG, Carpinelli L et al.: Randomized controlled trial of desmopressin plus terlipressin vs. terlipressin alone for the treatment of acute variceal hemorrhage in cirrhotic patients: A multicenter, double-blind study. New Italian Endoscopic Club. Hepatology 18(5):1102–1107, 1993. [PubMed: 8225214]

88.

Sharma P, McDonald GB, Banaji M: The risk of bleeding after percutaneous liver biopsy: Relation to platelet count. J Clin Gastroenterol 4(5):451–453, 1982. [PubMed: 6960080]

89.

Lisman T, Caldwell SH, Burroughs AK et al.: Hemostasis and thrombosis in patients with liver disease: The ups and downs. J Hepatol 53(2):362–371, 2010. [PubMed: 20546962]

90.

Violi F, Basili S, Raparelli V et al.: Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction? J Hepatol 55(6):1415–1427, 2011. [PubMed: 21718668]

91.

Slichter SJ: Evidence-based platelet transfusion guidelines. Hematology Am Soc Hematol Educ Program 2007:172–178.

92.

Afdhal NH, Giannini EG, Tayyab G et al.: Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med 367(8):716–724, 2012. [PubMed: 22913681]

93.

Lisman T, Porte RJ: Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med 367(21):2055–2056, 2012. [PubMed: 23171114]

94.

de Boer MT, Boonstra EA, Lisman T, Porte RJ: Role of fibrin sealants in liver surgery. Dig Surg 29(1):54–61, 2012. [PubMed: 22441621]

95.

Wang SC, Shieh JF, Chang KY et al.: Thromboelastography-guided transfusion decreases intraoperative blood transfusion during orthotopic liver transplantation: Randomized clinical trial. Transplant Proc 42(7):2590–2593, 2010. [PubMed: 20832550]

96.

Porte RJ, Molenaar IQ, Begliomini B et al.: Aprotinin and transfusion requirements in orthotopic liver transplantation: A multicentre randomised double-blind study. EMSALT Study Group. Lancet 355(9212):1303–1309, 2000. [PubMed: 10776742]

97.

Boylan JF, Klinck JR, Sandler AN et al.: Tranexamic acid reduces blood loss, transfusion requirements, and coagulation factor use in primary orthotopic liver transplantation. Anesthesiology 85(5):1043–1048; discussion 30A–31A, 1996. [PubMed: 8916821]

98.

Fergusson DA, Hebert PC, Mazer CD et al.: A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 358(22):2319–2331, 1996.

99.

Tripodi A, Anstee QM, Sogaard KK et al.: Hypercoagulability in cirrhosis: Causes and consequences. J Thromb Haemost 9(9):1713–1723, 2011. [PubMed: 21729237]

100.

Northup PG, Sundaram V, Fallon MB et al.: Hypercoagulation and thrombophilia in liver disease. J Thromb Haemost 6(1):2–9, 2008. [PubMed: 17892532]

101.

Villa E, Camma C, Marietta M et al.: Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 143(5):1253–1260, 2012. [PubMed: 22819864]

102.

Bechmann LP, Sichau M, Wichert M et al.: Low-molecular-weight heparin in patients with advanced cirrhosis. Liver Int 31(1):75–82, 2011. [PubMed: 20958919]

103.

Cerini F, Garcia-Pagán JC: Tromboprophylaxis with heparin in hospitalized patients with cirrhosis: Friend or foe. Liver Int 34(7):971–973, 2014. [PubMed: 24382271]

104.

Intagliata NM, Henry ZH, Shah N et al.: Prophylactic anticoagulation for venous thromboembolism in hospitalized cirrhosis patients is not associated with high rates of gastrointestinal bleeding. Liver Int 34(1):26–32, 2014. [PubMed: 23758818]

105.

Potze W, Arshad F, Adelmeijer J et al.: Routine coagulation assays underestimate levels of antithrombin-dependent drugs but not of direct anticoagulant drugs in plasma from patients with cirrhosis. Br J Haematol 163(5):666–673, 2013. [PubMed: 24219333]

106.

Amitrano L, Brancaccio V, Guardascione MA et al.: Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis. Hepatology 31(2):345–348, 2000. [PubMed: 10655256]

107.

Zocco MA, Di Stasio E, De Cristofaro R et al.: Thrombotic risk factors in patients with liver cirrhosis: Correlation with MELD scoring system and portal vein thrombosis development. J Hepatol 51(4):682–689, 2009. [PubMed: 19464747]

108.

Okuda K, Ohnishi K, Kimura K et al.: Incidence of portal vein thrombosis in liver cirrhosis. An angiographic study in 708 patients. Gastroenterology 89(2):279–286, 1985. [PubMed: 4007419]

109.

Senzolo M, M Sartori T, Rossetto V et al.: Prospective evaluation of anticoagulation and transjugular intrahepatic portosistemic shunt for the management of portal vein thrombosis in cirrhosis. Liver Int 32(6):919–927, 2012. [PubMed: 22435854]

110.

Plessier A, Darwish-Murad S, Hernandez-Guerra M et al.: Acute portal vein thrombosis unrelated to cirrhosis: A prospective multicenter follow-up study. Hepatology 51(1):210–218, 2010. [PubMed: 19821530]

111.

Confer BD, Hanouneh I, Gomes M, Alraies MC: Q: Is anticoagulation appropriate for all patients with portal vein thrombosis? Cleve Clin J Med 80(10):611–613, 2013. [PubMed: 24085803]

112.

Intagliata N, Maitland H, Northup P, Caldwell S: Treating thrombosis in cirrhosis patients with new oral agents: Ready or not? Hepatology 61(2):738–739, 2015. [PubMed: 24829112]

113.

Washington K: Update on post-liver transplantation infections, malignancies, and surgical complications. Adv Anat Pathol 12(4):221–226, 2005. [PubMed: 16096384]

114.

Silva MA, Jambulingam PS, Gunson BK et al.: Hepatic artery thrombosis following orthotopic liver transplantation: A 10-year experience from a single centre in the United Kingdom. Liver Transpl 12(1):146–151, 2006. [PubMed: 16382467]

115.

Bekker J, Ploem S, de Jong KP: Early hepatic artery thrombosis after liver transplantation: A systematic review of the incidence, outcome and risk factors. Am J Transplant 9(4):746–757, 2009. [PubMed: 19298450]

116.

Quiroga S, Sebastia MC, Margarit C et al.: Complications of orthotopic liver transplantation: Spectrum of findings with helical CT. Radiographics 21(5):1085–1102, 2001. [PubMed: 11553818]

117.

Hirshfield G, Collier JD, Brown K et al.: Donor factor V Leiden mutation and vascular thrombosis following liver transplantation. Liver Transpl Surg 4(1):58–61, 1998. [PubMed: 9457968]

118.

Vivarelli M, La Barba G, Cucchetti A et al.: Can antiplatelet prophylaxis reduce the incidence of hepatic artery thrombosis after liver transplantation? Liver Transpl 13(5):651–654, 2007. [PubMed: 17457885]

119.

Warnaar N, Molenaar IQ, Colquhoun SD et al.: Intraoperative pulmonary embolism and intracardiac thrombosis complicating liver transplantation: A systematic review. J Thromb Haemost 6(2):297–302, 2008. [PubMed: 18005235]

120.

Jairath V, Burroughs AK: Anticoagulation in patients with liver cirrhosis: Complication or therapeutic opportunity? Gut 62(4):479–482, 2013. [PubMed: 23300140]

121.

Wright M, Goldin R, Hellier S et al.: Factor V Leiden polymorphism and the rate of fibrosis development in chronic hepatitis C virus infection. Gut 52(8):1206–1210, 2003. [PubMed: 12865283]

122.

Papatheodoridis GV, Papakonstantinou E, Andrioti E et al.: Thrombotic risk factors and extent of liver fibrosis in chronic viral hepatitis. Gut 52(3):404–409, 2003. [PubMed: 12584224]

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.

Chapter 128: Hemostatic Alterations in Liver Disease and Liver Transplantation

Send Email

Citation

Jump to a Section

INTRODUCTION

HEMOSTATIC ALTERATIONS IN CHRONIC LIVER DISEASE

PRIMARY HEMOSTASIS

SECONDARY HEMOSTASIS: COAGULATION AND ANTICOAGULATION

FIBRINOLYSIS

A REBALANCED HEMOSTATIC SYSTEM IN CHRONIC LIVER DISEASE

HEMOSTATIC ALTERATIONS IN ACUTE LIVER FAILURE

HEMOSTATIC ALTERATIONS DURING LIVER TRANSPLANTATION

CLINICAL PROBLEMS ENCOUNTERED IN PATIENTS WITH LIVER DISEASE

BLEEDING IN PATIENTS WITH LIVER DISEASE

HEMOSTATIC MANAGEMENT OF PATIENTS WITH LIVER DISEASE

Hemostatic Management of Bleeding Episodes

Hemostatic Management Before Interventions and Surgical Procedures

Hemostatic Management During Liver Transplantation

THROMBOSIS IN PATIENTS WITH LIVER DISEASE

Deep Vein Thrombosis and Pulmonary Embolism

Portal Vein Thrombosis

Thrombosis Following Liver Transplantation

Role of Coagulation in Fibrosis of the Liver

REFERENCES

Pop-up div Successfully Displayed