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
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