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2194 Part XII: Hemostasis and Thrombosis Chapter 128: Hemostatic Alterations in Liver Disease and Liver Transplantation 2195

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Infusion of plasma may even lead to more bleeding as a result of an 50 × 10 /L, platelet transfusion is recommended before any intervention,
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increase of portal pressure. 71,72 Upper gastrointestinal bleeding from as in other patients without underlying liver disease. In case of neu-
peptic ulcer disease also occurs frequently in patients with liver dis- rosurgical interventions platelets should be transfused up to a level of
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ease. Infusion of recombinant factor VIIa did not result in reduction of 100 × 10 /L. A novel strategy to improve primary hemostasis in patients
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blood loss or mortality in randomized clinical studies in patients with with hepatitis C is the administration of a thrombopoietin analogue
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upper gastrointestinal bleeding and is not indicated. Recently the use (Eltrombopag). In the ELEVATE study, a short course of Eltrombopag
of hemostatic powder was used in patients who did not respond to was used to elevate the platelet count prior to invasive procedures. Use
other measures and was successfully used in some cases, but its value of Eltrombopag was associated with a higher rate of thrombosis, but no
should be tested in larger randomized studies before it will be regis- difference in bleeding was observed in this study, which may be related
tered and can be recommended in this setting. 73,74 The most important to the highly elevated VWF levels in patients with liver disease. 92,93
intervention is to prevent variceal bleeding by prophylactic measures, Eltrombopag is not indicated for the treatment of thrombocytopenia in
such as rubber band ligation. patients with chronic liver disease before surgical interventions.
Minor bleeding, including bruising, purpura and gingival bleeding In individuals with generalized mucosal bleeding symptoms,
occur more frequently in patients with liver disease, but do not always which may be indicative of disorders of primary hemostasis or hyper-
need treatment, or can be managed by local measures. Mucocutaneous fibrinolysis, treatment with fibrinolysis inhibitors such as tranexamic
bleeding, such as epistaxis, can be treated with fibrinolysis inhibitors, acid after the procedure should be considered. 68,89 Tranexamic acid is
for instance tranexamic acid, and menorrhagia by oral contracep- also advised in case of dental extractions because of the high fibrinolytic
tives. In case of bleeding in patients with severe thrombocytopenia activity in the oral mucosa.
(<50,000/μL) platelet transfusion should be given, as would also be indi- The use of fibrin sealant has been studied to reduce blood loss in
cated in patients without underlying liver disease. patient undergoing liver surgery. Although these products reduce the
time to hemostasis when applied on the transected liver surface, no
Hemostatic Management Before Interventions and Surgical improvement in postoperative complications was observed. Therefore
Procedures its value in these settings has not yet been established. 94
Traditional guidelines have advised not to perform invasive procedures
in patients with liver disease when routine hemostatic tests are abnor- Hemostatic Management During Liver Transplantation
mal unless they are corrected by blood products or pharmacologic pro- For many years excessive blood loss during liver transplantation has
hemostatic agents. The rationale for such a prophylactic approach has been recognized as an important cause of morbidity and mortality;
been questioned for several reasons. First and most important because consequently, transfusion of a combination of blood products has been
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abnormal coagulation tests in patients with liver disease are not nec- advocated for correction of the hemostatic derangements. Experiments
essarily associated with a bleeding risk. As mentioned before, these in experimental animal models have shown that the quality of the graft
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59a
results have been traditionally interpreted to reflect a hypocoagulable determines the extent of hemostatic changes following reperfusion.
state, but appeared to have no impact on the bleeding risk after inva- Indeed, blood loss following graft reperfusion is substantially increased in
sive procedures. 75–77 For instance, in a large prospective study there was recipients of “extended criteria” donor livers (i.e., grafts with poorer quality
no evidence that prolongation of the INR was associated with bleed- because of, e.g., elevated donor age or prolonged cold ischemia times). 59b
ing after large-volume paracentesis in patients with liver disease and Because prophylactic transfusion of blood products may be associ-
ascites. Furthermore normalization of traditional coagulation tests ated with serious side effects, many centers have discontinued to attempt
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is rarely achieved by infusion of plasma products and the efficacy of to improve hemostatic functions by administration of blood products
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prophylactic treatment has not been proven. 78,79 In addition, transfusion prior to liver transplantation. Liver transplantation procedures can now
of blood products carry a substantial risk of allergic reactions, volume be performed without a requirement for transfusion of blood products in
overload and potential transmission of pathogens. Consequently, the a substantial proportion of patients. One study reported that 79 percent of
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current guideline of the American Association for the Study of Liver patients could be transplanted without the use of any blood product, pro-
Diseases (AASLD) do not recommend the routine use of fresh-frozen vided the patient’s central venous pressure was controlled through restric-
plasma (FFP) transfusion for prophylactic correction of an abnormal tion of volume replacement, and by using intraoperative phlebotomy
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PT before interventions, such as liver biopsy, whereas other guidelines during the transplantation. Increased experience and improvements
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advise the use of FFP with low grade of evidence. Vitamin K is gen- in surgical technique, anesthesiologic care, and better graft preserva-
erally recommended in patients with liver disease and prolonged INR, tion methods have contributed to a steady decrease in blood transfusion
however its clinical benefit has been questioned. 83 requirements. When uncontrolled bleeding does occur, packed red cells,
Thrombocytopenia in patients with cirrhosis is often mild and platelets, FFP, or fibrinogen concentrate can be transfused guided by lab-
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does not cause spontaneous bleeding or bleeding following minimally oratory values or thromboelastography. Hyperfibrinolysis is thought
invasive procedures. There is little evidence that tests showing platelet to contribute significantly to impaired hemostasis during the anhepatic
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dysfunction, including prolonged bleeding time or closure time mea- and reperfusion phases. Use of synthetic antifibrinolytic agents, such
sured with the PFA-100 predict bleeding in patients with cirrhosis. as tranexamic acid (a lysine analogue) and aprotinin (a serine protease
Nevertheless, an early study showed that a prolonged bleeding time inhibitor) have reduced red cell and plasma transfusion. 96,97 Aprotinin
was associated with a fivefold increase in the risk of bleeding after was taken off the market in 2008 because of severe adverse events and
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liver biopsy. Although shortening of the bleeding time was achieved mortality in patients undergoing cardiac surgery. 98
by administration of 1-deamino-8-d-arginine vasopressin (DDAVP)
in patients with liver disease, no effect of DDAVP was observed in THROMBOSIS IN PATIENTS WITH
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patients with bleeding from esophageal varices or on the blood loss in
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patients undergoing hepatectomy or liver transplantation. Although LIVER DISEASE
this has not been addressed in many studies yet, it has been shown that Deep Vein Thrombosis and Pulmonary Embolism
bleeding complications during interventional procedures are associated The reappraisal of changes in the hemostatic system in patients with
with a low preprocedural platelet count. 88,89 If platelet counts are below liver disease has indicated that the coagulopathy of liver disease may not

Kaushansky_chapter 128_p2191-2198.indd 2194 9/18/15 10:38 AM