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CHAPTER 128 The liver plays a central role in the hemostatic system. Liver parenchy-
mal cells are the site of synthesis of most coagulation factors (except
HEMOSTATIC ALTERATIONS factor VIII), the natural inhibitors of coagulation, including protein C,
protein S, and antithrombin, and essential components of the fibrino-
IN LIVER DISEASE AND LIVER lytic system, such as plasminogen, α -antiplasmin, and thrombin acti-
2
vatable fibrinolysis inhibitor (TAFI). The liver also regulates hemostasis
and fibrinolysis by clearing activated coagulation factors and coagu-
TRANSPLANTATION lation 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
Frank W.G. Leebeek and Ton Lisman 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.
SUMMARY
HEMOSTATIC ALTERATIONS IN
In patients with acute liver failure or chronic liver disease, many changes in CHRONIC LIVER DISEASE
the hemostatic system occur. The liver is the site of synthesis of nearly all
coagulation factors, both pro- and anticoagulant proteins. A reduced synthesis PRIMARY HEMOSTASIS
function of the liver will lead to reduced levels of these factors in circulation. More than 75 percent of patients with chronic liver disease, especially
In addition, the liver is involved in the clearance of many activated coagu- in moderate to severe cirrhosis (Child B and C) have reduced levels of
lation factors and protein-inhibitor complexes from the circulation, which, platelets (<150,000/μL) and 13 percent have platelet counts between
in turn, can lead to activation of the coagulation system if liver function is 50,000 and 75,000/μL. This may be caused by splenomegaly resulting in
1
impaired. Furthermore, the liver is involved in the synthesis and clearance of sequestration of platelets in the spleen, reduced synthesis of thrombopoi-
pro- and antifibrinolytic proteins, which may lead to a shift in the balance of etin by the diseased liver, or consumption coagulopathy. In addition, it
2–5
the fibrinolytic system. Also primary hemostasis might be affected in liver dis- has been suggested that autoantibodies against platelets may reduce the
6
ease because of thrombocytopenia and impaired platelet function, which is half-life of platelets in cirrhosis. Primary hemostasis may also be defec-
frequently encountered in these patients. It is evident that patients with liver tive by a reduced platelet function. In vitro platelet aggregation studies
disease have frequent bleeding episodes, mainly in the gastrointestinal tract, in response to various agonists is frequently diminished in patients
with liver disease. Defective platelet function may result from impaired
such as variceal bleeding. It has been a longstanding dogma that patients with signal transduction, acquired storage pool deficiency, proteolysis of
liver disease are at a high risk of bleeding caused by the above mentioned platelet membrane proteins, and increased production of the endothelial-
hemostatic changes. However, in recent years this cause of the bleeding ten- derived platelet inhibitors, nitric oxide and prostacyclin. (reviewed in
dency has been questioned because of the concomitant reductions of pro- and Ref. 7). A reduced hematocrit may contribute to defective platelet–vessel
anticoagulant factors and pro- and antifibrinolytic factors. More recent studies wall interaction. Platelet adhesion defects were also found under con-
using more sophisticated coagulation tests showed that thrombin genera- ditions of flow, but were in some studies attributed to thrombocytope-
tion is normal in patients with chronic liver failure and that some may even nia and a low hematocrit. 8–10 Platelet procoagulant activity measured by
have a prothrombotic phenotype. This led to the development of a model of a a thrombin generation assay using platelet-rich plasma was similar in
rebalanced hemostatic system in these patients, which may have immediate patients and healthy controls, which casts additional doubt on the extent
implications for treatment. Hematologists and other clinicians taking care of of the functional defects of platelets in patients with liver disease. 11
VWF antigen levels are strongly elevated in patients with liver
patients with acute liver failure of chronic liver disease, such as cirrhosis, are disease. It has been suggested that this is the result from endothelial
still faced with the questions whether these patients need correction of the damage possibly mediated by endotoxemia (bacterial infection). 12,13
changes in hemostasis before interventions such as paracentesis, biopsies, VWF mRNA and protein expression in the liver itself are substan-
dental care, and surgery. It was generally believed that replacement therapy tially increased in cirrhosis, but VWF ristocetin cofactor activity is
with frozen plasma or prothrombin complex concentrate was indicated. How- variable. 10,14–16 The high levels of VWF may ameliorate the hemostatic
ever, based on these new findings, physicians should now be more restrictive defect caused by thrombocytopenia and platelet function defects.
13
in the use of hemostatic agents and blood products in these patients both in In a flow-based model, platelet adhesion to collagen was normalized
liver disease and during liver transplantation. in thrombocytopenia because of the high levels of VWF in cirrhotic
plasma. In patients with liver disease the regulation of VWF multi-
mer size and activity can be impaired because of reduced synthesis of
the VWF-cleaving protease ADAMTS13 by stellate cells in the liver.
17
Acronyms and Abbreviations: ADAMTS13, a disintegrin-like and metalloprotease Several studies showed, however, that the most active high-molecu-
with thrombospondin domain 13; aPTT, activated partial thromboplastin time; lar-weight multimers of VWF are diminished in plasma of patients with
DDAVP, 1-deamino-8-d-arginine vasopressin; DIC, disseminated intravascular coag- cirrhosis, which may be mediated by plasmin or other proteases. 18,19
ulation; FFP, fresh-frozen plasma; HAT, hepatic artery thrombosis; INR, international Classical tests of primary hemostasis, such as bleeding time, which is
normalized ratio; ISI, international sensitivity index; MELD, model of end-stage liver becoming obsolete as a result of its assay-variability and inability to pre-
disease; PAI-1, plasminogen activator inhibitor 1; PFA, platelet function analyzer; PT, dict bleeding, may still be abnormal in patients with liver disease. Also
prothrombin time; PVT, portal vein thrombosis; TAFI, thrombin-activatable fibrinoly- newer global tests of primary hemostasis, such as platelet function ana-
sis inhibitor; t-PA, tissue-type plasminogen activator; VWF, von Willebrand factor. lyzer (PFA), show prolonged closure times with various agonists, but its
value in prediction of bleeding in liver disease is unknown. 20

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