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Journal of Thrombosis and Haemostasis, 4: 717–720

DEBATE

Abnormal hemostasis tests and bleeding in chronic liver


disease: are they related? Yes
J. C. REVERTER
Haemotherapy and Haemostasis Department, Hospital Clı́nic, University of Barcelona, Barcelona, Spain

To cite this article: Reverter JC. Abnormal hemostasis tests and bleeding in chronic liver disease: are they related? Yes. J Thromb Haemost 2006; 4:
717–20.

See also Mannucci PM. Abnormal hemostasis tests and bleeding in chronic liver disease: are they related? No. This issue, pp 721–3.

commonly used prognostic indexes of chronic liver disease as


The concept that liver failure determines an acquired coagulo- the Child-Pugh or Mayo End-Stage Liver Disease (MELD)
pathy causing bleeding has been firmly established for many scores [5,6]. Because of the defective synthesis of FXII, FXI,
years [1]. However, the role played by coagulation defects in high-molecular-weight kininogen and prekallikrein, the APTT
determining bleeding in cirrhotics has recently been questioned is also prolonged in advanced liver cirrhosis [1]. These screening
[2]. It has been argued that patients with cirrhosis bleed more tests are cheap and easy to perform and have been considered
infrequently than patients with an apparently similar degree of clinically useful, but have several limitations. Firstly, they do
congenital coagulation deficiencies [2]. In addition, when not reproduce Ôin vivoÕ coagulation, because platelets and other
cirrhotics bleed, the sites and types of bleeding are different, blood cells are removed from platelet poor plasma and several
mainly involving the gastrointestinal tract. Moreover, global substances, non-physiological or in non-physiological concen-
coagulation tests fail to truly reflect the balance of procoag- trations, are employed to initiate or amplify clot formation.
ulant and anticoagulant factors in vivo [2]. Although these ideas Secondly, tests such as the PT and APTT measure only
are essentially valid, the relationship between abnormal procoagulant factors and it is known that the balance between
hemostasis tests and the risk of bleeding in cirrhotics cannot the procoagulant and anticoagulant pathways is critical [2].
be discarded. Thirdly, PT and APTT do not allow full activation of protein
C, whose levels are reduced in advanced cirrhosis [2]. Fourthly,
these tests have a relatively poor sensitivity for the detection of
Chronic liver disease: effect on hemostasis tests
low clotting factors [3] and clot formation occurs after only
Liver cirrhosis is characterized by a defective hepatic little of the whole thrombin is generated [7]. However, these
synthesis of clotting factors and thrombocytopenia, mainly limitations do not apply only to liver cirrhosis, but also to
caused by portal hypertension, and by hyperfibrinolysis that nearly all acquired coagulopathies associated with multiple
may further contribute to alterations in hemostasis [3]. Other factor deficiencies. They apply, for instance, to oral anticoagu-
abnormalities, such as disseminated intravascular coagulation lant therapy with anti-vitamin K drugs that, like liver disease,
(DIC), dysfibrinogenemia, vitamin K deficiency, or impaired affects multiple clotting factors and the protein C pathway
platelet function, may be the additional contributing factors simultaneously. Yet the value of the PT in predicting the risk of
[3]. bleeding is well established in patients on oral anticoagulant
It has long been considered, somewhat simplistically, that therapy. The International Normalized Ratio (INR), which
coagulation defects in liver disease may be measured through takes into account the sensitivity of the thromboplastin
the prolongation of such global screening tests as the employed, was a substantial advance for the standardization
prothrombin time (PT) and the activated partial thromboplas- of oral anticoagulant therapy, because it permits comparison of
tin time (APTT). In the early phases of cirrhosis, the PT is results obtained in different laboratories and the establishment
usually within the normal range or only moderately prolonged, of universally valid therapeutic ranges. In the other acquired
mainly because of low factor VII (FVII) levels [4]. In more coagulopathies, including liver cirrhosis, PT standardization
advanced cirrhosis, the prolonged PT is related to the severity using the INR is inadequate [8–10], because the slope of the
of liver failure and is one of the parameters used in such linear regression obtained in the comparison of thromboplas-
tins [which defines the International Sensitivity Index (ISI) used
Correspondence: J. C. Reverter, Haemotherapy and Haemostasis for INR calculation] is clearly different in warfarin-treated and
Department, Hospital Clı́nic, University of Barcelona, Barcelona, in liver cirrhosis patients [8]. Therefore, in liver cirrhosis the use
Spain. of the INR may increase, instead of reducing, between-
e-mail: reverter@clinic.ub.es laboratory variability.

Ó 2006 International Society on Thrombosis and Haemostasis


718 J. C. Reverter

In addition to such global screening tests such as the PT and mechanisms modulating the severity of gastrointestinal bleed-
APTT, single clotting factors may be measured in patients with ing in these patients (involving hemodynamic changes,
chronic liver disease, although there is currently little evidence thrombocytopenia and impaired platelet function, hyperfibrin-
of their clinical utility. Although the determination of FV and olysis and low coagulation factors) makes the assessment of the
FVII activity seems to be useful in acute hepatic failure, the separate role of each factor difficult. In a recent double-blind
measurement of single clotting factors adds little information to controlled trial, the use of recombinant activated FVII, a drug
screening tests in chronic liver disease [3]. More sensitive assays that improves clot formation [24], enhanced the initial control
such as the prothrombin fragment 1+2, fibrinopeptide A, of variceal bleeding achieved with state-of-the-art medical
soluble fibrin, D-dimer, thrombin–antithrombin complexes therapy and allowed a much higher rate of survival free from
and plasmin-a-2-antiplasmin complexes have been used to early rebleeding in patients with advanced liver disease [25].
diagnose intravascular coagulation in liver cirrhosis [11], but Moreover, in liver transplantation, prophylactic administration
their clinical relevance remains unclear. The same may be said of antifibrinolytic agents such as aprotinin and tranexamic acid
for hyperfibrinolysis, which can be diagnosed using such tests reduces transfusion requirements [26,27]. The clinical relevance
as the euglobulin clot lysis time and plasma D-dimer. The of hyperfibrinolysis in the bleeding tendency seen in chronic
majority of studies of primary hemostasis are on the platelet liver disease patients is unclear. Bleeding from esophageal
count. A relationship between moderate to severely reduced varices in cirrhosis patients overlaps the circadian rhythm of
platelet count and the presence of gastroesophageal bleeding fibrinolysis [28] and hyperfibrinolysis was found to be the main
has been demonstrated [12,13], whereas there is little informa- predictive marker of the first episode of upper gastrointestinal
tion on the predictive value of platelet function tests. bleeding in cirrhotic patients with portal hypertension [29].
However, no relationship between variceal bleeding and
hyperfibrinolysis was found in other studies [22]. Although
Bleeding in chronic liver disease: the role of hemostasis
accelerated fibrinolysis may increase bleeding from mucosal
Bleeding is a frequent and often severe complication of liver membranes and particularly gastrointestinal bleeding [29,30],
cirrhosis. The most frequent and potentially life-threatening its true role as a trigger of gastroesophageal bleeding remains
site is the gastrointestinal tract. However, cirrhotics may also speculative.
present with other signs of a bleeding tendency, including Taking all these data into account, it seems that the bleeding
bruising, petechiae, purpura, ecchymosis, epistaxis, gingival manifestations of patients with liver disease depend, at least in
bleeding and menorrhagia [3]. Hematomas occurring sponta- part, on the degree of hemostatic impairment. It is unlikely that
neously or after minimal trauma are common in advanced liver coagulopathy plays a crucial role in initiating variceal bleeding,
disease and may be severe in some cases [14]. In addition, but it may be clinically relevant in aggravating it and facilitating
patients with advanced liver disease have an increased risk of recurrences [31].
bleeding during invasive diagnostic and therapeutic proce-
dures. For instance, cirrhotics undergoing abdominal surgery
Hemostasis tests in the evaluation of the risk of bleeding
have a high risk of morbidity and mortality [15], with bleeding
in chronic liver disease
accounting for 60% of all deaths from this procedure [16].
Moreover, intraperitoneal bleeding is the main complication of In patients with congenital defects of hemostasis, cutaneous,
liver biopsy in cirrhotics: in 0.4–0.5% of these procedures subcutaneous, mucosal and muscular bleeding is related to
significant bleeding occurs [17] and in 0.01–0.1% it causes coagulation defects and to platelet alterations. In liver cirrhosis,
death [18]. Hemostasis abnormalities are one of the main a similar involvement of these alterations has been hypothes-
problems in patients undergoing liver transplantation and the ized but although a partial association between these types of
mortality of the procedure is positively associated with intra- bleeding and the degree of abnormalities of global coagulation
and postoperative bleeding [19]. tests was found [22], sufficient data to confirm this hypothesis
Hemodynamic alterations secondary to portal hypertension are not available.
are considered the main cause of gastrointestinal bleeding in Gastrointestinal bleeding is mainly hemodynamic in its
cirrhotics [2,20,21]. In addition, portal hypertension also mechanisms and is related to portal hypertension [21]. There-
contributes significantly to excessive intra- and postoperative fore, coagulation tests may have only a limited predictive value
blood loss during liver surgery [3]. The role played by the for bleeding tendency. In several studies, a prolonged PT has
coagulopathy of cirrhosis in gastrointestinal bleeding is still been associated with an increased risk of gastrointestinal
unclear. It does not seem to play a major role in initiating bleeding in chronic liver disease [32–34]. However, the PT may
bleeding; however, a relationship between the severity of reflect the risk in a way unrelated to the degree of coagulop-
bleeding and the degree of coagulation defect was reported [22]. athy, because the decreased hepatic synthesis of coagulation
Clinical evidence indicates that variceal bleeding is more severe, factors, reflected globally by the PT, is an excellent marker of
more difficult to control and more likely to recur in patients liver failure and a strong independent prognostic indicator of
with advanced liver failure (presenting with more prolonged survival in patients with chronic liver disease [23]. Patients with
PT and, often, lower platelet counts) than in patients with moderately or severely prolonged PT have 5- to 10-fold
relatively preserved liver function [1,23]. The complexity of the higher mortality rates than patients with normal PT [35]. For

Ó 2006 International Society on Thrombosis and Haemostasis


Abnormal hemostasis tests and bleeding in chronic liver disease 719

this reason, new and old prognostic indexes for patients with chronic liver disease, the PT will continue to be used to estimate
advanced liver disease include the PT as one component the bleeding tendency. In part because of its relationship with
[23,36]. The presence or absence of severe gastrointestinal coagulopathy but mainly as a good, simple, inexpensive,
bleeding is a major determinant of survival in these patients, quantitative and accurate prognostic marker of liver impair-
and the prognostic indexes, which include the PT, reflect this ment, which, in turn, is a predictor of bleeding [3].
fact. The degree of PT impairment as an expression of
decreased liver synthesis also predicts the severity of portal
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Ó 2006 International Society on Thrombosis and Haemostasis