You are on page 1of 4

Journal of Thrombosis and Haemostasis, 4: 717–720


Abnormal hemostasis tests and bleeding in chronic liver

disease: are they related? Yes
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:

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: 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
hypertension and the presence of esophageal varices [12].
Therefore, measuring the PT provides an indirect evaluation of 1 Hedner U, Erhardtsen E. Hemostatic disorders in liver diseases.
both the main components of the bleeding tendency in In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff’s Diseases
of the Liver. Philadelphia: Lippincott Williams & Wilkins, 2003: 625–
cirrhosis: portal hypertension and coagulopathy. 36.
The role of hemostasis tests in predicting bleeding accom- 2 Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M,
panying liver biopsy or surgical procedures in patients with Primignani M, Mannucci PM. Evidence of normal thrombin genera-
cirrhosis is controversial. Although the PT and the platelet tion in cirrhosis despite abnormal conventional coagulation tests.
count are used to evaluate the bleeding risk in patients Hepatology 2005; 41: 553–8.
3 Amitrano L, Guardascione MA, Brancaccio V, Balzano A. Coagula-
undergoing liver biopsy, several studies found no increased tion disorders in liver disease. Semin Liver Dis 2002; 22: 83–96.
risk of bleeding associated with moderate prolongations of 4 Green G, Poller L, Thomsen JM, Dymock IW. Factor VII as a marker
the PT [17,18]. However, when the prolongation of the PT is of hepatocellular synthetic function in liver disease. J Clin Pathol 1976;
severe, the risk of bleeding increases dramatically [37]. No 29: 971–5.
coagulation parameter was related to the bleeding time as 5 Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R.
Transection of the oesophagus for bleeding oesophageal varices. Br J
measured from the liver at laparoscopy [38] and a moderate Surg 1973; 60: 646–9.
to mild thrombocytopenia does not increase clinically 6 Forman LM, Lucey MR. Predicting the prognosis of chronic liver
relevant bleeding in liver biopsy [18,37]. Routine use of the disease: an evolution from child to MELD. Mayo end-stage liver
bleeding time as an indicator of the risk of bleeding during disease. Hepatology 2001; 33: 473–5.
liver biopsy remains controversial [39]. The preoperative PT 7 Mann KG, Brummel K, Butenas S. What is all that thrombin for?
J Thromb Haemost 2003; 1: 1504–14.
has been associated both with the risk of bleeding and 8 Robert A, Chazouillères O. Prothrombin time in liver failure: time,
mortality, (mainly because of bleeding), in surgical proce- ratio, activity percentage, or international normalized ratio? Hepatol-
dures in cirrhotics [16,35]. The PT and the platelet count have ogy 1996; 24: 1392–4.
also been reported to be predictive of bleeding during 9 Trotter JF, Brimhall B, Arjal R, Phillips C. Specific laboratory
laparoscopic procedures in cirrhotics [40]. However, other methodologies achieve higher model for endstage liver disease
(MELD) scores for patients listed for liver transplantation. Liver
reports indicate that the PT and APTT might be inadequate Transpl 2004; 10: 995–1000.
to assess the true risk of bleeding when patients with cirrhosis 10 WHO Expert Committee on Biological Standardization. Guideliness
undergo invasive procedures [2]. In liver transplantation this for Thromboplastins and Plasma used to Control Oral Anticoagulant
relationship is not so clear [41], but the impact of massive Therapy. Technical Report Series 889; 48th report, Geneva, Switzer-
transfusions and the relevance of local surgical wounds must land, 1999.
11 Joist JH. AICF and DIC in liver cirrhosis: Expressions of a hyper-
be considered. coagulable state. Am J Gastroenterol 1999; 94: 2801–3.
12 Schepis F, Cammà C, Niceforo D, Magnano A, Pallio S, Cinquegrani
M, D’amico G, Pasta L, Craxi A, Saitta A, Raimondo G. Which
Future developments and conclusions patients with cirrhosis should undergo endoscopic screening for eso-
New tests that evaluate more accurately than now hemostasis phageal varices detection?. Hepatology 2001; 33: 333–8.
13 Zaman A, Hapke R, Flora K, Rosen HR, Benner K. Factors
alterations in cirrhotics are needed to redefine the role of these predicting the presence of esophageal or gastric varices in patients with
alterations in the clinical bleeding tendency of these patients. advanced liver disease. Am J Gastroenterol 1999; 94: 3292–6.
The most promising is the endogenous thrombin potential [2], 14 Erlinger S, Benhamou P. Cirrhosis: clinical aspects. In: McIntyre N,
although technical complexity and cost make its introduction Benhamou JP, Bircher J, Rizzetto M, Rodes J, eds. Oxford Text-
into routine clinical evaluation difficult at the moment. For book of Clinical Hepatology. Oxford: Oxford University Press, 1991:
studies of platelet function, the limitations of classical aggrego- 15 Friedman LS. The risk of surgery in patients with liver disease. Hep-
metry may probably be circumvented by new automated global atology 1999; 29: 1617–23.
screening devices of platelet function such as the Platelet 16 Aranha GV. Cholecystectomy in cirrhotic patients: a formidable
Function Analyzer-100 (PFA-100) [42] or and the Clot operation. Am J Surg 1982; 143: 55–60.
Signature Analyzer [43]. However, there is currently little 17 McGill DB, Rakela J, Zinsmeister AR, Ott BJ. A 21-year experience
with major haemorrhage after percutaneous liver biopsy. Gastro-
information available on its use in liver disease. enterology 1990; 99: 1396–400.
In conclusion, although hemostasis does not contribute to 18 Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications follow-
bleeding in chronic liver disease as much as it was once thought, ing percutaneous liver biopsy. J Hepatol 1986; 2: 165–73.
this does not mean that the PT should no longer be used to 19 Ozier Y, Steib A, Ickx B, Nathan N, Derlon A, Guay J, De Moerloose
evaluate the bleeding risk in patients with liver cirrhosis. While P. Haemostatic disorders during liver transplantation. Eur J Anaes-
thesiol 2001; 18: 208–18.
waiting for more ÔphysiologicalÕ tests to evaluate hemostasis in

Ó 2006 International Society on Thrombosis and Haemostasis

720 J. C. Reverter

20 Escorsell A, Bordas JM, Castaneda B, Llach J, Garcia-Pagan JC, bleeding: the need for very early management. J Hepatol 2003; 39: 509–
Rodes J, Bosch J. Predictive value of the variceal pressure response to 14.
continued pharmacological therapy in patients with cirrhosis and 33 Patch D, Armonis A, Sabin C, Christopoulou K, Greenslade L,
portal hypertension. Hepatology 2000; 31: 1061–7. McCormick A, Dick R, Burroughs AK. Single portal pressure meas-
21 Dell’era A, Bosch J. Review article: the relevance of portal pressure urement predicts survival in cirrhotic patients with recent bleeding. Gut
and other risk factors in acute gastro-oesophageal variceal bleeding. 1999; 44: 264–9.
Aliment Pharmacol Ther 2004; 20(Suppl. 3): 8–15. 34 Lecleire S, Di Fiore F, Merle V, Herve S, Duhamel C, Rudelli A,
22 Boks AL, Brommer EJ, Schalm SW, Van Vliet HH. Hemostasis and Nousbaum JB, Amouretti M, Dupas JL, Gouerou H, Czernichow P,
fibrinolysis in severe liver failure and their relation to hemorrhage. Lerebours E. Acute upper gastrointestinal bleeding in patients with
Hepatology 1986; 6: 79–86. liver cirrhosis and in noncirrhotic patients: epidemiology and predic-
23 Bosch J, D’Amico G, Garcı́a-Pagán JC. Portal hypertension. In: Schiff tive factors of mortality in a prospective multicenter population-based
ER, Sorrell MF, Maddrey WC, eds. Schiff’s Diseases of The Liver. study. J Clin Gastroenterol 2005; 39: 321–7.
Philadelphia: Lippincott Williams & Wilkins, 2003: 429–86. 35 Garrison RN, Cryer HM, Howard DA, Polk HC Jr. Clarification of
24 Lisman T, Leebeek FW, Meijer K, Van Der Meer J, Nieuwenhuis HK, risk factor for abdominal operations in patients with hepatic cirrhosis.
De Groot PG. Recombinant factor VIIa improves clot formation but Ann Surg 1984; 199: 648–55.
not fibrolytic potential in patients with cirrhosis and during liver 36 Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM,
transplantation. Hepatology 2002; 35: 616–21. Kosberg CL, D’Amico G, Dickson ER, Kim WR. A model to predict
25 Bosch J, Thabut D, Bendtsen F, D’Amico G, Albillos A, Gonzalez survival in patients with end-stage liver disease. Hepatology 2001; 33:
Abraldes J, Fabricius S, Erhardtsen E, de Franchis R; European Study 464–70.
Group on rFVIIa in UGI Haemorrhage. Recombinant factor VIIa for 37 Gilmore IT, Burroughs A, Murray-Lyon IM, Williams R, Jenkins D,
upper gastrointestinal bleeding in patients with cirrhosis: a random- Hopkins A. Indications, methods, and outcomes of percutaneous liver
ized, double-blind trial. Gastroenterology 2004; 127: 1123–30. biopsy in England and Wales: an audit by the British Society of
26 Porte RJ, Molenaar IQ, Begliomini B, Groenland TH, Januszkiewicz Gastroenterology and the Royal College of Physicians of London. Gut
A, Lindgren L, Palareti G, Hermans J, Terpstra OT. Aprotinin and 1995; 36: 437–41.
transfusion requirements in orthotopic liver transplantation: a multi- 38 Ewe K. Bleeding after liver biopsy does not correlate with indices of
centre randomized double-blind study. EMSALT Study Group. peripheral coagulation. Dig Dis Sci 1981; 26: 388–93.
Lancet 2000; 355: 1303–9. 39 Bonnard P, Vitte RL, Barbare JC, Denis J, Stepani P, Di Martino V,
27 Dalmau A, Sabate A, Acosta F, Garcia-Huete L, Koo M, Sansano T, Coutarel P, Eugene C, Van Batten C, Cadranel JF. Is bleeding time
Rafecas A, Figueras J, Jaurrieta E, Parrilla P. Tranexamic acid reduces measurement useful for choosing the liver biopsy route? The results of
red cell transfusion better than epsilon-aminocaproic acid or placebo in a pragmatic, prospective multicentric study in 219 patients. J Clin
liver transplantation. Anesth Analg 2000; 91: 29–34. Gastroenterol 1999; 29: 347–9.
28 Piscaglia F, Siringo S, Hermida RC, Legnani C, Valgimigli M, Donati 40 Schiff J, Misra M, Rendon G, Rothschild J, Schwaitzberg S. Lapa-
G, Palareti G, Gramantieri L, Gaiani S, Burroughs AK, Bolondi L. roscopic cholecystectomy in cirrhotic patients. Surg Endosc 2005; 19:
Diurnal changes of fibrinolysis in patients with liver cirrhosis and 1278–81.
esophageal varices. Hepatology 2000; 31: 349–57. 41 Steib A, Freys G, Lehmann C, Meyer C, Mahoudeau G. Intraoper-
29 Violi F, Basili S, Ferro D, Quintarelli C, Alessandril C, Cordova C. ative blood losses and transfusion requirements during adult liver
Association between high values of D-dimer and tissue-plasminogen transplantation remain difficult to predict. Can J Anaesth 2001; 48:
activator activity and first gastrointestinal bleeding in cirrhotic 1075–9.
patients. Thromb Hemost 1996; 76: 177–83. 42 Escolar G, Cases A, Viñas M, Pino M, Calls J, Cirera I, Ordinas A.
30 Francis RB, Jr., Feinstein DI. Clinical significance of accelerated Evaluation of acquired platelet dysfunctions in uremic and cirrhotic
fibrinolysis in liver disease. Haemostasis 1984; 14: 460–5. patients using the platelet function analyzer (PFA-100 ): influence of
31 Bosch J, Reverter JC. The coagulopathy of cirrhosis: myth or reality? hematocrit elevation. Haematologica 1999; 84: 614–9.
Hepatology 2005; 41: 434–5. 43 Fricke W, Kouides P, Kessler C, Schmaier AH, Krijanovski Y,
32 Nidegger D, Ragot S, Berthelemy P, Masliah C, Pilette C, Martin T, Jagadeesan K, Joist J. A multicenter clinical evaluation of the Clot
Bianchi A, Paupard T, Silvain C, Beauchant M. Cirrhosis and Signature Analyzer. J Thromb Haemost 2004; 2: 763–8.

Ó 2006 International Society on Thrombosis and Haemostasis