www.elsevier.com/locate/jhep

Journal of Hepatology 48 (2008) 1000–1007

Review

Thrombocytopenia associated with chronic liver diseaseq

Nezam Afdhal1,*, John McHutchison2, Robert Brown3, Ira Jacobson4, Michael Manns5,Fred Poordad6, Babette Weksler4, Rafael Esteban7

1Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA2Duke University Medical Center, Durham, NC, USA

3Columbia University Medical Center, New York, NY, USA4Weill Medical College of Cornell University, New York, NY, USA

5Medizinische Hochschule Hannover, Hannover, Germany6Cedars-Sinai Medical Center, Center for Liver Disease and Transplantation, Los Angeles, CA, USA

7Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain

Thrombocytopenia (platelet count <150,000/lL) is a common complication in patients with chronic liver disease (CLD)

that has been observed in up to 76% of patients. Moderate thrombocytopenia (platelet count, 50,000/lL–75,000/lL)

occurs in approximately 13% of patients with cirrhosis. Multiple factors can contribute to the development of thrombo-

cytopenia, including splenic platelet sequestration, bone marrow suppression by chronic hepatitis C infection, and antiviral

treatment with interferon-based therapy. Reductions in the level or activity of the hematopoietic growth factor thrombo-poietin (TPO) may also play a role. Thrombocytopenia can impact routine care of patients with CLD, potentially post-

poning or interfering with diagnostic and therapeutic procedures including liver biopsy, antiviral therapy, and medically

indicated or elective surgery. Therapeutic options to safely and effectively raise platelet levels could have a significant effect

on care of these patients. Several promising novel agents that stimulate TPO and increase platelet levels, such as the oral

platelet growth factor eltrombopag, are currently in development for the prevention and/or treatment of thrombocytopenia.

The ability to increase platelet levels could significantly reduce the need for platelet transfusions and facilitate the use of

interferon-based antiviral therapy and other medically indicated treatments in patients with liver disease.

� 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Keywords: Chronic liver disease; Cirrhosis; Cytopenia; Platelets; Thrombocytopenia; Thrombopoietin; Platelet transfusion

0168-8278/$34.00 � 2008 European Association for the Study of the Liver.

doi:10.1016/j.jhep.2008.03.009

Associate Editor: M. Colomboq The authors acknowledge that this article is from the proceedings

of a round table discussion sponsored by Glaxo Smith Kline. NA, JB,RB, IJ and FP have received research support from GSK.

* Corresponding author. Tel.: +1 617 632 1069; fax: +1 617 6321125.

E-mail address: nafdhal@bidmc.harvard.edu (N. Afdhal).Abbreviations: ITP, immune thrombocytopenic purpura; IFN-a,

interferon alfa; TPO, thrombopoietin; TIPSS, transjugular intrahe-patic portosystemic stent shunt; HIV, human immunodeficiency virus;PT, prothrombin time; PTT, partial thromboplastin time; IL, inter-leukin; PEG-rHuMGDF, pegylated recombinant human megakaryo-cyte growth and development factor; rhTPO, recombinant humanthrombopoietin.

1. Introduction

Thrombocytopenia (platelet counts <150,000/lL) is acommon complication in patients with chronic liver dis-ease (CLD), reported in as many as 76% of cirrhoticpatients [1]. Platelets play an important role in hemosta-sis that has been the subject of a recent comprehensivereview [2]. The clinical significance of mild thrombocy-topenia (>75,000/lL–<150,000/lL) is minimal and usu-ally does not interfere with treatment or managementdecisions. Moderate thrombocytopenia (50,000/lL–75,000/lL) is observed in approximately 13% of cir-rhotic patients. Severe thrombocytopenia (<50,000/lL)can be associated with significant morbidity, oftencomplicating the medical management of patients with

Published by Elsevier B.V. All rights reserved.

N. Afdhal et al. / Journal of Hepatology 48 (2008) 1000–1007 1001

advanced liver disease [1,3], cancer [4], immune throm-bocytopenic purpura (ITP) [5], chronic hepatitis C virus(HCV) infection [6], and other disorders. Severe throm-bocytopenia requiring platelet transfusions occurs in 1%of patients. While mild to moderate thrombocytopeniararely leads to spontaneous bleeding during invasiveprocedures including liver biopsy [7,8] and liver trans-plantation [1], severe thrombocytopenia can signifi-cantly increase the risk of bleeding. Cerebralhemorrhage or hemorrhage from gastrointestinal (GI)sources is rare but can be fatal [7,8].

This review focuses on the causes of thrombocytope-nia, its impact, and its clinical significance for routinepatient care. This review also describes some novel treat-ment options.

2. Aetiology, consequences, and approaches to the

evaluation of thrombocytopenia

2.1. Aetiology

In patients with CLD or HCV, the pathogenesis ofthrombocytopenia is multifactorial. Possible causesinclude splenic sequestration of platelets, suppressionof platelet production in the bone marrow, anddecreased activity of the hematopoietic growth factorthrombopoietin (TPO) (Fig. 1). Historically, thrombo-cytopenia was thought to arise from increased poolingof platelets in the enlarged spleen due to portal hyper-tension [9,10]. However, treatments aimed at reversingportal hypertension do not always correct thrombocyto-penia, and decreased platelet production has been notedin patients without hypersplenism [11], suggesting thatother factors are involved. Increased destruction ofplatelets within the spleen, intrasplenic production ofautoantibodies, and plasma expansion resulting inhemodilution can also contribute to thrombocytopeniaas well as other cytopenias [10]. However, the absoluteplatelet number is not the only variable since there isalso a degree of thrombocytopathy due to defectivethromboxane A2 synthesis and abnormalities of theplatelet glycoprotein Ib [2]. There is a resulting increasein the bleeding time in 40% of cirrhotic patients, the clin-ical significance of which is unknown and it is alsounclear whether platelet factors can account for the pro-longed bleeding time. Tripodi et al. have, in fact, sug-gested that traditional tests to determine the risk ofhemorrhage such as bleeding time may have little rolein the evaluation of bleeding risk in cirrhotic patients [2].

Suppression of platelet production in the bone mar-row is also multifactorial and can be caused by theunderlying aetiology of the liver disease (e.g., HCV oralcohol) [12,13]. In CLD patients, autoantibodies direc-ted against platelet surface antigens can enhanceremoval of platelets by the splenic and hepatic reticulo-

endothelial systems and trigger their rapid destruction,as observed in chronic ITP [14]. In one small study ofpatients with chronic HCV, an increased prevalence ofITP was observed [15].

It is well established that antiviral therapy with inter-feron alfa (IFN-a) induces thrombocytopenia, necessi-tating dose reductions [16]. In two recent studies ofpatients with HCV, downward dose modifications wererequired in up to 6% of patients treated with PEG-IFN[17,18] and this is even more common in patients withHCV-related cirrhosis in which dose modification anddiscontinuation were necessary in 19% and 2% ofpatients, respectively [19]. Dose modification of IFNdue to thrombocytopenia and other hematological com-plications may result in a reduction in sustained virolog-ical response (SVR) [20].

2.2. Thrombocytopenia and coagulopathies of liver disease

Coagulopathies, defined as defects in clotting, arecommonly observed in patients with decompensated cir-rhosis and acute liver failure. Coagulopathy often resultsfrom liver damage and/or loss of liver synthetic func-tion, leading to diminished capacity to produce clottingfactors (e.g., factors I (fibrinogen), II (prothrombin), V,VII, IX, X, XI, protein C, and antithrombin) andincreased bleeding risk. Platelets have a dual role inhemostasis. During primary hemostasis, platelets adhereto the subendothelium at the site of liver injury throughthe adhesive protein von Willebrand factor (vWF) andthen platelets aggregate with each other through vWFand/or fibrinogen, producing the platelet plug. Recentobservations suggest that patients with chronic liver dis-ease have elevated levels of vWF [21] and that increasedvWF may at least partially compensate for decreasednumbers of platelets and/or reduced functional capacity.During secondary hemostasis (coagulation), plateletsexpose on their surface negatively charged phospholip-ids that act as receptors for the plasmatic coagulationfactors, thus triggering thrombin generation, fibrin for-mation, and platelet plug stabilization.

The current therapeutic approach is to identify thedeficient factors contributing to coagulopathy andreplace these deficient factors using platelets, fresh-fro-zen plasma, or cryoprecipitates as appropriate [22,23].

2.3. Role of TPO

TPO is a potent cytokine that regulates megakaryo-cyte and platelet production. TPO, produced primarilyin the liver but also in the bone marrow and kidney,binds to the TPO receptor (TPO-R) expressed on thesurface of stem cells, megakaryocyte progenitor cells,megakaryocytes, and platelets. TPO acts at all stagesof thrombopoiesis to regulate the development and mat-uration of megakaryocytes and subsequent release of

Fig. 1. Multiple factors can cause or contribute to the development of thrombocytopenia in patients with chronic liver disease. These include portal

hypertension with resulting hypersplenism, cirrhosis, hepatocellular carcinoma and chemotherapy, anti-platelet antibodies, decreased levels or activity of

the platelet growth factor thrombopoietin, and bone marrow suppression of thrombopoiesis due to antiviral therapy (e.g., IFN) and/or direct

myelosuppressive effects of HCV infection.

1002 N. Afdhal et al. / Journal of Hepatology 48 (2008) 1000–1007

platelets (Fig. 2) [24,25]. Depending on the stage ofmegakaryopoiesis, TPO can synergize with other cyto-kines such as IL-3, IL-11, erythropoietin, and granulo-cyte colony-stimulating factor (G-CSF) to promotemegakaryocyte proliferation and differentiation and ery-throid development. Additionally, TPO enhances plate-let activation and function.

Decreases in the level and/or activity of TPO mayplay a role in the pathogenesis of thrombocytopenia.In healthy subjects, circulating TPO levels are inverselyrelated to platelet count. Cirrhotic patients with throm-bocytopenia have lower circulating TPO levels than cir-rhotic patients with normal platelet counts, possibly as aresult of diminished TPO production. Response to TPOmay also be blunted in these patients [26]. Following

successful liver transplantation or splenic embolization,TPO levels appear to normalize, suggesting thatincreased TPO degradation by platelets sequestered inthe spleen may also contribute to thrombocytopenia incirrhotic patients [27].

3. Clinical significance and sequelae of thrombocytopenia

Thrombocytopenia has been used as a marker ofadvanced liver fibrosis and portal hypertension for manyyears, but surprisingly little is known about the clinicalsignificance of low counts. In particular, little is knownabout the impact of thrombocytopenia on either intrace-rebral bleeding or variceal bleeding in cirrhosis [28–31].

Fig. 2. Role of thrombopoietin in megakaryopoiesis and thrombopoiesis.

Thrombopoietin has a central role in regulating the megakaryocyte

maturation and development, acting at all stages of megakaryopoiesis. In

concert with other hematopoietic cytokines and growth factors such as

interleukin (IL)-3, IL-6, IL-11, erythropoietin, granulocyte colony-

stimulating factor (G-CSF), leukemia inhibitory factor, and steel factor,

thrombopoietin promotes the growth and differentiation of megakaryo-

cytes from bone marrow progenitor cells, culminating in the production

and release of platelets. Reprinted with permission from Kaushansky K,

N Engl J Med 1998;339:746–754.

N. Afdhal et al. / Journal of Hepatology 48 (2008) 1000–1007 1003

4. Procedures in patients with thrombocytopenia

CLD patients often require numerous medical proce-dures during diagnosis and therapy (Table 1) and thepresence of thrombocytopenia can significantly compli-cate routine patient care for these patients resulting indelayed or cancelled procedures. While liver biopsiesin CLD patients are generally associated with a low(0.3%) risk of bleeding complications [32], the numberof procedures postponed due to concern over such pos-sible complications is unknown. Many physiciansrequire platelet counts of P80,000/lL to safely performa percutaneous liver biopsy, but the data on the safety oflaparoscopic and transjugular liver biopsies suggeststhat few complications occur with a platelet count above50,000/lL [33–36].

In a retrospective analysis of 608 large-volume para-centesis (LVP) or thoracentesis procedures, the risk ofbleeding complications was not elevated in patients withmild to moderate thrombocytopenia or mild coagulopa-thies [37]. However, hemoglobin decreases occurred in8% of patients with severe thrombocytopenia comparedwith only 3% of patients with platelet counts P50,000/lL. In 628 thrombocytopenic patients (513 with cirrho-sis) undergoing LVP, no significant complications werenoted [38]. In a study in which 4729 patients with liverdisease-related ascites underwent abdominal paracente-sis, severe bleeding occurred in <0.2% of proceduresand was unrelated to platelet count or elevated INR(international normalized ratio) [39]. All available datasuggest that the invasive procedures (e.g., liver biopsy,large-volume parancentesis, thoracentesis, and dentalprocedures) may be performed in patients with plateletcounts P50,000/lL with little risk of bleeding. Thereis no consensus on the safety of procedures in patientswith platelet counts 620,000/lL. Guidelines are clearlyneeded to guide the practitioner.

5. Evidence-based therapy

Current treatment options for severe thrombocytope-nia include platelet transfusion, splenic artery emboliza-tion, splenectomy, and placement of a transjugularintrahepatic portosystemic stent shunt (TIPSS).

Patients with platelet counts below 50,000/lL maybenefit from prophylactic transfusions to increase plate-let counts above 50,000/lL before procedures. Guide-lines for when to use platelet transfusions areavailable, but the relevance of these published guidelinesfor CLD patients is unclear. The American Society ofClinical Oncology recommends platelet transfusionsfor cancer patients with platelet counts of 10,000/lL–20,000/lL, depending on the type of cancer [41]. Cur-rently, there is no consensus on the appropriate thresh-old values for prophylactic platelet transfusions in CLD

Table 1

Risk of bleeding or worsened thrombocytopenia with medical procedures/therapies in patients with thrombocytopenia, malignancies, and/or chronic liver

disease

Procedure Patient population studied Comments

Liver biopsy� Percutaneous liver biopsy [33]� Laparoscopic liver biopsy [34,35]� Transjugular liver biopsy [36]

291 patients with mild hemostatic abnormalities Bleeding risk greatest in patients withmalignancy�50 procedures in each of 2 studies

50 patients with severe thrombocytopeniaParacentesis/thoracentesis [37–39] 608 procedures in patients with mild to moderate

thrombocytopenia [37]; 628 thrombocytopenicpatients (513 with cirrhosis) [38]; 4729 patientswith liver disease-related ascites [39]

Low risk of bleeding complications if platelets>50,000/lL

IFN-based HCV antiviral therapy IFN therapy causes reductions in platelet countsin chronic HCV patients with and withoutcirrhosis [26]

Recommendations from AGA [5]: dosereduction of PEG-IFN-a2a for platelets25,000–50,000/lL, discontinuation if<25,000/lLDose reduction of PEG-IFN-a2b for platelets680,000/lL, discontinuation if 650,000/lL

Dental procedures [40] 142 dental extractions in patients withhematologic malignancies

Thrombocytopenia (platelet counts <100,000/lL) occurred in 80/142 extractions

Various medically indicated procedures� Cosmetic, emergency, or elective surgery� Prostate biopsy� Polypectomy/cholecystectomy

Low level of bleeding risk that maycomplicate and/or require postponement ofscheduled procedures

PT, prothrombin time.

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patients. The cut-off value varies considerably (e.g.,<20,000/lL, <50,000/lL, or <100,000/lL), dependingon the clinical setting and procedure planned. Whilelow cut-off values (<10,000/lL) may be appropriatefor uncomplicated thrombocytopenic patients, otherpatients (e.g., postsurgery or those with high fever,splenomegaly, or infection) often require higher platelettransfusion triggers (<50,000/lL or <100,000/lL)[42,43]. Complications and limitations of platelet trans-fusion include febrile nonhemolytic and allergic reac-tions, need for hospitalization, iron overload (withchronic transfusions), risk of infection, platelet refracto-riness due to HLA alloimmunization (occurring in up to40% of patients), and cost [44,45]. Furthermore, platelettransfusions do not ensure a hemostatic platelet level,especially when the risk of bleeding is highest [41].

Splenic artery embolization and splenectomy areoften, but not always, effective in increasing plateletcounts in patients with portal hypertension. Possiblecomplications of these procedures include splenicabscesses and portal vein thrombosis. TIPSS placementcan decrease sinusoidal portal pressure, but it is unclearif portal decompression can reduce the degree of throm-bocytopenia in cirrhotic patients [46,47].

6. Agents targeting the TPO receptor

The central role TPO plays in regulating thrombopoi-esis and the observed alterations in TPO production oractivity in patients with CLD suggest that TPO can

serve as a rational therapeutic target to stimulate plate-let production. Research has focused on developingcompounds specifically to stimulate TPO activity inorder to prevent or treat thrombocytopenia in CLDand other diseases. Several types of TPO agonists andtargeted agents have been evaluated, including IL-11,recombinant TPO, TPO mimetics, and other agents(Table 2).

6.1. IL-11

Interleukin-11, normally produced by bone marrowstromal cells, stimulates megakaryocyte maturation andplatelet production. Subcutaneous injection of recombi-nant human IL-11 (rhIL-11) stimulates progenitor stemcells and production of megakaryocytes and platelets,decreasing the incidence of severe thrombocytopenia.An open-label, phase II trial evaluated rhIL-11 in combi-nation with IFN in 13 previously treated or treatment-naı̈ve HCV patients with low platelet counts (30,000/lL–100,000/lL) [48]. All 10 patients who completed atleast 24 weeks of therapy maintained platelet counts>40,000/lL, with increases observed as early as week 2.HCV viral load decreased significantly throughouttreatment. rhIL-11 has been approved by the FDA forprevention of severe thrombocytopenia following myelo-suppressive chemotherapy for solid tumors. rhIL-11 cancause significant toxicities, including edema, fluid reten-tion, and cardiovascular events, and in some studies,myalgias and arthralgias, and it is relatively costly (esti-mated $5328 over a 3-week cycle of chemotherapy) [49].

Table 2

Investigational TPO-R agonists for treatment of TCP in CLD

Agent Class Activity Status

rhIL-11 Recombinant humaninterleukin-11

Modest increase in platelet counts,but can be associated with significanttoxicity and high cost

Approved for prevention of severeTCP following myelosuppressivechemotherapy for solid tumors

Eltrombopag Small-molecule plateletgrowth factor

Dose-dependent increase in plateletcounts, allowing initiation of HCVantiviral therapy

Phase II/III

rhTPO Recombinant humanthrombopoietin

Dose-dependent stimulation ofthrombopoiesis andmegakaryopoiesis

Clinical development halted

PEG-rHuMGDF Pegylated recombinant humanmegakaryocyte growth anddevelopment factor

Stimulates thrombopoiesis andmegakaryopoiesis, and enhancesplatelet recovery from chemotherapy

Clinical development halted due toneutralizing anti-TPO antibodies

Promegapoietin TPO agonist Increase in platelet counts whenadministered before chemotherapy

Clinical development halted due toneutralizing anti-TPO antibodies

NIP-004, AMG 531,AKR-501

TPO mimetics Platelet responses observed withsome agents to date

Phase I/II

N. Afdhal et al. / Journal of Hepatology 48 (2008) 1000–1007 1005

Other cytokines (e.g., IL-1, IL-3, and IL-6) exertpotent thrombopoietic activity and can stimulate plate-let production. Their clinical utility has been severelylimited by significant proinflammatory properties thatinduce flu-like symptoms including hypotension, fati-gue, and myalgias [50].

6.2. Eltrombopag

Eltrombopag is a small-molecule nonpeptide oralplatelet growth factor that acts as a TPO-R agonist.Binding of eltrombopag to the transmembrane domainof the TPO receptor activates intracellular signal trans-duction pathways that stimulate megakaryocyte prolif-eration and differentiation and increase platelet countsin a dose-dependent manner in healthy subjects andpatients with chronic ITP [51,52].

A phase II multicenter, randomized trial of dailyeltrombopag in patients with HCV-associated thrombo-cytopenia and compensated liver disease showed thatafter 4 weeks of therapy, platelet count increases toP100,000/lL were achieved in 75%, 79%, and 95% ofpatients treated with 30 mg, 50 mg, and 75 mg eltrombo-pag, respectively, compared to 0% of placebo patients(P < 0.001) [53]. Significantly more patients in theeltrombopag treatment groups (36%, 53%, and 65% inthe 30-mg, 50-mg, and 75-mg groups) completed 12weeks of antiviral therapy compared with 6% of placebopatients and 75% of these patients had platelet countsabove baseline values at the end of the antiviral treat-ment phase.

6.3. Recombinant TPO and other thrombopoietic agents

Two forms of recombinant human thrombopoietinhave been evaluated in clinical trials and shown toincrease megakaryopoiesis and thrombopoiesis: recom-

binant human TPO (rhTPO) and pegylated recombinanthuman megakaryocyte growth and development factor(PEG-rHuMGDF). rhTPO is a genetically engineered,full-length, glycosylated form of thrombopoietin thatcan significantly increase platelet counts, but reductionof thrombocytopenia is not always accompanied by adecrease in platelet transfusions [54].

PEG-rHuMGDF is an N-terminal TPO derivativethat is pegylated to extend its half-life and retain TPOactivity [25,55]. In initial trials in patients undergoingchemotherapy, PEG-rHuMGDF treatment increasedmedian platelet nadir counts and enhanced recovery ina dose-dependent manner [56–58]. Phase II trials dem-onstrated promising results for mobilization prior tostem cell transplantation [25]. However, some subjectsincluding normal platelet donors treated with PEG-rHu-MGDF developed neutralizing antibodies that cross-reacted with and inactivated endogenous TPO, resultingin severe thrombocytopenia, which resulted in termina-tion of clinical development of this drug [54].

Various other thrombopoietic compounds are in theearly stages of clinical development for the treatment ofthrombocytopenia. TPO mimetics (e.g., NIP-004, AMG531, and AKR-501) are small molecules that bind toand activate the TPO receptor, but because they do notshare sequence homology with TPO should not triggeran antigenic reaction [55,59,60]. The clinical potential ofthese agents in the treatment of thrombocytopenia inCLD patients remains to be determined.

7. Conclusions

Thrombocytopenia can adversely affect treatment ofCLD, limiting the ability to administer therapy anddelaying planned surgical/diagnostic procedures becauseof an increased risk of bleeding. The development of

1006 N. Afdhal et al. / Journal of Hepatology 48 (2008) 1000–1007

consensus guidelines defining threshold platelet countsin CLD patients below which procedures should bedelayed or below which platelet transfusions or plate-let-stimulating agents should be utilized needs to bedefined. Novel TPO-R agonists including eltrombopaghave a significant potential as both therapy and prophy-laxis in various clinical settings for patients with CLDand require further clinical investigation.

Acknowledgement

We would like to thank Mary Dominiecki for help inpreparation of this manuscript.

References

[1] Giannini EG. Review article: thrombocytopenia in chronic liverdisease and pharmacologic treatment options. Aliment PharmacolTher 2006;23:1055–1065.

[2] Tripodi A, Mannucci PM. Abnormalities of hemostasis in chronicliver disease: reappraisal of their clinical significance and need forclinical and laboratory research. J Hepatol 2007;46:727–733.

[3] Peck-Radosavljevic M. Thrombocytopenia in liver disease. Can JGastroenterol 2000;14:60D–66D.

[4] Heyman MR, Schiffer CA. Platelet transfusion therapy for thecancer patient. Semin Oncol 1990;17:198–209.

[5] George JN. Idiopathic thrombocytopenic purpura: current issuesfor pathogenesis, diagnosis, and management in children andadults. Curr Hematol Rep 2003;2:381–387.

[6] Dienstag JL, McHutchison JG. American GastroenterologicalAssociation technical review on the management of hepatitis C.Gastroenterology 2006;130:231–264.

[7] Madhotra R, Mulcahy HE, Willner I, Reuben A. Prediction ofesophageal varices in patients with cirrhosis. J Clin Gastroenterol2002;34:81–85.

[8] Thomopoulos KC, Labropoulou-Karatza C, Mimidis KP, Kat-sakoulis EC, Iconomou G, Nikolopoulou VN. Non-invasivepredictors of the presence of large oesophageal varices in patientswith cirrhosis. Dig Liver Dis 2003;35:473–478.

[9] Aster RH. Pooling of platelets in the spleen: role in thepathogenesis of ‘‘hypersplenic” thrombocytopenia. J Clin Invest1966;45:645–657.

[10] Toghill P. The syndromes of splenic dysfunction: a clinicaloverview. In: Bowdler AJ, editor. The spleen: structure, functionand clinical significance. New York, NY: Chapman & Hall; 1990. p.209–232.

[11] Garcia-Suarez J, Burgaleta C, Hernanz N, Albarran F, TobaruelaP, Alvarez-Mon M. HCV-associated thrombocytopenia: clinicalcharacteristics and platelet response after recombinant alpha2b-interferon therapy. Br J Haematol 2000;110:98–103.

[12] Wang CS, Yao WJ, Wang ST, Chang TT, Chou P. Strongassociation of hepatitis C virus (HCV) infection and thrombocy-topenia: implications from a survey of a community withhyperendemic HCV infection. Clin Infect Dis 2004;39:790–796.

[13] Ballard HS. Hematological complications of alcoholism. AlcoholClin Exp Res 1989;13:706–720.

[14] Pereira J, Accatino L, Alfaro J, Brahm J, Hidalgo P, Mezzano D.Platelet autoantibodies in patients with chronic liver disease. Am JHematol 1995;50:173–178.

[15] Pockros PJ, Duchini A, McMillan R, Nyberg LM, McHutchisonJ, Viernes E. Immune thrombocytopenic purpura in patients withchronic hepatitis C virus infection. Am J Gastroenterol2002;97:2040–2045.

[16] Oh S, Afdhal NH. Antiviral therapy for treatment naivepatients with hepatitis C virus. Infect Dis Clin North Am2006;20:99–113.

[17] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G,Goncales Jr FL, et al. Peginterferon alfa-2a plus ribavirin forchronic hepatitis C virus infection. N Engl J Med2002;347:975–982.

[18] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, ShiffmanM, Reindollar R, et al. Peginterferon alfa-2b plus ribavirincompared with interferon alfa-2b plus ribavirin for initial treat-ment of chronic hepatitis C: a randomised trial. Lancet2001;358:958–965.

[19] Heathcote EJ, Shiffman ML, Cooksley WG, Dusheiko GM,Lee SS, Balart L, et al. Peginterferon alfa-2a in patients withchronic hepatitis C and cirrhosis. N Engl J Med 2000;343:1673–1680.

[20] McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL,Trepo C, et al. Adherence to combination therapy enhancessustained response in genotype-1-infected patients with chronichepatitis C. Gastroenterology 2002;123:1061–1069.

[21] Lisman T, Bongers TN, Adelmeijer J, Janssen HL, de Maat MP,de Groot PG, et al. Elevated levels of von Willebrand factor incirrhosis support platelet adhesion despite reduced functionalcapacity. Hepatology 2006;44:53–61.

[22] Drews RE. Critical issues in hematology: anemia, thrombocyto-penia, coagulopathy, and blood product transfusions in criticallyill patients. Clin Chest Med 2003;24:607–622.

[23] Humphries JE. Transfusion therapy in acquired coagulopathies.Hematol Oncol Clin North Am 1994;8:1181–1201.

[24] Kaushansky K. Thrombopoietin. N Engl J Med1998;339:746–754.

[25] Kuter DJ, Begley CG. Recombinant human thrombopoietin:basic biology and evaluation of clinical studies. Blood2002;100:3457–3469.

[26] Peck-Radosavljevic M, Wichlas M, Pidlich J, Sims P, Meng G,Zacherl J, et al. Blunted thrombopoietin response to interferonalfa-induced thrombocytopenia during treatment for hepatitis C.Hepatology 1998;28:1424–1429.

[27] Rios R, Sangro B, Herrero I, Quiroga J, Prieto J. The role ofthrombopoietin in the thrombocytopenia of patients with livercirrhosis. Am J Gastroenterol 2005;100:1311–1316.

[28] Wang WL, Yang ZF, Lo CM, Liu CL, Fan ST. Intracerebralhemorrhage after liver transplantation. Liver Transpl2000;6:345–348.

[29] Wijdicks EF, de Groen PC, Wiesner RH, Krom RA. Intracerebralhemorrhage in liver transplant recipients. Mayo Clin Proc1995;70:443–446.

[30] Maltz GS, Siegel JE, Carson JL. Hematologic management ofgastrointestinal bleeding. Gastroenterol Clin North Am2000;29:169–187.

[31] Goh SH, Tan WP, Lee SW. Clinical predictors of bleedingesophageal varices in the ED. Am J Emerg Med 2005;23:531–535.

[32] Friedman LS. Controversies in liver biopsy: who, where, when,how, why? Curr Gastroenterol Rep 2004;6:30–36.

[33] McVay PA, Toy PT. Lack of increased bleeding after liver biopsyin patients with mild hemostatic abnormalities. Am J Clin Pathol1990;94:747–753.

[34] Cobb WS, Heniford BT, Burns JM, Carbonell AM, MatthewsBD, Kercher KW. Cirrhosis is not a contraindication to laparo-scopic surgery. Surg Endosc 2005;19:418–423.

[35] Inabnet WB, Deziel DJ. Laparoscopic liver biopsy in patients withcoagulopathy, portal hypertension, and ascites. Am Surg1995;61:603–606.

[36] Wallace MJ, Narvios A, Lichtiger B, Ahrar K, Morello Jr FA,Gupta S, et al. Transjugular liver biopsy in patients withhematologic malignancy and severe thrombocytopenia. J VascInterv Radiol 2003;14:323–327.

N. Afdhal et al. / Journal of Hepatology 48 (2008) 1000–1007 1007

[37] McVay PA, Toy PT. Lack of increased bleeding after paracentesisand thoracentesis in patients with mild coagulation abnormalities.Transfusion 1991;31:164–171.

[38] Grabau CM, Crago SF, Hoff LK, Simon JA, Melton CA, Ott BJ,et al. Performance standards for therapeutic abdominal paracen-tesis. Hepatology 2004;40:484–488.

[39] Pache I, Bilodeau M. Severe haemorrhage following abdominalparacentesis for ascites in patients with liver disease. AlimentPharmacol Ther 2005;21:525–529.

[40] Williford SK, Salisbury 3rd PL, Peacock Jr JE, Cruz JM, PowellBL, Lyerly ES, et al. The safety of dental extractions in patientswith hematologic malignancies. J Clin Oncol 1989;7:798–802.

[41] Schiffer CA, Anderson KC, Bennett CL, Bernstein S, Elting LS,Goldsmith M, et al. Platelet transfusion for patients with cancer:clinical practice guidelines of the American Society of ClinicalOncology. J Clin Oncol 2001;19:1519–1538.

[42] Rebulla P. Trigger for platelet transfusion. Vox Sang2000;78:179–182.

[43] Rinder HM, Arbini AA, Snyder EL. Optimal dosing and triggersfor prophylactic use of platelet transfusions. Curr Opin Hematol1999;6:437–441.

[44] McCullough J. Current issues with platelet transfusion in patientswith cancer. Semin Hematol 2000;37 (2 Suppl. 4):3–10.

[45] Perrotta PL, Snyder EL. Non-infectious complications of trans-fusion therapy. Blood Rev 2001;15:69–83.

[46] Wong F. The use of TIPS in chronic liver disease. Ann Hepatol2006;5:5–15.

[47] Jabbour N, Zajko A, Orons P, Irish W, Fung JJ, Selby RR. Doestransjugular intrahepatic portosystemic shunt (TIPS) resolvethrombocytopenia associated with cirrhosis? Dig Dis Sci1998;43:2459–2462.

[48] Rustgi VK, Lee P, Finnegan S, Ershler W. Safety and efficacy ofrecombinant human IL-11 (oprelvekin) in combination withinterferon/ribavirin therapy in hepatitis C patients with throm-bocytopenia. Annual Meeting of the American Society of Hema-tology; 2002; Philadelphia, PA. Blood 2002;100:361A.

[49] Cantor SB, Elting LS, Hudson Jr DV. Rubenstein EB. Pharmaco-economic analysis of oprelvekin (recombinant human interleukin-11) for secondary prophylaxis of thrombocytopenia in solid tumorpatients receiving chemotherapy. Cancer 2003;97:3099–3106.

[50] Demetri GD. Targeted approaches for the treatment of throm-bocytopenia. Oncologist 2001;6 (Suppl. 5):15–23.

[51] Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B,et al. Eltrombopag for the treatment of chronic idiopathicthrombocytopenic purpura. N Engl J Med 2007;357:2237–2247.

[52] Jenkins JM, Williams D, Deng Y, Uhl J, Kitchen V, Collins D,et al. Phase 1 clinical study of eltrombopag, an oral, nonpeptidethrombopoietin receptor agonist. Blood 2007;109:4739–4741.

[53] McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-TorresM, Sigal S, Bourliere M, et al. Eltrombopag for thrombocytope-nia in patients with cirrhosis associated with hepatitis C. N Engl JMed 2007;357:2227–2236.

[54] Vadhan-Raj S, Patel S, Bueso-Ramos C, Folloder J, Papadopo-lous N, Burgess A, et al. Importance of predosing of recombinanthuman thrombopoietin to reduce chemotherapy-induced earlythrombocytopenia. J Clin Oncol 2003;21:3158–3167.

[55] Vadhan-Raj S, Cohen V, Bueso-Ramos C. Thrombopoieticgrowth factors and cytokines. Curr Hematol Rep 2005;4:137–144.

[56] Basser RL, Rasko JE, Clarke K, Cebon J, Green MD, GriggAP, et al. Randomized, blinded, placebo-controlled phase Itrial of pegylated recombinant human megakaryocyte growthand development factor with filgrastim after dose-intensivechemotherapy in patients with advanced cancer. Blood1997;89:3118–3128.

[57] Basser RL, Rasko JE, Clarke K, Cebon J, Green MD, Hussein S,et al. Thrombopoietic effects of pegylated recombinant humanmegakaryocyte growth and development factor (PEG-rHu-MGDF) in patients with advanced cancer. Lancet1996;348:1279–1281.

[58] Hunt P, Li YS, Nichol JL, Hokom MM, Bogenberger JM, SwiftSE, et al. Purification and biologic characterization of plasma-derived megakaryocyte growth and development factor. Blood1995;86:540–547.

[59] Inagaki K, Oda T, Naka Y, Shinkai H, Komatsu N, Iwamura H.Induction of megakaryocytopoiesis and thrombocytopoiesis byJTZ-132, a novel small molecule with thrombopoietin mimeticactivities. Blood 2004;104:58–64.

[60] Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, et al.Thrombocytopenia caused by the development of antibodies tothrombopoietin. Blood 2001;98:3241–3248.