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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 dHebron, Universitat Autonoma de Barcelona, Barcelona, Spain

Thrombocytopenia (platelet count

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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 invasive

procedures 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 reversing

portal 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 vWF

and/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

N. Afdhal et al. / Journal of Hepatology 48 (2008) 10001007 1001

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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[2831].

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.

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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 in

delayed 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 ofP80,000/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[3336].

In a retrospective analysis of 608 large-volume para-centesis (LVP) or thoracentesis procedures, the risk ofbleeding complications was not elevated in patients with

mild 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

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patients. The cut-off value varies considerably (e.g.,

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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 domain

of 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 in

a dose-dependent manner [5658]. 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

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 platelet

growth factor

Dose-dependent increase in platelet

counts, 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


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