Journal of Hepatology 48 (2008) 10001007 www.elsevier.

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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
Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA 2 Duke University Medical Center, Durham, NC, USA 3 Columbia University Medical Center, New York, NY, USA 4 Weill Medical College of Cornell University, New York, NY, USA 5 Medizinische Hochschule Hannover, Hannover, Germany 6 Cedars-Sinai Medical Center, Center for Liver Disease and Transplantation, Los Angeles, CA, USA 7 Hospital Universitari Vall dHebron, Universitat Autonoma de Barcelona, Barcelona, Spain
1

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/lL75,000/lL) occurs in approximately 13% of patients with cirrhosis. Multiple factors can contribute to the development of thrombocytopenia, 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 thrombopoietin (TPO) may also play a role. Thrombocytopenia can impact routine care of patients with CLD, potentially postponing or interfering with diagnostic and therapeutic procedures including liver biopsy, antiviral therapy, and medically indicated or elective surgery. Therapeutic options to safely and eectively raise platelet levels could have a signicant eect 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 signicantly 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

1. Introduction Thrombocytopenia (platelet counts <150,000/lL) is a common complication in patients with chronic liver disease (CLD), reported in as many as 76% of cirrhotic patients [1]. Platelets play an important role in hemostasis that has been the subject of a recent comprehensive review [2]. The clinical signicance of mild thrombocytopenia (>75,000/lL<150,000/lL) is minimal and usually does not interfere with treatment or management decisions. Moderate thrombocytopenia (50,000/lL 75,000/lL) is observed in approximately 13% of cirrhotic patients. Severe thrombocytopenia (<50,000/lL) can be associated with signicant morbidity, often complicating the medical management of patients with

Associate Editor: M. Colombo q 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: +1 617 632 1125. E-mail address: nafdhal@bidmc.harvard.edu (N. Afdhal). Abbreviations: ITP, immune thrombocytopenic purpura; IFN-a, interferon alfa; TPO, thrombopoietin; TIPSS, transjugular intrahepatic portosystemic stent shunt; HIV, human immunodeciency virus; PT, prothrombin time; PTT, partial thromboplastin time; IL, interleukin; PEG-rHuMGDF, pegylated recombinant human megakaryocyte growth and development factor; rhTPO, recombinant human thrombopoietin.

0168-8278/$34.00 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2008.03.009

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advanced liver disease [1,3], cancer [4], immune thrombocytopenic purpura (ITP) [5], chronic hepatitis C virus (HCV) infection [6], and other disorders. Severe thrombocytopenia requiring platelet transfusions occurs in 1% of patients. While mild to moderate thrombocytopenia rarely leads to spontaneous bleeding during invasive procedures including liver biopsy [7,8] and liver transplantation [1], severe thrombocytopenia can signicantly increase the risk of bleeding. Cerebral hemorrhage or hemorrhage from gastrointestinal (GI) sources is rare but can be fatal [7,8]. This review focuses on the causes of thrombocytopenia, its impact, and its clinical signicance for routine patient care. This review also describes some novel treatment options.

endothelial systems and trigger their rapid destruction, as observed in chronic ITP [14]. In one small study of patients with chronic HCV, an increased prevalence of ITP was observed [15]. It is well established that antiviral therapy with interferon alfa (IFN-a) induces thrombocytopenia, necessitating dose reductions [16]. In two recent studies of patients with HCV, downward dose modications were required in up to 6% of patients treated with PEG-IFN [17,18] and this is even more common in patients with HCV-related cirrhosis in which dose modication and discontinuation were necessary in 19% and 2% of patients, respectively [19]. Dose modication of IFN due to thrombocytopenia and other hematological complications may result in a reduction in sustained virological response (SVR) [20]. 2.2. Thrombocytopenia and coagulopathies of liver disease Coagulopathies, dened as defects in clotting, are commonly observed in patients with decompensated cirrhosis and acute liver failure. Coagulopathy often results from liver damage and/or loss of liver synthetic function, leading to diminished capacity to produce clotting factors (e.g., factors I (brinogen), II (prothrombin), V, VII, IX, X, XI, protein C, and antithrombin) and increased bleeding risk. Platelets have a dual role in hemostasis. During primary hemostasis, platelets adhere to the subendothelium at the site of liver injury through the adhesive protein von Willebrand factor (vWF) and then platelets aggregate with each other through vWF and/or brinogen, producing the platelet plug. Recent observations suggest that patients with chronic liver disease have elevated levels of vWF [21] and that increased vWF may at least partially compensate for decreased numbers of platelets and/or reduced functional capacity. During secondary hemostasis (coagulation), platelets expose on their surface negatively charged phospholipids that act as receptors for the plasmatic coagulation factors, thus triggering thrombin generation, brin formation, and platelet plug stabilization. The current therapeutic approach is to identify the decient factors contributing to coagulopathy and replace these decient factors using platelets, fresh-frozen plasma, or cryoprecipitates as appropriate [22,23]. 2.3. Role of TPO TPO is a potent cytokine that regulates megakaryocyte and platelet production. TPO, produced primarily in the liver but also in the bone marrow and kidney, binds to the TPO receptor (TPO-R) expressed on the surface of stem cells, megakaryocyte progenitor cells, megakaryocytes, and platelets. TPO acts at all stages of thrombopoiesis to regulate the development and maturation of megakaryocytes and subsequent release of

2. Aetiology, consequences, and approaches to the evaluation of thrombocytopenia 2.1. Aetiology In patients with CLD or HCV, the pathogenesis of thrombocytopenia is multifactorial. Possible causes include splenic sequestration of platelets, suppression of platelet production in the bone marrow, and decreased activity of the hematopoietic growth factor thrombopoietin (TPO) (Fig. 1). Historically, thrombocytopenia was thought to arise from increased pooling of platelets in the enlarged spleen due to portal hypertension [9,10]. However, treatments aimed at reversing portal hypertension do not always correct thrombocytopenia, and decreased platelet production has been noted in patients without hypersplenism [11], suggesting that other factors are involved. Increased destruction of platelets within the spleen, intrasplenic production of autoantibodies, and plasma expansion resulting in hemodilution can also contribute to thrombocytopenia as well as other cytopenias [10]. However, the absolute platelet number is not the only variable since there is also a degree of thrombocytopathy due to defective thromboxane A2 synthesis and abnormalities of the platelet glycoprotein Ib [2]. There is a resulting increase in the bleeding time in 40% of cirrhotic patients, the clinical signicance of which is unknown and it is also unclear whether platelet factors can account for the prolonged bleeding time. Tripodi et al. have, in fact, suggested that traditional tests to determine the risk of hemorrhage such as bleeding time may have little role in the evaluation of bleeding risk in cirrhotic patients [2]. Suppression of platelet production in the bone marrow is also multifactorial and can be caused by the underlying aetiology of the liver disease (e.g., HCV or alcohol) [12,13]. In CLD patients, autoantibodies directed against platelet surface antigens can enhance removal of platelets by the splenic and hepatic reticulo-

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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 eects of HCV infection.

platelets (Fig. 2) [24,25]. Depending on the stage of megakaryopoiesis, TPO can synergize with other cytokines such as IL-3, IL-11, erythropoietin, and granulocyte colony-stimulating factor (G-CSF) to promote megakaryocyte proliferation and dierentiation and erythroid development. Additionally, TPO enhances platelet activation and function. Decreases in the level and/or activity of TPO may play a role in the pathogenesis of thrombocytopenia. In healthy subjects, circulating TPO levels are inversely related to platelet count. Cirrhotic patients with thrombocytopenia have lower circulating TPO levels than cirrhotic patients with normal platelet counts, possibly as a result of diminished TPO production. Response to TPO may also be blunted in these patients [26]. Following

successful liver transplantation or splenic embolization, TPO levels appear to normalize, suggesting that increased TPO degradation by platelets sequestered in the spleen may also contribute to thrombocytopenia in cirrhotic patients [27].

3. Clinical signicance and sequelae of thrombocytopenia Thrombocytopenia has been used as a marker of advanced liver brosis and portal hypertension for many years, but surprisingly little is known about the clinical signicance of low counts. In particular, little is known about the impact of thrombocytopenia on either intracerebral bleeding or variceal bleeding in cirrhosis [2831].

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4. Procedures in patients with thrombocytopenia CLD patients often require numerous medical procedures during diagnosis and therapy (Table 1) and the presence of thrombocytopenia can signicantly complicate routine patient care for these patients resulting in delayed or cancelled procedures. While liver biopsies in CLD patients are generally associated with a low (0.3%) risk of bleeding complications [32], the number of procedures postponed due to concern over such possible complications is unknown. Many physicians require platelet counts of P80,000/lL to safely perform a percutaneous liver biopsy, but the data on the safety of laparoscopic and transjugular liver biopsies suggests that few complications occur with a platelet count above 50,000/lL [3336]. In a retrospective analysis of 608 large-volume paracentesis (LVP) or thoracentesis procedures, the risk of bleeding complications was not elevated in patients with mild to moderate thrombocytopenia or mild coagulopathies [37]. However, hemoglobin decreases occurred in 8% of patients with severe thrombocytopenia compared with only 3% of patients with platelet counts P50,000/ lL. In 628 thrombocytopenic patients (513 with cirrhosis) undergoing LVP, no signicant complications were noted [38]. In a study in which 4729 patients with liver disease-related ascites underwent abdominal paracentesis, severe bleeding occurred in <0.2% of procedures and was unrelated to platelet count or elevated INR (international normalized ratio) [39]. All available data suggest that the invasive procedures (e.g., liver biopsy, large-volume parancentesis, thoracentesis, and dental procedures) may be performed in patients with platelet counts P50,000/lL with little risk of bleeding. There is no consensus on the safety of procedures in patients with platelet counts 620,000/lL. Guidelines are clearly needed to guide the practitioner.

5. Evidence-based therapy Current treatment options for severe thrombocytopenia include platelet transfusion, splenic artery embolization, splenectomy, and placement of a transjugular intrahepatic portosystemic stent shunt (TIPSS). Patients with platelet counts below 50,000/lL may benet from prophylactic transfusions to increase platelet counts above 50,000/lL before procedures. Guidelines for when to use platelet transfusions are available, but the relevance of these published guidelines for CLD patients is unclear. The American Society of Clinical Oncology recommends platelet transfusions for cancer patients with platelet counts of 10,000/lL 20,000/lL, depending on the type of cancer [41]. Currently, there is no consensus on the appropriate threshold values for prophylactic platelet transfusions in CLD

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 colonystimulating factor (G-CSF), leukemia inhibitory factor, and steel factor, thrombopoietin promotes the growth and dierentiation of megakaryocytes from bone marrow progenitor cells, culminating in the production and release of platelets. Reprinted with permission from Kaushansky K, N Engl J Med 1998;339:746754.

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Table 1 Risk of bleeding or worsened thrombocytopenia with medical procedures/therapies in patients with thrombocytopenia, malignancies, and/or chronic liver disease Procedure Liver biopsy  Percutaneous liver biopsy [33]  Laparoscopic liver biopsy [34,35]  Transjugular liver biopsy [36] Paracentesis/thoracentesis [3739] Patient population studied 291 patients with mild hemostatic abnormalities 50 procedures in each of 2 studies 50 patients with severe thrombocytopenia 608 procedures in patients with mild to moderate thrombocytopenia [37]; 628 thrombocytopenic patients (513 with cirrhosis) [38]; 4729 patients with liver disease-related ascites [39] IFN therapy causes reductions in platelet counts in chronic HCV patients with and without cirrhosis [26] Comments Bleeding risk greatest in patients with malignancy Low risk of bleeding complications if platelets >50,000/lL

IFN-based HCV antiviral therapy

Recommendations from AGA [5]: dose reduction of PEG-IFN-a2a for platelets 25,00050,000/lL, discontinuation if <25,000/lL Dose reduction of PEG-IFN-a2b for platelets 680,000/lL, discontinuation if 650,000/lL Thrombocytopenia (platelet counts <100,000/ lL) occurred in 80/142 extractions Low level of bleeding risk that may complicate and/or require postponement of scheduled procedures

Dental procedures [40] Various medically indicated procedures  Cosmetic, emergency, or elective surgery  Prostate biopsy  Polypectomy/cholecystectomy PT, prothrombin time.

142 dental extractions in patients with hematologic malignancies

patients. The cut-o value varies considerably (e.g., <20,000/lL, <50,000/lL, or <100,000/lL), depending on the clinical setting and procedure planned. While low cut-o values (<10,000/lL) may be appropriate for uncomplicated thrombocytopenic patients, other patients (e.g., postsurgery or those with high fever, splenomegaly, or infection) often require higher platelet transfusion triggers (<50,000/lL or <100,000/lL) [42,43]. Complications and limitations of platelet transfusion include febrile nonhemolytic and allergic reactions, need for hospitalization, iron overload (with chronic transfusions), risk of infection, platelet refractoriness due to HLA alloimmunization (occurring in up to 40% of patients), and cost [44,45]. Furthermore, platelet transfusions do not ensure a hemostatic platelet level, especially when the risk of bleeding is highest [41]. Splenic artery embolization and splenectomy are often, but not always, eective in increasing platelet counts in patients with portal hypertension. Possible complications of these procedures include splenic abscesses and portal vein thrombosis. TIPSS placement can decrease sinusoidal portal pressure, but it is unclear if portal decompression can reduce the degree of thrombocytopenia in cirrhotic patients [46,47].

serve as a rational therapeutic target to stimulate platelet production. Research has focused on developing compounds specically to stimulate TPO activity in order to prevent or treat thrombocytopenia in CLD and other diseases. Several types of TPO agonists and targeted 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 marrow stromal cells, stimulates megakaryocyte maturation and platelet production. Subcutaneous injection of recombinant human IL-11 (rhIL-11) stimulates progenitor stem cells and production of megakaryocytes and platelets, decreasing the incidence of severe thrombocytopenia. An open-label, phase II trial evaluated rhIL-11 in combination with IFN in 13 previously treated or treatmentna ve HCV patients with low platelet counts (30,000/ lL100,000/lL) [48]. All 10 patients who completed at least 24 weeks of therapy maintained platelet counts >40,000/lL, with increases observed as early as week 2. HCV viral load decreased signicantly throughout treatment. rhIL-11 has been approved by the FDA for prevention of severe thrombocytopenia following myelosuppressive chemotherapy for solid tumors. rhIL-11 can cause signicant toxicities, including edema, uid retention, and cardiovascular events, and in some studies, myalgias and arthralgias, and it is relatively costly (estimated $5328 over a 3-week cycle of chemotherapy) [49].

6. Agents targeting the TPO receptor The central role TPO plays in regulating thrombopoiesis and the observed alterations in TPO production or activity in patients with CLD suggest that TPO can

N. Afdhal et al. / Journal of Hepatology 48 (2008) 10001007 Table 2 Investigational TPO-R agonists for treatment of TCP in CLD Agent rhIL-11 Class Recombinant human interleukin-11 Small-molecule platelet growth factor Recombinant human thrombopoietin Pegylated recombinant human megakaryocyte growth and development factor TPO agonist TPO mimetics Activity Modest increase in platelet counts, but can be associated with signicant toxicity and high cost Dose-dependent increase in platelet counts, allowing initiation of HCV antiviral therapy Dose-dependent stimulation of thrombopoiesis and megakaryopoiesis Stimulates thrombopoiesis and megakaryopoiesis, and enhances platelet recovery from chemotherapy Increase in platelet counts when administered before chemotherapy Platelet responses observed with some agents to date Status

1005

Eltrombopag

Approved for prevention of severe TCP following myelosuppressive chemotherapy for solid tumors Phase II/III

rhTPO

Clinical development halted

PEG-rHuMGDF

Clinical development halted due to neutralizing anti-TPO antibodies Clinical development halted due to neutralizing anti-TPO antibodies Phase I/II

Promegapoietin NIP-004, AMG 531, AKR-501

Other cytokines (e.g., IL-1, IL-3, and IL-6) exert potent thrombopoietic activity and can stimulate platelet production. Their clinical utility has been severely limited by signicant proinammatory properties that induce u-like symptoms including hypotension, fatigue, and myalgias [50]. 6.2. Eltrombopag Eltrombopag is a small-molecule nonpeptide oral platelet growth factor that acts as a TPO-R agonist. Binding of eltrombopag to the transmembrane domain of the TPO receptor activates intracellular signal transduction pathways that stimulate megakaryocyte proliferation and dierentiation and increase platelet counts in a dose-dependent manner in healthy subjects and patients with chronic ITP [51,52]. A phase II multicenter, randomized trial of daily eltrombopag in patients with HCV-associated thrombocytopenia and compensated liver disease showed that after 4 weeks of therapy, platelet count increases to P100,000/lL were achieved in 75%, 79%, and 95% of patients treated with 30 mg, 50 mg, and 75 mg eltrombopag, respectively, compared to 0% of placebo patients (P < 0.001) [53]. Signicantly more patients in the eltrombopag treatment groups (36%, 53%, and 65% in the 30-mg, 50-mg, and 75-mg groups) completed 12 weeks of antiviral therapy compared with 6% of placebo patients and 75% of these patients had platelet counts above baseline values at the end of the antiviral treatment phase. 6.3. Recombinant TPO and other thrombopoietic agents Two forms of recombinant human thrombopoietin have been evaluated in clinical trials and shown to increase megakaryopoiesis and thrombopoiesis: recom-

binant human TPO (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). rhTPO is a genetically engineered, full-length, glycosylated form of thrombopoietin that can signicantly increase platelet counts, but reduction of thrombocytopenia is not always accompanied by a decrease in platelet transfusions [54]. PEG-rHuMGDF is an N-terminal TPO derivative that is pegylated to extend its half-life and retain TPO activity [25,55]. In initial trials in patients undergoing chemotherapy, PEG-rHuMGDF treatment increased median platelet nadir counts and enhanced recovery in a dose-dependent manner [5658]. Phase II trials demonstrated promising results for mobilization prior to stem cell transplantation [25]. However, some subjects including normal platelet donors treated with PEG-rHuMGDF developed neutralizing antibodies that crossreacted with and inactivated endogenous TPO, resulting in severe thrombocytopenia, which resulted in termination of clinical development of this drug [54]. Various other thrombopoietic compounds are in the early stages of clinical development for the treatment of thrombocytopenia. TPO mimetics (e.g., NIP-004, AMG 531, and AKR-501) are small molecules that bind to and activate the TPO receptor, but because they do not share sequence homology with TPO should not trigger an antigenic reaction [55,59,60]. The clinical potential of these agents in the treatment of thrombocytopenia in CLD patients remains to be determined.

7. Conclusions Thrombocytopenia can adversely aect treatment of CLD, limiting the ability to administer therapy and delaying planned surgical/diagnostic procedures because of an increased risk of bleeding. The development of

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