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Thrombocytopenia associated with chronic liver disease

Open AccessPublished:March 31, 2008DOI:https://doi.org/10.1016/j.jhep.2008.03.009
      Thrombocytopenia (platelet count <150,000/μL) 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/μL–75,000/μL) 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 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.

      Abbreviations:

      ITP (immune thrombocytopenic purpura), IFN-α (interferon alfa), TPO (thrombopoietin), TIPSS (transjugular intrahepatic portosystemic stent shunt), HIV (human immunodeficiency virus), PT (prothrombin time), PTT (partial thromboplastin time), IL (interleukin), PEG-rHuMGDF (pegylated recombinant human megakaryocyte growth and development factor), rhTPO (recombinant human thrombopoietin)

      Keywords

      1. Introduction

      Thrombocytopenia (platelet counts <150,000/μL) is a common complication in patients with chronic liver disease (CLD), reported in as many as 76% of cirrhotic patients [
      • Giannini E.G.
      Review article: thrombocytopenia in chronic liver disease and pharmacologic treatment options.
      ]. Platelets play an important role in hemostasis that has been the subject of a recent comprehensive review [
      • Tripodi A.
      • Mannucci P.M.
      Abnormalities of hemostasis in chronic liver disease: reappraisal of their clinical significance and need for clinical and laboratory research.
      ]. The clinical significance of mild thrombocytopenia (>75,000/μL–<150,000/μL) is minimal and usually does not interfere with treatment or management decisions. Moderate thrombocytopenia (50,000/μL–75,000/μL) is observed in approximately 13% of cirrhotic patients. Severe thrombocytopenia (<50,000/μL) can be associated with significant morbidity, often complicating the medical management of patients with advanced liver disease [
      • Giannini E.G.
      Review article: thrombocytopenia in chronic liver disease and pharmacologic treatment options.
      ,
      • Peck-Radosavljevic M.
      Thrombocytopenia in liver disease.
      ], cancer [
      • Heyman M.R.
      • Schiffer C.A.
      Platelet transfusion therapy for the cancer patient.
      ], immune thrombocytopenic purpura (ITP) [
      • George J.N.
      Idiopathic thrombocytopenic purpura: current issues for pathogenesis, diagnosis, and management in children and adults.
      ], chronic hepatitis C virus (HCV) infection [
      • Dienstag J.L.
      • McHutchison J.G.
      American Gastroenterological Association technical review on the management of hepatitis C.
      ], 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 [
      • Madhotra R.
      • Mulcahy H.E.
      • Willner I.
      • Reuben A.
      Prediction of esophageal varices in patients with cirrhosis.
      ,
      • Thomopoulos K.C.
      • Labropoulou-Karatza C.
      • Mimidis K.P.
      • Katsakoulis E.C.
      • Iconomou G.
      • Nikolopoulou V.N.
      Non-invasive predictors of the presence of large oesophageal varices in patients with cirrhosis.
      ] and liver transplantation [
      • Giannini E.G.
      Review article: thrombocytopenia in chronic liver disease and pharmacologic treatment options.
      ], severe thrombocytopenia can significantly increase the risk of bleeding. Cerebral hemorrhage or hemorrhage from gastrointestinal (GI) sources is rare but can be fatal [
      • Madhotra R.
      • Mulcahy H.E.
      • Willner I.
      • Reuben A.
      Prediction of esophageal varices in patients with cirrhosis.
      ,
      • Thomopoulos K.C.
      • Labropoulou-Karatza C.
      • Mimidis K.P.
      • Katsakoulis E.C.
      • Iconomou G.
      • Nikolopoulou V.N.
      Non-invasive predictors of the presence of large oesophageal varices in patients with cirrhosis.
      ].
      This review focuses on the causes of thrombocytopenia, its impact, and its clinical significance for routine patient care. This review also describes some novel treatment options.

      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 [
      • Aster R.H.
      Pooling of platelets in the spleen: role in the pathogenesis of “hypersplenic” thrombocytopenia.
      ,
      • Toghill P.
      The syndromes of splenic dysfunction: a clinical overview.
      ]. However, treatments aimed at reversing portal hypertension do not always correct thrombocytopenia, and decreased platelet production has been noted in patients without hypersplenism [
      • Garcia-Suarez J.
      • Burgaleta C.
      • Hernanz N.
      • Albarran F.
      • Tobaruela P.
      • Alvarez-Mon M.
      HCV-associated thrombocytopenia: clinical characteristics and platelet response after recombinant alpha2b-interferon therapy.
      ], 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 [
      • Toghill P.
      The syndromes of splenic dysfunction: a clinical overview.
      ]. 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 [
      • Tripodi A.
      • Mannucci P.M.
      Abnormalities of hemostasis in chronic liver disease: reappraisal of their clinical significance and need for clinical and laboratory research.
      ]. There is a resulting increase in the bleeding time in 40% of cirrhotic patients, the clinical significance 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 [
      • Tripodi A.
      • Mannucci P.M.
      Abnormalities of hemostasis in chronic liver disease: reappraisal of their clinical significance and need for clinical and laboratory research.
      ].
      Figure thumbnail gr1
      Fig. 1Multiple 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.
      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) [
      • Wang C.S.
      • Yao W.J.
      • Wang S.T.
      • Chang T.T.
      • Chou P.
      Strong association of hepatitis C virus (HCV) infection and thrombocytopenia: implications from a survey of a community with hyperendemic HCV infection.
      ,
      • Ballard H.S.
      Hematological complications of alcoholism.
      ]. In CLD patients, autoantibodies directed against platelet surface antigens can enhance removal of platelets by the splenic and hepatic reticuloendothelial systems and trigger their rapid destruction, as observed in chronic ITP [
      • Pereira J.
      • Accatino L.
      • Alfaro J.
      • Brahm J.
      • Hidalgo P.
      • Mezzano D.
      Platelet autoantibodies in patients with chronic liver disease.
      ]. In one small study of patients with chronic HCV, an increased prevalence of ITP was observed [
      • Pockros P.J.
      • Duchini A.
      • McMillan R.
      • Nyberg L.M.
      • McHutchison J.
      • Viernes E.
      Immune thrombocytopenic purpura in patients with chronic hepatitis C virus infection.
      ].
      It is well established that antiviral therapy with interferon alfa (IFN-α) induces thrombocytopenia, necessitating dose reductions [
      • Oh S.
      • Afdhal N.H.
      Antiviral therapy for treatment naive patients with hepatitis C virus.
      ]. In two recent studies of patients with HCV, downward dose modifications were required in up to 6% of patients treated with PEG-IFN [
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • Smith C.
      • Marinos G.
      • Goncales Jr., F.L.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      ,
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • Rustgi V.K.
      • Shiffman M.
      • Reindollar R.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.
      ] and this is even more common in patients with HCV-related cirrhosis in which dose modification and discontinuation were necessary in 19% and 2% of patients, respectively [
      • Heathcote E.J.
      • Shiffman M.L.
      • Cooksley W.G.
      • Dusheiko G.M.
      • Lee S.S.
      • Balart L.
      • et al.
      Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis.
      ]. Dose modification of IFN due to thrombocytopenia and other hematological complications may result in a reduction in sustained virological response (SVR) [
      • McHutchison J.G.
      • Manns M.
      • Patel K.
      • Poynard T.
      • Lindsay K.L.
      • Trepo C.
      • et al.
      Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C.
      ].

      2.2 Thrombocytopenia and coagulopathies of liver disease

      Coagulopathies, defined 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 (fibrinogen), 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 fibrinogen, producing the platelet plug. Recent observations suggest that patients with chronic liver disease have elevated levels of vWF [
      • Lisman T.
      • Bongers T.N.
      • Adelmeijer J.
      • Janssen H.L.
      • de Maat M.P.
      • de Groot P.G.
      • et al.
      Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity.
      ] 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, fibrin formation, and platelet plug stabilization.
      The current therapeutic approach is to identify the deficient factors contributing to coagulopathy and replace these deficient factors using platelets, fresh-frozen plasma, or cryoprecipitates as appropriate [
      • Drews R.E.
      Critical issues in hematology: anemia, thrombocytopenia, coagulopathy, and blood product transfusions in critically ill patients.
      ,
      • Humphries J.E.
      Transfusion therapy in acquired coagulopathies.
      ].

      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 platelets (Fig. 2) [
      • Kaushansky K.
      Thrombopoietin.
      ,
      • Kuter D.J.
      • Begley C.G.
      Recombinant human thrombopoietin: basic biology and evaluation of clinical studies.
      ]. 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 differentiation and erythroid development. Additionally, TPO enhances platelet activation and function.
      Figure thumbnail gr2
      Fig. 2Role 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 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;339:746–754.
      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 [
      • Peck-Radosavljevic M.
      • Wichlas M.
      • Pidlich J.
      • Sims P.
      • Meng G.
      • Zacherl J.
      • et al.
      Blunted thrombopoietin response to interferon alfa-induced thrombocytopenia during treatment for hepatitis C.
      ]. 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 [
      • Rios R.
      • Sangro B.
      • Herrero I.
      • Quiroga J.
      • Prieto J.
      The role of thrombopoietin in the thrombocytopenia of patients with liver cirrhosis.
      ].

      3. Clinical significance and sequelae of thrombocytopenia

      Thrombocytopenia has been used as a marker of advanced liver fibrosis and portal hypertension for many years, but surprisingly little is known about the clinical significance of low counts. In particular, little is known about the impact of thrombocytopenia on either intracerebral bleeding or variceal bleeding in cirrhosis [
      • Wang W.L.
      • Yang Z.F.
      • Lo C.M.
      • Liu C.L.
      • Fan S.T.
      Intracerebral hemorrhage after liver transplantation.
      ,
      • Wijdicks E.F.
      • de Groen P.C.
      • Wiesner R.H.
      • Krom R.A.
      Intracerebral hemorrhage in liver transplant recipients.
      ,
      • Maltz G.S.
      • Siegel J.E.
      • Carson J.L.
      Hematologic management of gastrointestinal bleeding.
      ,
      • Goh S.H.
      • Tan W.P.
      • Lee S.W.
      Clinical predictors of bleeding esophageal varices in the ED.
      ].

      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 significantly 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 [
      • Friedman L.S.
      Controversies in liver biopsy: who, where, when, how, why?.
      ], the number of procedures postponed due to concern over such possible complications is unknown. Many physicians require platelet counts of ⩾80,000/μL 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/μL [
      • McVay P.A.
      • Toy P.T.
      Lack of increased bleeding after liver biopsy in patients with mild hemostatic abnormalities.
      ,
      • Cobb W.S.
      • Heniford B.T.
      • Burns J.M.
      • Carbonell A.M.
      • Matthews B.D.
      • Kercher K.W.
      Cirrhosis is not a contraindication to laparoscopic surgery.
      ,
      • Inabnet W.B.
      • Deziel D.J.
      Laparoscopic liver biopsy in patients with coagulopathy, portal hypertension, and ascites.
      ,
      • Wallace M.J.
      • Narvios A.
      • Lichtiger B.
      • Ahrar K.
      • Morello Jr., F.A.
      • Gupta S.
      • et al.
      Transjugular liver biopsy in patients with hematologic malignancy and severe thrombocytopenia.
      ].
      Table 1Risk of bleeding or worsened thrombocytopenia with medical procedures/therapies in patients with thrombocytopenia, malignancies, and/or chronic liver disease
      ProcedurePatient population studiedComments
      Liver biopsy
      • Percutaneous liver biopsy
        • McVay P.A.
        • Toy P.T.
        Lack of increased bleeding after liver biopsy in patients with mild hemostatic abnormalities.
      • Laparoscopic liver biopsy
        • Cobb W.S.
        • Heniford B.T.
        • Burns J.M.
        • Carbonell A.M.
        • Matthews B.D.
        • Kercher K.W.
        Cirrhosis is not a contraindication to laparoscopic surgery.
        ,
        • Inabnet W.B.
        • Deziel D.J.
        Laparoscopic liver biopsy in patients with coagulopathy, portal hypertension, and ascites.
      • Transjugular liver biopsy
        • Wallace M.J.
        • Narvios A.
        • Lichtiger B.
        • Ahrar K.
        • Morello Jr., F.A.
        • Gupta S.
        • et al.
        Transjugular liver biopsy in patients with hematologic malignancy and severe thrombocytopenia.
      291 patients with mild hemostatic abnormalitiesBleeding risk greatest in patients with malignancy
      ∼50 procedures in each of 2 studies
      50 patients with severe thrombocytopenia
      Paracentesis/thoracentesis
      • McVay P.A.
      • Toy P.T.
      Lack of increased bleeding after paracentesis and thoracentesis in patients with mild coagulation abnormalities.
      ,
      • Grabau C.M.
      • Crago S.F.
      • Hoff L.K.
      • Simon J.A.
      • Melton C.A.
      • Ott B.J.
      • et al.
      Performance standards for therapeutic abdominal paracentesis.
      ,
      • Pache I.
      • Bilodeau M.
      Severe haemorrhage following abdominal paracentesis for ascites in patients with liver disease.
      608 procedures in patients with mild to moderate thrombocytopenia
      • McVay P.A.
      • Toy P.T.
      Lack of increased bleeding after paracentesis and thoracentesis in patients with mild coagulation abnormalities.
      ; 628 thrombocytopenic patients (513 with cirrhosis)
      • Grabau C.M.
      • Crago S.F.
      • Hoff L.K.
      • Simon J.A.
      • Melton C.A.
      • Ott B.J.
      • et al.
      Performance standards for therapeutic abdominal paracentesis.
      ; 4729 patients with liver disease-related ascites
      • Pache I.
      • Bilodeau M.
      Severe haemorrhage following abdominal paracentesis for ascites in patients with liver disease.
      Low risk of bleeding complications if platelets >50,000/μL
      IFN-based HCV antiviral therapyIFN therapy causes reductions in platelet counts in chronic HCV patients with and without cirrhosis
      • Peck-Radosavljevic M.
      • Wichlas M.
      • Pidlich J.
      • Sims P.
      • Meng G.
      • Zacherl J.
      • et al.
      Blunted thrombopoietin response to interferon alfa-induced thrombocytopenia during treatment for hepatitis C.
      Recommendations from AGA
      • George J.N.
      Idiopathic thrombocytopenic purpura: current issues for pathogenesis, diagnosis, and management in children and adults.
      : dose reduction of PEG-IFN-α2a for platelets 25,000–50,000/μL, discontinuation if <25,000/μL
      Dose reduction of PEG-IFN-α2b for platelets ⩽80,000/μL, discontinuation if ⩽50,000/μL
      Dental procedures
      • Williford S.K.
      • Salisbury 3rd, P.L.
      • Peacock Jr., J.E.
      • Cruz J.M.
      • Powell B.L.
      • Lyerly E.S.
      • et al.
      The safety of dental extractions in patients with hematologic malignancies.
      142 dental extractions in patients with hematologic malignanciesThrombocytopenia (platelet counts <100,000/μL) occurred in 80/142 extractions
      Various medically indicated procedures
      • Cosmetic, emergency, or elective surgery
      • Prostate biopsy
      • Polypectomy/cholecystectomy
      Low level of bleeding risk that may complicate and/or require postponement of scheduled procedures
      PT, prothrombin time.
      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 [
      • McVay P.A.
      • Toy P.T.
      Lack of increased bleeding after paracentesis and thoracentesis in patients with mild coagulation abnormalities.
      ]. However, hemoglobin decreases occurred in 8% of patients with severe thrombocytopenia compared with only 3% of patients with platelet counts ⩾50,000/μL. In 628 thrombocytopenic patients (513 with cirrhosis) undergoing LVP, no significant complications were noted [
      • Grabau C.M.
      • Crago S.F.
      • Hoff L.K.
      • Simon J.A.
      • Melton C.A.
      • Ott B.J.
      • et al.
      Performance standards for therapeutic abdominal paracentesis.
      ]. 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) [
      • Pache I.
      • Bilodeau M.
      Severe haemorrhage following abdominal paracentesis for ascites in patients with liver disease.
      ]. 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 ⩾50,000/μL with little risk of bleeding. There is no consensus on the safety of procedures in patients with platelet counts ⩽20,000/μL. 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/μL may benefit from prophylactic transfusions to increase platelet counts above 50,000/μL 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/μL–20,000/μL, depending on the type of cancer [
      • Schiffer C.A.
      • Anderson K.C.
      • Bennett C.L.
      • Bernstein S.
      • Elting L.S.
      • Goldsmith M.
      • et al.
      Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society of Clinical Oncology.
      ]. Currently, there is no consensus on the appropriate threshold values for prophylactic platelet transfusions in CLD patients. The cut-off value varies considerably (e.g., <20,000/μL, <50,000/μL, or <100,000/μL), depending on the clinical setting and procedure planned. While low cut-off values (<10,000/μL) 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/μL or <100,000/μL) [
      • Rebulla P.
      Trigger for platelet transfusion.
      ,
      • Rinder H.M.
      • Arbini A.A.
      • Snyder E.L.
      Optimal dosing and triggers for prophylactic use of platelet transfusions.
      ]. 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 [
      • McCullough J.
      Current issues with platelet transfusion in patients with cancer.
      ,
      • Perrotta P.L.
      • Snyder E.L.
      Non-infectious complications of transfusion therapy.
      ]. Furthermore, platelet transfusions do not ensure a hemostatic platelet level, especially when the risk of bleeding is highest [
      • Schiffer C.A.
      • Anderson K.C.
      • Bennett C.L.
      • Bernstein S.
      • Elting L.S.
      • Goldsmith M.
      • et al.
      Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society of Clinical Oncology.
      ].
      Splenic artery embolization and splenectomy are often, but not always, effective 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 [
      • Wong F.
      The use of TIPS in chronic liver disease.
      ,
      • Jabbour N.
      • Zajko A.
      • Orons P.
      • Irish W.
      • Fung J.J.
      • Selby R.R.
      Does transjugular intrahepatic portosystemic shunt (TIPS) resolve thrombocytopenia associated with cirrhosis?.
      ].

      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 serve as a rational therapeutic target to stimulate platelet production. Research has focused on developing compounds specifically 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).
      Table 2Investigational TPO-R agonists for treatment of TCP in CLD
      AgentClassActivityStatus
      rhIL-11Recombinant human interleukin-11Modest increase in platelet counts, but can be associated with significant toxicity and high costApproved for prevention of severe TCP following myelosuppressive chemotherapy for solid tumors
      EltrombopagSmall-molecule platelet growth factorDose-dependent increase in platelet counts, allowing initiation of HCV antiviral therapyPhase II/III
      rhTPORecombinant human thrombopoietinDose-dependent stimulation of thrombopoiesis and megakaryopoiesisClinical development halted
      PEG-rHuMGDFPegylated recombinant human megakaryocyte growth and development factorStimulates thrombopoiesis and megakaryopoiesis, and enhances platelet recovery from chemotherapyClinical development halted due to neutralizing anti-TPO antibodies
      PromegapoietinTPO agonistIncrease in platelet counts when administered before chemotherapyClinical development halted due to neutralizing anti-TPO antibodies
      NIP-004, AMG 531, AKR-501TPO mimeticsPlatelet responses observed with some agents to datePhase I/II

      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 treatment-naïve HCV patients with low platelet counts (30,000/μL–100,000/μL) [
      • Rustgi V.K.
      • Lee P.
      • Finnegan S.
      • Ershler W.
      Safety and efficacy of recombinant human IL-11 (oprelvekin) in combination with interferon/ribavirin therapy in hepatitis C patients with thrombocytopenia. Annual Meeting of the American Society of Hematology; 2002; Philadelphia, PA.
      ]. All 10 patients who completed at least 24 weeks of therapy maintained platelet counts >40,000/μL, with increases observed as early as week 2. HCV viral load decreased significantly 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 significant toxicities, including edema, fluid 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) [
      • Cantor S.B.
      • Elting L.S.
      • Hudson Jr., D.V.
      Rubenstein EB. Pharmacoeconomic analysis of oprelvekin (recombinant human interleukin-11) for secondary prophylaxis of thrombocytopenia in solid tumor patients receiving chemotherapy.
      ].
      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 significant proinflammatory properties that induce flu-like symptoms including hypotension, fatigue, and myalgias [
      • Demetri G.D.
      Targeted approaches for the treatment of thrombocytopenia.
      ].

      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 differentiation and increase platelet counts in a dose-dependent manner in healthy subjects and patients with chronic ITP [
      • Bussel J.B.
      • Cheng G.
      • Saleh M.N.
      • Psaila B.
      • Kovaleva L.
      • Meddeb B.
      • et al.
      Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura.
      ,
      • Jenkins J.M.
      • Williams D.
      • Deng Y.
      • Uhl J.
      • Kitchen V.
      • Collins D.
      • et al.
      Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist.
      ].
      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 ⩾100,000/μL 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) [
      • McHutchison J.G.
      • Dusheiko G.
      • Shiffman M.L.
      • Rodriguez-Torres M.
      • Sigal S.
      • Bourliere M.
      • et al.
      Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C.
      ]. Significantly 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: recombinant 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 significantly increase platelet counts, but reduction of thrombocytopenia is not always accompanied by a decrease in platelet transfusions [
      • Vadhan-Raj S.
      • Patel S.
      • Bueso-Ramos C.
      • Folloder J.
      • Papadopolous N.
      • Burgess A.
      • et al.
      Importance of predosing of recombinant human thrombopoietin to reduce chemotherapy-induced early thrombocytopenia.
      ].
      PEG-rHuMGDF is an N-terminal TPO derivative that is pegylated to extend its half-life and retain TPO activity [
      • Kuter D.J.
      • Begley C.G.
      Recombinant human thrombopoietin: basic biology and evaluation of clinical studies.
      ,
      • Vadhan-Raj S.
      • Cohen V.
      • Bueso-Ramos C.
      Thrombopoietic growth factors and cytokines.
      ]. In initial trials in patients undergoing chemotherapy, PEG-rHuMGDF treatment increased median platelet nadir counts and enhanced recovery in a dose-dependent manner [
      • Basser R.L.
      • Rasko J.E.
      • Clarke K.
      • Cebon J.
      • Green M.D.
      • Grigg A.P.
      • et al.
      Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filgrastim after dose-intensive chemotherapy in patients with advanced cancer.
      ,
      • Basser R.L.
      • Rasko J.E.
      • Clarke K.
      • Cebon J.
      • Green M.D.
      • Hussein S.
      • et al.
      Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer.
      ,
      • Hunt P.
      • Li Y.S.
      • Nichol J.L.
      • Hokom M.M.
      • Bogenberger J.M.
      • Swift S.E.
      • et al.
      Purification and biologic characterization of plasma-derived megakaryocyte growth and development factor.
      ]. Phase II trials demonstrated promising results for mobilization prior to stem cell transplantation [
      • Kuter D.J.
      • Begley C.G.
      Recombinant human thrombopoietin: basic biology and evaluation of clinical studies.
      ]. However, some subjects including normal platelet donors treated with PEG-rHuMGDF developed neutralizing antibodies that cross-reacted with and inactivated endogenous TPO, resulting in severe thrombocytopenia, which resulted in termination of clinical development of this drug [
      • Vadhan-Raj S.
      • Patel S.
      • Bueso-Ramos C.
      • Folloder J.
      • Papadopolous N.
      • Burgess A.
      • et al.
      Importance of predosing of recombinant human thrombopoietin to reduce chemotherapy-induced early thrombocytopenia.
      ].
      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 [
      • Vadhan-Raj S.
      • Cohen V.
      • Bueso-Ramos C.
      Thrombopoietic growth factors and cytokines.
      ,
      • Inagaki K.
      • Oda T.
      • Naka Y.
      • Shinkai H.
      • Komatsu N.
      • Iwamura H.
      Induction of megakaryocytopoiesis and thrombocytopoiesis by JTZ-132, a novel small molecule with thrombopoietin mimetic activities.
      ,
      • Li J.
      • Yang C.
      • Xia Y.
      • Bertino A.
      • Glaspy J.
      • Roberts M.
      • et al.
      Thrombocytopenia caused by the development of antibodies to thrombopoietin.
      ]. The clinical potential of these agents in the treatment of thrombocytopenia in CLD patients remains to be determined.

      7. Conclusions

      Thrombocytopenia can adversely affect 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 consensus guidelines defining threshold platelet counts in CLD patients below which procedures should be delayed or below which platelet transfusions or platelet-stimulating agents should be utilized needs to be defined. Novel TPO-R agonists including eltrombopag have a significant potential as both therapy and prophylaxis in various clinical settings for patients with CLD and require further clinical investigation.

      Acknowledgement

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

      References

        • Giannini E.G.
        Review article: thrombocytopenia in chronic liver disease and pharmacologic treatment options.
        Aliment Pharmacol Ther. 2006; 23: 1055-1065
        • Tripodi A.
        • Mannucci P.M.
        Abnormalities of hemostasis in chronic liver disease: reappraisal of their clinical significance and need for clinical and laboratory research.
        J Hepatol. 2007; 46: 727-733
        • Peck-Radosavljevic M.
        Thrombocytopenia in liver disease.
        Can J Gastroenterol. 2000; 14: 60D-66D
        • Heyman M.R.
        • Schiffer C.A.
        Platelet transfusion therapy for the cancer patient.
        Semin Oncol. 1990; 17: 198-209
        • George J.N.
        Idiopathic thrombocytopenic purpura: current issues for pathogenesis, diagnosis, and management in children and adults.
        Curr Hematol Rep. 2003; 2: 381-387
        • Dienstag J.L.
        • McHutchison J.G.
        American Gastroenterological Association technical review on the management of hepatitis C.
        Gastroenterology. 2006; 130: 231-264
        • Madhotra R.
        • Mulcahy H.E.
        • Willner I.
        • Reuben A.
        Prediction of esophageal varices in patients with cirrhosis.
        J Clin Gastroenterol. 2002; 34: 81-85
        • Thomopoulos K.C.
        • Labropoulou-Karatza C.
        • Mimidis K.P.
        • Katsakoulis E.C.
        • Iconomou G.
        • Nikolopoulou V.N.
        Non-invasive predictors of the presence of large oesophageal varices in patients with cirrhosis.
        Dig Liver Dis. 2003; 35: 473-478
        • Aster R.H.
        Pooling of platelets in the spleen: role in the pathogenesis of “hypersplenic” thrombocytopenia.
        J Clin Invest. 1966; 45: 645-657
        • Toghill P.
        The syndromes of splenic dysfunction: a clinical overview.
        in: Bowdler A.J. The spleen: structure, function and clinical significance. Chapman & Hall, New York, NY1990: 209-232
        • Garcia-Suarez J.
        • Burgaleta C.
        • Hernanz N.
        • Albarran F.
        • Tobaruela P.
        • Alvarez-Mon M.
        HCV-associated thrombocytopenia: clinical characteristics and platelet response after recombinant alpha2b-interferon therapy.
        Br J Haematol. 2000; 110: 98-103
        • Wang C.S.
        • Yao W.J.
        • Wang S.T.
        • Chang T.T.
        • Chou P.
        Strong association of hepatitis C virus (HCV) infection and thrombocytopenia: implications from a survey of a community with hyperendemic HCV infection.
        Clin Infect Dis. 2004; 39: 790-796
        • Ballard H.S.
        Hematological complications of alcoholism.
        Alcohol Clin Exp Res. 1989; 13: 706-720
        • Pereira J.
        • Accatino L.
        • Alfaro J.
        • Brahm J.
        • Hidalgo P.
        • Mezzano D.
        Platelet autoantibodies in patients with chronic liver disease.
        Am J Hematol. 1995; 50: 173-178
        • Pockros P.J.
        • Duchini A.
        • McMillan R.
        • Nyberg L.M.
        • McHutchison J.
        • Viernes E.
        Immune thrombocytopenic purpura in patients with chronic hepatitis C virus infection.
        Am J Gastroenterol. 2002; 97: 2040-2045
        • Oh S.
        • Afdhal N.H.
        Antiviral therapy for treatment naive patients with hepatitis C virus.
        Infect Dis Clin North Am. 2006; 20: 99-113
        • Fried M.W.
        • Shiffman M.L.
        • Reddy K.R.
        • Smith C.
        • Marinos G.
        • Goncales Jr., F.L.
        • et al.
        Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
        N Engl J Med. 2002; 347: 975-982
        • Manns M.P.
        • McHutchison J.G.
        • Gordon S.C.
        • Rustgi V.K.
        • Shiffman M.
        • Reindollar R.
        • et al.
        Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.
        Lancet. 2001; 358: 958-965
        • Heathcote E.J.
        • Shiffman M.L.
        • Cooksley W.G.
        • Dusheiko G.M.
        • Lee S.S.
        • Balart L.
        • et al.
        Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis.
        N Engl J Med. 2000; 343: 1673-1680
        • McHutchison J.G.
        • Manns M.
        • Patel K.
        • Poynard T.
        • Lindsay K.L.
        • Trepo C.
        • et al.
        Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C.
        Gastroenterology. 2002; 123: 1061-1069
        • Lisman T.
        • Bongers T.N.
        • Adelmeijer J.
        • Janssen H.L.
        • de Maat M.P.
        • de Groot P.G.
        • et al.
        Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity.
        Hepatology. 2006; 44: 53-61
        • Drews R.E.
        Critical issues in hematology: anemia, thrombocytopenia, coagulopathy, and blood product transfusions in critically ill patients.
        Clin Chest Med. 2003; 24: 607-622
        • Humphries J.E.
        Transfusion therapy in acquired coagulopathies.
        Hematol Oncol Clin North Am. 1994; 8: 1181-1201
        • Kaushansky K.
        Thrombopoietin.
        N Engl J Med. 1998; 339: 746-754
        • Kuter D.J.
        • Begley C.G.
        Recombinant human thrombopoietin: basic biology and evaluation of clinical studies.
        Blood. 2002; 100: 3457-3469
        • Peck-Radosavljevic M.
        • Wichlas M.
        • Pidlich J.
        • Sims P.
        • Meng G.
        • Zacherl J.
        • et al.
        Blunted thrombopoietin response to interferon alfa-induced thrombocytopenia during treatment for hepatitis C.
        Hepatology. 1998; 28: 1424-1429
        • Rios R.
        • Sangro B.
        • Herrero I.
        • Quiroga J.
        • Prieto J.
        The role of thrombopoietin in the thrombocytopenia of patients with liver cirrhosis.
        Am J Gastroenterol. 2005; 100: 1311-1316
        • Wang W.L.
        • Yang Z.F.
        • Lo C.M.
        • Liu C.L.
        • Fan S.T.
        Intracerebral hemorrhage after liver transplantation.
        Liver Transpl. 2000; 6: 345-348
        • Wijdicks E.F.
        • de Groen P.C.
        • Wiesner R.H.
        • Krom R.A.
        Intracerebral hemorrhage in liver transplant recipients.
        Mayo Clin Proc. 1995; 70: 443-446
        • Maltz G.S.
        • Siegel J.E.
        • Carson J.L.
        Hematologic management of gastrointestinal bleeding.
        Gastroenterol Clin North Am. 2000; 29: 169-187
        • Goh S.H.
        • Tan W.P.
        • Lee S.W.
        Clinical predictors of bleeding esophageal varices in the ED.
        Am J Emerg Med. 2005; 23: 531-535
        • Friedman L.S.
        Controversies in liver biopsy: who, where, when, how, why?.
        Curr Gastroenterol Rep. 2004; 6: 30-36
        • McVay P.A.
        • Toy P.T.
        Lack of increased bleeding after liver biopsy in patients with mild hemostatic abnormalities.
        Am J Clin Pathol. 1990; 94: 747-753
        • Cobb W.S.
        • Heniford B.T.
        • Burns J.M.
        • Carbonell A.M.
        • Matthews B.D.
        • Kercher K.W.
        Cirrhosis is not a contraindication to laparoscopic surgery.
        Surg Endosc. 2005; 19: 418-423
        • Inabnet W.B.
        • Deziel D.J.
        Laparoscopic liver biopsy in patients with coagulopathy, portal hypertension, and ascites.
        Am Surg. 1995; 61: 603-606
        • Wallace M.J.
        • Narvios A.
        • Lichtiger B.
        • Ahrar K.
        • Morello Jr., F.A.
        • Gupta S.
        • et al.
        Transjugular liver biopsy in patients with hematologic malignancy and severe thrombocytopenia.
        J Vasc Interv Radiol. 2003; 14: 323-327
        • McVay P.A.
        • Toy P.T.
        Lack of increased bleeding after paracentesis and thoracentesis in patients with mild coagulation abnormalities.
        Transfusion. 1991; 31: 164-171
        • Grabau C.M.
        • Crago S.F.
        • Hoff L.K.
        • Simon J.A.
        • Melton C.A.
        • Ott B.J.
        • et al.
        Performance standards for therapeutic abdominal paracentesis.
        Hepatology. 2004; 40: 484-488
        • Pache I.
        • Bilodeau M.
        Severe haemorrhage following abdominal paracentesis for ascites in patients with liver disease.
        Aliment Pharmacol Ther. 2005; 21: 525-529
        • Williford S.K.
        • Salisbury 3rd, P.L.
        • Peacock Jr., J.E.
        • Cruz J.M.
        • Powell B.L.
        • Lyerly E.S.
        • et al.
        The safety of dental extractions in patients with hematologic malignancies.
        J Clin Oncol. 1989; 7: 798-802
        • Schiffer C.A.
        • Anderson K.C.
        • Bennett C.L.
        • Bernstein S.
        • Elting L.S.
        • Goldsmith M.
        • et al.
        Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society of Clinical Oncology.
        J Clin Oncol. 2001; 19: 1519-1538
        • Rebulla P.
        Trigger for platelet transfusion.
        Vox Sang. 2000; 78: 179-182
        • Rinder H.M.
        • Arbini A.A.
        • Snyder E.L.
        Optimal dosing and triggers for prophylactic use of platelet transfusions.
        Curr Opin Hematol. 1999; 6: 437-441
        • McCullough J.
        Current issues with platelet transfusion in patients with cancer.
        Semin Hematol. 2000; 37: 3-10
        • Perrotta P.L.
        • Snyder E.L.
        Non-infectious complications of transfusion therapy.
        Blood Rev. 2001; 15: 69-83
        • Wong F.
        The use of TIPS in chronic liver disease.
        Ann Hepatol. 2006; 5: 5-15
        • Jabbour N.
        • Zajko A.
        • Orons P.
        • Irish W.
        • Fung J.J.
        • Selby R.R.
        Does transjugular intrahepatic portosystemic shunt (TIPS) resolve thrombocytopenia associated with cirrhosis?.
        Dig Dis Sci. 1998; 43: 2459-2462
        • Rustgi V.K.
        • Lee P.
        • Finnegan S.
        • Ershler W.
        Safety and efficacy of recombinant human IL-11 (oprelvekin) in combination with interferon/ribavirin therapy in hepatitis C patients with thrombocytopenia. Annual Meeting of the American Society of Hematology; 2002; Philadelphia, PA.
        Blood. 2002; 100: 361A
        • Cantor S.B.
        • Elting L.S.
        • Hudson Jr., D.V.
        Rubenstein EB. Pharmacoeconomic analysis of oprelvekin (recombinant human interleukin-11) for secondary prophylaxis of thrombocytopenia in solid tumor patients receiving chemotherapy.
        Cancer. 2003; 97: 3099-3106
        • Demetri G.D.
        Targeted approaches for the treatment of thrombocytopenia.
        Oncologist. 2001; 6: 15-23
        • Bussel J.B.
        • Cheng G.
        • Saleh M.N.
        • Psaila B.
        • Kovaleva L.
        • Meddeb B.
        • et al.
        Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura.
        N Engl J Med. 2007; 357: 2237-2247
        • Jenkins J.M.
        • Williams D.
        • Deng Y.
        • Uhl J.
        • Kitchen V.
        • Collins D.
        • et al.
        Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist.
        Blood. 2007; 109: 4739-4741
        • McHutchison J.G.
        • Dusheiko G.
        • Shiffman M.L.
        • Rodriguez-Torres M.
        • Sigal S.
        • Bourliere M.
        • et al.
        Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C.
        N Engl J Med. 2007; 357: 2227-2236
        • Vadhan-Raj S.
        • Patel S.
        • Bueso-Ramos C.
        • Folloder J.
        • Papadopolous N.
        • Burgess A.
        • et al.
        Importance of predosing of recombinant human thrombopoietin to reduce chemotherapy-induced early thrombocytopenia.
        J Clin Oncol. 2003; 21: 3158-3167
        • Vadhan-Raj S.
        • Cohen V.
        • Bueso-Ramos C.
        Thrombopoietic growth factors and cytokines.
        Curr Hematol Rep. 2005; 4: 137-144
        • Basser R.L.
        • Rasko J.E.
        • Clarke K.
        • Cebon J.
        • Green M.D.
        • Grigg A.P.
        • et al.
        Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filgrastim after dose-intensive chemotherapy in patients with advanced cancer.
        Blood. 1997; 89: 3118-3128
        • Basser R.L.
        • Rasko J.E.
        • Clarke K.
        • Cebon J.
        • Green M.D.
        • Hussein S.
        • et al.
        Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer.
        Lancet. 1996; 348: 1279-1281
        • Hunt P.
        • Li Y.S.
        • Nichol J.L.
        • Hokom M.M.
        • Bogenberger J.M.
        • Swift S.E.
        • et al.
        Purification and biologic characterization of plasma-derived megakaryocyte growth and development factor.
        Blood. 1995; 86: 540-547
        • Inagaki K.
        • Oda T.
        • Naka Y.
        • Shinkai H.
        • Komatsu N.
        • Iwamura H.
        Induction of megakaryocytopoiesis and thrombocytopoiesis by JTZ-132, a novel small molecule with thrombopoietin mimetic activities.
        Blood. 2004; 104: 58-64
        • Li J.
        • Yang C.
        • Xia Y.
        • Bertino A.
        • Glaspy J.
        • Roberts M.
        • et al.
        Thrombocytopenia caused by the development of antibodies to thrombopoietin.
        Blood. 2001; 98: 3241-3248