Thrombocytopenia in chronic liver disease: Lessons from transplanted patients

Abstract

Patients with advanced cirrhosis have a complex hemostatic disturbance [1Zwicker J.I. Drews R.E. Hematologic disorders and the liver.in: Schiff E.R. Sorrell M.F. Maddrey W.C. Schiff’s diseases of the liver. Lippincott Williams& Wilkins, Philadelphia2007: 49-363Google Scholar, 2Hedner U. Erhardtsen E. Hemostatic disorders in liver diseases.in: Schiff E.R. Sorrell M.F. Maddrey W.C. Schiff’s diseases of the Liver. Lippincott Williams& Wilkins, Philadelphia2003: 625-636Google Scholar, 3Fiore L.D. Brophy M.T. Deykin D. Hemostasis.in: Zakim D. Boyer T.D. Hepatology. A textbook of liver disease. Saunders, Philadelphia2003: 49-580Google Scholar], and thrombocytopenia is a common feature of this derangement [1Zwicker J.I. Drews R.E. Hematologic disorders and the liver.in: Schiff E.R. Sorrell M.F. Maddrey W.C. Schiff’s diseases of the liver. Lippincott Williams& Wilkins, Philadelphia2007: 49-363Google Scholar, 2Hedner U. Erhardtsen E. Hemostatic disorders in liver diseases.in: Schiff E.R. Sorrell M.F. Maddrey W.C. Schiff’s diseases of the Liver. Lippincott Williams& Wilkins, Philadelphia2003: 625-636Google Scholar, 3Fiore L.D. Brophy M.T. Deykin D. Hemostasis.in: Zakim D. Boyer T.D. Hepatology. A textbook of liver disease. Saunders, Philadelphia2003: 49-580Google Scholar]. The pathogenesis of this phenomenon is complex, and splenic pooling, increased platelet consumption and/or impaired production have been variably suggested to contribute as etiologic factors [1Zwicker J.I. Drews R.E. Hematologic disorders and the liver.in: Schiff E.R. Sorrell M.F. Maddrey W.C. Schiff’s diseases of the liver. Lippincott Williams& Wilkins, Philadelphia2007: 49-363Google Scholar, 2Hedner U. Erhardtsen E. Hemostatic disorders in liver diseases.in: Schiff E.R. Sorrell M.F. Maddrey W.C. Schiff’s diseases of the Liver. Lippincott Williams& Wilkins, Philadelphia2003: 625-636Google Scholar, 3Fiore L.D. Brophy M.T. Deykin D. Hemostasis.in: Zakim D. Boyer T.D. Hepatology. A textbook of liver disease. Saunders, Philadelphia2003: 49-580Google Scholar]. Kinetic studies using radiolabelled platelets indicate an increase in platelet sequestration together with a reduction in mean platelet survival [[4]Stein S.F. Harker L.A. Kinetic and functional studies of platelets, fibrinogen, and plasminogen in patients with hepatic cirrhosis.J Lab Clin Med. 1982; 99: 217-230PubMed Google Scholar]. Nevertheless, the mean platelet count in patients with mild disease has been found to be nearly normal, because platelet production by the bone marrow is increased nearly twice above normal values [[4]Stein S.F. Harker L.A. Kinetic and functional studies of platelets, fibrinogen, and plasminogen in patients with hepatic cirrhosis.J Lab Clin Med. 1982; 99: 217-230PubMed Google Scholar]. Several studies have provided evidence for the hypothesis that when liver function progressively fails, reduced synthesis of thrombopoietin (TPO) results in an inappropriate stimulation of the bone marrow, and thrombocytopenia develops [5Nascimbene A. Iannacone M. Brando B. De Gasperi A. Acute thrombocytopenia after liver transplant: Role of platelet activation, thrombopoietin deficiency and response to high dose intravenous IgG treatment.J Hepatol. 2007; 47: 651-657Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 6Peck-Radosavljevic M. Zacherl J. Meng Y.G. Pidlich J. Lipinski E. Langle F. et al.Is inadequate thrombocytopenia in cirrhosis of the liver?.J Hepatol. 1997; 27: 127-131Abstract Full Text PDF PubMed Scopus (152) Google Scholar, 7Martin T.G. Somberg K.A. Meng G. Cohen R.L. Heid C.A. Sauvage F.J. et al.Thrombopoietin levels in patients with cirrhosis before and after orthotopic liver transplantation.Ann Int Med. 1997; 127: 285-288Crossref PubMed Scopus (149) Google Scholar, 8Goulis J. Chau T.N. Jordan S. Mehta A.B. Watkinson A. Rolles K. et al.Thrombopoietin concentrations are low in patients with cirrhosis and thrombocytopenia and are restored after orthotopic liver transplantation.Gut. 1999; 44: 754-758Crossref PubMed Scopus (126) Google Scholar, 9Faeh M. Hauser S.P. Nydegger U.E. Transient thrombopoietin peak after liver transplantation for end-stage liver disease.Br J Haematol. 2001; 112: 493-498Crossref PubMed Scopus (24) Google Scholar, 10Peck-Radosavljevic M. Wichlas M. Zacherl J. Stiegler G. Stohlawetz P. Fuchsjager M. et al.Thrombopoietin induces a rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production.Blood. 2000; 95: 795-801PubMed Google Scholar]. Besides quantitative changes, abnormalities of platelet function are also present in cirrhotics. An intrinsic platelet defect was suggested to be the most likely cause, related to impaired transmembrane signalling mechanisms, together with alterations in TxB2 production and in cholesterol content of the platelet membrane [11Laffi G. Cominelli F. Ruggiero M. Fedi S. Chiarugi V.P. La Villa G. et al.Altered platelet function in cirrhosis of the liver: impairment of inositol lipid and arachidonic acid metabolism in response to agonists.Hepatology. 1988; 8: 1620-1626Crossref PubMed Scopus (70) Google Scholar, 12Owen J.S.A. Hutton R.A. Day R.C. Platelet lipid composition and platelet aggregation in human liver disease.J Lipid Res. 1981; 22: 423-430PubMed Google Scholar]. Evidence for an acquired platelet storage pool defect has also been obtained [[13]Laffi G. Marra F. Gresele P. Romagnoli P. Palermo A. Bartolini O. et al.Evidence for a storage pool defect in platelets from cirrhotic patients with detective aggregation.Gastroenterology. 1992; 103: 641-646PubMed Google Scholar]. Extrinsic causes, such as abnormal high-density lipoproteins, reduced hematocrit, or nitric oxide overproduction due to altered platelet-vessel wall interaction, may also contribute to the platelet defect [14Desai K. Mistry P. Bagget C. Burroughs A.K. Bellamy M.F. Owen J.S. Inhibition of platelet aggregation by abnormal high density lipoprotein particles in plasma from patients with hepatic cirrhosis.Lancet. 1989; 1: 693-695Abstract PubMed Scopus (58) Google Scholar, 15Turitto V.T. Baumgartner H.R. Platelet interaction with subendothelium in a perfusion system: a physical role of red blood cells.Microvasc Res. 1975; 9: 335-344Crossref PubMed Scopus (178) Google Scholar, 16Laffi G. Marra F. Failli P. Ruggiero M. Cecchi E. Carloni V. et al.Defective signal transduction in platelets from cirrhotics is associated with increased cyclic nucleotides.Gastroenterology. 1993; 105: 148-156Abstract PubMed Google Scholar]. Clinical relevance of defective platelet function remains uncertain and recently Lisman et al. have suggested that reduced platelet number and function may be compensated by the presence of elevated levels of von Willebrand Factor [[17]Lisman T. Bongers T.N. Adelmeijer J. Janssen H.L.A. de Maat M.P.M. deGroot P.G. et al.Elevated levels of von Willebrand Factor in Cirrhosis support platelet adhesion despite reduced functional capacity.Hepatology. 2006; 44: 53-61Crossref PubMed Scopus (422) Google Scholar]. Moreover, Tripodi et al. [[18]Tripodi A. Salerno F. Chantarangkul V. Clerici M. Cazzaniga M. Primignani M. et al.Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests.Hepatology. 2005; 4: 553-558Crossref Scopus (511) Google Scholar] suggested that when blood coagulation capacity is globally measured using thrombin generation assay, as a function of coagulant and anticoagulant factors, patients with cirrhosis and abnormal standard coagulation tests form thrombin in amounts similar to healthy subjects. On the basis of these data, even the relevance of hemostatic derangement as a major cause of bleeding in liver disease has been questioned [[19]Mannucci P.M. Abnormal hemostasis tests and bleeding in chronic liver disease: are they related? No.J Thromb Haemost. 2006; 4: 721-723Crossref PubMed Scopus (74) Google Scholar]. However, in daily practice, patients with cirrhosis are still considered at risk for surgery, and several guidelines indicate defined limits in platelet number below which invasive manoeuvres, including liver biopsy, are not recommended [20Laffi G. Marra F. Tarquini R. Abbate R. Coagulation defects in cirrhosis – old dogmas not yet ready for burial.J Thromb Haemost. 2006; 4: 2068-2069Crossref PubMed Scopus (8) Google Scholar, 21Grant A. Neuberger J. Guidelines on the use of liver biopsy in clinical practice.Gut. 1999; 45: 1-11PubMed Google Scholar, 22Bravo A.A. Sheth S.G. Chopra S. Liver biopsy.N Engl J Med. 2001; 344: 495-500Crossref PubMed Scopus (1801) Google Scholar]. In a recent elegant study, Tripodi et al. [[23]Tripodi A. Primignani M. Chantarangkul V. Clerici M. Dell’Era A. Fabris F. et al.Thrombin generation in patients with cirrhosis: the role of platelets.Hepatology. 2006; 44: 440-445Crossref PubMed Scopus (279) Google Scholar] provided evidence that thrombocytopenia plays a key role in thrombin generation, suggesting the need for correction of this defect in patients with severe thrombocytopenia and risk of bleeding. The study by Nascimbene et al. [[5]Nascimbene A. Iannacone M. Brando B. De Gasperi A. Acute thrombocytopenia after liver transplant: Role of platelet activation, thrombopoietin deficiency and response to high dose intravenous IgG treatment.J Hepatol. 2007; 47: 651-657Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar], published in this issue of the Journal, focuses on some interesting aspects related to thrombocytopenia in the transplanted patient, another relevant problem in this scenario, and adds relevant data on the pathogenesis and treatment of this defect. Thrombocytopenia due to hypersplenism is extremely common in transplant candidates, but even after transplantation (OLT) thrombocytopenia is frequent, and during the first post-operative week a moderate reduction in platelet count (20,000–50,000/μl) occurs in about half of the patients, and counts below 20,000/μl are reported in about 8% of patients [24Plevak D.J. Halma G.A. Forstrom L.A. Dewanjee M.K. O Connor M.K. Moore S.B. et al.Thrombocytopenia after liver transplantation.Transplant Proc. 1988; 20: 630-633PubMed Google Scholar, 25Munoz S.J. Carabasi A.R. Moritz M.J. Jarrell B.E. Maddrey W.C. Postoperative thrombocytopenia in liver transplant recipients: prognostic implications and treatment with high dose of gamma-globulin.Transplant Proc. 1989; 21: 3545-3546PubMed Google Scholar, 26McCaughan G.W. Herkes R. Powers B. Rickard K. Gallagher N.D. Thompson J.F. et al.Thrombocytopenia postliver transplantation. Correlations with pre-operative platelet count,blood transfusion requirements, allograft function and outcome.J Hepatol. 1992; 16: 16-22Abstract Full Text PDF PubMed Scopus (67) Google Scholar, 27Richards E.M. Alexander G.J.M. Calne R.Y. Baglin T.P. Thrombocytopenia following liver transplantation is associated with platelet consumption and thrombin generation.Br J Haematol. 1997; 98: 315-321Crossref PubMed Scopus (53) Google Scholar]. Spontaneous resolution usually begins during the second week, and by the third week platelet count reaches or exceeds the levels measured before OLT. Persistence of thrombocytopenia increases the risk of bleeding-related complications, and therefore worsens the prognosis of the transplanted patients [24Plevak D.J. Halma G.A. Forstrom L.A. Dewanjee M.K. O Connor M.K. Moore S.B. et al.Thrombocytopenia after liver transplantation.Transplant Proc. 1988; 20: 630-633PubMed Google Scholar, 25Munoz S.J. Carabasi A.R. Moritz M.J. Jarrell B.E. Maddrey W.C. Postoperative thrombocytopenia in liver transplant recipients: prognostic implications and treatment with high dose of gamma-globulin.Transplant Proc. 1989; 21: 3545-3546PubMed Google Scholar, 26McCaughan G.W. Herkes R. Powers B. Rickard K. Gallagher N.D. Thompson J.F. et al.Thrombocytopenia postliver transplantation. Correlations with pre-operative platelet count,blood transfusion requirements, allograft function and outcome.J Hepatol. 1992; 16: 16-22Abstract Full Text PDF PubMed Scopus (67) Google Scholar]. Intra-abdominal bleeding after OLT is a common complication, and an exploratory laparotomy for bleeding is required in up to 14.5% of patients undergoing OLT [24Plevak D.J. Halma G.A. Forstrom L.A. Dewanjee M.K. O Connor M.K. Moore S.B. et al.Thrombocytopenia after liver transplantation.Transplant Proc. 1988; 20: 630-633PubMed Google Scholar, 25Munoz S.J. Carabasi A.R. Moritz M.J. Jarrell B.E. Maddrey W.C. Postoperative thrombocytopenia in liver transplant recipients: prognostic implications and treatment with high dose of gamma-globulin.Transplant Proc. 1989; 21: 3545-3546PubMed Google Scholar]. McCaughan et al. [[26]McCaughan G.W. Herkes R. Powers B. Rickard K. Gallagher N.D. Thompson J.F. et al.Thrombocytopenia postliver transplantation. Correlations with pre-operative platelet count,blood transfusion requirements, allograft function and outcome.J Hepatol. 1992; 16: 16-22Abstract Full Text PDF PubMed Scopus (67) Google Scholar] described the occurrence of intracranial hemorrhage in recently transplanted patients with severe thrombocytopenia. Finally, use of liver biopsy in the early post-operative period to diagnose allograft rejection can be precluded. All these aspects highlight the fact that thrombocytopenia may continue to be a relevant problem also after OLT. Several mechanisms may potentially account for thrombocytopenia in the transplanted patient. Post-transplant thrombocytopenia has been attributed to decreased platelet production, increased platelet consumption, or sepsis [24Plevak D.J. Halma G.A. Forstrom L.A. Dewanjee M.K. O Connor M.K. Moore S.B. et al.Thrombocytopenia after liver transplantation.Transplant Proc. 1988; 20: 630-633PubMed Google Scholar, 25Munoz S.J. Carabasi A.R. Moritz M.J. Jarrell B.E. Maddrey W.C. Postoperative thrombocytopenia in liver transplant recipients: prognostic implications and treatment with high dose of gamma-globulin.Transplant Proc. 1989; 21: 3545-3546PubMed Google Scholar, 26McCaughan G.W. Herkes R. Powers B. Rickard K. Gallagher N.D. Thompson J.F. et al.Thrombocytopenia postliver transplantation. Correlations with pre-operative platelet count,blood transfusion requirements, allograft function and outcome.J Hepatol. 1992; 16: 16-22Abstract Full Text PDF PubMed Scopus (67) Google Scholar, 27Richards E.M. Alexander G.J.M. Calne R.Y. Baglin T.P. Thrombocytopenia following liver transplantation is associated with platelet consumption and thrombin generation.Br J Haematol. 1997; 98: 315-321Crossref PubMed Scopus (53) Google Scholar, 28Miyata T. Yokoyama I. Todo S. Tzakis A. Selby R. Starzl T.E. Endotoxaemia, pulmonary complications and thrombocytopenia in liver transplantation.Lancet. 1989; 2: 189-191Abstract PubMed Scopus (80) Google Scholar]. Pre-existing hypersplenism also makes an important contribution, because the spleen gradually shrinks over a period of months, and up to a year after OLT, until a normal portal pressure can be restored [[29]Witte M. Langnas A.N. Hirst K. Stratta R.J. Shaw B.W. Impact of liver transplantation on the reversal of hypersplenism.Transplant Proc. 1993; 25: 1987PubMed Google Scholar]. A decrease in platelet count starts after reperfusion and platelet sequestration in the newly grafted liver has been suggested to occur [[24]Plevak D.J. Halma G.A. Forstrom L.A. Dewanjee M.K. O Connor M.K. Moore S.B. et al.Thrombocytopenia after liver transplantation.Transplant Proc. 1988; 20: 630-633PubMed Google Scholar]. Nascimbene et al. [[5]Nascimbene A. Iannacone M. Brando B. De Gasperi A. Acute thrombocytopenia after liver transplant: Role of platelet activation, thrombopoietin deficiency and response to high dose intravenous IgG treatment.J Hepatol. 2007; 47: 651-657Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] have performed an accurate and thorough study on platelet turnover before and after OLT, serially measuring thrombopoietin levels and reticulated platelets. They also analyzed specific surface markers which indicate the extent of platelet activation, both in basal conditions and after ADP exposure. Moreover, antibodies directed against human platelet antigens, class I major histocompatibility complex and cardiolipin were also measured. In selected cases, bone marrow aspirate was obtained. An important point is that the authors excluded a pathogenetic role of infection, drug-induced myelosuppression, and autoimmunity, since in all patients antiplatelet antibodies were absent. The data obtained in the present study not only offer novel and compelling information on the pathogenesis of thrombocytopenia in the transplanted patient, but are also valuable to better elucidate the pathogenesis of thrombocytopenia in patients with advanced cirrhosis, awaiting OLT. Nonetheless, a possible limitation of the study is its difficulty to explain why in some patients the degree of reduction in platelet count is extremely severe. A combination of chronic peripheral activation in the presence of a central maturation deficit are considered the factors responsible for thrombocytopenia in the recently transplanted patient. According to several reports [5Nascimbene A. Iannacone M. Brando B. De Gasperi A. Acute thrombocytopenia after liver transplant: Role of platelet activation, thrombopoietin deficiency and response to high dose intravenous IgG treatment.J Hepatol. 2007; 47: 651-657Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 6Peck-Radosavljevic M. Zacherl J. Meng Y.G. Pidlich J. Lipinski E. Langle F. et al.Is inadequate thrombocytopenia in cirrhosis of the liver?.J Hepatol. 1997; 27: 127-131Abstract Full Text PDF PubMed Scopus (152) Google Scholar, 7Martin T.G. Somberg K.A. Meng G. Cohen R.L. Heid C.A. Sauvage F.J. et al.Thrombopoietin levels in patients with cirrhosis before and after orthotopic liver transplantation.Ann Int Med. 1997; 127: 285-288Crossref PubMed Scopus (149) Google Scholar, 8Goulis J. Chau T.N. Jordan S. Mehta A.B. Watkinson A. Rolles K. et al.Thrombopoietin concentrations are low in patients with cirrhosis and thrombocytopenia and are restored after orthotopic liver transplantation.Gut. 1999; 44: 754-758Crossref PubMed Scopus (126) Google Scholar, 9Faeh M. Hauser S.P. Nydegger U.E. Transient thrombopoietin peak after liver transplantation for end-stage liver disease.Br J Haematol. 2001; 112: 493-498Crossref PubMed Scopus (24) Google Scholar, 10Peck-Radosavljevic M. Wichlas M. Zacherl J. Stiegler G. Stohlawetz P. Fuchsjager M. et al.Thrombopoietin induces a rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production.Blood. 2000; 95: 795-801PubMed Google Scholar], once synthesis of TPO is restored by liver replacement, platelet count progressively normalizes, despite the persistence of peripheral activation, thus pointing at reduced TPO levels as a cause of thrombocytopenia. On the other hand, although the pathogenesis of platelet activation is complex, the liver graft appears to be the most likely site of platelet activation and sequestration immediately after OLT. This hypothesis is supported by several lines of evidence, including basic science data [[30]Cywes R. Packham M.A. Tietze L. Sanabria J.R. Harvey P.R. Phillips M.J. et al.Role of platelets in hepatic allograft preservation injury in the rat.Hepatology. 1993; 18: 635-647Crossref PubMed Scopus (145) Google Scholar]. Platelets are blood constituents that play a pivotal role not only in hemostais, but also in inflammation and wound healing. Upon activation, platelets can release inflammatory mediators and growth factors, that can either enhance or limit/repair tissue injury of the liver [31Mannaioni P.F. Di Bello M.G. Masini E. Platelets and inflammation:role of platelet-derived growth factor, adhesion molecules and istamine.Inflamm Res. 1997; 46: 4-18Crossref PubMed Scopus (174) Google Scholar, 32Nocito A. Georgiev P. Dahm F. Jochum W. Bader M. Graf R. et al.Platelets and platelet-derived serotonin promote tissue repair after normothermic hepatic ischemia in mice.Gastroenterology. 2007; 45: 369-376Crossref Scopus (7) Google Scholar]. In this situation, apoptosis has been extensively indicated as an important mechanism of graft failure in the preserved and reperfused liver [[33]Sindram D. Porte R.J. Hoffman M.R. Bentley R.C. Clavien P.A. Platelets induce sinusoidal endothelial cell apoptosis upon reperfusion of the cold ischemic rat liver.Gastroenterology. 2000; 118: 183-191Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar]. Studies on the isolated perfused rat liver model have shown that platelets, sequestered in the ischemic liver after reperfusion, induce sinusoidal endothelial cell apoptosis through a mechanism dependent on platelet adhesion on the sinusoidal lumen [[33]Sindram D. Porte R.J. Hoffman M.R. Bentley R.C. Clavien P.A. Platelets induce sinusoidal endothelial cell apoptosis upon reperfusion of the cold ischemic rat liver.Gastroenterology. 2000; 118: 183-191Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar]. More recent experimental data also indicate that hepatic ischemia and reperfusion are followed by tissue repair and liver regeneration that are mediated by platelets [[32]Nocito A. Georgiev P. Dahm F. Jochum W. Bader M. Graf R. et al.Platelets and platelet-derived serotonin promote tissue repair after normothermic hepatic ischemia in mice.Gastroenterology. 2007; 45: 369-376Crossref Scopus (7) Google Scholar]. In an experimental model of orthotopic and heterotopic liver graft in the pig, Porte et al. [[34]Porte R.J. Blauw E. Knot E.A.R. de Maat M.P.M. de Ruiter C. Bakker C.M. et al.Role of the donor liver in the origin of platelet disorders and hyperfibrinolysis in liver transplantation.J Hepatol. 1994; 21: 592-600Abstract Full Text PDF PubMed Scopus (58) Google Scholar] demonstrated a sharp drop in platelet count in the venous outflow of the graft after reperfusion, and histologic examination by electron microscopic of the liver biopsy taken after reperfusion demonstrated, as in a previous study [[35]Hutchison D.E. Genton E. Porter K.A. Daloze P.M. Huguet C. Brettschneider L. et al.Platelet changes following clinical and experimental hepatic homotransplantations.Arch Surg. 1968; 97: 27-33Crossref PubMed Scopus (35) Google Scholar], platelet accumulation in the sinusoids, where most platelets showed cell processes and many seemed to have lost their granuli, compatible with their activation. Studies on labelled platelets performed in patients confirm accumulation of platelets in the newly grafted liver [[24]Plevak D.J. Halma G.A. Forstrom L.A. Dewanjee M.K. O Connor M.K. Moore S.B. et al.Thrombocytopenia after liver transplantation.Transplant Proc. 1988; 20: 630-633PubMed Google Scholar]. Finally, McCaughan et al. [[26]McCaughan G.W. Herkes R. Powers B. Rickard K. Gallagher N.D. Thompson J.F. et al.Thrombocytopenia postliver transplantation. Correlations with pre-operative platelet count,blood transfusion requirements, allograft function and outcome.J Hepatol. 1992; 16: 16-22Abstract Full Text PDF PubMed Scopus (67) Google Scholar], who studied the extent and time-course of thrombocytopenia in a large group of patients undergoing OLT, found that allograft dysfunction (maximum post-operative bilirubin and/or AST/ALT) is the most consistent predictor of the extent and duration of thrombocytopenia. Thus, platelet activation in vivo is confirmed to be a common occurrence in transplanted patients, similar to what has been demonstrated in cirrhotics, although the sites and mechanisms of activation are likely to be different. Additional important information is provided by the paper of Nascimbene et al. [[5]Nascimbene A. Iannacone M. Brando B. De Gasperi A. Acute thrombocytopenia after liver transplant: Role of platelet activation, thrombopoietin deficiency and response to high dose intravenous IgG treatment.J Hepatol. 2007; 47: 651-657Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] on the therapeutic approaches for post-transplant thrombocytopenia. For management of thrombocytopenia in transplanted patients, it is first critical to rule out the occurrence of sepsis, intravascular coagulation, immunological causes and drug-induced thrombocytopenia. Administration of high-dose intravenous immunoglobulins (IVIG) and steroids, although based on anecdotical reports, is the first line therapy, while plasma exchange has been used to treat cyclosporine-associated thrombotic thrombocytopenic purpura [[36]Dzik W.H. Georgi B.A. Khettry U. Jenkins R.L. Cyclosporine-associated thrombotic thrombocytopenic purpura following liver transplantation: successful treatment with plasma exchange.Transplantation. 1987; 44: 570-572Crossref PubMed Scopus (51) Google Scholar] and splenectomy is reserved to severe and persistent thrombocytopenia [[37]Altaca G. Scigliano E. Guy S. Scheiner P. Reich D. Schwartz M. et al.Persistent hypersplenism early after liver transplant: The role of splenectomy.Transplantation. 1997; 64: 1481-1483Crossref PubMed Scopus (23) Google Scholar]. High-dose IVIG, the treatment of choice in idiopathic thrombocytopenic purpura and other autoimmune diseases, exert their therapeutic effect by modulating Fcgamma-mediated platelet destruction in the spleen [38Lazarus A.H. Crow A.R. Mechanism of action of IVIG and anti-D in ITP.Transfus Apher Sci. 2003; 28: 249-255Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 39Jin F. Balthasar J.P. Mechanisms of intravenous immunoglobulin action in Immune Thrombocytopenic Purpura.Hum Immunol. 2005; 66: 403-410Crossref PubMed Scopus (57) Google Scholar]. In fact, the spleen, the major site of platelet destruction, contains a large number of Fc receptor-bearing phagocytic cells, such as monocytes and macrophages, which can bind and destroy opsonized platelets. The more likely mechanism of action advocated for IVIG is the inhibition of Fcgamma RII and RIII receptors [38Lazarus A.H. Crow A.R. Mechanism of action of IVIG and anti-D in ITP.Transfus Apher Sci. 2003; 28: 249-255Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 39Jin F. Balthasar J.P. Mechanisms of intravenous immunoglobulin action in Immune Thrombocytopenic Purpura.Hum Immunol. 2005; 66: 403-410Crossref PubMed Scopus (57) Google Scholar]. Alternative mechanisms of action, albeit not definitively proven, may be related to the presence of anti-idiotypic antibodies within IVIG, that may mediate the elimination of antiplatelet antibodies [[39]Jin F. Balthasar J.P. Mechanisms of intravenous immunoglobulin action in Immune Thrombocytopenic Purpura.Hum Immunol. 2005; 66: 403-410Crossref PubMed Scopus (57) Google Scholar]. Data obtained by Nascimbene et al. [[5]Nascimbene A. Iannacone M. Brando B. De Gasperi A. Acute thrombocytopenia after liver transplant: Role of platelet activation, thrombopoietin deficiency and response to high dose intravenous IgG treatment.J Hepatol. 2007; 47: 651-657Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] are important in that they provide indication, even though from a retrospective and not controlled study, that IVIG induce a rapid and efficient resolution of non-immune thrombocytopenia in post-transplanted patients. How can these data, obtained in the transplanted patient, provide help for the treatment of thrombocytopenia in cirrhotic patients, a problem that the hepatologist faces every day? At the moment, the available therapeutic armamentarium to correct thrombocytopenia, even in selected conditions such as bleeding, surgery or invasive manoeuvres, is scarce. Platelet transfusion would provide a suitable phospholipid surface to complement the normal thrombin generation provided by plasma, thus securing normal coagulation even in those patients with severe thrombocytopenia [[23]Tripodi A. Primignani M. Chantarangkul V. Clerici M. Dell’Era A. Fabris F. et al.Thrombin generation in patients with cirrhosis: the role of platelets.Hepatology. 2006; 44: 440-445Crossref PubMed Scopus (279) Google Scholar]. Platelet transfusion is effective when there is a rise of 10,000 plt/ml for each unit transfused [[3]Fiore L.D. Brophy M.T. Deykin D. Hemostasis.in: Zakim D. Boyer T.D. Hepatology. A textbook of liver disease. Saunders, Philadelphia2003: 49-580Google Scholar]. Because of splenic pooling and accelerated consumption, cirrhotic patients seldom respond with this optimal rise in platelet count [[3]Fiore L.D. Brophy M.T. Deykin D. Hemostasis.in: Zakim D. Boyer T.D. Hepatology. A textbook of liver disease. Saunders, Philadelphia2003: 49-580Google Scholar]. Moreover, platelet transfusion may induce alloimmunization and refractoriness to new transfusions, and a low risk of transferring infectious pathogens still exists [[2]Hedner U. Erhardtsen E. Hemostatic disorders in liver diseases.in: Schiff E.R. Sorrell M.F. Maddrey W.C. Schiff’s diseases of the Liver. Lippincott Williams& Wilkins, Philadelphia2003: 625-636Google Scholar]. Stimulation of megakaryocytes in the bone marrow would appear a promising therapeutic strategy in cirrhotics with defective TPO synthesis. Recombinant human TPO (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rhMGDF) are synthetic peptides available as therapeutic TPOs [[40]Vadhan-Raj S. Cohen V. Bueso-Ramos C. Thrombopoietin growth factors and cytokines.Curr Hematol Rep. 2005; 4: 137-144PubMed Google Scholar]. PEG-rhMGDF showed good therapeutic efficacy in favouring platelet recovery in patients with ITP, but its administration was followed by development of antibodies against the recombinant drug, cross-reacting with endogenous TPO and causing severe thrombocytopenia [41Nomura S. Dan K. Hotta T. Fujimura K. Ikeda Y. Effects of pegylated recombinant human megakaryocyte growth and development factor in patients with ITP.Blood. 2002; 100: 728-730Crossref PubMed Scopus (113) Google Scholar, 42Li J. Yang C. Xia Y. Bertino A. Glaspry J. Roberts M. et al.Thrombocytopenia caused by the development of antibodies to thrombopoietin.Blood. 2001; 98: 3241-3248Crossref PubMed Scopus (582) Google Scholar]. The aminoterminal domain of TPO shares a remarkable homology with erythropoietin. This domain is the one that binds to the c-Mpl receptor and is sufficient for signalling and to support cellular proliferation [[43]Cosman D. The hematopoietin receptor superfamily.Cytokine. 1993; 5: 95-106Crossref PubMed Scopus (266) Google Scholar]. Pirisi et al. [[44]Pirisi M. Fabris C. Soardo G. Cecchin E. Toniutto P. Bartoli E. Thrombocytopenia of chronic liver disease corrected by erythropoietin treatment.J Hepatol. 1994; 21: 376-380Abstract Full Text PDF PubMed Scopus (22) Google Scholar] administered a short-term course (7–20 days) of recombinant human erythropoietin (4000 IU/day s.c.) to 12 patients with chronic liver disease (in 11 of whom diagnosis of cirrhosis was confirmed) and placebo to seven patients with cirrhosis with a platelet count <85 × 109/L. After treatment, platelets increased in the group treated with rhEPO from 70,000 to 101,250/μl while no differences were observed in the placebo group. Four of the patients (33%) did not respond to the treatment, and remarkably, these patients had the lower baseline platelet count (58,500/μl vs 75,750/μl). The reduced response could be related to enhanced hemocathartic activity in these patients. Homoncik et al. [[45]Homoncik M. Jilma-Stohlawetz P. Schmid M. Ferlitsch A. Peck-Radosavljevic M. Erythropoietin increases platelet reactivity and platelets counts in patients with alcoholic liver cirrhosis: a randomized, double-blind placebo-controlled study.Aliment Pharmacol Ther. 2004; 20: 437-443Crossref PubMed Scopus (41) Google Scholar] administered 100 IE/kg erythropoietin or placebo in a randomized, double-blind fashion to 22 patients with alcoholic cirrhosis (platelet count <120 × 109/L). The treatment increased platelet count by 25% and reactivity, indicated by activator-stimulated expression of P-selectin, was increased by twofold versus baseline. The increase in platelet count was more pronounced in patients with platelet count <80 × 109/L. Taken together, the data from Nascimbene et al. [[5]Nascimbene A. Iannacone M. Brando B. De Gasperi A. Acute thrombocytopenia after liver transplant: Role of platelet activation, thrombopoietin deficiency and response to high dose intravenous IgG treatment.J Hepatol. 2007; 47: 651-657Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar], indicating the relevance of the defect in TPO secretion, highlight the need for a safe and effective agent acting on this pathway. Along these lines, interleukin-11 acts synergistically with IL-3, TPO and stem cell factor to increase the number and maturation of megakaryocytic progenitors. Ghalib et al. [[46]Ghalib R. Levine C. Hassan M. McClelland T. Goss J. Stribling R. et al.Recombinant human Interleukin-11 improves thrombocytopenia in patients with cirrhosis.Hepatology. 2003; 37: 1165-1171Crossref PubMed Scopus (27) Google Scholar] administered rhIL-11 to patients with cirrhosis and thrombocytopenia and observed an increase in platelet count. Nonetheless, its wide use is limited by the relevant side effects, such as fluid retention, observed in about 60% of treated patients. An additional final suggestion that may be derived from the study by Nascimbene et al. [[5]Nascimbene A. Iannacone M. Brando B. De Gasperi A. Acute thrombocytopenia after liver transplant: Role of platelet activation, thrombopoietin deficiency and response to high dose intravenous IgG treatment.J Hepatol. 2007; 47: 651-657Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] is the possible use of IVIG in cirrhotic patients. However, more solid data based on controlled trials must be first obtained in post-transplant thrombocytopenia, before a possible extrapolation to the wide area of patients with end-stage liver disease. In this latter setting, patients with increased hemocathartic activity are the most likely candidates to benefit from this approach. The nice study published in this issue of the Journal has the merit of providing non-anecdotical evidence on a severe and difficult complication such as that of thrombocytopenia in liver-transplanted patients, and to focus attention to the needs of the scores of patients with cirrhosis that are at risk of dying of bleeding-related complications.