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Editorial

Thrombocytopenia in chronic liver disease: Lessons

from transplanted patients q

Giacomo Laffi*, Roberto Tarquini, Fabio Marra

Dipartimento di Medicina Interna, UniversitaDi Firenze, Viale Morgagni 85 50134 Firenze, Italy

See Article, pages 651657

Patients with advanced cirrhosis have a complexhemostatic disturbance [13], and thrombocytopeniais a common feature of this derangement [13]. Thepathogenesis of this phenomenon is complex, andsplenic pooling, increased platelet consumption and/orimpaired production have been variably suggested tocontribute as etiologic factors [13]. Kinetic studiesusing radiolabelled platelets indicate an increase inplatelet sequestration together with a reduction in meanplatelet survival [4]. Nevertheless, the mean plateletcount in patients with mild disease has been found to

be nearly normal, because platelet production by thebone marrow is increased nearly twice above normalvalues [4]. Several studies have provided evidence forthe hypothesis that when liver function progressivelyfails, reduced synthesis of thrombopoietin (TPO) resultsin an inappropriate stimulation of the bone marrow,and thrombocytopenia develops[510]. Besides quanti-tative changes, abnormalities of platelet function arealso present in cirrhotics. An intrinsic platelet defectwas suggested to be the most likely cause, relatedto impaired transmembrane signalling mechanisms,together with alterations in TxB2production and in cho-

lesterol content of the platelet membrane [11,12]. Evi-dence for an acquired platelet storage pool defect hasalso been obtained[13]. Extrinsic causes, such as abnor-mal high-density lipoproteins, reduced hematocrit, or

nitric oxide overproduction due to altered platelet-vesselwall interaction, may also contribute to the plateletdefect [1416]. Clinical relevance of defective plateletfunction remains uncertain and recently Lisman et al.have suggested that reduced platelet number and func-tion may be compensated by the presence of elevatedlevels of von Willebrand Factor[17]. Moreover, Tripodiet al.[18]suggested that when blood coagulation capac-ity is globally measured using thrombin generationassay, as a function of coagulant and anticoagulant fac-tors, patients with cirrhosis and abnormal standard

coagulation tests form thrombin in amounts similar tohealthy subjects. On the basis of these data, even the rel-evance of hemostatic derangement as a major cause ofbleeding in liver disease has been questioned[19]. How-ever, in daily practice, patients with cirrhosis are stillconsidered at risk for surgery, and several guidelinesindicate defined limits in platelet number below whichinvasive manoeuvres, including liver biopsy, are not rec-ommended [2022]. In a recent elegant study, Tripodiet al. [23] provided evidence that thrombocytopeniaplays a key role in thrombin generation, suggesting theneed for correction of this defect in patients with severe

thrombocytopenia and risk of bleeding.The study by Nascimbene et al. [5], published in thisissue of the Journal, focuses on some interesting aspectsrelated to thrombocytopenia in the transplanted patient,another relevant problem in this scenario, and addsrelevant data on the pathogenesis and treatment of thisdefect. Thrombocytopenia due to hypersplenism is extre-mely common in transplant candidates, but even aftertransplantation (OLT) thrombocytopenia is frequent,and during the first post-operative week a moderate

0168-8278/$32.00 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.jhep.2007.08.006

Associate Editor: Massimo Colomboq The authors declare that they have nothing to disclose regarding

funding or conflict of interest with respect to this manuscript.* Corresponding author. Tel.: +39 0554296466; fax: +39 055417123.

E-mail address:g.laffi@dmi.unifi.it(G. Laffi).

www.elsevier.com/locate/jhep

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reduction in platelet count (20,00050,000/ll) occurs inabout half of the patients, and counts below 20,000/llare reported in about 8% of patients[2427]. Spontane-ous resolution usually begins during the second week,and by the third week platelet count reaches or exceedsthe levels measured before OLT. Persistence of thrombo-

cytopenia increases the risk of bleeding-related complica-tions, and therefore worsens the prognosis of thetransplanted patients[2426]. Intra-abdominal bleedingafter OLT is a common complication, and an explor-atory laparotomy for bleeding is required in up to14.5% of patients undergoing OLT[24,25]. McCaughanet al. [26] described the occurrence of intracranialhemorrhage in recently transplanted patients with severethrombocytopenia. Finally, use of liver biopsy in theearly post-operative period to diagnose allograft rejec-tion can be precluded. All these aspects highlight the factthat thrombocytopenia may continue to be a relevantproblem also after OLT. Several mechanisms may poten-

tially account for thrombocytopenia in the transplantedpatient. Post-transplant thrombocytopenia has beenattributed to decreased platelet production, increasedplatelet consumption, or sepsis [2428]. Pre-existinghypersplenism also makes an important contribution,because the spleen gradually shrinks over a period ofmonths, and up to a year after OLT, until a normalportal pressure can be restored [29]. A decrease inplatelet count starts after reperfusion and platelet seques-tration in the newly grafted liver has been suggested tooccur[24].

Nascimbene et al.[5]have performed an accurate and

thorough study on platelet turnover before and afterOLT, serially measuring thrombopoietin levels and retic-ulated platelets. They also analyzed specific surface mark-ers which indicate the extent of platelet activation, bothinbasal conditions and after ADP exposure. Moreover,antibodies directed against human platelet antigens, classI major histocompatibility complex and cardiolipin werealso measured. In selected cases, bone marrow aspiratewas obtained. An important point is that the authorsexcluded a pathogenetic role of infection, drug-inducedmyelosuppression, and autoimmunity, since in allpatients antiplatelet antibodies were absent. The dataobtained in the present study not only offer novel andcompelling information on the pathogenesis of thrombo-cytopenia in the transplanted patient, but are alsovaluable to better elucidate the pathogenesis of thrombo-cytopenia in patients with advanced cirrhosis, awaitingOLT. Nonetheless, a possible limitation of the study isits difficulty to explain why in some patients the degreeof reduction in platelet count is extremely severe.

A combination of chronic peripheral activation in thepresence of a central maturation deficit are considered thefactors responsible for thrombocytopenia in the recentlytransplanted patient. According to several reports [510],once synthesis of TPO is restored by liver replacement,

platelet count progressively normalizes, despite the per-sistence of peripheral activation, thus pointing at reducedTPO levels as a cause of thrombocytopenia. On the otherhand, although the pathogenesis of platelet activation iscomplex, the liver graft appears to be the most likely siteof platelet activation and sequestration immediately after

OLT. This hypothesis is supported by several lines of evi-dence, including basic science data[30].Platelets are blood constituents that play a pivotal

role not only in hemostais, but also in inflammationand wound healing. Upon activation, platelets canrelease inflammatory mediators and growth factors, thatcan either enhance or limit/repair tissue injury of theliver[31,32]. In this situation, apoptosis has been exten-sively indicated as an important mechanism of graft fail-ure in the preserved and reperfused liver[33]. Studies onthe isolated perfused rat liver model have shown thatplatelets, sequestered in the ischemic liver after reperfu-sion, induce sinusoidal endothelial cell apoptosis

through a mechanism dependent on platelet adhesionon the sinusoidal lumen[33].

More recent experimental data also indicate thathepatic ischemia and reperfusion are followed by tissuerepair and liver regeneration that are mediated byplatelets [32]. In an experimental model of orthotopicand heterotopic liver graft in the pig, Porte et al. [34]demonstrated a sharp drop in platelet count in thevenous outflow of the graft after reperfusion, and histo-logic examination by electron microscopic of the liverbiopsy taken after reperfusion demonstrated, as in aprevious study [35], platelet accumulation in the sinu-

soids, where most platelets showed cell processes andmany seemed to have lost their granuli, compatiblewith their activation. Studies on labelled platelets per-formed in patients confirm accumulation of plateletsin the newly grafted liver [24]. Finally, McCaughanet al. [26], who studied the extent and time-course ofthrombocytopenia in a large group of patients undergo-ing OLT, found that allograft dysfunction (maximumpost-operative bilirubin and/or AST/ALT) is the mostconsistent predictor of the extent and duration ofthrombocytopenia. Thus, platelet activation in vivo isconfirmed to be a common occurrence in transplantedpatients, similar to what has been demonstrated in cir-rhotics, although the sites and mechanisms of activa-tion are likely to be different.

Additional important information is provided by thepaper of Nascimbene et al. [5] on the therapeuticapproaches for post-transplant thrombocytopenia. Formanagement of thrombocytopenia in transplantedpatients, it is first critical to rule out the occurrence ofsepsis, intravascular coagulation, immunological causesand drug-induced thrombocytopenia. Administration ofhigh-dose intravenous immunoglobulins (IVIG) and ste-roids, although based on anecdotical reports, is the firstline therapy, while plasma exchange has been used to

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treat cyclosporine-associated thrombotic thrombocyto-penic purpura[36]and splenectomy is reserved to severeand persistent thrombocytopenia[37]. High-dose IVIG,the treatment of choice in idiopathic thrombocytopenicpurpura and other autoimmune diseases, exert theirtherapeutic effect by modulating Fcgamma-mediated

platelet destruction in the spleen [38,39]. In fact, thespleen, the major site of platelet destruction, containsa large number of Fc receptor-bearing phagocytic cells,such as monocytes and macrophages, which can bindand destroy opsonized platelets. The more likely mecha-nism of action advocated for IVIG is the inhibition ofFcgamma RII and RIII receptors [38,39]. Alternativemechanisms of action, albeit not definitively proven,may be related to the presence of anti-idiotypic antibod-ies within IVIG, that may mediate the elimination ofantiplatelet antibodies [39]. Data obtained by Nascim-bene et al.[5] are important in that they provide indica-tion, even though from a retrospective and not

controlled study, that IVIG induce a rapid and efficientresolution of non-immune thrombocytopenia in post-transplanted patients.

How can these data, obtained in the transplantedpatient, provide help for the treatment of thrombocyto-penia in cirrhotic patients, a problem that the hepatolo-gist faces every day? At the moment, the availabletherapeutic armamentarium to correct thrombocytope-nia, even in selected conditions such as bleeding, surgeryor invasive manoeuvres, is scarce. Platelet transfusionwould provide a suitable phospholipid surface to com-plement the normal thrombin generation provided by

plasma, thus securing normal coagulation even in thosepatients with severe thrombocytopenia [23]. Platelettransfusion is effective when there is a rise of10,000 plt/ml for each unit transfused [3]. Because ofsplenic pooling and accelerated consumption, cirrhoticpatients seldom respond with this optimal rise in plateletcount [3]. Moreover, platelet transfusion may inducealloimmunization and refractoriness to new transfu-sions, and a low risk of transferring infectious pathogensstill exists [2]. Stimulation of megakaryocytes in thebone marrow would appear a promising therapeuticstrategy in cirrhotics with defective TPO synthesis.Recombinant human TPO (rhTPO) and pegylatedrecombinant human megakaryocyte growth and devel-opment factor (PEG-rhMGDF) are synthetic peptidesavailable as therapeutic TPOs [40]. PEG-rhMGDFshowed good therapeutic efficacy in favouring plateletrecovery in patients with ITP, but its administrationwas followed by development of antibodies against therecombinant drug, cross-reacting with endogenousTPO and causing severe thrombocytopenia [41,42].The aminoterminal domain of TPO shares a remarkablehomology with erythropoietin. This domain is the onethat binds to the c-Mpl receptor and is sufficient for sig-nalling and to support cellular proliferation [43]. Pirisi

et al.[44]administered a short-term course (720 days)of recombinant human erythropoietin (4000 IU/days.c.) to 12 patients with chronic liver disease (in 11 ofwhom diagnosis of cirrhosis was confirmed) and placeboto seven patients with cirrhosis with a platelet count

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