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Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction?

Open AccessPublished:June 29, 2011DOI:https://doi.org/10.1016/j.jhep.2011.06.008
      Patients with cirrhosis can have abnormalities in laboratory tests reflecting changes in primary haemostasis, including bleeding time, platelet function tests, markers of platelet activation, and platelet count. Such changes have been considered particularly relevant in the bleeding complications that occur in cirrhosis.
      However, several studies have shown that routine diagnostic tests, such as platelet count, bleeding time, PFA-100, thromboelastography are not clinically useful to stratify bleeding risk in patients with cirrhosis. Moreover, treatments used to increase platelet count or to modulate platelet function could potentially do harm. Consequently the optimal management of bleeding complications is still a matter of discussion.
      Moreover, in the last two decades there has been an increased recognition that not only bleeding but also thrombosis complicates the clinical course of cirrhosis. Thus, we performed a literature search looking at publications studying both qualitative and quantitative aspects of platelet function to verify which primary haemostasis defects occur in cirrhosis. In addition, we evaluated the contribution of qualitative and quantitative aspects of platelet function to the clinical outcome in cirrhosis and their therapeutic management according to the data available in the literature.
      From the detailed analysis of the literature, it appears clear that primary haemostasis may not be defective in cirrhosis, and a low platelet count should not necessarily be considered as an automatic index of an increased risk of bleeding. Conversely, caution should be observed in patients with severe thrombocytopenia where its correction is advised if bleeding occurs and before invasive diagnostic and therapeutic procedures.

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      • Platelet function in patients with cirrhosis
        Journal of HepatologyVol. 56Issue 4
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          In an elegant and comprehensive review of the literature, Violi and coworkers conclude that primary hemostasis may not be defective in patients with cirrhosis, and that a low platelet count in these patients should not necessarily be considered as a bleeding risk [1]. Whilst we concur with these conclusions, we wish to make additional comments on platelet function in patients with cirrhosis.
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      • Reply to: Platelet function in patients with cirrhosis
        Journal of HepatologyVol. 56Issue 4
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          We thank Drs. Lisman and Porte for their very interesting comments concerning our review on the presence or absence of platelet dysfunction in liver cirrhosis. We agree that extrinsic and intrinsic factors may contribute to maintain a normal primary hemostasis in cirrhosis, despite potential defects due to thrombocytopenia and anemia. Among the extrinsic factors, we agree that the enhanced ratio von Willebrand factor/ADAMTS 13 may have a role. However, we have recently demonstrated the existence of a novel intrinsic factor that could contribute to maintain a normal hemostasis.
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      Introduction

      Complex haemostatic changes coexist in liver cirrhosis (LC) [
      • Violi F.
      • Ferro D.
      • Quintarelli C.
      • Saliola M.
      • Cordova C.
      • Balsano F.
      Clotting abnormalities in chronic liver disease.
      ,
      • Violi F.
      • Ferro D.
      • Basili S.
      • Quintarelli C.
      • Musca A.
      • Cordova C.
      • et al.
      Hyperfibrinolysis resulting from clotting activation in patients with different degrees of cirrhosis. The CALC Group. Coagulation abnormalities in liver cirrhosis.
      ,
      • Lisman T.
      • Caldwell S.H.
      • Burroughs A.K.
      • Northup P.G.
      • Senzolo M.
      • Stravitz R.T.
      • et al.
      Hemostasis and thrombosis in patients with liver disease: the ups and downs.
      ,
      • Violi F.
      • Ferro D.
      • Basili S.
      • Saliola M.
      • Quintarelli C.
      • Alessandri C.
      • et al.
      Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis.
      ]. These changes include defects in primary haemostasis, abnormalities of the clotting system due to impaired synthesis of pro-coagulant and anti-coagulant factors, low-grade coagulation activation, and hyperfibrinolysis. Patients with cirrhosis can have abnormalities in laboratory tests reflecting changes in primary haemostasis, including bleeding time (BT), platelet aggregation tests, and platelet count. Laboratory tests of platelet function consistently show that primary haemostasis is impaired in cirrhosis as a consequence of reduced platelet function and/or low platelet count [
      • Hugenholtz G.G.
      • Porte R.J.
      • Lisman T.
      The platelet and platelet function testing in liver disease.
      ]. Such changes have been considered particularly relevant in the bleeding complications that occur in cirrhosis, so that the clinical effect of drugs that improve platelet function [
      • Violi F.
      • Ferro D.
      • Basili S.
      • D’Angelo A.
      • Mazzola G.
      • Quintarelli C.
      • et al.
      Relation between lupus anticoagulant and splanchnic venous thrombosis in cirrhosis of the liver.
      ,
      • Amitrano L.
      • Guardascione M.A.
      • Brancaccio V.
      • Iannaccone L.
      • Ames P.R.
      • Balzano A.
      Portal and mesenteric venous thrombosis in cirrhotic patients.
      ,
      • Fimognari F.L.
      • Violi F.
      Portal vein thrombosis in liver cirrhosis.
      ,
      • Tsochatzis E.A.
      • Senzolo M.
      • Germani G.
      • Gatt A.
      • Burroughs A.K.
      Systematic review: portal vein thrombosis in cirrhosis.
      ], or number of platelets [
      • 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.
      ] has been investigated in cirrhosis.
      However, in the last two decades, there has been an increased recognition that not only bleeding but also thrombosis complicates the clinical course of cirrhosis. Portal vein thrombosis is a frequent finding in cirrhosis (without concomitant hepatocellular carcinoma) occurring in about 10–20% of LC [
      • Violi F.
      • Ferro D.
      • Basili S.
      • D’Angelo A.
      • Mazzola G.
      • Quintarelli C.
      • et al.
      Relation between lupus anticoagulant and splanchnic venous thrombosis in cirrhosis of the liver.
      ,
      • Amitrano L.
      • Guardascione M.A.
      • Brancaccio V.
      • Iannaccone L.
      • Ames P.R.
      • Balzano A.
      Portal and mesenteric venous thrombosis in cirrhotic patients.
      ,
      • Fimognari F.L.
      • Violi F.
      Portal vein thrombosis in liver cirrhosis.
      ,
      • Tsochatzis E.A.
      • Senzolo M.
      • Germani G.
      • Gatt A.
      • Burroughs A.K.
      Systematic review: portal vein thrombosis in cirrhosis.
      ]. Moreover, the occurrence of thrombosis in other vascular territories, such as peripheral veins, is increasingly being reported. Patients with cirrhosis are prone to deep vein thrombosis and embolic disease [
      • Gulley D.
      • Teal E.
      • Suvannasankha A.
      • Chalasani N.
      • Liangpunsakul S.
      Deep vein thrombosis and pulmonary embolism in cirrhosis patients.
      ,
      • Lesmana C.R.
      • Inggriani S.
      • Cahyadinata L.
      • Lesmana L.A.
      Deep vein thrombosis in patients with advanced liver cirrhosis: a rare condition?.
      ,
      • Northup P.G.
      • McMahon M.M.
      • Ruhl A.P.
      • Altschuler S.E.
      • Volk-Bednarz A.
      • Caldwell S.H.
      • et al.
      Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism.
      ], as evidenced by epidemiological data [
      • Søgaard K.K.
      • Horváth-Puhó E.
      • Grønbaek H.
      • Jepsen P.
      • Vilstrup H.
      • Sørensen H.T.
      Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study.
      ]. Thus, a review of primary haemostasis within the newly accepted paradigm of preserved haemostasis in cirrhosis, with normal thrombin formation [
      • Tripodi A.
      • Primignani M.
      • Chantarangkul V.
      • Dell’Era A.
      • Clerici M.
      • de Franchis R.
      • et al.
      An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis.
      ], or increased thrombin generation [
      • Gatt A.
      • Riddell A.
      • Calvaruso V.
      • Tuddenham E.G.
      • Makris M.
      • Burroughs A.K.
      Enhanced thrombin generation in patients with cirrhosis induced coagulopathy.
      ], and the coexistence of bleeding and thrombotic complications in cirrhosis [
      • Lisman T.
      • Caldwell S.H.
      • Burroughs A.K.
      • Northup P.G.
      • Senzolo M.
      • Stravitz R.T.
      • et al.
      Hemostasis and thrombosis in patients with liver disease: the ups and downs.
      ], and its possible role in these abnormalities is pertinent.
      We performed a literature search looking at publications studying both qualitative and quantitative aspects of platelet function to verify which primary hemostasis defects occur in cirrhosis, and if so, how they contribute to clinical outcome.

      Primary haemostasis: physiology

      Haemostasis is the process that maintains the integrity of the circulatory system after vascular damage. Platelets are recruited to the site of injury where they become a major component of the developing thrombus. When pathologic processes overwhelm the regulatory mechanisms of haemostasis either thrombosis or bleeding can occur.
      The endothelium is crucial in providing a defense against thrombus formation: it contains thromboregulators able to inhibit platelet activation such as nitric oxide, [
      • Ignarro L.J.
      • Buga G.M.
      • Wood K.S.
      • Byrns R.E.
      • Chaudhuri G.
      Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.
      ,
      • Palmer R.M.
      • Ferrige A.G.
      • Moncada S.
      Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor.
      ], prostacyclin, [
      • Marcus A.J.
      • Broekman M.J.
      • Pinsky D.J.
      COX inhibitors and thromboregulation.
      ] and the endothelial ectoadenosine diphosphatase (ecto-ADPase) pathway [
      • Rodvein R.
      • Lindon J.N.
      • Levine P.H.
      Physiology and ultrastructure of the blood platelet following exposure to hydrogen peroxide.
      ]. When the endothelium is disrupted, collagen triggers the adhesion and activation of platelets, whereas tissue factor (TF) initiates the generation of thrombin, which not only converts fibrinogen to fibrin but also activates platelets. The initial platelet adhesion is followed by activation which is characterized by these phases: (i) platelet granule release reaction that facilitates further platelet activation and platelet recruitment, (ii) cytoskeletal rearrangements (necessary for shape change including spreading, pseudopodia formation, and clot retraction), (iii) mobilization of arachidonic acid to amplify intracellular signaling, (iv) glycoprotein (Gp) IIb/IIIa expression on the surface of the platelet for aggregation mediated by the receptors and fibrinogen and (v) exposure of procoagulant phospholipids to facilitate coagulation.
      Recent studies of thrombus formation in genetically altered mice [
      • Dubois C.
      • Panicot-Dubois L.
      • Merrill-Skoloff G.
      • Furie B.
      • Furie B.C.
      Glycoprotein VI-dependent and -independent pathways of thrombus formation in vivo.
      ,
      • Mangin P.
      • Yap C.L.
      • Nonne C.
      • Sturgeon S.A.
      • Goncalves I.
      • Yuan Y.
      • et al.
      Thrombin overcomes the thrombosis defect associated with platelet GPVI/FcRgamma deficiency.
      ] show two distinct pathways acting in parallel or separately, for platelet activation. In the first pathway, exposure of sub-endothelial collagen initiates platelet activation via Gp VI binding to the collagen and Gp Ib-V-IX binding to collagen-bound von Willebrand factor (vWf). In the second one, TF initiates platelet activation independently of vWf [
      • Dubois C.
      • Panicot-Dubois L.
      • Gainor J.F.
      • Furie B.C.
      • Furie B.
      Thrombin-initiated platelet activation in vivo is vWF independent during thrombus formation in a laser injury model.
      ] and GpVI [
      • Mangin P.
      • Yap C.L.
      • Nonne C.
      • Sturgeon S.A.
      • Goncalves I.
      • Yuan Y.
      • et al.
      Thrombin overcomes the thrombosis defect associated with platelet GPVI/FcRgamma deficiency.
      ]. It forms a complex with factor VIIa, initiating a proteolytic cascade that generates thrombin. Thrombin thereby activates platelets [
      • Vu T.K.
      • Hung D.T.
      • Wheaton V.I.
      • Coughlin S.R.
      Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation.
      ] through PAR4 receptors causing them to release adenosine diphosphate (ADP), serotonin, and thromboxane (Tx) A2. The consequences of platelet activation triggered by these pathways are identical [
      • Dubois C.
      • Panicot-Dubois L.
      • Merrill-Skoloff G.
      • Furie B.
      • Furie B.C.
      Glycoprotein VI-dependent and -independent pathways of thrombus formation in vivo.
      ,
      • Mangin P.
      • Yap C.L.
      • Nonne C.
      • Sturgeon S.A.
      • Goncalves I.
      • Yuan Y.
      • et al.
      Thrombin overcomes the thrombosis defect associated with platelet GPVI/FcRgamma deficiency.
      ].

      Platelet activation and aggregation

      Thrombus formation is a dynamic process in which some platelets adhere to and others separate from the developing thrombus [
      • Dubois C.
      • Panicot-Dubois L.
      • Gainor J.F.
      • Furie B.C.
      • Furie B.
      Thrombin-initiated platelet activation in vivo is vWF independent during thrombus formation in a laser injury model.
      ]. Activation of platelets bound to the injured vessel wall causes a conformational transition in GpIIb/IIIa that increases its affinity for fibrinogen and vWf [
      • Du X.
      • Gu M.
      • Weisel J.W.
      • Nagaswami C.
      • Bennett J.S.
      • Bowditch R.
      • et al.
      Long range propagation of conformational changes in integrin alpha IIb beta 3.
      ]. At low shear rates fibrinogen is the predominant ligand, whereas vWf plays an important role at higher shear rates [
      • Ruggeri Z.M.
      Old concepts and new developments in the study of platelet aggregation.
      ,
      • Goto S.
      • Ikeda Y.
      • Saldívar E.
      • Ruggeri Z.M.
      Distinct mechanisms of platelet aggregation as a consequence of different shearing flow conditions.
      ]. Neither vWf nor fibrinogen is required for platelet accumulation [
      • Ni H.
      • Denis C.V.
      • Subbarao S.
      • Degen J.L.
      • Sato T.N.
      • Hynes R.O.
      • et al.
      Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen.
      ]. Propagation of platelet activation depends upon interaction of several agonists with receptors expressed on platelets themselves. Three outside-in signals of particular relevance are mediated by ADP, thrombin and TxA2 [
      • Davì G.
      • Patrono C.
      Platelet activation and atherothrombosis.
      ] and responsible for platelet activation and aggregation.
      Platelets express at least two ADP receptors, P2Y1 and P2Y12. The activation of P2Y12 inhibits adenylate cyclase causing a decrease in the cyclic AMP (cAMP) level and the activation of P2Y1 causes an increase in the intracellular Ca2+ level. The P2Y12 receptor is the major receptor able to amplify and sustain platelet activation in response to ADP, by facilitating the release of intracellular calcium stores by decreasing cAMP levels in the platelet.
      Platelets produce two eicosanoids, namely TXA2 and isoprostanes with pro-aggregating properties. TXA2 derives from enzymatic oxidation of arachidonic acid by COX1 while isoprostanes derive from non-enzymatic oxidation of arachidonic acid by reactive oxidant species (ROS)-generated nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase [
      • Morrow J.D.
      • Hill K.E.
      • Burk R.F.
      • Nammour T.M.
      • Badr K.F.
      • Roberts 2nd, L.J.
      A series of prostaglandin F2-like compounds are produced in vivo in humans by a non cyclooxygenase, free radical-catalyzed mechanism.
      ]. While TXA2 serves for the initial phase of platelet activation, isoprostanes are implicated in the propagation of platelet aggregation along with ROS and ADP release from activated platelets (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Primary haemostasis: physiology. Platelets, anucleated cells derived from megakaryocytes, at the side of vessel wall injury, adhere to exposed collagen or vWf. Adhesion and activation is initiated by two distinct pathways acting in parallel or separately: (A) exposure of sub-endothelial collagen initiates platelet activation via Gp VI binding to the collagen and Gp Ib-V-IX exposure of collagen triggers the adhesion and activation of platelets; (B) TF initiates the generation of thrombin. (C) After adhesion to endothelium, in the activation phase, thrombin derived by coagulation cascade and platelets-derived mediators, such as ADP, TXA2 and isoprostanes, activate several pathways resulting in glycoprotein IIb/IIIa activation and in turn platelet aggregation. AA, arachidonic acid; ADP, adenosine diphosphate; COX1, cyclo-oxygenase 1; GP, glycoprotein; NADPH-Ox, NADPH oxidase; TF, tissue factor; TP, thromboxane receptor; TXA2, thromboxane A2; vWf, Von Willebrand factor.

      Global tests for primary haemostasis and bleeding

      Bleeding time

      The skin bleeding time (BT) (Table 1) is an easy and frequently used global test for primary haemostasis [
      • Hamblin T.J.
      What about the bleeding time?.
      ,
      • Poller L.
      • Thomson J.M.
      • Tomenson J.A.
      The bleeding time: current practice in the UK.
      ]. Because the BT is prolonged in congenital and acquired platelet defects, it has been common reasoning for years that this test could provide a screening for hemorrhagic tendencies in other platelet disorders.
      Table 1Tests for assessing primary hemostasis.
      The Simplate® template device is the technique most commonly used to measure BT with an upper limit of normal being between 9 and 10 minutes [
      • Poller L.
      • Thomson J.M.
      • Tomenson J.A.
      The bleeding time: current practice in the UK.
      ]. However, this test may be sensitive to a variety of variables that may produce false-positive and false-negative results. Thus, it is not only influenced by the platelet count and function, but may also be affected by the packed cell volume, blood urea concentration, platelet volume, and the nature of skin connective tissue. In haematological (bone marrow) causes of thrombocytopenia (TCP) there is a direct correlation between BT and platelet count <100 × 109/L [
      • Harker L.A.
      • Slichter S.J.
      The bleeding time as a screening test for evaluation of platelet function.
      ].
      On this basis, BT has been used to measure primary haemostasis in cirrhosis [
      • Blake J.C.
      • Sprengers D.
      • Grech P.
      • McCormick P.A.
      • McIntyre N.
      • Burroughs A.K.
      Bleeding time in patients with hepatic cirrhosis.
      ,
      • Violi F.
      • Leo R.
      • Basili S.
      • Ferro D.
      • Cordova C.
      • Balsano F.
      Association between prolonged bleeding time and gastrointestinal hemorrhage in 102 patients with liver cirrhosis: results of a retrospective study.
      ]. However, in 100 patients with cirrhosis, Blake et al. [
      • Blake J.C.
      • Sprengers D.
      • Grech P.
      • McCormick P.A.
      • McIntyre N.
      • Burroughs A.K.
      Bleeding time in patients with hepatic cirrhosis.
      ] showed that only 42% had BT prolongation, which could be explained only in part by a concomitant TCP. In fact, there was only a weak correlation between BT and platelet count. A prolonged BT in LC patients with platelet counts greater than 100 × 109/L, a level typically regarded within “safe limits” for invasive procedures, was observed in some patients, and conversely there was a normal BT in some patients with platelet count <100 × 109/L. Liver failure itself is associated with prolongation of BT. A prospective study conducted in seventy LC patients demonstrated a progressive prolongation of BT from Child-Pugh class A to class C patients [
      • Violi F.
      • Leo R.
      • Vezza E.
      • Basili S.
      • Cordova C.
      • Balsano F.
      Bleeding time in patients with cirrhosis: relation with degree of liver failure and clotting abnormalities. C.A.L.C. group. Coagulation abnormalities in cirrhosis study group.
      ]. Nevertheless, the clinical value of BT prolongation as risk factor for bleeding in liver cirrhosis remains uncertain. Boberg et al. [
      • Boberg K.M.
      • Brosstad F.
      • Egeland T.
      • Egge T.
      • Schrumpf E.
      Is a prolonged bleeding time associated with an increased risk of hemorrhage after liver biopsy?.
      ] reported that a prolonged BT was associated with a 5-fold increase risk of hemoglobin reduction after liver biopsy. Two retrospective studies [
      • Violi F.
      • Leo R.
      • Basili S.
      • Ferro D.
      • Cordova C.
      • Balsano F.
      Association between prolonged bleeding time and gastrointestinal hemorrhage in 102 patients with liver cirrhosis: results of a retrospective study.
      ,
      • Audhuy B.
      • Doffoel M.
      • Wiesel M.L.
      • Hemmendinger S.
      • Cazenave J.P.
      • Bockel R.
      Importance of disorders of primary hemostasis in the occurrence of upper digestive hemorrhage in cirrhosis.
      ] showed a significant association between BT and a previous history of gastrointestinal-haemorrhage, but a prospective study failed to confirm this association [
      • Basili S.
      • Ferro D.
      • Leo R.
      • Juliano L.
      • Alessandri C.
      • Cordova C.
      • et al.
      Bleeding time does not predict gastrointestinal bleeding in patients with cirrhosis. The CALC group. Coagulation abnormalities in liver cirrhosis.
      ]. Thus, in patients with cirrhosis without previous bleeding, only variceal size and severe liver failure, but not BT, significantly predicted bleeding events during one-year follow-up [
      • Basili S.
      • Ferro D.
      • Leo R.
      • Juliano L.
      • Alessandri C.
      • Cordova C.
      • et al.
      Bleeding time does not predict gastrointestinal bleeding in patients with cirrhosis. The CALC group. Coagulation abnormalities in liver cirrhosis.
      ]. It is therefore possible that the prolongation of BT will have a different impact on provoked (liver biopsy) or spontaneous (gastrointestinal bleeding) bleeding but literature data are not sufficient to support such hypothesis.
      The poor association of BT as risk factor for bleeding in cirrhosis is supported by interventional studies with drugs that increase platelet vascular adherence and activation [
      • Mannucci P.M.
      • Vicente V.
      • Vianello L.
      • Cattaneo M.
      • Alberca I.
      • Coccato M.P.
      • et al.
      Controlled trial of desmopressin in liver cirrhosis and other conditions associated with a prolonged bleeding time.
      ,
      • Burroughs A.K.
      • Matthews K.
      • Quadiri M.
      Desmopressin and bleeding time in cirrhosis.
      ,
      • de Franchis R.
      • Arcidiacono P.G.
      • Carpinelli L.
      • Andreoni B.
      • Cestari L.
      • Brunati S.
      • et al.
      Randomized controlled trial of desmopressin plus terlipressin vs. terlipressin alone for the treatment of acute variceal hemorrhage in cirrhotic patients: a multicenter, double-blind study. New Italian endoscopic club.
      ,
      • Wong A.Y.
      • Irwin M.G.
      • Hui T.W.
      • Fung S.K.
      • Fan S.T.
      • Ma E.S.
      Desmopressin does not decrease blood loss and transfusion requirements in patients undergoing hepatectomy.
      ]. Thus, treatment with desmopressin (DDAVP), a synthetic peptide homologous to human vasopressin that is usually employed in congenital bleeding disorders such as von Willebrand’s disease, was able to shorten the prolonged BT in patients with cirrhosis [
      • Mannucci P.M.
      • Vicente V.
      • Vianello L.
      • Cattaneo M.
      • Alberca I.
      • Coccato M.P.
      • et al.
      Controlled trial of desmopressin in liver cirrhosis and other conditions associated with a prolonged bleeding time.
      ,
      • Burroughs A.K.
      • Matthews K.
      • Quadiri M.
      Desmopressin and bleeding time in cirrhosis.
      ]. This is probably due to the increase in von Willebrand factor (vWF) and FVIII seen after administration of DDAVP which possibly compensates for the thrombocytopenia. However, de Franchis et al. [
      • de Franchis R.
      • Arcidiacono P.G.
      • Carpinelli L.
      • Andreoni B.
      • Cestari L.
      • Brunati S.
      • et al.
      Randomized controlled trial of desmopressin plus terlipressin vs. terlipressin alone for the treatment of acute variceal hemorrhage in cirrhotic patients: a multicenter, double-blind study. New Italian endoscopic club.
      ] showed that in LC patients with active variceal hemorrhage, on treatment with terlipressin, recurrence of bleeding occurred more frequently in patients who received desmopressin compared to those who did not (54% vs. 27%, respectively). In addition, desmopressin did not reduce the transfusion requirement in patients undergoing hepatectomy [
      • Wong A.Y.
      • Irwin M.G.
      • Hui T.W.
      • Fung S.K.
      • Fan S.T.
      • Ma E.S.
      Desmopressin does not decrease blood loss and transfusion requirements in patients undergoing hepatectomy.
      ]. The limited effect of desmopressin in increasing the size of the vWF complexes [
      • Cardin F.
      • Taylor L.
      • Hutton R.
      • McIntyre N.
      • Kernoff P.
      • Burroughs A.K.
      Qualitative assessment of von Willebrand factor (vWF) in cirrhotics following repeated doses of desmopressin acetate.
      ], also suggests a reduced or ineffective action of this drug in cirrhosis.
      As platelet activation is not diminished but can be increased in cirrhosis, it is possible that BT prolongation in these patients results more from changes in vasoreactivity and/or arterial dysfunction which are well documented in cirrhosis [
      • Ferro D.
      • Quintarelli C.
      • Lattuada A.
      • Leo R.
      • Alessandroni M.
      • Mannucci P.M.
      • et al.
      High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia.
      ], than from platelet number or function. Enhanced platelet activation could also explain the normal BT found in some patients with cirrhosis despite low platelet counts [
      • Burroughs A.K.
      • Matthews K.
      • Quadiri M.
      Desmopressin and bleeding time in cirrhosis.
      ,
      • Blake J.C.
      • Sprengers D.
      • Grech P.
      • McCormick P.A.
      • McIntyre N.
      • Burroughs A.K.
      Bleeding time in patients with hepatic cirrhosis.
      ].

      Platelet function assay (PFA)-100®

      The PFA-100 (Table 1) test attempts to mimic in vivo shear-dependent platelet function. It measures the closure time (CT), by platelets, of an aperture in a membrane coated with either collagen/ADP or collagen/epinephrine. While it may substitute for skin bleeding-time testing in the assessment of suspected von Willebrand’s disease and qualitative platelet disorders [
      • Harrison P.
      • Robinson M.
      • Liesner R.
      • Khair K.
      • Cohen H.
      • Mackie I.
      • et al.
      The PFA-100: a potential rapid screening tool for the assessment of platelet dysfunction.
      ], it appears to be of limited value in other settings compared to healthy controls. Prolonged CT occurs in patients with end stage liver disease [
      • Kujovich J.L.
      Hemostatic defects in end stage liver disease.
      ] as well as in stable cirrhotic patients [
      • Escolar G.
      • Cases A.
      • Viñas M.
      • Pino M.
      • Calls J.
      • Cirera I.
      • et al.
      Evaluation of acquired platelet dysfunctions in uremic and cirrhotic patients using the platelet function analyzer (PFA-100): influence of hematocrit elevation.
      ,
      • Pihusch R.
      • Rank A.
      • Göhring P.
      • Pihusch M.
      • Hiller E.
      • Beuers U.
      Platelet function rather than plasmatic coagulation explains hypercoagulable state in cholestatic liver disease.
      ]. Nevertheless, the prognostic value of abnormal PFA-100 in predicting bleeding complications in LC patients has never been investigated [
      • Lisman T.
      • Caldwell S.H.
      • Porte R.J.
      • Leebeek F.W.
      Consequences of abnormal hemostasis tests for clinical practice.
      ].

      Thromboelastography (TEG®)

      Recently, other global in vitro laboratory tests such as Thrombelastography (TEG) have been developed to explore both platelet and clotting function. TEG gives information on clotting factor activity, platelet function, and fibrinolysis. TEG abnormalities indicating hypercoagulability have been reported in LC [
      • Senzolo M.
      • Cholongitas E.
      • Thalheimer U.
      • Riddell A.
      • Agarwal S.
      • Mallett S.
      • et al.
      Heparin-like effect in liver disease and liver transplantation.
      ,
      • Tripodi A.
      • Primignani M.
      • Chantarangkul V.
      • Viscardi Y.
      • Dell’Era A.
      • Fabris F.M.
      • et al.
      The coagulopathy of cirrhosis assessed by thromboelastometry and its correlation with conventional coagulation parameters.
      ]. Recently, PlateletMapping using TEG technology has been suggested as a potentially useful and novel approach to evaluate platelet function in patients with cirrhosis [
      • James K.
      • Bertoja E.
      • O’Briene J.
      • Mallett S.
      Use of thromboelastography Platelet Mapping™ to monitor antithrombotic therapy in a patient with Budd–Chiari syndrome.
      ,
      • Pivalizza E.G.
      • Melnikov V.
      • Guzman-Reyes S.
      • Marasigan B.
      Thrombelastograph platelet mapping in a patient receiving antiplatelet therapy.
      ] (Table 1). These tests require further evaluation to verify their utility in various clinical situations.

      Thrombocytopenia and cirrhosis

      Thrombocytopenia is defined as any decrease in platelet count below the lower normal limit, which is usually around 140 x 109/L. TCP is a common finding in cirrhosis and reported in as many as 76% of patients [
      • Giannini E.
      • Botta F.
      • Borro P.
      • Risso D.
      • Romagnoli P.
      • Fasoli A.
      • et al.
      Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis.
      ].
      However, thrombocytopenia has not been associated with an increased risk of bleeding from esophageal varices or other sites, although it is correlated with blood loss during surgery [
      • Clavien P.A.
      • Camargo Jr., C.A.
      • Croxford R.
      • Langer B.
      • Levy G.A.
      • Greig P.D.
      Definition and classification of negative outcomes in solid organ transplantation. Application in liver transplantation.
      ]. Moderate TCP (50–75 × 109/L) is observed in approximately 13% of patients with cirrhosis. Severe TCP, defined as platelet count less than 50 × 109/L occurs in only 1% of patients [
      • Afdhal N.
      • McHutchison J.
      • Brown R.
      • Jacobson I.
      • Manns M.
      • Poordad F.
      • et al.
      Thrombocytopenia associated with chronic liver disease.
      ]. This threshold is often used as a cut-off when managing patients with cirrhosis, as a contraindication for elective invasive procedures for example liver biopsy, paracentesis, thoracentesis, because of an assumed increased risk of bleeding [
      • De Gottardi A.
      • Thevenot T.
      • Spahr L.
      • Morard I.
      • Bresson-Hadni S.
      • Torres F.
      • et al.
      Risk of complications after abdominal paracentesis in cirrhotic patients: a prospective study.
      ,
      • 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.
      ,
      • McVay P.A.
      • Toy P.T.
      Lack of increased bleeding after paracentesis and thoracentesis in patients with mild coagulation abnormalities.
      ,
      • McVay P.A.
      • Toy P.T.
      Lack of increased bleeding after liver biopsy in patients with mild hemostatic abnormalities.
      ]. Often platelet transfusions are used prophylactically to cover similar procedures.
      Thus, as in any critically ill patient [
      • Hui P.
      • Cook D.J.
      • Lim W.
      • Fraser G.A.
      • Arnold D.M.
      The frequency and clinical significance of thrombocytopenia complicating critical illness: a systematic review.
      ], severe TCP could impact the routine care of liver cirrhosis patients [
      • Giannini E.G.
      • Greco A.
      • Marenco S.
      • Andorno E.
      • Valente U.
      • Savarino V.
      Incidence of bleeding following invasive procedures in patients with thrombocytopenia and advanced liver disease.
      ], potentially postponing or interfering with diagnostic and therapeutic procedures including liver biopsy, antiviral therapy, and medically indicated or elective surgery.
      Accordingly, Tripodi et al. [
      • 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.
      ] documented that thrombocytopenia limits thrombin generation in LC patients so potentially predisposing to bleeding tendency. Thus, platelet transfusion might be useful only in patients with low platelet counts during acute bleeding or before undergoing surgery or liver biopsy.

      Mechanisms of thrombocytopenia

      The pathogenesis of TCP in cirrhosis is still not fully understood. Multiple factors have been proposed for the pathogenesis of TCP in advanced liver cirrhosis. Traditionally TCP is believed to result from an imbalance between platelet production and platelet survival (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Mechanisms of thrombocytopenia in liver cirrhosis. Thrombocytopenia in liver cirrhosis is traditionally believed to be the result from an imbalance between (1) platelet production and (2) platelet survival. Factors that decrease platelet production: (a) direct bone marrow suppression caused by the underlying etiology o liver disease and (b) the inadequate thrombocytopoiesis for abnormal thrombopoietin production or activity. Factors decreasing platelet survival include: (a) enhanced splenic and splanchnic sequestration secondary to portal hypertension (b) autoantibodies directed against platelet surface antigens that produce an augmented removal of platelets by the splenic and hepatic reticulo-endothelial systems (c) increased platelet consumption as a result of platelet activation.

      Decreased platelet production

      Bone marrow suppression

      Suppression of platelet production in the bone marrow can be caused by the underlying etiology of the liver disease [
      • Garcia-Suarez J.
      • Burgaleta C.
      • Hernanz N.
      • Albarran F.
      • Tobaruela P.
      • Alvarez-Mon M.
      HCV-associated thrombocytopenia: clinical characteristics and platelet response after recombinant alpha2binterferon therapy.
      ,
      • 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.
      ]. Thus, in chronically infected hepatitis C (HCV) patients, either HCV itself or interferon treatments [
      • Louie K.S.
      • Micallef J.M.
      • Pimenta J.M.
      • Forssen U.M.
      Prevalence of thrombocytopenia among patients with chronic hepatitis C: a systematic review.
      ] seem to be responsible for bone marrow suppression and eventually TCP [
      • Weksler B.B.
      Review article: the pathophysiology of thrombocytopenia in hepatitis C virus infection and chronic liver disease.
      ]. Alcohol is another factor causing TCP via direct inhibition of megakaryocyte maturation and ultimately platelet formation [
      • Latvala J.
      • Parkkila S.
      • Niemelä O.
      Excess alcohol consumption is common in patients with cytopenia: studies in blood and bone marrow cells.
      ,
      • Levine R.F.
      • Spivak J.L.
      • Meagher R.C.
      • Sieber F.
      Effect of ethanol on thrombopoiesis.
      ]. Cirrhotic patients might also have dietary deficiencies like in the case of vitamin B12, folic acid and iron that could also contribute towards thrombocytopenia.

      Altered thrombopoietin metabolism

      Liver cells produce thrombopoietin (TPO), an important cytokine affecting megakaryocytes ploid amount, growth, and size [
      • Rios R.
      • Sangro B.
      • Herrero I.
      • Quiroga J.
      • Prieto J.
      The role of thrombopoietin in the thrombocytopenia of patients with liver cirrhosis.
      ]. Low TPO-mRNA expression was detected in the liver of patients with advanced liver disease and could be responsible for a deficient hepatic thrombopoietin production [
      • Sungaran R.
      • Markovic B.
      • Chong B.H.
      Localization and regulation of thrombopoietin m-RNA expression in human kidney, liver, bone marrow, and spleen using in situ hybridization.
      ,
      • Martin 3rd, T.G.
      • Somberg K.A.
      • Meng Y.G.
      • Cohen R.L.
      • Heid C.A.
      • de Sauvage F.J.
      • et al.
      Thrombopoietin levels in patients with cirrhosis before and after orthotopic liver transplantation.
      ]. Accordingly, patients with LC and TCP revealed significantly lower reticulated platelet levels than LC patients without TCP [
      • Rios R.
      • Sangro B.
      • Herrero I.
      • Quiroga J.
      • Prieto J.
      The role of thrombopoietin in the thrombocytopenia of patients with liver cirrhosis.
      ,
      • Koike Y.
      • Yoneyama A.
      • Shirai J.
      • Ishida T.
      • Shoda E.
      • Miyazaki K.
      • et al.
      Evaluation of thrombopoiesis in thrombocytopenic disorders by simultaneous measurement of reticulated platelets of whole blood and serum thrombopoietin concentrations.
      ]. Moreover, after orthotopic liver transplantation an increase of TPO was observed [
      • Goulis 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.
      ,
      • Peck-Radosavljevic M.
      • Wichlas M.
      • Zacherl J.
      • Stiegler G.
      • Stohlawetz P.
      • Fuchsjäger M.
      • et al.
      Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production.
      ].
      However, the clinical impact of these data is confused by the divergent results on serum TPO levels, including normal, decreased or increased in LC [
      • Rios R.
      • Sangro B.
      • Herrero I.
      • Quiroga J.
      • Prieto J.
      The role of thrombopoietin in the thrombocytopenia of patients with liver cirrhosis.
      ,
      • Martin 3rd, T.G.
      • Somberg K.A.
      • Meng Y.G.
      • Cohen R.L.
      • Heid C.A.
      • de Sauvage F.J.
      • et al.
      Thrombopoietin levels in patients with cirrhosis before and after orthotopic liver transplantation.
      ,
      • Koike Y.
      • Yoneyama A.
      • Shirai J.
      • Ishida T.
      • Shoda E.
      • Miyazaki K.
      • et al.
      Evaluation of thrombopoiesis in thrombocytopenic disorders by simultaneous measurement of reticulated platelets of whole blood and serum thrombopoietin concentrations.
      ,
      • Goulis 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.
      ,
      • Peck-Radosavljevic M.
      • Wichlas M.
      • Zacherl J.
      • Stiegler G.
      • Stohlawetz P.
      • Fuchsjäger M.
      • et al.
      Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production.
      ,
      • Panasiuk A.
      • Prokopowicz D.
      • Zak J.
      • Panasiuk B.
      Reticulated platelets as a marker of megakaryopoiesis in liver cirrhosis; relation to thrombopoietin and hepatocyte growth factor serum concentration.
      ,
      • Kajihara M.
      • Okazaki Y.
      • Kato S.
      • Ishii H.
      • Kawakami Y.
      • Ikeda Y.
      • et al.
      Evaluation of platelet kinetics in patients with liver cirrhosis: similarity to idiopathic thrombocytopenic purpura.
      ,
      • Sanjo A.
      • Satoi J.
      • Ohnishi A.
      • Maruno J.
      • Fukata M.
      • Suzuki N.
      Role of elevated platelet-associated immunoglobulin G and hypersplenism in thrombocytopenia of chronic liver diseases.
      ,
      • Sezai S.
      • Kamisaka K.
      • Ikegami F.
      • Usuki K.
      • Urabe A.
      • Tahara T.
      • et al.
      Regulation of hepatic thrombopoietin production by portal hemodynamics in liver cirrhosis.
      ,
      • Koruk M.
      • Onuk M.D.
      • Akçay F.
      • Savas M.C.
      Serum thrombopoietin levels in patients with chronic hepatitis and liver cirrhosis, and its relationship with circulating thrombocyte counts.
      ,
      • Aref S.
      • Mabed M.
      • Selim T.
      • Goda T.
      • Khafagy N.
      Thrombopoietin (TPO) levels in hepatic patients with thrombocytopenia.
      ]. This issue may be consequent to an inadequate standardization of TPO laboratory assays that should be solved in the future [
      • Wolber E.
      • Jelkmann W.
      Thrombopoietin: the novel hepatic hormone.
      ].

      Decreased platelet survival

      Hypersplenism and portal hypertension

      The original theory by Aster et al. [
      • Aster R.H.
      Pooling of platelets in the spleen: role in the pathogenesis of “hypersplenic” thrombocytopenia.
      ] suggested that in LC, TCP could exclusively be explained by an increased pooling of platelets in the enlarged spleen because of portal hypertension. Thus, kinetic radiolabelled platelet studies showed shorter platelet survival time [
      • Stein S.F.
      • Harker L.A.
      Kinetic and functional studies of platelets, fibrinogen, and plasminogen in patients with hepatic cirrhosis.
      ]. Additionally, partial splenic embolization demonstrated an increase in platelet count suggesting a contribution of splenic sequestration in TCP [
      • Lee C.M.
      • Leung T.K.
      • Wang H.J.
      • Lee W.H.
      • Shen L.K.
      • Liu J.D.
      • et al.
      Evaluation of the effect of partial splenic embolization on platelet values for liver cirrhosis patients with thrombocytopenia.
      ,
      • Noguchi H.
      • Hirai K.
      • Aoki Y.
      • Sakata K.
      • Tanikawa K.
      Changes in platelet kinetics after a partial splenic arterial embolization in cirrhotic patients with hypersplenism.
      ]. Despite these findings, a direct correlation between portal pressure or spleen size and platelet count was never firmly demonstrated.
      Gastroesophageal varices (GEV), a direct consequence of portal hypertension, appear to be associated with a wide range of TCP (ranging from 68 to 160 × 109/L) as showed by several cross-sectional studies [
      • Zein C.O.
      • Lindor K.D.
      • Angulo P.
      Prevalence and predictors of esophageal varices in patients with primary sclerosing cholangitis.
      ,
      • Pilette C.
      • Oberti F.
      • Aube C.
      • Rousselet M.C.
      • Bedossa P.
      • Gallois Y.
      • et al.
      Non-invasive diagnosis of esophageal varices in chronic liver diseases.
      ,
      • Zaman A.
      • Hapke R.
      • Flora K.
      • Rosen H.R.
      • Benner K.
      Factors predicting the presence of esophageal or gastric varices in patients with advanced liver disease.
      ,
      • Madhotra R.
      • Mulcahy H.E.
      • Willner I.
      • Reuben A.
      Prediction of esophageal varices in patients with cirrhosis.
      ,
      • Sanyal A.J.
      • Fontana R.J.
      • Di Bisceglie A.M.
      • Everhart J.E.
      • Doherty M.C.
      • Everson G.T.
      • et al.
      The prevalence and risk factors associated with esophageal varices in subjects with hepatitis C and advanced fibrosis.
      ] performed in decompensated and compensated LC patients [
      • Groszmann R.J.
      • Garcia-Tsao G.
      • Bosch J.
      • Grace N.D.
      • Burroughs A.K.
      • Planas R.
      • et al.
      Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.
      ,
      • Qamar A.A.
      • Grace N.D.
      • Groszmann R.J.
      • Garcia-Tsao G.
      • Bosch J.
      • Burroughs A.K.
      • et al.
      Platelet count is not a predictor of the presence or development of gastroesophageal varices in cirrhosis.
      ]. Thus, Giannini et al. [
      • Giannini E.
      • Botta F.
      • Borro P.
      • Risso D.
      • Romagnoli P.
      • Fasoli A.
      • et al.
      Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis.
      ] proposed platelet count/spleen diameter ratio as a non-invasive predictor of GEV; the diagnostic accuracy of this ratio for GEV was 86% with a negative predictive value of 87% [
      • Giannini E.G.
      • Zaman A.
      • Kreil A.
      • Floreani A.
      • Dulbecco P.
      • Testa E.
      • et al.
      Platelet count/spleen diameter ratio of esophageal varices: results of a multicenter, prospective, validation study.
      ]. However, normalization of portal pressure with transjugular portosystemic shunts (TIPS) could not consistently demonstrate a benefit in terms of platelet count [
      • Karasu Z.
      • Gurakar A.
      • Kerwin B.
      • Hulagu S.
      • Jazzar A.
      • McFadden R.
      • et al.
      Effect of transjugular intrahepatic portosystemic shunt on thrombocytopenia associated with cirrhosis.
      ,
      • 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?.
      ].

      Platelet-associated antibodies

      Increased levels of immunoglobulin G (IgG) bound to platelets, suggest the presence of autoantibodies reactive with platelets in patients with chronic liver disease [
      • Kajihara M.
      • Okazaki Y.
      • Kato S.
      • Ishii H.
      • Kawakami Y.
      • Ikeda Y.
      • et al.
      Evaluation of platelet kinetics in patients with liver cirrhosis: similarity to idiopathic thrombocytopenic purpura.
      ,
      • Pereira J.
      • Accatino L.
      • Alfaro J.
      • Brahm J.
      • Hidalgo P.
      • Mezzano D.
      Platelet autoantibodies in patients with chronic liver disease.
      ]. Autoantibodies directed against platelet surface antigens can enhance removal of platelets by the splenic and hepatic reticulo-endothelial systems. This is clearly the case in certain patients with hepatitis C [
      • Aref S.
      • Sleem T.
      • El Menshawy N.
      • Ebrahiem L.
      • Abdella D.
      • Fouda M.
      • et al.
      Antiplatelet antibodies contribute to thrombocytopenia associated with chronic hepatitis C virus infection.
      ]. Nevertheless, the role of these antiplatelet antibodies in TCP in other causes of cirrhosis is still unclear because of their nonspecific binding to platelet surface [
      • Aref S.
      • Sleem T.
      • El Menshawy N.
      • Ebrahiem L.
      • Abdella D.
      • Fouda M.
      • et al.
      Antiplatelet antibodies contribute to thrombocytopenia associated with chronic hepatitis C virus infection.
      ,
      • Kajihara M.
      • Kato S.
      • Okazaki Y.
      • Kawakami Y.
      • Ishii H.
      • Ikeda Y.
      • et al.
      A role of autoantibody-mediated platelet destruction in thrombocytopenia in patients with cirrhosis.
      ].

      Platelet consumption

      Platelet activation, with ensuing platelet consumption, could be implicated in TCP of LC (see paragraph: Thrombocytopathy). Low-grade disseminated intravascular coagulation may play a role as suggested by the concomitant increase of prothrombin fragment 1+2 (F1+2) and D-dimer in advanced LC [
      • Violi F.
      • Ferro D.
      • Basili S.
      • Saliola M.
      • Quintarelli C.
      • Alessandri C.
      • et al.
      Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis.
      ]. Endotoxemia may be implicated as LC patients treated with non-absorbable antibiotics showed a significant and simultaneous reduction of endotoxemia, F1+2, and D-dimer plasma levels [
      • Violi F.
      • Ferro D.
      • Basili S.
      • Saliola M.
      • Quintarelli C.
      • Alessandri C.
      • et al.
      Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis.
      ]. Furthermore, endotoxemia per se could reduce peripheral blood counts either directly or indirectly though the release of cytokines [
      • Itoh H.
      • Cicala C.
      • Douglas G.J.
      • Page C.P.
      Platelet accumulation induced by bacterial endotoxin in rats.
      ,
      • Aslam R.
      • Speck E.R.
      • Kim M.
      • Crow A.R.
      • Bang K.W.
      • Nestel F.P.
      • et al.
      Platelet toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-α production in vivo.
      ]. Thus, Kalambokis et al. showed that intestinal decontamination lowered endotoxaemia and raised peripheral blood counts by inhibiting cytokines and enhancing the production of nitric oxide (NO), a potent vasodilator and anti-aggregating molecule [
      • Kalambokis G.
      • Tsianos E.V.
      Endotoxaemia in the pathogenesis of cytopenias in liver cirrhosis. Could oral antibiotics raise blood counts?.
      ].

      Co-existing conditions and bleeding risk in LC patients

      Anemia may complicate the clinical course of cirrhosis and could theoretically predispose to bleeding by impairing platelet function. Thus, red cells activate platelet COX1 [
      • Violi F.
      • Ghiselli A.
      • Alessandri C.
      • Frattaroli S.
      • Iuliano L.
      • Balsano F.
      Activation of platelet cyclooxygenase by red cells in vitro.
      ], inactivate NO [
      • Gkaliagkousi E.
      • Ferro A.
      Nitric oxide signalling in the regulation of cardiovascular and platelet function.
      ] and greatly contribute to vessel repair by favoring platelet attachment to damaged vasculature [
      • Thachil J.
      Anemia – the overlooked factor in bleeding related to liver disease.
      ]. However, the impact of anemia on bleeding complication of cirrhotic patients needs to be further investigated along with exploring the cost/benefit of red cell transfusion in case of cirrhosis with associated anemia [
      • Thachil J.
      Anemia – the overlooked factor in bleeding related to liver disease.
      ]. It has been shown that a restrictive transfusion approach (target hemoglobin level: 7.0 and 9.0 g/dl) was as effective as and possibly superior to a more liberal transfusion policy [
      • Hébert P.C.
      • Wells G.
      • Blajchman M.A.
      • Marshall J.
      • Martin C.
      • Pagliarello G.
      • et al.
      A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion requirements in critical care investigators, Canadian critical care trials group.
      ], accompanied by reduction of transfusion-related side effects.
      A restrictive transfusion policy should also be adopted during liver transplantation procedures. Indeed, it has been shown that transfusion of red cell concentrates, as well as the amount of transfused blood product, could be associated with a reduced graft and patient survival [
      • de Boer M.T.
      • Christensen M.C.
      • Asmussen M.
      • van der Hilst C.S.
      • Hendriks H.G.
      • Slooff M.J.
      • et al.
      The impact of intraoperative transfusion of platelets and red blood cells on survival after liver transplantation.
      ].
      Patients with cirrhosis have increased risk to develop sepsis and sepsis-related complications [
      • Foreman M.G.
      • Mannino D.M.
      • Moss M.
      Cirrhosis as a risk factor for sepsis and death: analysis of the national hospital discharge survey.
      ,
      • Gustot T.
      • Durand F.
      • Lebrec D.
      • Vincent J.L.
      • Moreau R.
      Severe sepsis in cirrhosis.
      ]. Endotoxemia-related sepsis could promote platelet aggregation, microvascular obstruction, and tissue injury [
      • Whitworth N.H.
      • Barradas M.A.
      • Mikhailidis D.P.
      • Dandona P.
      An investigation into the effects of bacterial lipopolysaccharide on human platelets.
      ] and eventually platelet exhaustion with subsequent enhanced risk of bleeding [
      • Thalheimer U.
      • Triantos C.K.
      • Samonakis D.N.
      • Patch D.
      • Burroughs A.K.
      Infection, coagulation, and variceal bleeding in cirrhosis.
      ]. Of note, prophylactic antibiotic therapy can reduce the early re-bleeding after a first bleeding episode and permits a better control of active bleeding [
      • Chavez-Tapia N.C.
      • Barrientos-Gutierrez T.
      • Tellez-Avila F.I.
      • Soares-Weiser K.
      • Uribe M.
      Antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding.
      ].

      Treatment of thrombocytopenia in liver cirrhosis

      Thrombocytopenia may have a negative impact on clinical management of patients. Therapeutic platelet transfusions are unequivocally indicated for patients with active bleeding associated with thrombocytopenia [

      British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of platelet transfusions. Br J Haematol 2003;122:10–23.

      ]. There is consensus that the platelet count should not be allowed to fall below 50 × 109/L in patients with acute bleeding.
      According to the guidelines for the general use of platelet transfusions [

      British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of platelet transfusions. Br J Haematol 2003;122:10–23.

      ], a threshold of 10 × 109/L is as safe as higher levels for patients without additional risk factors such as sepsis, concurrent use of antibiotics or other abnormalities of haemostasis.
      However, in patients with advanced liver disease there is a lack of consensus regarding the degree of thrombocytopenia that may be associated with an increased risk of bleeding [
      • Caldwell S.H.
      • Hoffman M.
      • Lisman T.
      • Macik B.G.
      • Northup P.G.
      • Reddy K.R.
      • et al.
      Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management.
      ,
      • Tripodi A.
      • Primignani M.
      • Mannucci P.M.
      Abnormalities of hemostasis and bleeding in chronic liver disease: the paradigm is challenged.
      ]. Thus, specific guidelines in LC are lacking to indicate the platelet cut-off below which procedures (as well as liver transplantation) should be delayed and/or platelet transfusions or platelet-stimulating agents should be administrated.
      Several therapeutic options (Table 2) are currently available to raise platelet count to a safe level for invasive procedures or in case of active bleeding.
      Table 2The advantages and disadvantages of strategies available to prevent bleeding in patients with liver cirrhosis: focus on platelet count and function.

      Therapeutic options

      Platelet transfusion (PT)

      Platelet transfusion (PT) is the standard-of-care in general to temporarily increase platelet counts prior to invasive procedures [

      British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of platelet transfusions. Br J Haematol 2003;122:10–23.

      ]. Current recommendations for PT [

      British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of platelet transfusions. Br J Haematol 2003;122:10–23.

      ] concerning liver biopsy, lumbar puncture, epidural anaesthesia, or similar procedures in patients with chronic and stable thrombocytopenia suggest that the platelet count should be raised to at least 50 × 109/L.
      Recently, the American Association for the Study of Liver Disease guidelines [
      • Rockey D.C.
      • Caldwell S.H.
      • Goodman Z.D.
      • Nelson R.C.
      • Smith A.D.
      American association for the study of liver diseases. Liver biopsy.
      ] recommend that platelet transfusion before liver biopsy, transcutaneously or transvenously, should be considered when levels of platelet count are less than 50–60 × 109/L (Class 1, Level C i.e. without evidence from randomized studies). Thus, in LC randomized controlled studies, assessing efficacy and safety of restrictive PT strategies in thrombocytopenic patients during invasive procedures such as liver biopsy, are needed [
      • Lisman T.
      • Porte R.J.
      Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences.
      ]. Moreover, PT seems to be inappropriate for long-term management partially due to potential allo-immunization and also because shortened allogeneic platelet survival due to sequestration in enlarged spleens. In addition, in liver transplant patients, platelet transfusions have been associated with increased post-operative mortality, as a result of an increased risk of acute lung injury [
      • Pereboom I.T.
      • de Boer M.T.
      • Haagsma E.B.
      • Hendriks H.G.
      • Lisman T.
      • Porte R.J.
      Platelet transfusion during liver transplantation is associated with increased postoperative mortality due to acute lung injury.
      ]. Additionally, there are no data to support benefit of PT strategies in subjects with TCP and variceal bleeding [
      • Garcia-Tsao G.
      • Bosch J.
      • Groszmann R.J.
      Portal hypertension and variceal bleeding-unresolved issues. Summary of an American association for the study of liver diseases and European association for the study of the liver single-topic conference.
      ].

      Splenectomy or partial splenectomy

      Splenectomy or partial splenectomy by embolization can partially reverse TCP in patients with liver disease [
      • Wang H.Y.
      • Shih S.C.
      • Lin S.C.
      • Chang W.S.
      • Wang T.E.
      • Lin F.J.
      • et al.
      Partial splenic embolization: 12-month hematological effects and complications.
      ]. However, these procedures are not routinely recommended for their immunological consequence (impaired immunity and bacterial vaccination) and the non-negligible associated mortality and morbidity [
      • Mourtzoukou E.G.
      • Pappas G.
      • Peppas G.
      • Falagas M.E.
      Vaccination of asplenic or hyposplenic adults.
      ].

      TPO targeting agents

      Recently, the role of TPO targeting agents (Table 3) has also been tested. Currently, only two TPO mimetics, Romiplostin and Eltrombopag, have been approved for the treatment of idiopathic thrombocytopenic purpura [
      • Ghanima W.
      • Bussel J.B.
      Thrombopoietic agents in immune thrombocytopenia.
      ]. They seem to be potentially useful before invasive procedure in TCP patients. Nevertheless, the higher incidence of portal axis thrombosis in patients with advanced liver disease, observed in a recent trial, prompted the FDA to advise against use of TPO mimetics in LC patients (ClinicalTrials.gov Identifier: NCT00678587).
      Table 3Agents targeting thrombopoietin (TPO) pathway.

      Thrombocytopathy in liver cirrhosis

      The belief that cirrhosis is associated with impaired platelet activation has been based on the existence of changes of laboratory tests exploring platelet aggregation. Thus, decreased agonist-induced platelet aggregation (PA) by common agonists such as thrombin, collagen, ADP, epinephrine, and arachidonic acid has been detected in LC [
      • Laffi 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.
      ,
      • 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 defective aggregation.
      ,
      • Laffi 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.
      ,
      • Desai 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.
      ]. Intra- and extra-platelet mechanisms including multiple defects in signal transduction or storage pool defect and membrane-related defects caused by enhanced high-density lipoprotein (HDL) apolipoprotein E content were all considered to account for platelet dysfunction [
      • Laffi 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.
      ,
      • 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 defective aggregation.
      ,
      • Laffi 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.
      ,
      • Desai 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.
      ] (Table 4).
      Table 4Platelet function tests in patients with liver cirrhosis.
      • Ingeberg S.
      • Jacobsen P.
      • Fischer E.
      • Bentsen K.D.
      Platelet aggregation and release of ATP in patients with hepatic cirrhosis.
      ,
      • Laffi 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.
      ,
      • Desai 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.
      ,
      • 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 defective aggregation.
      ,
      • Laffi 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.
      ,
      • Laffi G.
      • Cinotti S.
      • Filimberti E.
      • Ciabattoni G.
      • Caporale R.
      • Marra F.
      • et al.
      Defective aggregation in cirrhosis is independent of in vivo platelet activation.
      ,
      • Ferro D.
      • Quintarelli C.
      • Lattuada A.
      • Leo R.
      • Alessandroni M.
      • Mannucci P.M.
      • et al.
      High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia.
      ,
      • Davi G.
      • Ferro D.
      • Basili S.
      • Iuliano L.
      • Camastra C.
      • Giammarresi C.
      • et al.
      Increased thromboxane metabolites excretion in liver cirrhosis.
      ,
      • Panasiuk A.
      • Prokopowicz D.
      • Zak J.
      • Matowicka-Karna J.
      • Osada J.
      • Wysocka J.
      Activation of blood platelets in chronic hepatitis and liver cirrhosis P-selectin expression on blood platelets and secretory activity of beta-thromboglobulin and platelet factor-4.
      ,
      • Ferroni P.
      • Mammarella A.
      • Martini F.
      • Paoletti V.
      • Cardarello C.M.
      • Labbadia G.
      • et al.
      Increased soluble P-selectin levels in hepatitis C virus-related chronic hepatitis: correlation with viral load.
      ,
      • Pihusch R.
      • Rank A.
      • Göhring P.
      • Pihusch M.
      • Hiller E.
      • Beuers U.
      Platelet function rather than plasmatic coagulation explains hypercoagulable state in cholestatic liver disease.
      ,
      • Ogasawara F.
      • Fusegawa H.
      • Haruki Y.
      • Shiraishi K.
      • Watanabe N.
      • Matsuzaki S.
      Platelet activation in patients with alcoholic liver disease.
      ,
      • 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.
      ,
      • Vardareli E.
      • Saricam T.
      • Demirustu C.
      • Gulbas Z.
      Soluble P selectin levels in chronic liver disease: relationship to disease severity.
      ,
      • Sayed D.
      • Amin N.F.
      • Galal G.M.
      Monocyte-platelet aggregates and platelet micro-particles in patients with post-hepatitic liver cirrhosis.
      ,
      • Ozhan H.
      • Aydin M.
      • Yazici M.
      • Yazgan O.
      • Basar C.
      • Gungor A.
      • et al.
      Mean platelet volume in patients with non-alcoholic fatty liver disease.
      ,
      • Ercin C.N.
      • Dogru T.
      • Tapan S.
      • Karslioglu Y.
      • Haymana C.
      • Kilic S.
      • et al.
      Levels of soluble CD40 ligand and P-Selectin in nonalcoholic fatty liver disease.
      ,
      • Kilciler G.
      • Genc H.
      • Tapan S.
      • Ors F.
      • Kara M.
      • Karadurmus N.
      • et al.
      Mean platelet volume and its relationship with carotid atherosclerosis in subjects with non-alcoholic fatty liver disease.
      AFLD, alcoholic fatty liver disease; BTG, beta-thromboglobulin; CH, Chronic hepatitis; LC, Liver Cirrhosis; MPV, mean platelet volume, NAFLD, non alcoholic fatty liver disease; PA, platelet aggregation; PBC, primary biliary cirrhosis; PF4, platelet factor 4; PMP, platelet micro-particles; PSC, primary sclerosing cholangitis; sPs, soluble P selectin; vWF, von Willebrand Factor.
      However, more recent data have questioned this hypothesis. For instance, the urinary excretion of 11-deydro-thromboxane (Tx) B2, a stable metabolite of TxA2, was increased in cirrhosis suggesting that platelets could be activated [
      • Davi G.
      • Ferro D.
      • Basili S.
      • Iuliano L.
      • Camastra C.
      • Giammarresi C.
      • et al.
      Increased thromboxane metabolites excretion in liver cirrhosis.
      ]. Although this interpretation cannot be fully supported by the data of 11-deydro-TxB2 urinary excretion as it only partly reflects the activation of platelet COX1 [
      • Catella F.
      • Healy D.
      • Lawson J.A.
      • FitzGerald G.A.
      11-Dehydrothromboxane B2: a quantitative index of thromboxane A2 formation in the human circulation.
      ], other studies also seem to support the existence of enhanced platelet activation in cirrhosis. Soluble P-selectin (sPs), which is an in vivo marker of platelet activation is consistently elevated in plasma particularly in cases of severe liver disease and correlated with markers of hepatic protein synthesis and low platelet counts [
      • Vardareli E.
      • Saricam T.
      • Demirustu C.
      • Gulbas Z.
      Soluble P selectin levels in chronic liver disease: relationship to disease severity.
      ,
      • Ferroni P.
      • Mammarella A.
      • Martini F.
      • Paoletti V.
      • Cardarello C.M.
      • Labbadia G.
      • et al.
      Increased soluble P-selectin levels in hepatitis C virus-related chronic hepatitis: correlation with viral load.
      ,
      • Panasiuk A.
      • Prokopowicz D.
      • Zak J.
      • Matowicka-Karna J.
      • Osada J.
      • Wysocka J.
      Activation of blood platelets in chronic hepatitis and liver cirrhosis P-selectin expression on blood platelets and secretory activity of beta-thromboglobulin and platelet factor-4.
      ].
      More recent flow cytometry analysis of platelet activation, as well as platelet-monocyte aggregates, is consistent with hyper-activation of platelets in cirrhosis [
      • Ogasawara F.
      • Fusegawa H.
      • Haruki Y.
      • Shiraishi K.
      • Watanabe N.
      • Matsuzaki S.
      Platelet activation in patients with alcoholic liver disease.
      ,
      • Sayed D.
      • Amin N.F.
      • Galal G.M.
      Monocyte-platelet aggregates and platelet micro-particles in patients with post-hepatitic liver cirrhosis.
      ].
      The discrepancy between the early studies of platelet aggregation suggesting platelet hypo-aggregability secondary to impairment of platelet activation, and more recent studies showing platelet over-secretion of P-selectin, suggesting increased platelet COX1 activation, is not easy to explain. One issue is that aggregation tests in cirrhosis are intrinsically difficult because the reduced platelet count makes them difficult to interpret since these tests are dependent on platelet count.
      The biological plausibility of platelet activation in cirrhosis does not have a clear-cut mechanism either. Thrombin is the key player in the clotting cascade and through platelet receptors PAR1 and 4 acts as a potent platelet activator. It is possible that an enhanced in vivo formation of thrombin may account in part for platelet activation. This is suggested by the correlation between plasma levels of F1+2 and the urinary excretion of 11-dehydro-TxB2 [
      • Davi G.
      • Ferro D.
      • Basili S.
      • Iuliano L.
      • Camastra C.
      • Giammarresi C.
      • et al.
      Increased thromboxane metabolites excretion in liver cirrhosis.
      ]. The evidence that thrombin generation in cirrhosis is normal or even increased [
      • Violi F.
      • Ferro D.
      • Basili S.
      • Saliola M.
      • Quintarelli C.
      • Alessandri C.
      • et al.
      Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis.
      ,
      • Tripodi A.
      • Primignani M.
      • Chantarangkul V.
      • Dell’Era A.
      • Clerici M.
      • de Franchis R.
      • et al.
      An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis.
      ,
      • Gatt A.
      • Riddell A.
      • Calvaruso V.
      • Tuddenham E.G.
      • Makris M.
      • Burroughs A.K.
      Enhanced thrombin generation in patients with cirrhosis induced coagulopathy.
      ] would “allow” for sufficient thrombin despite the relatively low prothrombin levels found in patients with cirrhosis.
      Changes in vWF may also play a role. vWF is a large, multimeric protein with a crucial role in primary haemostasis, since platelet–vWF interaction is one of the first steps in platelet adhesion [
      • De Meyer S.F.
      • Deckmyn H.
      • Vanhoorelbeke K.
      Von Willebrand factor to the rescue.
      ]. Accordingly, severe bleeding tendency has been associated with vWF deficiency [
      • Lillicrap D.
      Von Willebrand disease – phenotype versus genotype: deficiency versus disease.
      ]. We have shown that higher molecular weight multimers (HMWMs) of vWF are present in cirrhosis. These HMWMs are more active in binding platelets [
      • Cardin F.
      • Taylor L.
      • Hutton R.
      • McIntyre N.
      • Kernoff P.
      • Burroughs A.K.
      Qualitative assessment of von Willebrand factor (vWF) in cirrhotics following repeated doses of desmopressin acetate.
      ]. These data were confirmed by Lisman et al. [
      • 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.
      ] who demonstrated that in cirrhosis elevated vWF plasma levels resulted in a substantially elevated platelet deposition on collagen in a vWF-dependent, flow-driven, platelet adhesion assay. The increased adhesion induced by plasma from patients with cirrhosis was observed with both normal and patients’ platelets, and was independent of platelet count. This indicates that the increase in vWF might in part compensate for the quantitative platelet defects described in these patients.

      Conclusions

      Recent data from the literature indicate that stable patients with LC may seldom have defects in primary haemostasis that predisposes them to bleeding. The prolongation of BT is not related directly to platelet count unless a severe thrombocytopenia defined arbitrarily as 50 x 109/L or less is present.
      The increased platelet activation by chronic inflammation including increased endotoxemia, coupled with increased levels of vWF may improve primary haemostasis. Similar compensatory mechanisms need further elucidation.
      To date the clinical impact of platelet hyperactivity in LC patients has never been studied and needs to be clarified. An important aspect is whether platelet hyper-function has some relationship with the thrombotic outcomes that may complicate the clinical course of cirrhosis. Also, experimental data demonstrate that platelet hyperactivity might be implicated in the progression of liver disease [
      • Kodama T.
      • Takehara T.
      • Hikita H.
      • Shimizu S.
      • Li W.
      • Miyagi T.
      • et al.
      Thrombocytopenia exacerbates cholestasis-induced liver fibrosis in mice.
      ,
      • Iannacone M.
      • Sitia G.
      • Isogawa M.
      • Marchese P.
      • Castro M.G.
      • Lowenstein P.R.
      • et al.
      Platelets mediate cytotoxic T lymphocyte-induced liver damage.
      ], and fibrosis [
      • Calvaruso V.
      • Maimone S.
      • Gatt A.
      • Pinzani M.
      • Thursz M.
      • Tuddenham E.
      • et al.
      Coagulation and fibrosis in chronic liver disease.
      ].
      Accordingly, platelet activation is necessary to accumulate virus-specific cytotoxic T lymphocytes and determine organ damage in mouse models of acute viral hepatitis and antiplatelet treatment seems capable of modulating it [
      • Iannacone M.
      • Sitia G.
      • Isogawa M.
      • Marchese P.
      • Castro M.G.
      • Lowenstein P.R.
      • et al.
      Platelets mediate cytotoxic T lymphocyte-induced liver damage.
      ,
      • Fujita K.
      • Nozaki Y.
      • Wada K.
      • Yoneda M.
      • Endo H.
      • Takahashi H.
      • et al.
      Effectiveness of antiplatelet drugs against experimental non-alcoholic fatty liver disease.
      ].
      If a relationship with clinical outcomes is proven, then anti-platelet or anticoagulant treatment may have a place in the management of compensated cirrhosis [
      • Tsochatzis E.A.
      • Bosch J.
      • Burroughs A.K.
      Prolonging survival in cirrhosis: old drugs with new indications.
      ] but this hypothesis needs to be carefully and cautiously explored.
      In conclusion, our review indicates that platelet function or primary haemostasis may not be defective in cirrhosis, and a low platelet count should not necessarily be considered as an automatic index of an increased risk of bleeding.
      Figure thumbnail fx5

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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