Reply to: Platelet function in patients with cirrhosis
Authors: Francesco Violi, Stefania Basili, Valeria Raparelli, Pratima Chowdary, Alexander Gatt, Andrew K. Burroughs
Journal: Journal of Hepatology (2012)

Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction?Journal of HepatologyVol. 55Issue 6PreviewPatients 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. Full-Text PDF Open AccessPlatelet function in patients with cirrhosisJournal of HepatologyVol. 56Issue 4PreviewIn 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. Full-Text PDF Open Access 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. We demonstrated that, upon stimulation, platelets produce physiologic amounts of isoprostanes [[1]Pignatelli P. Carnevale R. Di Santo S. Bartimoccia S. Sanguigni V. Lenti L. et al.Inherited human gp91phox deficiency is associated with impaired isoprostane formation and platelet dysfunction.Arterioscler Thromb Vasc Biol. 2011; 31: 423-434Crossref PubMed Scopus (115) Google Scholar], which are chemically stable eicosanoids derived from arachidonic acid interaction with reactive oxidant species (ROS) [[2]Morrow J.D. Hill K.E. Burk R.F. Nammour T.M. Badr K.F. Roberts II, L.J. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism.Proc Natl Acad Sci U S A. 1990; 87: 9383-9387Crossref PubMed Scopus (1704) Google Scholar]. In virtue of these chemical characteristics, isoprostanes are useful in the late phase of platelet activation, where they serve to propagate platelet aggregation via activation of the glycoprotein IIb/IIIa [[1]Pignatelli P. Carnevale R. Di Santo S. Bartimoccia S. Sanguigni V. Lenti L. et al.Inherited human gp91phox deficiency is associated with impaired isoprostane formation and platelet dysfunction.Arterioscler Thromb Vasc Biol. 2011; 31: 423-434Crossref PubMed Scopus (115) Google Scholar]. We have recently discovered that the enzyme NADPH oxidase, one of the most important cellular producers of ROS, has a key role in the formation of platelet isoprostanes. Thus, in patients with hereditary deficiency of the enzyme, platelet formation of isoprostanes is down-regulated. In particular, platelets from these patients have impaired platelet activation, reinforcing the formation of isoprostanes as a relevant intracellular pathway for platelet function [[1]Pignatelli P. Carnevale R. Di Santo S. Bartimoccia S. Sanguigni V. Lenti L. et al.Inherited human gp91phox deficiency is associated with impaired isoprostane formation and platelet dysfunction.Arterioscler Thromb Vasc Biol. 2011; 31: 423-434Crossref PubMed Scopus (115) Google Scholar]. On the basis of these findings, we analyzed the behavior of platelet isoprostanes and NADPH oxidase activation in a population affected by cirrhosis. We found that platelet production of isoprostanes was increased coincidentally with an up-regulation of platelet NADPH oxidase, suggesting a cause-effect relationship between them [[3]Basili S. Raparelli V. Riggio O. Merli M. Carnevale R. Angelico F. et al.NADPH oxidase-mediated platelet isoprostane over-production in cirrhotic patients: implication for platelet activation.Liver Int. 2011; 31: 1533-1540Crossref PubMed Scopus (36) Google Scholar]. These changes were more evident in patients with Child-Pugh’s classes B and C, indicating the platelet over-expression of this pro-aggregating molecule typically occurs in patients with severe liver failure. This finding was associated with systemic signs of platelet activation such as enhanced soluble CD40L, corroborating the concept that in liver cirrhosis platelets are more prone to be activated. The fact that platelets possess all the armamentarium to activate NADPH oxidase [4Pignatelli P. Sanguigni V. Lenti L. Ferro D. Finocchi A. Rossi P. et al.gp91phox-dependent expression of platelet CD40 ligand.Circulation. 2004; 110: 1326-1329Crossref PubMed Scopus (135) Google Scholar, 5Seno T. Inoue N. Gao D. Okuda M. Sumi Y. Matsui K. et al.Involvement of NADH/NADPH oxidase in human platelet ROS production.Thromb Res. 2001; 103: 399-409Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar] is of relevance, not only for the hemostatic system, but also for the extra-hemostatic effects potentially played by platelets. The important issue raised by Drs. Lisman and Porte is still to be adequately addressed, even if there is evidence of a role of platelets in tumor metastasis, wound healing and, overall, inflammation. Our data contribute to further expand the knowledge on the pro-inflammatory role of platelets in as much as NADPH oxidase is an enzyme of the innate immune system with a crucial role for the bacterial killing via the production of ROS [[6]Cox D. Kerrigan S.W. Watson S.P. Platelets and the innate immune system: mechanisms of bacterial-induced platelet activation.J Thromb Haemost. 2011; 9: 1097-1107Crossref PubMed Scopus (196) Google Scholar]. In this regard, platelets may represent another important component of the innate immune system, potentially involved in the atherosclerotic process [7Li Z. Yang F. Dunn S. Gross A.K. Smyth S.S. Platelets as immune mediators: their role in host defense responses and sepsis.Thromb Res. 2011; 127: 184-188Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 8Hansson G.K. Hermansson A. The immune system in atherosclerosis.Nat Immunol. 2011; 12: 204-212Crossref PubMed Scopus (1518) Google Scholar]. Thus, ROS generation by NADPH oxidase is used by platelets to oxidize LDL which are ultimately taken up by macrophages via scavenger receptors [[9]Carnevale R. Pignatelli P. Lenti L. Buchetti B. Sanguigni V. Di Santo S. et al.LDL are oxidatively modified by platelets via GP91(phox) and accumulate in human monocytes.FASEB J. 2007; 21: 927-934Crossref PubMed Scopus (49) Google Scholar]. Such an extra-hemostatic effect may implicate a key role for platelets in the inflammatory process that initiates atherosclerotic disease. The impact of this phenomenon in liver cirrhosis remains, however, to be established. How the complexity of these platelet functions relates to the progression of liver cirrhosis, including bleeding and thrombosis, is still a matter of debate and needs further investigation. For this reason, we fully agree with Drs. Lisman and Porte that, currently, the use of routine in vivo and ex vivo tests to explore global platelet function in cirrhosis is not useful for clinicians. However, future research may identify new platelet biomarkers that will help better understand the role of platelets in the bleeding and thrombotic events that complicate the clinical course of cirrhosis. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.