Platelet function in patients with cirrhosis
Authors: Ton Lisman, Robert J. Porte
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 AccessReply to: Platelet function in patients with cirrhosisJournal of HepatologyVol. 56Issue 4PreviewWe 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. Full-Text PDF Open Access 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]Violi F. Basili S. Raparelli V. Chowdary P. Gatt A. Burroughs A.K. Patients with liver cirrhosis suffer from primary haemostatic defects?.Fact or fiction J Hepatol. 2011; 55: 1415-1427Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar]. Whilst we concur with these conclusions, we wish to make additional comments on platelet function in patients with cirrhosis.(1)Whereas routine diagnostic tests of platelet function such as the skin bleeding time and suspension aggregometry are frequently abnormal, in vivo platelet function may be adequate as pointed out by Violi et al. Although intrinsic platelet function under physiological flow conditions has been shown to be preserved, defective platelet–vessel wall interactions due to anemia and thrombocytopenia are present [[2]Lisman T. Adelmeijer J. de Groot P.G. Janssen H.L. Leebeek F.W. No evidence for an intrinsic platelet defect in patients with liver cirrhosis – studies under flow conditions.J Thromb Haemost. 2006; 9: 2070-2072Crossref Scopus (54) Google Scholar]. A dysbalanced von Willebrand factor (vWF)/ADAMTS13 balance may (in part) compensate for these indirect platelet defects. The net effect of all possible changes in primary hemostasis in patients with cirrhosis appears to be a system which is in physiological hemostatic balance [[3]Lisman T. Porte R.J. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences.Blood. 2010; 6: 878-885Crossref Scopus (468) Google Scholar]. Nevertheless, the balance in primary hemostasis in these patients is presumably precarious, and patients may experience either bleeding or thrombotic complications as a result of poorly understood mechanisms that upset the balance in the primary hemostatic system. We agree with Violi and coworkers that studies testing the predictive value of different platelet function tests for either bleeding or thrombosis are required. However, until results of such studies are available, we argue against routine use of platelet function tests, including bleeding time and suspension aggregometry, in the diagnostic work-up of hemostasis of patients with cirrhosis, as it is at present unclear how these test results should be interpreted. Even the interpretation of the platelet count in a patient with cirrhosis is difficult, as potential compensatory mechanisms may be present. A recent study showed that ultrasound-guided thoracentesis can be safely performed in patients with platelet counts below 50,000/μl [[4]Patel M.D. Joshi S.D. Abnormal preprocedural international normalized ratio and platelet counts are not associated with increased bleeding complications after ultrasound-guided thoracentesis.AJR Am J Roentgenol. 2011; 1: W164-W168Crossref Scopus (35) Google Scholar], although a platelet count below this level is considered a contraindication for small invasive procedures such as thoracentesis, as pointed out by Violi and coworkers. These findings reinforce the need for prospective clinical studies on safety of invasive procedures in patients with cirrhosis and a moderate to severe thrombocytopenia.(2)Platelet transfusions are frequently administered before or during larger invasive procedures (including liver transplantation) in patients with cirrhosis. We have recently demonstrated that platelet function is preserved throughout liver transplantation [[5]Pereboom I.T. Adelmeijer J. van Leeuwen Y. Hendriks H.G. Porte R.J. Lisman T. No evidence for systemic platelet activation during or after orthotopic liver transplantation.Liver Transpl. 2009; 8: 956-962Crossref Scopus (13) Google Scholar], although profound hemostatic changes, including further changes in levels of coagulation proteins and the potential occurrence of hyperfibrinolysis, are known to occur during this procedure. Moreover, a hyper-reactive VWF system characterized by substantially elevated levels of VWF and a temporary ADAMTS13 deficiency develops during liver transplantation [[6]Pereboom I.T. Adelmeijer J. van Leeuwen Y. Hendriks H.G. Porte R.J. Lisman T. Development of a severe von Willebrand factor/ADAMTS13 dysbalance during orthotopic liver transplantation.Am J Transplant. 2009; 5: 1189-1196Crossref Scopus (66) Google Scholar]. Not only may this hyper-reactive primary hemostatic system constitute a risk for development of intra- or post-operative thrombosis (such as hepatic artery thrombosis), these findings also reinforce that a restrictive platelet transfusion policy is warranted, given the detrimental effects of perioperative platelet transfusions. Importantly, routine diagnostic tests of platelet function do not take alterations in the VWF/ADAMTS13 balance into account. Also during liver transplantation, the interpretation of available platelet function tests should be performed with care, and platelet tests other than a platelet count may have little value in guiding hemostatic management.(3)Although platelet function in patients with cirrhosis is presumably sufficient to support hemostasis, and platelet reactivity may in some cases be such that it even precipitates thrombosis, little is known about the function of cirrhotic platelets in processes other than cessation of bleeding. It is well recognized that platelets have multiple extra-hemostatic functions in processes including inflammation, host defense, angiogenesis, tumor metastasis, and wound healing. In liver biology, the extra-hemostatic functions of platelet may do both good and harm [[7]Pereboom I.T. Lisman T. Porte R.J. Platelets in liver transplantation: friend or foe?.Liver Transpl. 2008; 7: 923-931Crossref Scopus (95) Google Scholar]. A variety of molecules stored within platelet granules play a role in the above mentioned processes. Furthermore, it may be that de novo synthesis of proteins by platelets contributes to extra-hemostatic functions of platelets [[8]Zimmerman G.A. Weyrich A.S. Signal-dependent protein synthesis by activated platelets: new pathways to altered phenotype and function.Arterioscler Thromb Vasc Biol. 2008; 3: s17-24Crossref Scopus (168) Google Scholar]. The competence of platelets to perform these extra-hemostatic functions in patients with cirrhosis is incompletely known and requires further study. It has been established that important platelet-derived molecules including 5-hydroxytryptamine (serotonin) are deficient in patients with cirrhosis [[9]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.Gastroenterology. 1992; 2: 641-646Google Scholar]. Given the important role of serotonin in repair of damaged liver tissue [[10]Lesurtel M. Graf R. Aleil B. Walther D.J. Tian Y. Jochum W. et al.Platelet-derived serotonin mediates liver regeneration.Science. 2006; 5770: 104-107Crossref Scopus (635) Google Scholar], platelets may be defective in repair as a result of reduced serotonin content. It is not unthinkable that also de novo platelet protein synthesis is compromised in platelets from patients with cirrhosis. In conclusion, although the available literature strongly supports that defects in primary hemostasis in patients with cirrhosis are more fiction than fact, many open questions remain. Future studies should not only focus on the role of platelets in bleeding and thrombosis, but also extra hemostatic functions of platelets should be considered. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.