Coagulopathy in cirrhosis – The role of the platelet in hemostasis
Authors: Elliot B. Tapper, Simon C. Robson, Raza Malik
Journal: Journal of Hepatology (2013)

Circulating platelet derived microparticles are not increased in patients with cirrhosisJournal of HepatologyVol. 59Issue 4PreviewIn their Snapshot, Tapper, Robson, and Malik suggest that circulating platelet-derived microparticles are increased in cirrhosis as a function of systemic inflammation [1]. Ogasawara and colleagues observed higher levels of circulating platelet microparticles in 22 patients with cirrhosis as compared to 17 healthy controls [2]. However, the results of two other independent studies assessing circulating platelet microparticle levels in patients with cirrhosis do not concur. Sayed and colleagues included 60 patients with hepatitis C related cirrhosis and 20 healthy controls [3]. Full-Text PDF Open AccessReply to: "Circulating platelet derived microparticles are not increased in patients with cirrhosis"Journal of HepatologyVol. 59Issue 4PreviewWe thank Dr. Rautou et al. for their interest in our Snapshot review (in which we sought to summarize the important role that platelets play in mediating coagulation and thrombosis in patients with cirrhosis) [1]. We proposed that microparticles could have important effects on coagulation and thrombosis in these clinical settings. We mentioned the possibility of circulating cell-derived, and by inference (given the current state of the field), platelet microparticles as possible mediators of inflammation. Full-Text PDF Open Access Cirrhotic patients are at increased risk of bleeding, particularly gastrointestinal bleeding, as a consequence of portal hypertension and/or coagulopathy attributed to liver synthetic dysfunction. Paradoxically, they are also at risk of thrombosis, predominantly in the splanchnic circulation, especially when platelet counts are increased by transfusion or drug therapy [1Violi 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 (132) Google Scholar, 2Afdhal N.H. Giannini E.G. Tayyab G. Mohsin A. Lee J.W. Andriulli A. et al.Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia.N Engl J Med. 2012; 367: 716-724Crossref PubMed Scopus (234) Google Scholar]. A major problem in clinical practice is the inadequacy of coagulation tests, which do not predict bleeding or thrombotic events, but may result in the inappropriate administration of therapies (e.g., plasma transfusions prior to procedures). Additionally, these tests cannot provide information on the dynamic interaction between the coagulation and anticoagulation pathways. Evidence is mounting to highlight the central role of the platelet, of which the quantitative and qualitative properties may determine the dynamic hemostatic forces in cirrhosis. Cirrhotic thrombocytopenia and platelet dysfunction are multifactorial with many simultaneous contributions [[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 (132) Google Scholar]. Portal hypertension leads to splenic pooling, sequestering platelets from the circulation. Portosystemic shunting and gut barrier disruption result in endotoxaemia with systemic immune activation, antiplatelet antibody production, aberrant fibronolysis, and activation of coagulation with platelet consumption [[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 (132) Google Scholar]. Cirrhosis and decreased functional liver mass result in lower thrombopoetin levels and platelet underproduction. There are 3 phases of clotting in which platelets play a crucial role: primary hemostasis (platelet-vessel wall interactions), coagulation (thrombin generation), and fibrinolysis (clot dissolution). In general, thrombocytopenia, with a reduced number of functional platelets, appears to impact blood coagulation the most, by limiting thrombin generation. Despite prolonged prothrombin times, thrombin generation appears to be maintained in cirrhosis as a result of protein C deficiency [[3]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.Gastroenterology. 2009; 137: 2105-2111Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar]. Using techniques that assess protein C activity, cirrhotic plasma appears hypercoagulable until severe thrombocytopenia occurs. In vitro studies of platelet-rich plasma from cirrhotic patients support normal thrombin generation if platelets are at least 60,000 [[4]Tripodi A. Primignani M. Chantarangkul V. Clerici M. Dell'Era A. Fabris F. et al.Thrombin generation in patients with cirrhosis: the role of platelets.Hepatology. 2006; 44: 440-445Crossref PubMed Scopus (302) Google Scholar]. Interestingly, disturbing the new procoagulant and anticoagulant balance in cirrhosis, by raising platelet counts using pharmacological therapy (e.g., eltrombopag), increases the risk of thrombosis, mainly in the portal circulation [[2]Afdhal N.H. Giannini E.G. Tayyab G. Mohsin A. Lee J.W. Andriulli A. et al.Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia.N Engl J Med. 2012; 367: 716-724Crossref PubMed Scopus (234) Google Scholar]. Qualitative platelet defects in cirrhosis are dynamic and reflect the patient's overall health. They manifest in each step of the multiphasic platelet-vessel wall interaction: adhesion, aggregation, and activation. Adhesion: compared to healthy patients, cirrhotic platelet adherence to the subendothelium of injured vessels is defective, akin to that observed in uremia [[5]Ordinas A. Escolar G. Cirera I. Viñas M. Cobo F. Bosch J. et al.Existence of a platelet-adhesion defect in patients with cirrhosis independent of hematocrit: studies under flow conditions.Hepatology. 1996; 24: 1137-1142Crossref PubMed Google Scholar]. A weak but significant correlation exists between the platelet count and bleeding time [[6]Blake J.C. Sprengers D. Grech P. McCormick P.A. McIntyre N. Burroughs A.K. Bleeding time in patients with hepatic cirrhosis.BMJ. 1990; 301: 12-15Crossref PubMed Scopus (37) Google Scholar]. The correlation is weak as platelet defects are partially compensated by a concomitant increase in the adhesive protein von Willebrand factor [[7]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.Hepatology. 2006; 44: 53-61Crossref PubMed Scopus (463) Google Scholar]. Aggregation: in response to any number of stimuli – ADP, thrombin, collagen, epinephrine, or ristocetin – the degree of platelet aggregation is significantly less in cirrhosis compared to healthy controls [[8]Thomas D.P. Ream V.J. Stuart R.K. Platelet aggregation in patients with Laennec's cirrhosis of the liver.N Engl J Med. 1967; 276: 1344-1348Crossref PubMed Scopus (86) Google Scholar]. Activation: the cirrhotic platelet is said to be 'exhausted,' exhibiting reduced transmembrane signaling and a progressive inability to activate in response to appropriate stimuli. Many reasons account for this observation: (i) cirrhotic platelets have a 'storage pool defect' whereby dense granule concentrations of prothrombotic signaling molecules (e.g., platelet factor 4, beta-thromboglobulin, and serotonin) are abnormally low; (ii) cirrhotic platelets secrete disproportionately high levels of ATP. Excess extracellular ATP antagonizes ADP-induced activation of receptor P2Y12 (i.e., clopidogrel's target) and desensitizes P2Y1 resulting in lower intraplatelet ionized calcium levels [9Witters P. Freson K. Verslype C. Peerlinck K. Hoylaerts M. Nevens F. et al.Review article: blood platelet number and function in chronic liver disease and cirrhosis.Aliment Pharmacol Ther. 2008; 27: 1017-1029Crossref PubMed Scopus (135) Google Scholar, 10Enjyoji K. Sévigny J. Lin Y. Frenette P.S. Christie P.D. Esch 2nd, J.S. et al.Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation.Nat Med. 1999; 5: 1010-1017Crossref PubMed Scopus (483) Google Scholar]; (iii) there is an intraplatelet accumulation of inhibitory messengers (cyclic nucleotides), sharply limiting phospholipase activity, resulting in lower concentrations of inositol phosphate and calcium [[11]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.Gastroenterology. 1993; 105: 148-156Abstract Full Text PDF PubMed Google Scholar]. The end-result is platelets that produce less thromboxane and serotonin, precipitating cascading defects in platelet aggregation [[9]Witters P. Freson K. Verslype C. Peerlinck K. Hoylaerts M. Nevens F. et al.Review article: blood platelet number and function in chronic liver disease and cirrhosis.Aliment Pharmacol Ther. 2008; 27: 1017-1029Crossref PubMed Scopus (135) Google Scholar]. Each qualitative platelet defect is progressive with increasing Child's class. This allows us to generate hypotheses regarding underlying mechanisms. Diminished intrinsic liver function, however, will not suffice, as features of cirrhotic coagulopathy can be seen in non-cirrhotic patients with portal vein thrombosis or other causes of extrahepatic portal hypertension. Qualitative platelet defects are likely reflective of increased bloodstream endotoxin concentration vis-à-vis portosystemic shunting and gut barrier disruption [1Violi 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 (132) Google Scholar, 12Sayed D. Amin N.F. Galal G.M. Monocyte-platelet aggregates and platelet micro-particles in patients with post-hepatitic liver cirrhosis.Thromb Res. 2010; 125: e228-e233Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. Platelet-derived microparticles, in turn, are increased in cirrhosis as a function of systemic inflammation. Microparticles have a known procoagulant effect and may play an important role in the relative hypercoagulability of early cirrhosis [[12]Sayed D. Amin N.F. Galal G.M. Monocyte-platelet aggregates and platelet micro-particles in patients with post-hepatitic liver cirrhosis.Thromb Res. 2010; 125: e228-e233Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. The literature offers a number of strategies that may reduce endotoxin load or the effects of the consequent inflammation: gut decontamination (e.g., rifaximin), treatment of intrahepatic endothelial dysfunction (e.g., antioxidants) or prevention of gut bacterial translocation (e.g., beta blockers, anticoagulants). A recent trial of enoxaparin in highly selected non-thrombocytopenic cirrhotics has shown dramatic reductions in the frequency of hepatic decompensation. This landmark study may reverse dogma, should further investigation confirm that anticoagulation reduces bacterial translocation and microthrombi in the hepatic circulation, improving liver function in this selected population [[13]Villa E. Cammà C. Marietta M. Luongo M. Critelli R. Colopi S. et al.Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis.Gastroenterology. 2012; 143: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar]. It is yet to be determined if this is a viable therapeutic option in more advanced liver disease without promoting bleeding. In summary, in cirrhosis, the normal homeostatic reserve capacity to control bleeding and thrombosis events is lost, with the predilection toward bleeding or thrombosis dependent on the individual and the precipitant. Evidence is emerging on the central role of the platelet in this process. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.