Download PDF
Semin Thromb Hemost 2018; 44(02): 114-125
DOI: 10.1055/s-0037-1604091
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Platelets as Modulators of Liver Diseases

Ton Lisman
1   Section of Hepatobiliary Surgery and Liver Transplantation, Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
,
James P. Luyendyk
2   Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan
› Author Affiliations
Further Information

Publication History

Publication Date:
12 September 2017 (online)

    Permissions and Reprints

Abstract

Platelets are key players in thrombosis and hemostasis. Alterations in platelet count and function are common in liver disease, and may contribute to bleeding or thrombotic complications in liver diseases and during liver surgery. In addition to their hemostatic function, platelets may modulate liver diseases by mechanisms that are incompletely understood. Here, we present clinical evidence for a role of platelets in the progression of chronic and acute liver diseases, including cirrhosis, acute liver failure, and hepatocellular carcinoma. We also present clinical evidence that platelets promote liver regeneration following partial liver resection. Subsequently, we summarize studies in experimental animal models that support these clinical observations, and also highlight studies that are in contrast with clinical observations. The combined results of clinical and experimental studies suggest that platelets may be a therapeutic target in the treatment of liver injury and repair, but the gaps in our understanding of mechanisms involved in platelet-mediated modulation of liver diseases call for caution in clinical application of these findings.

Keywords

platelet - liver cirrhosis - regeneration - inflammation
 

  • References

  • 1 Lisman T, Leebeek FW, de Groot PG. Haemostatic abnormalities in patients with liver disease. J Hepatol 2002; 37 (02) 280-287
    CrossrefPubMedGoogle Scholar
  • 2 Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116 (06) 878-885
    CrossrefPubMedGoogle Scholar
  • 3 Lisman T, Stravitz RT. Rebalanced hemostasis in patients with acute liver failure. Semin Thromb Hemost 2015; 41 (05) 468-473
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (02) 147-156
    CrossrefPubMedGoogle Scholar
  • 5 Violi F, Basili S, Raparelli V, Chowdary P, Gatt A, Burroughs AK. Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction?. J Hepatol 2011; 55 (06) 1415-1427
    CrossrefPubMedGoogle Scholar
  • 6 Witters P, Freson K, Verslype C. , et al. Review article: blood platelet number and function in chronic liver disease and cirrhosis. Aliment Pharmacol Ther 2008; 27 (11) 1017-1029
    CrossrefPubMedGoogle Scholar
  • 7 Peck-Radosavljevic M, Wichlas M, Zacherl J. , et al. Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production. Blood 2000; 95 (03) 795-801
    CrossrefPubMedGoogle Scholar
  • 8 Schiødt FV, Balko J, Schilsky M, Harrison ME, Thornton A, Lee WM. ; Acute Liver Failure Study Group. Thrombopoietin in acute liver failure. Hepatology 2003; 37 (03) 558-561
    CrossrefPubMedGoogle Scholar
  • 9 Levine RF, Spivak JL, Meagher RC, Sieber F. Effect of ethanol on thrombopoiesis. Br J Haematol 1986; 62 (02) 345-354
    CrossrefPubMedGoogle Scholar
  • 10 García-Suárez J, Burgaleta C, Hernanz N, Albarran F, Tobaruela P, Alvarez-Mon M. HCV-associated thrombocytopenia: clinical characteristics and platelet response after recombinant alpha2b-interferon therapy. Br J Haematol 2000; 110 (01) 98-103
    CrossrefPubMedGoogle Scholar
  • 11 Kajihara M, Kato S, Okazaki Y. , et al. A role of autoantibody-mediated platelet destruction in thrombocytopenia in patients with cirrhosis. Hepatology 2003; 37 (06) 1267-1276
    CrossrefPubMedGoogle Scholar
  • 12 Bakker CM, Knot EA, Stibbe J, Wilson JH. Disseminated intravascular coagulation in liver cirrhosis. J Hepatol 1992; 15 (03) 330-335
    CrossrefPubMedGoogle Scholar
  • 13 Kondo R, Yano H, Nakashima O, Tanikawa K, Nomura Y, Kage M. Accumulation of platelets in the liver may be an important contributory factor to thrombocytopenia and liver fibrosis in chronic hepatitis C. J Gastroenterol 2013; 48 (04) 526-534
    CrossrefPubMedGoogle Scholar
  • 14 Ikura Y, Ohsawa M, Okada M, Iwai Y, Wakasa K. The significance of platelet consumption in the development of thrombocytopenia in patients with cirrhosis. Am J Med Sci 2013; 346 (03) 199-203
    CrossrefPubMedGoogle Scholar
  • 15 Aster RH. Splenic platelet pooling as a cause of “hypersplenic” thrombocytopenia. Trans Assoc Am Physicians 1965; 78: 362-373
    PubMedGoogle Scholar
  • 16 Boyer TD, Habib S. Big spleens and hypersplenism: fix it or forget it?. Liver Int 2015; 35 (05) 1492-1498
    CrossrefPubMedGoogle Scholar
  • 17 Drolz A, Horvatits T, Roedl K. , et al. Coagulation parameters and major bleeding in critically ill patients with cirrhosis. Hepatology 2016; 64 (02) 556-568
    CrossrefPubMedGoogle Scholar
  • 18 Raparelli V, Basili S, Carnevale R. , et al. Low-grade endotoxemia and platelet activation in cirrhosis. Hepatology 2017; 65 (02) 571-581
    CrossrefPubMedGoogle Scholar
  • 19 Basili S, Raparelli V, Riggio O. , et al; CALC Group. NADPH oxidase-mediated platelet isoprostane over-production in cirrhotic patients: implication for platelet activation. Liver Int 2011; 31 (10) 1533-1540
    CrossrefPubMedGoogle Scholar
  • 20 Caldwell S, Lisman T. The cirrhotic platelet: shedding light on an enigma. Hepatology 2017; 65 (02) 407-410
    CrossrefPubMedGoogle Scholar
  • 21 Lisman T, Porte RJ. Pitfalls in assessing platelet activation status in patients with liver disease. Liver Int 2012; 32 (06) 1027 , author reply 1028
    CrossrefPubMedGoogle Scholar
  • 22 Lisman T, Adelmeijer J, de Groot PG, Janssen HL, Leebeek FW. No evidence for an intrinsic platelet defect in patients with liver cirrhosis--studies under flow conditions. J Thromb Haemost 2006; 4 (09) 2070-2072
    CrossrefPubMedGoogle Scholar
  • 23 Potze W, Siddiqui MS, Boyett SL. , et al. Preserved hemostatic status in patients with non-alcoholic fatty liver disease. J Hepatol 2016; 65 (05) 980-987
    CrossrefPubMedGoogle Scholar
  • 24 Lisman T, Bongers TN, Adelmeijer J. , et al. Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006; 44 (01) 53-61
    CrossrefPubMedGoogle Scholar
  • 25 Hugenholtz GC, Adelmeijer J, Meijers JC, Porte RJ, Stravitz RT, Lisman T. An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: implications for hemostasis and clinical outcome. Hepatology 2013; 58 (02) 752-761
    CrossrefPubMedGoogle Scholar
  • 26 Uemura M, Fujimura Y, Matsumoto M. , et al. Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis. Thromb Haemost 2008; 99 (06) 1019-1029
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Napolitano G, Iacobellis A, Merla A. , et al. Bleeding after invasive procedures is rare and unpredicted by platelet counts in cirrhotic patients with thrombocytopenia. Eur J Intern Med 2017; 38: 79-82
    CrossrefPubMedGoogle Scholar
  • 28 Giannini EG, Greco A, Marenco S, Andorno E, Valente U, Savarino V. Incidence of bleeding following invasive procedures in patients with thrombocytopenia and advanced liver disease. Clin Gastroenterol Hepatol 2010; 8 (10) 899-902 , quiz e109
    CrossrefPubMedGoogle Scholar
  • 29 Weeder PD, Porte RJ, Lisman T. Hemostasis in liver disease: implications of new concepts for perioperative management. Transfus Med Rev 2014; 28 (03) 107-113
    CrossrefPubMedGoogle Scholar
  • 30 Tripodi A, Primignani M, Chantarangkul V. , et al. Global hemostasis tests in patients with cirrhosis before and after prophylactic platelet transfusion. Liver Int 2013; 33 (03) 362-367
    CrossrefPubMedGoogle Scholar
  • 31 Bos S, Bernal W, Porte RJ, Lisman T. Hemostatic complications in hepatobiliary surgery. Semin Thromb Hemost 2017; 43 (07) 732-741
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Pereboom IT, Lisman T, Porte RJ. Platelets in liver transplantation: friend or foe?. Liver Transpl 2008; 14 (07) 923-931
    CrossrefPubMedGoogle Scholar
  • 33 Starlinger P, Haegele S, Offensperger F. , et al. The profile of platelet α-granule released molecules affects postoperative liver regeneration. Hepatology 2016; 63 (05) 1675-1688
    CrossrefPubMedGoogle Scholar
  • 34 Nijsten MW, ten Duis HJ, Zijlstra JG. , et al. Blunted rise in platelet count in critically ill patients is associated with worse outcome. Crit Care Med 2000; 28 (12) 3843-3846
    CrossrefPubMedGoogle Scholar
  • 35 Trotter JF, Gillespie BW, Terrault NA. , et al; Adult-to-Adult Living Donor Liver Transplantation Cohort Study Group. Laboratory test results after living liver donation in the adult-to-adult living donor liver transplantation cohort study. Liver Transpl 2011; 17 (04) 409-417
    CrossrefPubMedGoogle Scholar
  • 36 Haegele S, Offensperger F, Pereyra D. , et al. Deficiency in thrombopoietin induction after liver surgery is associated with postoperative liver dysfunction. PLoS One 2015; 10 (01) e0116985
    CrossrefPubMedGoogle Scholar
  • 37 Groeneveld DJ, Alkozai EM, Adelmeijer J, Porte RJ, Lisman T. Balance between von Willebrand factor and ADAMTS13 following major partial hepatectomy. Br J Surg 2016; 103 (06) 735-743
    CrossrefPubMedGoogle Scholar
  • 38 Reiter RA, Knöbl P, Varadi K, Turecek PL. Changes in von Willebrand factor-cleaving protease (ADAMTS13) activity after infusion of desmopressin. Blood 2003; 101 (03) 946-948
    CrossrefPubMedGoogle Scholar
  • 39 Schwameis M, Schörgenhofer C, Assinger A, Steiner MM, Jilma B. VWF excess and ADAMTS13 deficiency: a unifying pathomechanism linking inflammation to thrombosis in DIC, malaria, and TTP. Thromb Haemost 2015; 113 (04) 708-718
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Pereboom IT, Adelmeijer J, van Leeuwen Y, Hendriks HG, Porte RJ, Lisman T. Development of a severe von Willebrand factor/ADAMTS13 dysbalance during orthotopic liver transplantation. Am J Transplant 2009; 9 (05) 1189-1196
    CrossrefPubMedGoogle Scholar
  • 41 Arshad F, Lisman T, Porte RJ. Hypercoagulability as a contributor to thrombotic complications in the liver transplant recipient. Liver Int 2013; 33 (06) 820-827
    CrossrefPubMedGoogle Scholar
  • 42 Weyrich AS. Platelets: more than a sack of glue. Hematology (Am Soc Hematol Educ Program) 2014; 2014 (01) 400-403
    CrossrefPubMedGoogle Scholar
  • 43 Gremmel T, Frelinger III AL, Michelson AD. Platelet physiology. Semin Thromb Hemost 2016; 42 (03) 191-204
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Thachil J. Platelets in inflammatory disorders: a pathophysiological and clinical perspective. Semin Thromb Hemost 2015; 41 (06) 572-581
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Smyth SS, McEver RP, Weyrich AS. , et al; 2009 Platelet Colloquium Participants. Platelet functions beyond hemostasis. J Thromb Haemost 2009; 7 (11) 1759-1766
    CrossrefPubMedGoogle Scholar
  • 46 Poujol-Robert A, Boëlle PY, Conti F. , et al. Aspirin may reduce liver fibrosis progression: evidence from a multicenter retrospective study of recurrent hepatitis C after liver transplantation. Clin Res Hepatol Gastroenterol 2014; 38 (05) 570-576
    CrossrefPubMedGoogle Scholar
  • 47 Sahasrabuddhe VV, Gunja MZ, Graubard BI. , et al. Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma. J Natl Cancer Inst 2012; 104 (23) 1808-1814
    CrossrefPubMedGoogle Scholar
  • 48 Shen H, Shahzad G, Jawairia M, Bostick RM, Mustacchia P. Association between aspirin use and the prevalence of nonalcoholic fatty liver disease: a cross-sectional study from the Third National Health and Nutrition Examination Survey. Aliment Pharmacol Ther 2014; 40 (09) 1066-1073
    CrossrefPubMedGoogle Scholar
  • 49 Jiang ZG, Feldbrügge L, Tapper EB. , et al. Aspirin use is associated with lower indices of liver fibrosis among adults in the United States. Aliment Pharmacol Ther 2016; 43 (06) 734-743
    CrossrefPubMedGoogle Scholar
  • 50 Botting RM. Vane's discovery of the mechanism of action of aspirin changed our understanding of its clinical pharmacology. Pharmacol Rep 2010; 62 (03) 518-525
    CrossrefPubMedGoogle Scholar
  • 51 Imaeda AB, Watanabe A, Sohail MA. , et al. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J Clin Invest 2009; 119 (02) 305-314
    PubMedGoogle Scholar
  • 52 Stravitz RT, Ellerbe C, Durkalski V, Reuben A, Lisman T, Lee WM. ; Acute Liver Failure Study Group. Thrombocytopenia is associated with multi-organ system failure in patients with acute liver failure. Clin Gastroenterol Hepatol 2016; 14 (04) 613-620.e4
    CrossrefPubMedGoogle Scholar
  • 53 Miyakawa K, Joshi N, Sullivan BP. , et al. Platelets and protease-activated receptor-4 contribute to acetaminophen-induced liver injury in mice. Blood 2015; 126 (15) 1835-1843
    CrossrefPubMedGoogle Scholar
  • 54 Stravitz RT, Bowling R, Bradford RL. , et al. Role of procoagulant microparticles in mediating complications and outcome of acute liver injury/acute liver failure. Hepatology 2013; 58 (01) 304-313
    CrossrefPubMedGoogle Scholar
  • 55 Levi M. Platelets in critical illness. Semin Thromb Hemost 2016; 42 (03) 252-257
    Article in Thieme ConnectPubMedGoogle Scholar
  • 56 Stravitz RT, Ellerbe C, Durkalski V, Schilski ML, Lee WM. Spontaneous bleeding complications in acute liver failure (ALF). Hepatology 2013; 58: 347A
    PubMedGoogle Scholar
  • 57 Erpenbeck L, Schön MP. Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood 2010; 115 (17) 3427-3436
    CrossrefPubMedGoogle Scholar
  • 58 Franco AT, Corken A, Ware J. Platelets at the interface of thrombosis, inflammation, and cancer. Blood 2015; 126 (05) 582-588
    CrossrefPubMedGoogle Scholar
  • 59 Sharma D, Brummel-Ziedins KE, Bouchard BA, Holmes CE. Platelets in tumor progression: a host factor that offers multiple potential targets in the treatment of cancer. J Cell Physiol 2014; 229 (08) 1005-1015
    CrossrefPubMedGoogle Scholar
  • 60 Lin RJ, Afshar-Kharghan V, Schafer AI. Paraneoplastic thrombocytosis: the secrets of tumor self-promotion. Blood 2014; 124 (02) 184-187
    CrossrefPubMedGoogle Scholar
  • 61 Cho MS, Bottsford-Miller J, Vasquez HG. , et al. Platelets increase the proliferation of ovarian cancer cells. Blood 2012; 120 (24) 4869-4872
    CrossrefPubMedGoogle Scholar
  • 62 Stone RL, Nick AM, McNeish IA. , et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med 2012; 366 (07) 610-618
    CrossrefPubMedGoogle Scholar
  • 63 Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011; 377 (9759): 31-41
    CrossrefPubMedGoogle Scholar
  • 64 Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012; 379 (9826): 1591-1601
    CrossrefPubMedGoogle Scholar
  • 65 Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol 2012; 13 (05) 518-527
    CrossrefPubMedGoogle Scholar
  • 66 Rothwell PM, Price JF, Fowkes FG. , et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 2012; 379 (9826): 1602-1612
    CrossrefPubMedGoogle Scholar
  • 67 Carr BI, Guerra V. Hepatocellular carcinoma size: platelets, γ-glutamyl transpeptidase, and alkaline phosphatase. Oncology 2013; 85 (03) 153-159
    CrossrefPubMedGoogle Scholar
  • 68 Lee CH, Lin YJ, Lin CC. , et al. Pretreatment platelet count early predicts extrahepatic metastasis of human hepatoma. Liver Int 2015; 35 (10) 2327-2336
    CrossrefPubMedGoogle Scholar
  • 69 Pang Q, Qu K, Zhang JY. , et al. The prognostic value of platelet count in patients with hepatocellular carcinoma: a systematic review and meta-analysis. Medicine (Baltimore) 2015; 94 (37) e1431
    CrossrefPubMedGoogle Scholar
  • 70 Pereyra D, Padickakudy R, Haegele S. , et al. Preoperative intra-platelet serotonin levels are associated with early disease recurrence after liver resection in humans. J Hepatol 2017; 66: s439
    PubMedGoogle Scholar
  • 71 Margonis GA, Amini N, Buettner S. , et al. Impact of early postoperative platelet count on volumetric liver gain and perioperative outcomes after major liver resection. Br J Surg 2016; 103 (07) 899-907
    CrossrefPubMedGoogle Scholar
  • 72 Wang HQ, Yang J, Yang JY, Wang WT, Yan LN. Low immediate postoperative platelet count is associated with hepatic insufficiency after hepatectomy. World J Gastroenterol 2014; 20 (33) 11871-11877
    CrossrefPubMedGoogle Scholar
  • 73 Alkozai EM, Nijsten MW, de Jong KP. , et al. Immediate postoperative low platelet count is associated with delayed liver function recovery after partial liver resection. Ann Surg 2010; 251 (02) 300-306
    CrossrefPubMedGoogle Scholar
  • 74 Han S, Park HW, Song JH. , et al. Association between intraoperative platelet transfusion and early graft regeneration in living donor liver transplantation. Ann Surg 2016; 264 (06) 1065-1072
    CrossrefPubMedGoogle Scholar
  • 75 Li L, Wang H, Yang J. , et al. Immediate postoperative low platelet counts after living donor liver transplantation predict early allograft dysfunction. Medicine (Baltimore) 2015; 94 (34) e1373
    CrossrefPubMedGoogle Scholar
  • 76 Maruyama T, Murata S, Takahashi K. , et al. Platelet transfusion improves liver function in patients with chronic liver disease and cirrhosis. Tohoku J Exp Med 2013; 229 (03) 213-220
    CrossrefPubMedGoogle Scholar
  • 77 Starlinger P, Assinger A, Haegele S. , et al. Evidence for serotonin as a relevant inducer of liver regeneration after liver resection in humans. Hepatology 2014; 60 (01) 257-266
    CrossrefPubMedGoogle Scholar
  • 78 Kirschbaum M, Jenne CN, Veldhuis ZJ. , et al. Transient von Willebrand factor-mediated platelet influx stimulates liver regeneration after partial hepatectomy in mice. Liver Int 2017 ; DOI: 10.1111/liv.13386
    PubMedGoogle Scholar
  • 79 Starlinger P, Haegele S, Wanek D. , et al. Plasma thrombospondin 1 as a predictor of postoperative liver dysfunction. Br J Surg 2015; 102 (07) 826-836
    CrossrefPubMedGoogle Scholar
  • 80 Kirschbaum M, Adelmeijer J, Alkozai EM, Porte RJ, Lisman T. Evidence against a role for platelet-derived molecules in liver regeneration after partial hepatectomy in humans. J Clin Transl Res 2016; 2: 97-106
    PubMedGoogle Scholar
  • 81 Alkozai EM, van Faassen M, Kema IP, Porte RJ, Lisman T. Evidence against a role of serotonin in liver regeneration in humans. Hepatology 2015; 62 (03) 983
    CrossrefPubMedGoogle Scholar
  • 82 Lang PA, Contaldo C, Georgiev P. , et al. Aggravation of viral hepatitis by platelet-derived serotonin. Nat Med 2008; 14 (07) 756-761
    CrossrefPubMedGoogle Scholar
  • 83 Iannacone M, Sitia G, Isogawa M. , et al. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat Med 2005; 11 (11) 1167-1169
    CrossrefPubMedGoogle Scholar
  • 84 Sitia G, Aiolfi R, Di Lucia P. , et al. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc Natl Acad Sci U S A 2012; 109 (32) E2165-E2172
    CrossrefPubMedGoogle Scholar
  • 85 Sitia G, Iannacone M, Guidotti LG. Anti-platelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma. J Hepatol 2013; 59 (05) 1135-1138
    CrossrefPubMedGoogle Scholar
  • 86 Fujita K, Nozaki Y, Wada K. , et al. Effectiveness of antiplatelet drugs against experimental non-alcoholic fatty liver disease. Gut 2008; 57 (11) 1583-1591
    CrossrefPubMedGoogle Scholar
  • 87 Yoshida S, Ikenaga N, Liu SB. , et al. Extrahepatic platelet-derived growth factor-β, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice. Gastroenterology 2014; 147 (06) 1378-1392
    CrossrefPubMedGoogle Scholar
  • 88 Khandoga A, Hanschen M, Kessler JS, Krombach F. CD4+ T cells contribute to postischemic liver injury in mice by interacting with sinusoidal endothelium and platelets. Hepatology 2006; 43 (02) 306-315
    CrossrefPubMedGoogle Scholar
  • 89 Massaguer A, Perez-Del-Pulgar S, Engel P, Serratosa J, Bosch J, Pizcueta P. Concanavalin-A-induced liver injury is severely impaired in mice deficient in P-selectin. J Leukoc Biol 2002; 72 (02) 262-270
    PubMedGoogle Scholar
  • 90 Pearson JM, Schultze AE, Jean PA, Roth RA. Platelet participation in liver injury from gram-negative bacterial lipopolysaccharide in the rat. Shock 1995; 4 (03) 178-186
    CrossrefPubMedGoogle Scholar
  • 91 Hisakura K, Murata S, Takahashi K. , et al. Platelets prevent acute hepatitis induced by anti-Fas antibody. J Gastroenterol Hepatol 2011; 26 (02) 348-355
    CrossrefPubMedGoogle Scholar
  • 92 Lee WM. . Acetaminophen and the U.S. Acute Liver Failure Study Group. Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure. Hepatology 2004; 40 (01) 6-9
    CrossrefPubMedGoogle Scholar
  • 93 Ramachandran A, Jaeschke H. Mechanisms of acetaminophen hepatotoxicity and their translation to the human pathophysiology. J Clin Transl Res 2017; 3: 157-169
    PubMedGoogle Scholar
  • 94 Kopec AK, Joshi N, Cline-Fedewa H. , et al. Fibrin(ogen) drives repair after acetaminophen-induced liver injury via leukocyte αMβ2 integrin-dependent upregulation of Mmp12. J Hepatol 2017; 66 (04) 787-797
    CrossrefPubMedGoogle Scholar
  • 95 Ganey PE, Luyendyk JP, Newport SW. , et al. Role of the coagulation system in acetaminophen-induced hepatotoxicity in mice. Hepatology 2007; 46 (04) 1177-1186
    CrossrefPubMedGoogle Scholar
  • 96 Sullivan BP, Kopec AK, Joshi N. , et al. Hepatocyte tissue factor activates the coagulation cascade in mice. Blood 2013; 121 (10) 1868-1874
    CrossrefPubMedGoogle Scholar
  • 97 Goubran HA, Stakiw J, Radosevic M, Burnouf T. Platelet-cancer interactions. Semin Thromb Hemost 2014; 40 (03) 296-305
    Article in Thieme ConnectPubMedGoogle Scholar
  • 98 Carr BI, Cavallini A, D'Alessandro R. , et al. Platelet extracts induce growth, migration and invasion in human hepatocellular carcinoma in vitro. BMC Cancer 2014; 14: 43
    CrossrefPubMedGoogle Scholar
  • 99 Kirschbaum M, Karimian G, Adelmeijer J, Giepmans BN, Porte RJ, Lisman T. Horizontal RNA transfer mediates platelet-induced hepatocyte proliferation. Blood 2015; 126 (06) 798-806
    CrossrefPubMedGoogle Scholar
  • 100 He A, Liang M, Liu G. , et al. The role of FcγRIIa and TGF-β1/KLF6 pathway in platelet's promoting hepatocellular carcinoma cells growth. Blood 2014; 124: 1429
    PubMedGoogle Scholar
  • 101 Bihari C, Rastogi A, Shasthry SM. , et al. Platelets contribute to growth and metastasis in hepatocellular carcinoma. APMIS 2016; 124 (09) 776-786
    CrossrefPubMedGoogle Scholar
  • 102 Liang C, Chen W, Zhi X. , et al. Serotonin promotes the proliferation of serum-deprived hepatocellular carcinoma cells via upregulation of FOXO3a. Mol Cancer 2013; 12: 14
    CrossrefPubMedGoogle Scholar
  • 103 Soll C, Jang JH, Riener MO. , et al. Serotonin promotes tumor growth in human hepatocellular cancer. Hepatology 2010; 51 (04) 1244-1254
    CrossrefPubMedGoogle Scholar
  • 104 Fabregat I, Moreno-Càceres J, Sánchez A. , et al; IT-LIVER Consortium. TGF-β signalling and liver disease. FEBS J 2016; 283 (12) 2219-2232
    CrossrefPubMedGoogle Scholar
  • 105 Lu L, Sun HC, Zhang W. , et al. Aspirin minimized the pro-metastasis effect of sorafenib and improved survival by up-regulating HTATIP2 in hepatocellular carcinoma. PLoS One 2013; 8 (05) e65023
    CrossrefPubMedGoogle Scholar
  • 106 Hossain MA, Kim DH, Jang JY. , et al. Aspirin induces apoptosis in vitro and inhibits tumor growth of human hepatocellular carcinoma cells in a nude mouse xenograft model. Int J Oncol 2012; 40 (04) 1298-1304
    CrossrefPubMedGoogle Scholar
  • 107 Zhang R, Guo H, Xu J. , et al. Activated platelets inhibit hepatocellular carcinoma cell differentiation and promote tumor progression via platelet-tumor cell binding. Oncotarget 2016; 7 (37) 60609-60622
    CrossrefPubMedGoogle Scholar
  • 108 Milsom C, Rak J. Tissue factor and cancer. Pathophysiol Haemost Thromb 2008; 36 (3-4): 160-176
    PubMedGoogle Scholar
  • 109 Ruf W, Mueller BM. Thrombin generation and the pathogenesis of cancer. Semin Thromb Hemost 2006; 32 (Suppl. 01) 61-68
    Article in Thieme ConnectPubMedGoogle Scholar
  • 110 Lesurtel M, Graf R, Aleil B. , et al. Platelet-derived serotonin mediates liver regeneration. Science 2006; 312 (5770): 104-107
    CrossrefPubMedGoogle Scholar
  • 111 Murata S, Ohkohchi N, Matsuo R, Ikeda O, Myronovych A, Hoshi R. Platelets promote liver regeneration in early period after hepatectomy in mice. World J Surg 2007; 31 (04) 808-816
    CrossrefPubMedGoogle Scholar
  • 112 Matsuo R, Nakano Y, Ohkohchi N. Platelet administration via the portal vein promotes liver regeneration in rats after 70% hepatectomy. Ann Surg 2011; 253 (04) 759-763
    CrossrefPubMedGoogle Scholar
  • 113 Balasubramanian S, Paulose CS. Induction of DNA synthesis in primary cultures of rat hepatocytes by serotonin: possible involvement of serotonin S2 receptor. Hepatology 1998; 27 (01) 62-66
    CrossrefPubMedGoogle Scholar
  • 114 Matsuo R, Ohkohchi N, Murata S. , et al. Platelets strongly induce hepatocyte proliferation with IGF-1 and HGF in vitro. J Surg Res 2008; 145 (02) 279-286
    CrossrefPubMedGoogle Scholar
  • 115 Takahashi K, Murata S, Fukunaga K, Ohkohchi N. Human platelets inhibit liver fibrosis in severe combined immunodeficiency mice. World J Gastroenterol 2013; 19 (32) 5250-5260
    CrossrefPubMedGoogle Scholar
  • 116 Watanabe M, Murata S, Hashimoto I. , et al. Platelets contribute to the reduction of liver fibrosis in mice. J Gastroenterol Hepatol 2009; 24 (01) 78-89
    CrossrefPubMedGoogle Scholar
  • 117 Kodama T, Takehara T, Hikita H. , et al. Thrombocytopenia exacerbates cholestasis-induced liver fibrosis in mice. Gastroenterology 2010; 138 (07) 2487-2498 , 2498.e1–2498.e7
    CrossrefPubMedGoogle Scholar
  • 118 Laschke MW, Dold S, Menger MD, Jeppsson B, Thorlacius H. Platelet-dependent accumulation of leukocytes in sinusoids mediates hepatocellular damage in bile duct ligation-induced cholestasis. Br J Pharmacol 2008; 153 (01) 148-156
    CrossrefPubMedGoogle Scholar
  • 119 Sullivan BP, Wang R, Tawfik O, Luyendyk JP. Protective and damaging effects of platelets in acute cholestatic liver injury revealed by depletion and inhibition strategies. Toxicol Sci 2010; 115 (01) 286-294
    CrossrefPubMedGoogle Scholar
  • 120 Joshi N, Kopec AK, O'Brien KM. , et al. Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice. J Thromb Haemost 2015; 13 (01) 57-71
    CrossrefPubMedGoogle Scholar
  • 121 Joshi N, Kopec AK, Ray JL, Luyendyk JP. Inhibition of PAR-4 and P2Y12 receptor-mediated platelet activation produces distinct hepatic pathologies in experimental xenobiotic-induced cholestatic liver disease. Toxicology 2016; 365: 9-16
    CrossrefPubMedGoogle Scholar
  • 122 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. J Hepatol 2002; 37 (05) 548-555
    CrossrefPubMedGoogle Scholar
  • 123 Ben-Ari Z, Panagou M, Patch D. , et al. Hypercoagulability in patients with primary biliary cirrhosis and primary sclerosing cholangitis evaluated by thrombelastography. J Hepatol 1997; 26 (03) 554-559
    CrossrefPubMedGoogle Scholar
  • 124 Zhang J, Song S, Pang Q. , et al. Serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice. Sci Rep 2015; 5: 8098
    CrossrefPubMedGoogle Scholar
  • 125 Myronovych A, Murata S, Chiba M. , et al. Role of platelets on liver regeneration after 90% hepatectomy in mice. J Hepatol 2008; 49 (03) 363-372
    CrossrefPubMedGoogle Scholar
  • 126 López ML, Kieling CO, Uribe Cruz C. , et al. Platelet increases survival in a model of 90% hepatectomy in rats. Liver Int 2014; 34 (07) 1049-1056
    CrossrefPubMedGoogle Scholar
  • 127 Meyer J, Lejmi E, Fontana P, Morel P, Gonelle-Gispert C, Bühler L. A focus on the role of platelets in liver regeneration: do platelet-endothelial cell interactions initiate the regenerative process?. J Hepatol 2015; 63 (05) 1263-1271
    CrossrefPubMedGoogle Scholar
  • 128 Lisman T, Porte RJ. Mechanisms of platelet-mediated liver regeneration. Blood 2016; 128 (05) 625-629
    CrossrefPubMedGoogle Scholar
  • 129 Walther DJ, Peter JU, Winter S. , et al. Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release. Cell 2003; 115 (07) 851-862
    CrossrefPubMedGoogle Scholar
  • 130 Selzner N, Selzner M, Odermatt B, Tian Y, Van Rooijen N, Clavien PA. ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-alpha/IL-6 in mice. Gastroenterology 2003; 124 (03) 692-700
    CrossrefPubMedGoogle Scholar
  • 131 Hosoya S, Ikejima K, Takeda K. , et al. Innate immune responses involving natural killer and natural killer T cells promote liver regeneration after partial hepatectomy in mice. Am J Physiol Gastrointest Liver Physiol 2013; 304 (03) G293-–G299
    CrossrefPubMedGoogle Scholar
  • 132 Rao R, Graffeo CS, Gulati R. , et al. Interleukin 17-producing γδT cells promote hepatic regeneration in mice. Gastroenterology 2014; 147 (02) 473-84.e2
    CrossrefPubMedGoogle Scholar
  • 133 Slaba I, Wang J, Kolaczkowska E, McDonald B, Lee WY, Kubes P. Imaging the dynamic platelet-neutrophil response in sterile liver injury and repair in mice. Hepatology 2015; 62 (05) 1593-1605
    CrossrefPubMedGoogle Scholar
  • 134 Anstee QM, Dhar A, Thursz MR. The role of hypercoagulability in liver fibrogenesis. Clin Res Hepatol Gastroenterol 2011; 35 (8-9): 526-533
    CrossrefPubMedGoogle Scholar
  • 135 Zaldivar MM, Pauels K, von Hundelshausen P. , et al. CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis. Hepatology 2010; 51 (04) 1345-1353
    CrossrefPubMedGoogle Scholar
  • 136 Poisson J, Lemoinne S, Boulanger C. , et al. Liver sinusoidal endothelial cells: Physiology and role in liver diseases. J Hepatol 2017; 66 (01) 212-227
    CrossrefPubMedGoogle Scholar
  • 137 Tamura T, Kondo T, Pak S. , et al. Interaction between Kupffer cells and platelets in the early period of hepatic ischemia-reperfusion injury--an in vivo study. J Surg Res 2012; 178 (01) 443-451
    CrossrefPubMedGoogle Scholar
  • 138 Sindram D, Porte RJ, Hoffman MR, Bentley RC, Clavien PA. Synergism between platelets and leukocytes in inducing endothelial cell apoptosis in the cold ischemic rat liver: a Kupffer cell-mediated injury. FASEB J 2001; 15 (07) 1230-1232
    CrossrefPubMedGoogle Scholar
  • 139 Tiedt R, Schomber T, Hao-Shen H, Skoda RC. Pf4-Cre transgenic mice allow the generation of lineage-restricted gene knockouts for studying megakaryocyte and platelet function in vivo. Blood 2007; 109 (04) 1503-1506
    CrossrefPubMedGoogle Scholar
  • 140 Sung JJ, Go MY. Reversible Kupffer cell suppression in biliary obstruction is caused by hydrophobic bile acids. J Hepatol 1999; 30 (03) 413-418
    CrossrefPubMedGoogle Scholar
  • 141 Sabrkhany S, Griffioen AW, Oude Egbrink MG. The role of blood platelets in tumor angiogenesis. Biochim Biophys Acta 2011; 1815 (02) 189-196
    PubMedGoogle Scholar
  • 142 Alkozai EM, Porte RJ, Adelmeijer J. , et al. Levels of angiogenic proteins in plasma and platelets are not different between patients with hepatitis B/C-related cirrhosis and patients with cirrhosis and hepatocellular carcinoma. Platelets 2015; 26 (06) 577-582
    CrossrefPubMedGoogle Scholar
  • 143 Laffi G, Marra F, Gresele P. , et al. Evidence for a storage pool defect in platelets from cirrhotic patients with defective aggregation. Gastroenterology 1992; 103 (02) 641-646
    CrossrefPubMedGoogle Scholar