Platelets as Modulators of Liver Diseases

Ton Lisman; James P. Luyendyk

doi:10.1055/s-0037-1604091

Seminars in Thrombosis and Hemostasis, Table of Contents

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

Authors

Ton Lisman

¹Section 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

²Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan

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

Full Text

References

References
1 Lisman T, Leebeek FW, de Groot PG. Haemostatic abnormalities in patients with liver disease. J Hepatol 2002; 37 (02) 280-287
2 Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116 (06) 878-885
3 Lisman T, Stravitz RT. Rebalanced hemostasis in patients with acute liver failure. Semin Thromb Hemost 2015; 41 (05) 468-473
4 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (02) 147-156
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
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
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
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
9 Levine RF, Spivak JL, Meagher RC, Sieber F. Effect of ethanol on thrombopoiesis. Br J Haematol 1986; 62 (02) 345-354
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
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
12 Bakker CM, Knot EA, Stibbe J, Wilson JH. Disseminated intravascular coagulation in liver cirrhosis. J Hepatol 1992; 15 (03) 330-335
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
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
15 Aster RH. Splenic platelet pooling as a cause of “hypersplenic” thrombocytopenia. Trans Assoc Am Physicians 1965; 78: 362-373
16 Boyer TD, Habib S. Big spleens and hypersplenism: fix it or forget it?. Liver Int 2015; 35 (05) 1492-1498
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
18 Raparelli V, Basili S, Carnevale R. , et al. Low-grade endotoxemia and platelet activation in cirrhosis. Hepatology 2017; 65 (02) 571-581
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
20 Caldwell S, Lisman T. The cirrhotic platelet: shedding light on an enigma. Hepatology 2017; 65 (02) 407-410
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
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
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
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
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
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
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
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
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
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
31 Bos S, Bernal W, Porte RJ, Lisman T. Hemostatic complications in hepatobiliary surgery. Semin Thromb Hemost 2017; 43 (07) 732-741
32 Pereboom IT, Lisman T, Porte RJ. Platelets in liver transplantation: friend or foe?. Liver Transpl 2008; 14 (07) 923-931
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
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
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
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
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
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
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
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
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
42 Weyrich AS. Platelets: more than a sack of glue. Hematology (Am Soc Hematol Educ Program) 2014; 2014 (01) 400-403
43 Gremmel T, Frelinger III AL, Michelson AD. Platelet physiology. Semin Thromb Hemost 2016; 42 (03) 191-204
44 Thachil J. Platelets in inflammatory disorders: a pathophysiological and clinical perspective. Semin Thromb Hemost 2015; 41 (06) 572-581
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
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
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
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
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
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
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
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
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
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
55 Levi M. Platelets in critical illness. Semin Thromb Hemost 2016; 42 (03) 252-257
56 Stravitz RT, Ellerbe C, Durkalski V, Schilski ML, Lee WM. Spontaneous bleeding complications in acute liver failure (ALF). Hepatology 2013; 58: 347A
57 Erpenbeck L, Schön MP. Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood 2010; 115 (17) 3427-3436
58 Franco AT, Corken A, Ware J. Platelets at the interface of thrombosis, inflammation, and cancer. Blood 2015; 126 (05) 582-588
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
60 Lin RJ, Afshar-Kharghan V, Schafer AI. Paraneoplastic thrombocytosis: the secrets of tumor self-promotion. Blood 2014; 124 (02) 184-187
61 Cho MS, Bottsford-Miller J, Vasquez HG. , et al. Platelets increase the proliferation of ovarian cancer cells. Blood 2012; 120 (24) 4869-4872
62 Stone RL, Nick AM, McNeish IA. , et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med 2012; 366 (07) 610-618
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
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
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
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
67 Carr BI, Guerra V. Hepatocellular carcinoma size: platelets, γ-glutamyl transpeptidase, and alkaline phosphatase. Oncology 2013; 85 (03) 153-159
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
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
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
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
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
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
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
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
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
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
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
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
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
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
82 Lang PA, Contaldo C, Georgiev P. , et al. Aggravation of viral hepatitis by platelet-derived serotonin. Nat Med 2008; 14 (07) 756-761
83 Iannacone M, Sitia G, Isogawa M. , et al. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat Med 2005; 11 (11) 1167-1169
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
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
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
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
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
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
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
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
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
93 Ramachandran A, Jaeschke H. Mechanisms of acetaminophen hepatotoxicity and their translation to the human pathophysiology. J Clin Transl Res 2017; 3: 157-169
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
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
96 Sullivan BP, Kopec AK, Joshi N. , et al. Hepatocyte tissue factor activates the coagulation cascade in mice. Blood 2013; 121 (10) 1868-1874
97 Goubran HA, Stakiw J, Radosevic M, Burnouf T. Platelet-cancer interactions. Semin Thromb Hemost 2014; 40 (03) 296-305
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
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
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
101 Bihari C, Rastogi A, Shasthry SM. , et al. Platelets contribute to growth and metastasis in hepatocellular carcinoma. APMIS 2016; 124 (09) 776-786
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
103 Soll C, Jang JH, Riener MO. , et al. Serotonin promotes tumor growth in human hepatocellular cancer. Hepatology 2010; 51 (04) 1244-1254
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
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
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
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
108 Milsom C, Rak J. Tissue factor and cancer. Pathophysiol Haemost Thromb 2008; 36 (3-4): 160-176
109 Ruf W, Mueller BM. Thrombin generation and the pathogenesis of cancer. Semin Thromb Hemost 2006; 32 (Suppl. 01) 61-68
110 Lesurtel M, Graf R, Aleil B. , et al. Platelet-derived serotonin mediates liver regeneration. Science 2006; 312 (5770): 104-107
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
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
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
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
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
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
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
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
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
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
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
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
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
124 Zhang J, Song S, Pang Q. , et al. Serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice. Sci Rep 2015; 5: 8098
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
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
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
128 Lisman T, Porte RJ. Mechanisms of platelet-mediated liver regeneration. Blood 2016; 128 (05) 625-629
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
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
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
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
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
134 Anstee QM, Dhar A, Thursz MR. The role of hypercoagulability in liver fibrogenesis. Clin Res Hepatol Gastroenterol 2011; 35 (8-9): 526-533
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
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
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
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
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
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
141 Sabrkhany S, Griffioen AW, Oude Egbrink MG. The role of blood platelets in tumor angiogenesis. Biochim Biophys Acta 2011; 1815 (02) 189-196
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
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