Subscribe to RSS
DOI: 10.1055/s-0040-1715450
Hemostasis and Liver Regeneration
Funding This research was supported by grants from the National Institutes of Health (NIH) to J. P. L. (R01 ES017537, DK122813 and DK120289), support from the U.S. Department of Agriculture's National Institute of Food and Agriculture, and an EHA Research Grant from the European Hematology Association to D. G. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the NIH.![](https://www.thieme-connect.de/media/sth/202006/lookinside/thumbnails/10-1055-s-0040-1715450_02764-1.jpg)
Abstract
The liver is unique in its remarkable regenerative capacity, which enables the use of liver resection as a treatment for specific liver diseases, including removal of neoplastic liver disease. After resection, the remaining liver tissue (i.e, liver remnant) regenerates to maintain normal hepatic function. In experimental settings as well as patients, removal of up to two-thirds of the liver mass stimulates a rapid and highly coordinated process resulting in the regeneration of the remaining liver. Mechanisms controlling the initiation and termination of regeneration continue to be discovered, and many of the fundamental signaling pathways controlling the proliferation of liver parenchymal cells (i.e., hepatocytes) have been uncovered. Interestingly, while hemostatic complications (i.e., bleeding and thrombosis) are primarily thought of as a complication of surgery itself, strong evidence suggests that components of the hemostatic system are, in fact, powerful drivers of liver regeneration. This review focuses on the clinical and translational evidence supporting a link between the hemostatic system and liver regeneration, and the mechanisms whereby the hemostatic system directs liver regeneration discovered using experimental settings.
Keywords
partial hepatectomy - platelets - fibrinogen - von Willebrand factor - serotonin - platelet-derived growth factors - hemostasis - liver regeneration - liver failurePublication History
Article published online:
09 September 2020
© 2020. Thieme. All rights reserved.
Thieme Medical Publishers
333 Seventh Avenue, New York, NY 10001, USA.
-
References
- 1 Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ, Rees M. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer 2006; 94 (07) 982-999
- 2 Van Cutsem E, Nordlinger B, Adam R. , et al; European Colorectal Metastases Treatment Group. Towards a pan-European consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer 2006; 42 (14) 2212-2221
- 3 Bramhall SR, Gur U, Coldham C. , et al. Liver resection for colorectal metastases. Ann R Coll Surg Engl 2003; 85 (05) 334-339
- 4 Adam R, de Haas RJ, Wicherts DA. , et al. Is hepatic resection justified after chemotherapy in patients with colorectal liver metastases and lymph node involvement?. J Clin Oncol 2008; 26 (22) 3672-3680
- 5 Kopetz S, Chang GJ, Overman MJ. , et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 2009; 27 (22) 3677-3683
- 6 Abdalla EK, Adam R, Bilchik AJ, Jaeck D, Vauthey JN, Mahvi D. Improving resectability of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006; 13 (10) 1271-1280
- 7 Wei AC, Tung-Ping Poon R, Fan ST, Wong J. Risk factors for perioperative morbidity and mortality after extended hepatectomy for hepatocellular carcinoma. Br J Surg 2003; 90 (01) 33-41
- 8 Mullen JT, Ribero D, Reddy SK. , et al. Hepatic insufficiency and mortality in 1,059 noncirrhotic patients undergoing major hepatectomy. J Am Coll Surg 2007; 204 (05) 854-862 , discussion 862–864
- 9 Truant S, Scatton O, Dokmak S. , et al; e-HPBchir Study Group from the Association de Chirurgie Hépato-Biliaire et de Transplantation (ACHBT). Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): impact of the inter-stages course on morbi-mortality and implications for management. Eur J Surg Oncol 2015; 41 (05) 674-682
- 10 Schadde E, Schnitzbauer AA, Tschuor C, Raptis DA, Bechstein WO, Clavien PA. Systematic review and meta-analysis of feasibility, safety, and efficacy of a novel procedure: associating liver partition and portal vein ligation for staged hepatectomy. Ann Surg Oncol 2015; 22 (09) 3109-3120
- 11 Szijártó A, Fülöp A. Triggered liver regeneration: from experimental model to clinical implications. Eur Surg Res 2015; 54 (3-4): 148-161
- 12 Deal R, Frederiks C, Williams L. , et al. Rapid liver hypertrophy after portal vein occlusion correlates with the degree of collateralization between lobes-a study in pigs. J Gastrointest Surg 2018; 22 (02) 203-213
- 13 Panaro F, Giannone F, Riviere B. , et al. Perioperative impact of liver venous deprivation compared with portal venous embolization in patients undergoing right hepatectomy: preliminary results from the pioneer center. Hepatobiliary Surg Nutr 2019; 8 (04) 329-337
- 14 Abshagen K, Eipel C, Vollmar B. A critical appraisal of the hemodynamic signal driving liver regeneration. Langenbecks Arch Surg 2012; 397 (04) 579-590
- 15 Mitchell C, Willenbring H. A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice. Nat Protoc 2008; 3 (07) 1167-1170
- 16 Michalopoulos GK. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol 2010; 176 (01) 2-13
- 17 Nevzorova YA, Tolba R, Trautwein C, Liedtke C. Partial hepatectomy in mice. Lab Anim 2015; 49 (1, Suppl): 81-88
- 18 Michalopoulos GK. Liver regeneration. J Cell Physiol 2007; 213 (02) 286-300
- 19 Clavien PA. Liver regeneration: a spotlight on the novel role of platelets and serotonin. Swiss Med Wkly 2008; 138 (25-26): 361-370
- 20 Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007; 356 (15) 1545-1559
- 21 Michalopoulos GK. Hepatostat: liver regeneration and normal liver tissue maintenance. Hepatology 2017; 65 (04) 1384-1392
- 22 Michalopoulos GK. Advances in liver regeneration. Expert Rev Gastroenterol Hepatol 2014; 8 (08) 897-907
- 23 Paranjpe S, Bowen WC, Mars WM. , et al. Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation. Hepatology 2016; 64 (05) 1711-1724
- 24 Strain AJ, McGowan JA, Bucher NL. Stimulation of DNA synthesis in primary cultures of adult rat hepatocytes by rat platelet-associated substance(s). In Vitro 1982; 18 (02) 108-116
- 25 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; 37 (11) 1731-1737
- 26 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
- 27 Lesurtel M, Graf R, Aleil B. , et al. Platelet-derived serotonin mediates liver regeneration. Science 2006; 312 (5770): 104-107
- 28 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
- 29 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
- 30 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
- 31 Lisman T, Porte RJ. Mechanisms of platelet-mediated liver regeneration. Blood 2016; 128 (05) 625-629
- 32 Starlinger P, Pereyra D, Haegele S. , et al. Perioperative von Willebrand factor dynamics are associated with liver regeneration and predict outcome after liver resection. Hepatology 2017; 67 (04) 1516-1530
- 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 Starlinger P, Assinger A. Importance of platelet-derived growth factors in liver regeneration. Expert Rev Gastroenterol Hepatol 2016; 10 (05) 557-559
- 35 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
- 36 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
- 37 Papadimas GK, Tzirogiannis KN, Panoutsopoulos GI. , et al. Effect of serotonin receptor 2 blockage on liver regeneration after partial hepatectomy in the rat liver. Liver Int 2006; 26 (03) 352-361
- 38 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
- 39 Padickakudy R, Pereyra D, Offensperger F. , et al. Bivalent role of intra-platelet serotonin in liver regeneration and tumor recurrence in humans. J Hepatol 2017; 67 (06) 1243-1252
- 40 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
- 41 Duerschmied D, Canault M, Lievens D. , et al. Serotonin stimulates platelet receptor shedding by tumor necrosis factor-alpha-converting enzyme (ADAM17). J Thromb Haemost 2009; 7 (07) 1163-1171
- 42 Matondo RB, Punt C, Homberg J. , et al. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration. Am J Physiol Gastrointest Liver Physiol 2009; 296 (04) G963-G968
- 43 Italiano Jr JE, Richardson JL, Patel-Hett S. , et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 2008; 111 (03) 1227-1233
- 44 Sehgal S, Storrie B. Evidence that differential packaging of the major platelet granule proteins von Willebrand factor and fibrinogen can support their differential release. J Thromb Haemost 2007; 5 (10) 2009-2016
- 45 Battinelli EM, Markens BA, Italiano Jr JE. Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis. Blood 2011; 118 (05) 1359-1369
- 46 Chatterjee M, Huang Z, Zhang W. , et al. Distinct platelet packaging, release, and surface expression of proangiogenic and antiangiogenic factors on different platelet stimuli. Blood 2011; 117 (14) 3907-3911
- 47 van Nispen tot Pannerden H, de Haas F, Geerts W, Posthuma G, van Dijk S, Heijnen HF. The platelet interior revisited: electron tomography reveals tubular alpha-granule subtypes. Blood 2010; 116 (07) 1147-1156
- 48 Peters CG, Michelson AD, Flaumenhaft R. Granule exocytosis is required for platelet spreading: differential sorting of α-granules expressing VAMP-7. Blood 2012; 120 (01) 199-206
- 49 Starlinger P, Assinger A. Reply. Hepatology 2016; 64 (03) 992-993
- 50 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 (03) 97-106
- 51 Mussbacher M, Schrottmaier WC, Salzmann M. , et al. Optimized plasma preparation is essential to monitor platelet-stored molecules in humans. PLoS One 2017; 12 (12) e0188921
- 52 Kawasaki T, Murata S, Takahashi K. , et al. Activation of human liver sinusoidal endothelial cell by human platelets induces hepatocyte proliferation. J Hepatol 2010; 53 (04) 648-654
- 53 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
- 54 Schubert S, Weyrich AS, Rowley JW. A tour through the transcriptional landscape of platelets. Blood 2014; 124 (04) 493-502
- 55 Risitano A, Beaulieu LM, Vitseva O, Freedman JE. Platelets and platelet-like particles mediate intercellular RNA transfer. Blood 2012; 119 (26) 6288-6295
- 56 Starlinger P, Pereyra D, Haegele S. , et al. Perioperative von Willebrand factor dynamics are associated with liver regeneration and predict outcome after liver resection. Hepatology 2018; 67 (04) 1516-1530
- 57 Takahashi K, Kozuma Y, Suzuki H. , et al. Human platelets promote liver regeneration with Kupffer cells in SCID mice. J Surg Res 2013; 180 (01) 62-72
- 58 Murata S, Matsuo R, Ikeda O. , et al. Platelets promote liver regeneration under conditions of Kupffer cell depletion after hepatectomy in mice. World J Surg 2008; 32 (06) 1088-1096
- 59 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
- 60 Jenne CN, Kubes P. Platelets in inflammation and infection. Platelets 2015; 26 (04) 286-292
- 61 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
- 62 Duerschmied D, Suidan GL, Demers M. , et al. Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood 2013; 121 (06) 1008-1015
- 63 Groeneveld D, Pereyra D, Veldhuis Z. , et al. Intrahepatic fibrin(ogen) deposition drives liver regeneration after partial hepatectomy in mice and humans. Blood 2019; 133 (11) 1245-1256
- 64 Beier JI, Guo L, Ritzenthaler JD, Joshi-Barve S, Roman J, Arteel GE. Fibrin-mediated integrin signaling plays a critical role in hepatic regeneration after partial hepatectomy in mice. Ann Hepatol 2016; 15 (05) 762-772
- 65 Kim TH, Mars WM, Stolz DB, Petersen BE, Michalopoulos GK. Extracellular matrix remodeling at the early stages of liver regeneration in the rat. Hepatology 1997; 26 (04) 896-904
- 66 Roselli HT, Su M, Washington K, Kerins DM, Vaughan DE, Russell WE. Liver regeneration is transiently impaired in urokinase-deficient mice. Am J Physiol 1998; 275 (06) G1472-G1479
- 67 Drixler TA, Vogten JM, Gebbink MF, Carmeliet P, Voest EE, Borel Rinkes IH. Plasminogen mediates liver regeneration and angiogenesis after experimental partial hepatectomy. Br J Surg 2003; 90 (11) 1384-1390
- 68 Miura A, Ishiguro K, Koizumi K. , et al. Effects of pharmacological inhibition of plasminogen binding on liver regeneration in rats. Biosci Biotechnol Biochem 2017; 81 (11) 2105-2111
- 69 Bezerra JA, Bugge TH, Melin-Aldana H. , et al. Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver. Proc Natl Acad Sci U S A 1999; 96 (26) 15143-15148
- 70 Kahn ML, Zheng YW, Huang W. , et al. A dual thrombin receptor system for platelet activation. Nature 1998; 394 (6694): 690-694
- 71 Meijer C, Wiezer MJ, Diehl AM. , et al. Kupffer cell depletion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy. Liver 2000; 20 (01) 66-77
- 72 Abshagen K, Eipel C, Kalff JC, Menger MD, Vollmar B. Kupffer cells are mandatory for adequate liver regeneration by mediating hyperperfusion via modulation of vasoactive proteins. Microcirculation 2008; 15 (01) 37-47
- 73 Giovannini I, Chiarla C, Giuliante F, Vellone M, Nuzzo G. Modulation of plasma fibrinogen levels in acute-phase response after hepatectomy. Clin Chem Lab Med 2004; 42 (03) 261-265
- 74 Marubashi S, Sakon M, Nagano H. , et al. Effect of portal hemodynamics on liver regeneration studied in a novel portohepatic shunt rat model. Surgery 2004; 136 (05) 1028-1037
- 75 Niiya T, Murakami M, Aoki T, Murai N, Shimizu Y, Kusano M. Immediate increase of portal pressure, reflecting sinusoidal shear stress, induced liver regeneration after partial hepatectomy. J Hepatobiliary Pancreat Surg 1999; 6 (03) 275-280
- 76 Sato Y, Tsukada K, Hatakeyama K. Role of shear stress and immune responses in liver regeneration after a partial hepatectomy. Surg Today 1999; 29 (01) 1-9
- 77 Braet F, Shleper M, Paizi M. , et al. Liver sinusoidal endothelial cell modulation upon resection and shear stress in vitro. Comp Hepatol 2004; 3 (01) 7
- 78 Lalor PF, Herbert J, Bicknell R, Adams DH. Hepatic sinusoidal endothelium avidly binds platelets in an integrin-dependent manner, leading to platelet and endothelial activation and leukocyte recruitment. Am J Physiol Gastrointest Liver Physiol 2013; 304 (05) G469-G478
- 79 Baruch Y, Neubauer K, Shenkar L. , et al. Von Willebrand factor in plasma and in liver tissue after partial hepatectomy in the rat. J Hepatol 2002; 37 (04) 471-477
- 80 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
- 81 Kopec AK, Luyendyk JP. Coagulation in liver toxicity and disease: role of hepatocyte tissue factor. Thromb Res 2014; 133 (Suppl. 01) S57-S59
- 82 Lopez M, Kopec AK, Joshi N. , et al. Fas-induced apoptosis increases hepatocyte tissue factor procoagulant activity in vitro and in vivo. Toxicol Sci 2014; 141 (02) 453-464
- 83 Weerasinghe SV, Moons DS, Altshuler PJ, Shah YM, Omary MB. Fibrinogen-γ proteolysis and solubility dynamics during apoptotic mouse liver injury: heparin prevents and treats liver damage. Hepatology 2011; 53 (04) 1323-1332
- 84 Kopec AK, Spada AP, Contreras PC, Mackman N, Luyendyk JP. Caspase inhibition reduces hepatic tissue factor-driven coagulation in vitro and in vivo. Toxicol Sci 2018; 162 (02) 396-405
- 85 Hong F, Nguyen VA, Shen X, Kunos G, Gao B. Rapid activation of protein kinase B/Akt has a key role in antiapoptotic signaling during liver regeneration. Biochem Biophys Res Commun 2000; 279 (03) 974-979
- 86 Lin MC, Almus-Jacobs F, Chen HH. , et al. Shear stress induction of the tissue factor gene. J Clin Invest 1997; 99 (04) 737-744
- 87 Houston P, Dickson MC, Ludbrook V. , et al. Fluid shear stress induction of the tissue factor promoter in vitro and in vivo is mediated by Egr-1. Arterioscler Thromb Vasc Biol 1999; 19 (02) 281-289
- 88 Murata S, Hashimoto I, Nakano Y, Myronovych A, Watanabe M, Ohkohchi N. Single administration of thrombopoietin prevents progression of liver fibrosis and promotes liver regeneration after partial hepatectomy in cirrhotic rats. Ann Surg 2008; 248 (05) 821-828
- 89 Afdhal NH, Giannini EG, Tayyab G. , et al; ELEVATE Study Group. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med 2012; 367 (08) 716-724
- 90 de Boer MT, Christensen MC, Asmussen M. , et al. The impact of intraoperative transfusion of platelets and red blood cells on survival after liver transplantation. Anesth Analg 2008; 106 (01) 32-44
- 91 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
- 92 Fahrner R, Patsenker E, de Gottardi A. , et al. Elevated liver regeneration in response to pharmacological reduction of elevated portal venous pressure by terlipressin after partial hepatectomy. Transplantation 2014; 97 (09) 892-900
- 93 Kohler A, Perrodin S, De Gottardi A, Candinas D, Beldi G. Effectiveness of terlipressin for prevention of complications after major liver resection - A randomized placebo-controlled trial. HPB (Oxford) 2020; 22 (06) 884-891
- 94 Arshad F, Stoof SC, Leebeek FW. , et al. Infusion of DDAVP does not improve primary hemostasis in patients with cirrhosis. Liver Int 2015; 35 (07) 1809-1815