Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation
Abstract
Background Intraportal transplantation of pancreatic islets offers improved glycaemic control and insulin independence in type 1 diabetes mellitus, but intraportal thrombosis remains a possible complication. The thrombotic reaction may explain why graft loss occurs and islets from more than one donor are needed, since contact between human islets and ABO-compatible blood in vitro triggers a thrombotic reaction that damages the islets. We investigated the possible mechanism and treatment of such thrombotic reactions. Methods Coagulation activation and islet damage were monitored in four patients undergoing clinical islet transplantation according to a modified Edmonton protocol. Expression of tissue factor (TF) in the islet preparations was investigated by immunohistochemistry, immunoprecipitation, electron microscopy, and RT-PCR. To assess TF activity in purified islets, human islets were mixed with non-anticoagulated ABO-compatible blood in tubing loops coated with heparin. Findings Coagulation activation and subsequent release of insulin were found consistently after clinical islet transplantation, even in the absence of signs of intraportal thrombosis. The endocrine, but not the exocrine, cells of the pancreas were found to synthesise and secrete active TF. The clotting reaction triggered by pancreatic islets in vitro could be abrogated by blocking the active site of TF with specific antibodies or site-inactivated factor VIIa, a candidate drug for inhibition of TF activity…
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One consequence of direct blood contact during portal vein islet infusion is an immune response called the instant blood-mediated inflammatory reaction (IBMIR).
“One consequence of this direct blood contact is an immune response called the instant blood-mediated inflammatory reaction (IBMIR).”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [139]
It is thought that a major cause of the initial islet death observed in the immediate aftermath of portal vein islet infusion is due to IBMIR.
“It is thought that a major cause of the initial islet death observed in the immediate aftermath of portal vein islet infusion is due to IBMIR.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [139]
Within 15 minutes of contact with host blood, islets are encapsulated within a layer of platelets, reducing nutrient diffusion.
“Within 15 minutes of contact with host blood, islets are encapsulated within a layer of platelets, reducing nutrient diffusion.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [139]
Leukocytes infiltrate the islets within an hour, leading to cell death.
“Furthermore, leukocytes infiltrate the islets within an hour, leading to cell death.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [139]
Conventional islet transplantation by infusion into the hepatic portal vein suffers from limitations, such as acute graft loss triggered by an instant blood-mediated inflammatory response (IBMIR).
“Because conventional islet transplantation by infusion into the hepatic portal vein suffers from certain limitations, such as acute graft loss triggered by an instant blood-mediated inflammatory response (IBMIR)”
From Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. (2024) · cites this paper as [24]
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“Islet transplantation is associated with activation of the coagulation cascade and an increase in serum cross-linked fibrin degradation products (21,22).”
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“A clinical example is the instant blood-mediated inflammatory reaction (IBMIR) that occurs in clinical islet transplantation and other cell transplantation procedures, in which both cascade systems participate [ 71 ].”
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“…[7,13,20 – 22], and infusion of procoagulant TF-expressing cell products, such as MSCs, hepatocytes, and pancreatic islets, triggers innate immune attack (IBMIR) that compromises cell engraftment, safety, and ef fi cacy (Figure 3; Tables S1 and S2 in the supplemental information online) [44,53,54].”
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“IBMIR was first used to describe the procoagulant activity of pancreatic islet cells and hepatocytes in relation to their expression of procoagulant tissue factor (TF/CD142) (112, 113).”
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“A number of drugs have been identified that inhibit IBMIR, including the thrombin inhibitor Melagtran (10), the tissue factor inhibitor active site-inactivated FVIIa (active site inactivated seven) (4), activated protein C (APC) (11), and dextran sulfate (12).”
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“IBMIR in allogenic islet transplantation is characterized by consumption of platelets and activation of the coagulation and complement system (3,25).”
InfluentialHuman polymorphonuclear leukocytes produce and express functional tissue factor upon stimulation 1
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“IBMIR has been reported in pigs after intraportal islet transplantation (46) and in human islet allotransplantation (36,46,47).”
BackgroundSelf-citationControl of instant blood-mediated inflammatory reaction to improve islets of Langerhans engraftment
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“These inflammatory processes are triggered by tissue factor secreted by endocrine cells, which leads to the generation of thrombin [23–25].”
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“Tissue factor expression and release in isolated islets may also negatively influence the engraftment of transplanted islets through the instant blood-mediated inflammatory reaction (IBMIR) and subsequent platelet activation, clot formation, and lymphocyte recruitment (12,13).”
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“This possibility is supported by the individual variations that are observed in TF and MCP-1, at both the mRNA and protein levels, between islet preparations from different donors (1, 4).”
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“Significant percentages of islets die shortly after intraportal transplantation due to activation of hemostasis and thrombotic mechanisms [3–6], macrophage and Kupffer cell– mediated inflammation [7, 8], as well as higher levels of immune suppressive medication such as sirolimus and tacrolimus in the portal circulatio…”
BackgroundThe ADP/ATP Ratio: A Novel Predictive Assay for Quality Assessment of Isolated Pancreatic Islets
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“We recently found that the amount of tissue factor (TF) expression, both in pancreatic biopsies taken just prior to islet isolation and in isolated islets, was closely correlated with the outcome of clinical islet transplantation, suggesting that this assay could be used as a reliable marker for ‘islet stress’ (20,21).”
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“The immediate physiological burden faced by transplanted islets is also exacerbated by high levels of tissue factor expression in islets (10,11).”
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“First, endothelial cells were thought to act as a barrier between factor VIIa in flowing blood and cellular sources of TF in the vessel wall, preventing, in this way, the Figure 1.”
BackgroundInfluentialIslet transplantation in type 1 diabetes
de Kort, H. D., de Koning, E. D., Rabelink, T., Bruijn, J., & Bajema, I. (2011) · British medical journal · doi:10.1136/bmj.d217 · Cited by 113 · see citing works
Macroporous Three Dimensional PDMS Scaffolds for Extrahepatic Islet Transplantation
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“This phenomenon has been primarily associated with islet exposure to mechanical stress and inflammatory responses immediately after infusion, as well as high drug and toxin loads in the liver (6,31,33,41,49,52,56,59,69,75).”
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“Despite the fact that hyperacute rejection and IBMIR are similar in inducing thrombosis, IBMIR is triggered by isletexpressed tissue factor (6) and not by preformed natural antibodies (e.”
BackgroundSelf-citationIntraportal islet transplantation: the impact of the liver microenvironment
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“It is associated with increased levels of pro-coagulating fac- tors XIIa-antithrombin, XIa-antithrombin and the thrombin–antithrombin III complex, and the generation of D-dimer [9,12].”
BackgroundProspective and challenges of islet transplantation for the therapy of autoimmune diabetes.
Balamurugan, A., Bottino, R., Giannoukakis, N., & Smetanka, C. (2006) · Pancreas · doi:10.1097/01.mpa.0000203961.16630.2f · Cited by 105 · see citing works
“A major cause of islet cell loss is, as mentioned before, the instant IBMIR characterized by rapid platelet deposition on the islet surface, activation of the coagulation and complement cascades, and leukocyte infiltration of the islets.(117) Islet cells produce tissue factor, which is a triggering mediator of the coa…”
BackgroundRickels, M. R., Liu, C., Shlansky-Goldberg, R. D., Soleimanpour, S. A., Vivek, K., Kamoun, M., Min, Z., Markmann, E., Palangian, M., Dalton-Bakes, C., et al. (2013) · Diabetes · doi:10.2337/db12-1802 · Cited by 103 · see citing works
“Because isolated islets express tissue factor that may induce an instant blood-mediated inflammatory reaction (33,34), anticoagulation beyond what is required to prevent portal vein thrombosis may further decrease localized inflammation and microthrombus formation during islet revascularization and engraftment.”
BackgroundEngineering immunomodulatory biomaterials for type 1 diabetes
Stabler, C. L., Li, Y., Stewart, J. M., & Keselowsky, B. G. (2019) · Nature Reviews Materials · doi:10.1038/s41578-019-0112-5 · Cited by 126 · see citing works
Islets surface modification prevents blood-mediated inflammatory responses.
Teramura, Y., & Iwata, H. (2008) · Bioconjugate chemistry · doi:10.1021/bc800064t · Cited by 102 · see citing works
Control of IBMIR in Neonatal Porcine Islet Xenotransplantation in Baboons
Hawthorne, W. J., Salvaris, E., Phillips, P., Hawkes, J., Liuwantara, D., Burns, H., Barlow, H., Stewart, A. B., Peirce, S., Hu, M., et al. (2014) · American Journal of Transplantation · doi:10.1111/ajt.12722 · Cited by 101 · see citing works
“A similar reaction occurs when human islets weremixedwith human blood, suggesting that nonspecific factors such as exposure of pro-coagulants contribute to this instant blood-mediated inflammatory reaction (IBMIR) (6,7).”
BackgroundClinical Islet Xenotransplantation
van der Windt, D. J., Bottino, R., Kumar, G., Wijkstrom, M., Hara, H., Ezzelarab, M., Ekser, B., Phelps, C., Murase, N., Casu, A., et al. (2012) · Diabetes · doi:10.2337/db12-0033 · Cited by 100 · see citing works
Motté, E., Szepessy, E., Suenens, K., Stangé, G., Bomans, M., Jacobs-Tulleneers-Thevissen, D., Ling, Z., Kroon, E., Pipeleers, D., & Beta Cell Therapy Consortium EU-FP7 (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00219.2014 · Cited by 100 · see citing works
“Human islet (hu-islet) cell grafts can restore a functional -cell mass and correct metabolic control, but this effect fades out during the next 5 years partly as a result of an insufficient initial -cell number and -cell loss during engraftment (14, 24, 33).”
BackgroundAdvances in pancreatic islet transplantation in humans
Nanji, S., & Shapiro, A. M. J. (2006) · Diabetes, obesity and metabolism · doi:10.1111/j.1463-1326.2005.00476.x · Cited by 99 · see citing works
Autologous Pancreatic Islet Transplantation in Human Bone Marrow
Maffi, P., Balzano, G., Ponzoni, M., Nano, R., Sordi, V., Melzi, R., Mercalli, A., Scavini, M., Esposito, A., Peccatori, J., et al. (2013) · Diabetes · doi:10.2337/db13-0465 · Cited by 98 · see citing works
“As reported by many studies, an estimated 60–80% of the transplanted islet mass is lost within hours or days after intrahepatic islet infusion (12,14,15), mainly because of immediate blood-mediated inflammatory reaction (16), thrombosis (11,17), and hepatic tissue ischemia (18,19) with release of liver enzymes (20,21).”
BackgroundSurface re-engineering of pancreatic islets with recombinant azido-thrombomodulin.
Stabler, C., Sun, X.-L., Cui, W., Wilson, J. T., Haller, C., & Chaikof, E. (2007) · Bioconjugate chemistry · doi:10.1021/bc7002814 · Cited by 96 · see citing works
Latres, E., Finan, D. A., Greenstein, J. L., Kowalski, A. J., & Kieffer, T. J. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.02.007 · Cited by 118 · see citing works
Yin, D., Ding, J.-W., Shen, J.-K., Ma, L.-L., Hara, M., & Chong, A. S. (2006) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2005.01157.x · Cited by 93 · see citing works
Yu, M., Agarwal, D., Korutla, L., May, C., Wang, W., Griffith, N. N., Hering, B., Kaestner, K., Velazquez, O., Markmann, J., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0269-7 · Cited by 92 · see citing works
Bone marrow as an alternative site for islet transplantation.
Cantarelli, E., Melzi, R., Mercalli, A., Sordi, V., Ferrari, G., Lederer, C., Mrak, E., Rubinacci, A., Ponzoni, M., Sitia, G., et al. (2009) · Blood · doi:10.1182/blood-2009-03-209973 · Cited by 92 · see citing works
Teramura, Y., & Iwata, H. (2009) · Transplantation · doi:10.1097/tp.0b013e3181b230ac · Cited by 92 · see citing works
Eich, T., Eriksson, O., Sundin, A., Estrada, S., Brandhorst, D., Brandhorst, H., Langstrom, B., Nilsson, B., Korsgren, O., & Lundgren, T. (2007) · Transplantation · doi:10.1097/01.tp.0000284730.86567.9f · Cited by 106 · see citing works
Self-citationEcheverri, G., Mcgrath, K., Bottino, R., Hara, H., Dons, E., van der Windt, D. J., Ekser, B., Casu, A., Houser, S., Ezzelarab, M., et al. (2009) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2009.02815.x · Cited by 91 · see citing works
Tjernberg, J., Ekdahl, K., Lambris, J. D., Korsgren, O., & Nilsson, B. (2008) · Transplantation · doi:10.1097/tp.0b013e31816b22f3 · Cited by 91
Self-citationMoberg, L., Korsgren, O., & Nilsson, B. (2005) · Clinical and Experimental Immunology · doi:10.1111/j.1365-2249.2005.02883.x · Cited by 90
Self-citationVenturini, M., Angeli, E., Maffi, P., Fiorina, P., Bertuzzi, F., Salvioni, M., de Cobelli, F., Socci, C., Aldrighetti, L., Losio, C., et al. (2005) · Radiology · doi:10.1148/radiol.2342031356 · Cited by 89 · see citing works
The Instant Blood-Mediated Inflammatory Reaction Characterized in Hepatocyte Transplantation
Gustafson, E., Elgue, G., Hughes, R. D., Mitry, R., Sánchez, J., Haglund, U., Meurling, S., Dhawan, A., Korsgren, O., & Nilsson, B. (2011) · Transplantation · doi:10.1097/tp.0b013e31820ae459 · Cited by 88 · see citing works
“TAT (19), FXIa-AT, FXIIa-AT (39), C3a, and sC5 (40) were analyzed as”
BackgroundMethodSelf-citationImplantation Site–Dependent Dysfunction of Transplanted Pancreatic Islets
Lau, J., Mattsson, G., Carlsson, C., Nyqvist, D., Köhler, M., Berggren, P., Jansson, L., & Carlsson, P. (2007) · Diabetes · doi:10.2337/db06-1258 · Cited by 87 · see citing works
“These observations, together with the occurrence of an instant blood-mediated inflammatory reaction (when exposing human islets to blood [3,4]), have in recent years seriously questioned the liver as the implantation organ of choice for pancreatic islets.”
BackgroundReduction of Early Graft Loss After Intraportal Porcine Islet Transplantation in Monkeys
Rood, P., Bottino, R., Balamurugan, A., Smetanka, C., Ayares, D., Groth, C., Murase, N., Cooper, D., & Trucco, M. (2007) · Transplantation · doi:10.1097/01.tp.0000250680.36942.c6 · Cited by 87
“Islets injected intraportally, whether they are allo- (6, 7) or xeno- (5) islets, are subject to this reaction, which is manifest by activation and consumption of platelets, activation of neutrophils and monocytes, and activation of the coagulation and complement systems (5, 8).”
BackgroundCoronel, M. M., Liang, J.-P., Li, Y., & Stabler, C. L. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.04.017 · Cited by 85 · see citing works
“Yet, as much as 80% of the graft is estimated to be lost in the early post-transplant period due to hypoxia and initial inflammatory events [60, 61].”
BackgroundIschaemia is linked to inflammation and induction of angiogenesis in pancreatic islets
Linn, T., Schmitz, J., Hauck‐Schmalenberger, I., Lai, Y., Bretzel, R., Brandhorst, H., & Brandhorst, D. (2006) · Clinical and Experimental Immunology · doi:10.1111/j.1365-2249.2006.03066.x · Cited by 85 · see citing works
Borg, D. J., Weigelt, M., Wilhelm, C., Gerlach, M., Bickle, M., Speier, S., Bonifacio, E., & Hommel, A. (2014) · Diabetologia · doi:10.1007/s00125-013-3109-4 · Cited by 83 · see citing works
“The transplantation procedure is associated with a rapid loss of islets immediately after their infusion into the hepatic vein, due to instant blood-mediated immune reactions [9, 10] and low oxygen tension [11].”
BackgroundOxygenation of islets and its role in transplantation
Lau, J., Henriksnäs, J., Svensson, J., & Carlsson, P. (2009) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0b013e32833239ff · Cited by 82 · see citing works
Biofabrication of a vascularized islet organ for type 1 diabetes
Citro, A., Moser, P. T., Dugnani, E., Rajab, T. K., Ren, X., Evangelista-Leite, D., Charest, J. M., Peloso, A., Podesser, B. K., Manenti, F., et al. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.01.035 · Cited by 82 · see citing works
Human Islets Express a Marked Proinflammatory Molecular Signature Prior to Transplantation
Cowley, M., Weinberg, A., Zammit, N., Walters, S., Hawthorne, W., Loudovaris, T., Thomas, H., Kay, T., Gunton, J., Alexander, S., et al. (2012) · Cell Transplantation · doi:10.3727/096368911x627372 · Cited by 81 · see citing works
“Thus, islet intrinsic activation of the NF-kB pathway (1,8) and subsequent elaboration of proinflammatory genes (35,40) during organ preservation and islet isolation (44) could Figure 5.”
BackgroundInfluentialClinical islet transplant: current and future directions towards tolerance
Shapiro, A. M. J., Nanji, S., & Lakey, J. (2003) · Immunological Reviews · doi:10.1046/j.1600-065x.2003.00085.x · Cited by 81 · see citing works
“A further compounding factor is that human islets express high levels of tissue factor and become rapidly injured by intense binding of platelets, which has been known as the instant blood-mediated inflammatory reaction (IBMIR) (93, 94).”
BackgroundFroud, T., Yrizarry, J., Alejandro, R., & Ricordi, C. (2004) · Cell Transplantation · doi:10.3727/000000004772664897 · Cited by 80 · see citing works
Silicon Micro- and Nanofabrication for Medicine
Fine, D., Grattoni, A., Goodall, R., Bansal, S., Chiappini, C., Hosali, S., van de Ven, A. L., Srinivasan, S., Liu, X.-W., Godin, B., et al. (2013) · Advanced Healthcare Materials · doi:10.1002/adhm.201200214 · Cited by 78 · see citing works
Emamaullee, J., Stanton, L., Schur, C. D., & Shapiro, A. M. J. (2007) · Diabetes · doi:10.2337/db06-1653 · Cited by 78 · see citing works
- Authors
- Moberg, L., Johansson, H., Lukinius, A., Berne, C., Foss, A., Källen, R., Østraat, Ø., Salmela, K., Tibell, A., Tufveson, G., Elgue, G., Ekdahl, K. N., Korsgren, O., & Nilsson, B.
- Affiliations
- Uppsala University (SE)
- Uppsala University Hospital (SE)
- University of Helsinki (FI)
- Corresponding author
- Nilsson, B
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2002-12
- Volume
- 360
- Issue
- 9350
- Pages
- 2039-2045
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2158070939
- Cited by
- 568
- References
- 0
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 13 · 2023: 17 · 2022: 16 · 2021: 13 · 2020: 24 · 2019: 37 · 2018: 23 · 2017: 24 · 2016: 35 · 2015: 25 · 2014: 26 · 2013: 29 · 2012: 29
- FWCI
- 16.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Knut och Alice Wallenbergs Stiftelse
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- tissue factor, islet transplantation, type 1 diabetes, coagulation activation, islet damage, factor VIIa, islet endocrine cells, graft loss, insulin secretion
- MeSH terms
- Adult, Blood Cell Count, Diabetes Mellitus, Type 1, Female, Humans, Islets of Langerhans, Male, Middle Aged, Postoperative Complications, Precipitin Tests, Thromboplastin, Thrombosis, Islets of Langerhans Transplantation
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