Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation.
1Surgery, Duke Transplant Center, Durham, NC
2Renal and Transplant, Guy's and St Thomas's NHS Foundation Trust, Sondon, United Kingdom
3MRC Centre for Transplantation, London, United Kingdom
Meeting: 2017 American Transplant Congress
Abstract number: 17
Keywords: Anticoagulation, Endothelial cells
Session Information
Session Name: Concurrent Session: B Cells in Alloimmunity
Session Type: Concurrent Session
Date: Sunday, April 30, 2017
Session Time: 2:30pm-4:00pm
Presentation Time: 3:30pm-3:42pm
Location: E350
Introduction:
Thrombotic microangiopathy (TMA) is a phenomenon observed in antibody-mediated rejection (AMR) of the kidney transplant, particularly in highly sensitized individuals. Following promising data in a rodent model of sensitized transplantation, we used Thrombalexin (TLN), a cytotopic anti-thrombin therapy in a highly sensitized non-human primate (NHP) model of kidney transplantation to reduce the incidence and severity of TMA.
Methods:
TLN (4uM) in University of Wisconsin (UW) solution was infused into a donor kidney after an initial UW flush. All kidneys were flushed again with UW alone prior to implantation in a pre-sensitised rhesus macaque. Post reperfusion tissue, plasma & serum samples were obtained for immunohistochemistry, TLN detection, coagulation studies & ELISA.
Results:
TLN was detected bound to the glomeruli of the transplanted kidney, in the absence of any systemic detection. There was no difference in observed mean survival time (MST) in treated animals compared to controls. Histologically, there was a difference in severity of TMA (p=0.005), and microvascular inflammation (MVI = glomerulitis, g score + peritubular capillaritis, ptc score, p=0.03) score on histology of TLN treated animals compared to controls .jpg)
. Platelet (CD61) & fibrinogen staining was also reduced in the TLN treated kidneys, compared to controls. Inhibiting thrombin resulted in trend for less detectable serum complement activation (C3a) in the early post-operative time period.
Discussion:
Localised inhibition of thrombin using Thrombalexin reduces TMA, as well as early microvascular injury scores. There is evidence that inhibition of coagulation may reduce complement activation by crosstalk mechanisms in highly sensitized NHP, however there is no survival benefit, and more work is required to understand the optimal dosing of this compound.
CITATION INFORMATION: Manook M, Kwun J, Yoon J, Samy K, MacDonlad A, Xu H, Smith R, Sacks S, Dorling A, Mamode N, Knechtle S. Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Manook M, Kwun J, Yoon J, Samy K, MacDonlad A, Xu H, Smith R, Sacks S, Dorling A, Mamode N, Knechtle S. Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/thrombalexin-use-of-a-cytotopic-anticoagulant-to-reduce-thrombotic-microangiopathy-in-a-highly-sensitized-model-of-kidney-transplantation/. Accessed November 22, 2024.« Back to 2017 American Transplant Congress