Thrombin Inhibition in discordant xenograft rejection

Lesnikoski, Beth‐Ann; Candinas, Daniel; Otsu, Ichiro; Metternich, Rainer; Bach, Fritz H.; Robson, Simon C.

doi:10.1111/j.1399-3089.1997.tb00177.x

Cited by 8 publications

(6 citation statements)

References 17 publications

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“…Clear evidence for the importance of coagulation factors or thrombotic mediators in xenograft rejection can be inferred by the salutatory effects incurred by their inhibition that have been noted in several experimental models. Positive and beneficial results are usually comparable to those seen with C inhibition [9,10]. Inhibition of platelet aggregation by treatment of xenograft recipients with antagonists to the platelet fibrinogen receptor, GPIIbIIIa [11,12], by the use of P‐selectin or PAF antagonists [13–15], or by administration of a soluble ATPDase [16] has been generally shown to prolong graft survival in several discordant xenotransplantation models.…”

Section: Endothelial Activation: Type 1 Vs Typementioning

confidence: 99%

“…The effect of thrombin inhibition was also tested following decomplementation with cobra venom factor (CVF) in normal Lewis (Lew) rats and intrinsically C6 deficient PVG (C6‐/PVG) recipient rats. Thrombin inhibition significantly improved graft survival in HAR, but the agent tested failed to prolong survival in CVF treated Lew rats or the PVG (C6‐/PVG) recipient rats [10]. This discrepancy appeared related to non‐specificity of the evaluated serine protease inhibitor studied with the potential activation of alternative pathway of C via the inhibition of factor I.…”

Section: Proposed Anti‐thrombotic Interventionsmentioning

confidence: 99%

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Disordered regulation of coagulation and platelet activation in xenotransplantation

Robson

Cooper

d’Apice

2000

Xenotransplantation

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168

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Rejection of xenografts is associated with vascular-based inflammation, thrombocytopenia and the consumption of coagulation factors that may evolve into disseminated intravascular coagulation (DIC). Similarly, bone marrow-derived cellular xenotransplantation procedures are associated with endothelial cell activation and thrombotic microangiopathic injury. These complications generally develop despite the best available measures for depletion of xenoreactive natural antibody, inhibition of complement activation and suppression of T- and B-cell mediated immune responses. The mechanisms underlying the DIC and thrombotic microangiopathy associated with xenotransplantation are unclear. A proposed primary biological dysfunction of xenografts with respect to regulation of clotting could amplify vascular injury, promote immunological responses and independently contribute to graft failure. Disordered thromboregulation could have deleterious effects, comparable to unregulated complement activation, in the pathogenesis of xenograft rejection and may therefore represent a substantive barrier to xenotransplantation.

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Section: Endothelial Activation: Type 1 Vs Typementioning

confidence: 99%

Section: Proposed Anti‐thrombotic Interventionsmentioning

confidence: 99%

Disordered regulation of coagulation and platelet activation in xenotransplantation

Robson

Cooper

d’Apice

2000

Xenotransplantation

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168

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“…Intravascular thrombosis has been identified as a reliable marker of early acute humoral rejection (3). However, its precise pathophysiological significance is uncertain, since both anti‐graft antibody and complement are known to induce coagulation‐independent pathology in vitro (17–19) and systemic anticoagulants or anti‐platelet agents, although known to enhance graft performance, have failed to inhibit AHXR (20–24). We have previously described novel anticoagulant fusion proteins, based on TFPI or the leech anticoagulant protein hirudin, designed to be expressed on the EC of transplanted xenografts (25).…”

Section: Introductionmentioning

confidence: 99%

Complete Inhibition of Acute Humoral Rejection Using Regulated Expression of Membrane-tethered Anticoagulants on Xenograft Endothelium

Chen¹,

Weber²,

McVey

et al. 2004

American Journal of Transplantation

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Xenotransplantation promises an unlimited supply of organs for clinical transplantation. However, an aggressive humoral immune response continues to limit the survival of pig organs after transplantation into primates. Because intravascular thrombosis and systemic coagulopathy are prominent features of acute humoral xenograft rejection, we hypothesized that expression of anticoagulants on xenogeneic vascular endothelium might inhibit the process. Hearts from novel transgenic mice, expressing membrane-tethered fusion proteins based on human tissue factor pathway inhibitor and hirudin, respectively, were transplanted into rats. In contrast to control non-transgenic mouse hearts, which were all rejected within 3 days, 100% of the organs from both strains of transgenic mice were completely resistant to humoral rejection and survived for more than 100 days when T-cell-mediated rejection was inhibited by administration of ciclosporin A. These results demonstrate the critical role of coagulation in the pathophysiology of acute humoral rejection and the potential for inhibiting rejection by targeting the expression of anticoagulants to graft endothelial cells. This genetic strategy could be applied in a clinically relevant species such as the pig.

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“…44 Further evidence for the importance of coagulation mediators in vascular inflammation can be inferred by the beneficial effects of their inhibition that have been noted in models of discordant xenograft rejection to be comparable to complement inhibition. 120,121 In addition, the loss of TFPI 58 and vascular ATPDase/CD39 activity following EC activation responses in vivo 70,122 would potentiate any procoagulant changes within the graft. 20 Such developments could exacerbate vascular damage from whatever cause and potentiate the activation of platelets and coagulation pathways within xenografts resulting in graft infarction.…”

Section: Putative Molecular Incompatibility Of Natural Anticoagulantsmentioning

confidence: 99%

Factors in Xenograft Rejection

Robson

Esch

Bach

1999

Annals of the New York Academy of Sciences

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Important mechanisms underlying immediate xenograft loss by hyperacute rejection (HAR), in the pig-to-primate combination, have been recently delineated. There are now several proposed therapies that deal with the problem of complement activation and xenoreactive natural antibody (XNA) binding to the vasculature that have been shown to prevent HAR. However, vascularized xenografts are still lost, typically within days, by delayed xenograft rejection (DXR), alternatively known as acute vascular rejection (AVR). This process is characterized by endothelial cell (EC) perturbation, localization of XNA within the graft vasculature, host NK cell and monocyte activation with platelet sequestration and vascular thrombosis. Alternative immunosuppressive strategies, additive anti-complement therapies with the control of any resulting EC activation processes and induction of protective responses have been proposed to ameliorate this pathological process. In addition, several potentially important molecular incompatibilities between activated human coagulation factors and the natural anticoagulants expressed on porcine EC have been noted. Such incompatibilities may be analogous to cross-species alterations in the function of complement regulatory proteins important in HAR. Disordered thromboregulation is potentially relevant to the progression of inflammatory events in DXR and the disseminated intravascular coagulation seen in primate recipients of porcine renal xenografts. We have recently demonstrated the inability of porcine tissue factor pathway inhibitor (TFPI) to adequately neutralize human factor Xa (FXa), the aberrant activation of both human prothrombin and FXa by porcine EC and the failure of the porcine natural anticoagulant, thrombomodulin to bind human thrombin and hence activate human protein C. The enhanced potential of porcine von Willebrand factor to associate with human platelet GPIb has been demonstrated to be dependent upon the isolated A1 domain of von Willebrand factor. In addition, the loss of TFPI and vascular ATPDase/CD39 activity following EC activation responses would potentiate any procoagulant changes within the xenograft. These developments could exacerbate vascular damage from whatever cause and enhance the activation of platelets and coagulation pathways within xenografts resulting in graft infarction and loss. Analysis of these and the other putative factors underlying DXR should lead to the development and testing of genetic approaches that, in conjunction with selected pharmacological means, may further prolong xenograft survival to a clinically relevant extent.

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Thrombin Inhibition in discordant xenograft rejection

Cited by 8 publications

References 17 publications

Disordered regulation of coagulation and platelet activation in xenotransplantation

Disordered regulation of coagulation and platelet activation in xenotransplantation

Complete Inhibition of Acute Humoral Rejection Using Regulated Expression of Membrane-tethered Anticoagulants on Xenograft Endothelium

Factors in Xenograft Rejection

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