Hyperacute lung rejection in the pig-to-human model. III. platelet receptor inhibitors synergistically modulate complement activation and lung injury

Pfeiffer, Steffen; Zorn, George L.; Zhang, Jianping; Giorgio, Todd D.; Robson, Simon C.; Azimzadeh, Agnes M.; Pierson, Richard N.

doi:10.1097/01.tp.0000058517.07194.90

Cited by 30 publications

(47 citation statements)

References 23 publications

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“…Immediate or early thrombocytopenia is not seen after Tx of pig hearts or kidneys into baboons under similar experimental conditions (19)(20)(21)(22), though it is seen early after pig lung Tx (35) …”

Section: (A) Macroscopic Appearance Of the Pig Liver In B18908 At Necmentioning

confidence: 99%

Impact of Thrombocytopenia on Survival of Baboons with Genetically Modified Pig Liver Transplants: Clinical Relevance

Ekser

Long

Echeverri

et al. 2010

American Journal of Transplantation

107

179

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A lack of deceased human donor livers leads to a significant mortality in patients with acute-on-chronic or acute (fulminant) liver failure or with primary nonfunction of an allograft. Genetically engineered pigs could provide livers that might bridge the patient to allotransplantation. Orthotopic liver transplantation in baboons using livers from a 1,3-galactosyltransferase gene-knockout (GTKO) pigs (n = 2) or from GTKO pigs transgenic for CD46 (n = 8) were carried out with a clinically acceptable immunosuppressive regimen. Six of 10 baboons survived for 4-7 days. In all cases, liver function was adequate, as evidenced by tests of detoxification, protein synthesis, complement activity and coagulation parameters. The major problem that prevented more prolonged survival beyond 7 days was a profound thrombocytopenia that developed within 1 h after reperfusion, ultimately resulting in spontaneous hemorrhage at various sites. We postulate that this is associated with the expression of tissue factor on platelets after contact with pig endothelium, resulting in platelet and platelet-peripheral blood mononuclear cell(s) aggregation and deposition of aggregates in the liver graft, though we were unable to confirm this conclusively. If this problem can be resolved, we would anticipate that a pig liver could provide a period during which a patient in liver failure could be successfully bridged to allotransplantation.

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Section: (A) Macroscopic Appearance Of the Pig Liver In B18908 At Necmentioning

confidence: 99%

Impact of Thrombocytopenia on Survival of Baboons with Genetically Modified Pig Liver Transplants: Clinical Relevance

Ekser

Long

Echeverri

et al. 2010

American Journal of Transplantation

107

179

View full text Add to dashboard Cite

show abstract

“…According to Fiane et al, a more effective inhibition of inflammatory pathways, especially the complement system, seems necessary to achieve prolonged survival of xenografts (15). Currently it is hypothesized that platelet aggregation is an early important step in hyperacute rejection, required for amplification of the complement cascade (17).…”

Section: Discussionmentioning

confidence: 98%

“…In a pig-to-human lung perfusion model, blockade of GPI/von Willebrand factor alone or in combination with the GPIIb/ IIIa axes of platelet activation was able to blunt complement activation and prolonged xenograft survival (33). Pfeiffer et al showed that, among other factors, the GPIIb/IIIa receptordependent adhesive interactions between platelets and the vessel wall or other platelets are required for efficient activation of the complement cascade (17). Although combined blockade of GPIb and GPIIb/IIIa demonstrated synergy with respect to limited inhibition of complement activation, formation of activated complement factor C3b was not prevented.…”

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confidence: 97%

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Reduced Fibrin Deposition and Intravascular Thrombosis in hDAF Transgenic Pig Hearts Perfused With Tirofiban

et al. 2007

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“…It was reported that approximately 82% of the platelets disappeared from the perfusate during the first minute of perfusion of swine lung with human blood [2]. Therapy with anti-GPIb monoclonal antibody inhibited platelet deposition on the xenograft [15] and inhibitors for the interaction between GPIb or GPIIIa and vWF attenuated the increase of pulmonary vascular resistance and release of thrombin and histamine [15]. However, an anti-platelet monoclonal antibody can lead to sequestration of platelets to the reticuloendothelial system [16] and thus, non-selective inhibition of the recipient's platelet function can cause possible hemorrhagic complications or systemic shock.…”

Section: Discussionmentioning

confidence: 99%

Pre-treatment of donor with 1-deamino-8-d-arginine vasopressin could alleviate early failure of porcine xenograft in a cobra venom factor treated canine recipient☆

Kang

Lee

Kim

et al. 2005

European Journal of Cardio-Thoracic Surgery

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Objective: Unlike cardiac or renal xenotransplants, the depletion of complement using cobra venom factor (CVF) does not improve pulmonary xenograft survival. Several cases suggest that the swine von Willebrand factor (vWF) may play a major role in presenting a different pathogenesis of pulmonary xenograft dysfunction from other organs. To evaluate the role of vWF and the complement system in mediating hyperacute vascular injury of pulmonary xenografts and elucidate pathogenesis of the injury, we performed swine-to-canine orthotropic single lung xenotransplantation after pre-treatment of 1-deamino-8-D-arginine vasopressin (DDAVP) and CVF. Methods: We set up three groups for lung xenotransplantation: group I served as the control group; group II, recipients pre-treated with CVF; group III, donors pre-treated with DDAVP (9 mg/kg, 3 days)/recipients pre-treated with CVF (60 u/kg). Hemodynamic data, coagulation and complement system parameters, and grafted lung pathologies were examined serially for 3 h after transplantation. Results: DDAVP infusion reduced the vWF content in swine lung tissue in vivo (7.7G2.4 AU/mg vs 16.0G5.6 AU/mg, P!0.0001). Infusion of CVF 24 h prior to transplantation effectively depleted the recipient's serum C3 and complement hemolytic activity below the detectable range. Regardless of the use of CVF, both groups I and II transplanted with unmodified grafts showed an immediate drop in leukocytes and platelet counts after transplantation. However, in group III, in recipients transplanted with DDAVP pre-treated swine lung, the platelet count did not decrease after transplantation (PZ0.0295). The decrease of plasma antithrombin and fibrinogen tended to be attenuated in group III. Light microscopic examination revealed extensive vascular thromboses in both capillary and larger vessels, as well as early pulmonary parenchymal damage in groups I and II, but were rarely observed in group III. Conclusions: Complement inhibition alone was not enough to alleviate intravascular thrombosis, the main pathology in pulmonary xenotransplantation. Pre-infusion of DDAVP to the donor animal was effective in preventing platelet sequestration and attenuated intravascular thrombosis. It is suggested that the strategies targeting vWF would be promising for successful pulmonary xenotransplantation.

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Hyperacute lung rejection in the pig-to-human model. III. platelet receptor inhibitors synergistically modulate complement activation and lung injury

Cited by 30 publications

References 23 publications

Impact of Thrombocytopenia on Survival of Baboons with Genetically Modified Pig Liver Transplants: Clinical Relevance

Impact of Thrombocytopenia on Survival of Baboons with Genetically Modified Pig Liver Transplants: Clinical Relevance

Reduced Fibrin Deposition and Intravascular Thrombosis in hDAF Transgenic Pig Hearts Perfused With Tirofiban

Pre-treatment of donor with 1-deamino-8-d-arginine vasopressin could alleviate early failure of porcine xenograft in a cobra venom factor treated canine recipient☆

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