2011 - CTS-IXA


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Parallel Session 15- Coagulation and Thrombosis I (Xeno Track)

32.393 - Elevated C-reactive protein and IL-6 levels precede consumptive coagulopathy in GTKO pig organ xenograft recipients

Presenter: Mohamed, Ezzelarab, Pittsburgh, United States
Authors: Mohamed Ezzelarab1, Burcin Ekser1,2, Kumiko Isse1, Cassandra Long1, Jnanesh Thacker1, Noriko Murase1, Ron Shapiro1, David Ayares3, David K.C. Cooper1

393

Elevated C-reactive protein and IL-6 levels precede consumptive coagulopathy in GTKO pig organ xenograft recipients

Mohamed Ezzelarab1, Burcin Ekser1,2, Kumiko Isse1, Cassandra Long1, Jnanesh Thacker1, Noriko Murase1, Ron Shapiro1, David Ayares3, David K.C. Cooper1

1Surgery, University of Pittsburgh, Thomas E. Starzl Institute, Pittsburgh, PA, United States; 2Surgery, Transplantation and Advanced Technologies, University Hospital of Catania, Catania, Italy; 3Revivicor Inc., Blacksburg, VA, United States

Background: The adaptive immune responses to pig antigens have been well-characterized. The role of innate immunity in xenograft rejection is less well elucidated. Inflammation is known to amplify activation of coagulation. C-reactive protein (CRP) is a marker of innate immunity and systemic inflammatory response. We investigated activation of coagulation and the development of consumptive coagulopathy in relation to CRP in baboons receiving GTKO pig organ xenograft.

Methods: Baboons received either heart (n=7) or kidney (n=5) grafts from GTKO pigs, where 3 heart and 2 kidney recipients received either no or minimal immunosuppressive therapy (IS). Full IS was with ATG, anti-CD154mAb, and MMF. The fold increase of post-Tx CRP level (compared with pre-Tx level) was measured, and mean values were calculated (mean Fi-CRP). Mean platelet count (x103/µl), D-dimers, fibrin degradation products (FDP, µg/ml), and IL-6 levels (pg/ml) were measured. CRP deposition in grafts and native lungs was detected by immunohistochemistry.

Results: When kidney or heart graft survival was <16 days, mean platelet count was 300 on day 1 and fell to 120 on day 7, and 57 at the time of euthanasia. Mean D-dimers rose from 8 on day 1 to 34 on day 7. Mean Fi-CRP was 5.5 on day 1 and 5.7 on day 7 and rose to 7.6 on day 14. With longer-term heart grafts survival (35-56 days), mean platelet count remained high for a longer period (277, 306, and 399 on days 7, 14, and 28), but fell to 83 at the time of euthanasia. Mean D-dimers and FDP rose only slightly during the first 2-4 weeks, but then rose more markedly until the day of euthanasia. Mean D-dimers rose from 2 to 8, while FDP rose from 20 to and 240, at 2 weeks before euthanasia. Mean Fi-CRP increased from 1.7 to 6.7 by day 14, and further increased to 10.2 at euthanasia. A significant positive correlation was found between Fi-CRP and IL-6 levels (r2= 0.964; p<0.01). By immunohistochemistry, mild CRP deposition was seen in the grafts 30 minutes after reperfusion. Significant CRP deposition was detected in kidney xenograft; mostly in the tubules and less in the glomeruli. Minimal CRP deposition was detected in heart xenografts. CRP-positive macrophage were detected in native lungs of both kidney and heart xenograft recipients.

Conclusions: In pig organ graft recipients, high levels of CRP and IL-6 developed before signs of consumptive coagulopathy. Short kidney and heart graft survival is associated with higher levels of CRP and IL-6 early after Tx. Intense CRP deposition in kidney grafts (in contrast to heart grafts) suggests a stronger innate immune response. Deposition of CRP in native lungs suggested a systemic inflammatory innate response. Prevention or control of the systemic inflammatory responses in xenograft recipients may prevent or delay the development of consumptive coagulopathy.


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