Tirofiban and Activated Protein C Synergistically Inhibit the Instant Blood Mediated Inflammatory Reaction (IBMIR) from Allogeneic Islet Cells Exposure to Human Blood
Tirofiban and Activated Protein C Synergistically Inhibit the Instant Blood Mediated Inflammatory Reaction (IBMIR) from Allogeneic Islet Cells Exposure to Human Blood
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DOI：
10.1111/j.1600-6143.2009.02673.x
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发表时间：
2009-07-01
影响因子：
8.8
通讯作者：
O'Connell, P. J.
中科院分区：
文献类型：
--
作者：
Akima, S.;Hawthorne, W. J.;O'Connell, P. J.
当胰岛暴露于血液时，会发生即时血液介导的炎症反应（IBMIR），临床表现为门静脉血栓形成和移植失败。本研究的目的是确定重组人活化蛋白 C (rhAPC) 和血小板抑制对 IBMIR 的影响，以便针对这种情况开发更好的靶向治疗方法。将 5000 个人类胰岛细胞当量 (IEQ) 在 PVC 环路系统中与 7 mL ABO 相容的人类血液混合，并与 rhAPC 单独或与替罗非班联合孵育。人类胰岛和血液混合会导致快速凝块形成，消耗血小板、白细胞、纤维蛋白原、凝血因子和升高的 D-二聚体。胰岛被纤维蛋白和血小板凝块包裹，并被中性粒细胞严重浸润。替罗非班单一疗法无效，而 rhAPC 单一疗法以剂量依赖性方式预防 IBMIR，保留胰岛完整性，同时维持血小板和白细胞计数、纤维蛋白原和凝血因子水平，并减少 d-二聚体形成。替罗非班和低剂量rhAPC的组合可协同抑制IBMIR，其功效与高剂量rhAPC相同。替罗非班和 rhAPC 协同作用以保护胰岛，这表明协同抑制血小板和凝血途径对凝血酶生成的贡献是获得最佳抗 IBMIR 效果所必需的。
Instant blood mediated inflammatory reaction (IBMIR) occurs when islets are exposed to blood and manifests clinically as portal vein thrombosis and graft failure. The aim of this study was to determine the impact of recombinant human activated protein C (rhAPC) and platelet inhibition on IBMIR in order to develop a better targeted treatment for this condition. Five thousand human islet cell equivalents (IEQ) were mixed in a PVC loop system with 7 mL of ABO compatible human blood and incubated with rhAPC, either alone or in combination with tirofiban. Admixing human islets and blood caused rapid clot formation, consumption of platelets, leukocytes, fibrinogen, coagulation factors and raised d-dimers. Islets were encased in a fibrin and platelet clot heavily infiltrated with neutrophils. Tirofiban monotherapy was ineffective, whereas rhAPC monotherapy prevented IBMIR in a dose-dependent manner, preserving islet integrity while maintaining platelet and leukocyte counts, fibrinogen and coagulation factor levels, and reducing d-dimer formation. The combination of tirofiban and low-dose rhAPC inhibited IBMIR synergistically with an efficacy equal to high dose rhAPC. Tirofiban and rhAPC worked synergistically to preserve islets, suggesting that co-inhibition of the platelet and coagulation pathways' contribution to thrombin generation is required for the optimal anti-IBMIR effect.