Background/Purpose: Impaired fibrinolysis in systemic lupus erythematosus (SLE) contributes to disease magnifications including increased risk of thrombosis and tissue ischemia. Aberrant complement activation is a major factor in tissue injury in SLE. Previous work has focused on the role of complement activation in tissue injury due to ischemia in the MRL/lprmice, an autoimmune prone mouse strain with a propensity to develop lymphadenopathy, glomerulonephritis, and polyarthritis. Complement inhibition at varying points in the cascade resulted in differing efficacies in tissue injury attenuation of tissue injury. A potential role for thrombin, a coagulation component was identified. The current work elucidates the mechanism by which the two pathways interact to contribute to hypercoagulability and increased risk of thrombosis in SLE.

Methods: Complement C1q inhibitor and coagulation inhibitors targeting the intrinsic and extrinsic pathways (Tissue Factor Pathway Inhibitor (TFPI) and Anti-thrombin III) were used to evaluate and compare resulting tissue pathology, generation of secondary inflammatory mediators involved ischemic/reperfusion injury. Using a superior mesenteric artery ischemia model, we compared the pathology of mesenteric ischemia/reperfusion (IR) induced tissue injury between immune competent (C57BL/6) and autoimmune prone (B6.MRL/lpr) mice after administration of complement or specific coagulation pathway inhibitors. The pathology was assessed by immunohistochemistry/ immunofluorescence analysis and western blot analysis of complement and coagulation components.

Results: Tissue Factor Pathway Inhibitor (TFPI) and Anti-thrombin III (ATIII) resulted in reduction of tissue injury, as determined by histopathology scoring. However, TFPI was significantly more effective in attenuating tissue injury in the MRL/lpr mice with less edema and villous destruction in the intestine. Western blot analysis was used to determine if there reductions in thrombin levels and if this corresponded with decreased levels of activated complement components. As expected if C5 was the interaction point between the pathways, there were no differences in C3 activation between the groups. The level of C5 activation and thrombin levels are being analyzed. Immunofluorescent analysis of tissue sections confirm these results and assess changes in the molecular components such as C3/Ig deposition, membrane attack complex formation, glycoprotein Ia/IIa exposure, and thrombin localization.

Conclusion: The interaction between thrombin and the complement pathway in SLE has significant clinical implications. The results from this study indicate inhibition of the coagulation cascade, prior to prothrombin activation is the most effective point to inhibit tissue injury. Inhibiting with TFPI does not affect C3 activation but reduces edema and disruption of the vascular and lamina propria structure, suggesting a positive feedback loop between the complement and coagulation cascades downstream of C3. CIP/Protocol number: MED-09-349

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/coagulation-pathway-function-in-ischemiareperfusion-tissue-injury-in-autoimmune-prone-mice/