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Potential Mechanisms for the Storage Lesion: Role of RBC Microparticles

Potential Mechanisms for the Storage Lesion: Role of RBC Microparticles. Janet S. Lee, M.D. University of Pittsburgh September 22, 2012. Society for the Advancement of Blood Management. Objectives. To introduce potential pathways involved in transfusion effects of the storage lesion.

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Potential Mechanisms for the Storage Lesion: Role of RBC Microparticles

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  1. Potential Mechanisms for the Storage Lesion: Role of RBC Microparticles Janet S. Lee, M.D. University of Pittsburgh September 22, 2012 Society for the Advancement of Blood Management

  2. Objectives • To introduce potential pathways involved in transfusion effects of the storage lesion. • Red cell breakdown products (ie. microparticles) • To discuss components of red cell storage on host innate immune response. • To refine the concept of transfusion immunomodulation as it relates to red cell storage.

  3. Case Report 62 yo woman admitted for L hip arthroplasty Transfusion. 2012 Mar;52(3):589-94

  4. Case Report Transfusion. 2012 Mar;52(3):589-94 Developed anemia, transfused with 5 units of RBCs over the course HD 2-3. 5 units: nonLR, 35-38 days old. Scheduled to be discharged HD 4—patient complained of dyspnea, RA sats 92% Despite supportive care and diuresis, profound hypoxemia with infiltrates that progressed to fibrosis.

  5. Case Report Diffuse bilateral infiltrates 24 hours following last RBC unit. TBBx of RLL --active organizing pneumonia and underlying interstitial fibrosis. BAL showed DAH. No viral inclusions, fungal elements, pneumocystis, or bacterial organisms

  6. Case Report Day 57 Day 4 What was the cause of the patient’s respiratory deterioration? Transfusion. 2012 Mar;52(3):589-94

  7. Susceptible Host • Human ALI/ARDS is seldom caused by any single event. • ARDS in humans is associated with complex interactions between • primary risk factors (sepsis, aspiration, pneumonia, blood transfusion) • comorbidities (alcoholism, underlying lung disease) • additional factors inherent to the host, such as genetic determinants. Am J Physiol Lung Cell Mol Physiol 2008;295: L379–L399.

  8. Annals of Internal Medicine. 1983;98:593-597.

  9. NEJM. 2005; 353:1685-93.

  10. Host factors that minimize susceptibility to lung inflammation and injury • Not everyone gets lung injury after an insult • Endogenous protective mechanisms of the host • Serum proteins scavenge cytotoxic, pro-oxidative, inflammatory elements • Additional countering mechanisms that mitigate inflammatory signals

  11. Host factors that minimize susceptibility to lung inflammation and injury

  12. Host factors that minimize susceptibility to lung inflammation and injury • De-activating signal • Ingestion or recognition of apoptotic bodies • curtails inflammation • promotes resolution phase of injury • When disrupted, the host is left vulnerable to the harmful effects of RBC transfusion • persistence of inflammation • impaired Mφ deactivation

  13. Increase in RBC microparticles expressing surface PS with storage • Does ingestion of apoptotic bodies impart deactivating signals in macrophages (Mφ)? Transfusion. 2011 Mar;51(3):610-21.

  14. RBC microparticlesare rapidly taken up by the mononuclear phagocyte system of the liver and spleen in vivo

  15. SN from RBC units increase IL-10 and suppress LPS-induced TNF-aproduction Murine macrophages standard non-LR RBC units SN1=day 31, SN2=day 37, SN3=day 37, SN4=day 37, SN5=day 38 of storage

  16. Macrophages produce IL-10 following incubation with apoptotic neutrophils in vitro

  17. CD36 TSP-1 avb3 J Clin Invest. 1992;90: 1513-22.

  18. TSP1-/- macrophages show defective IL-10 production following incubation with apoptotic neutrophils in vitro

  19. Creation of RBCs bearing surface phosphatidylserine

  20. TSP1-/- mice show defective IL-10 production following transfusion of senescent RBC

  21. TSP-1 (Extracellular, bridging molecule) TSR3 TSR2 HBD (RGDS seq) (CSVTCG seq) (KKTRG seq) COOH TSP-1 CD36

  22. Reconstitution of TSR 2 domain in TSP-1 null macrophages restores IL-10 production

  23. Does the impaired ability to trigger IL-10 production upon encounter of apoptotic bodies predispose the lungs to injury?

  24. Mice deficient in TSP-1 show persistent lung inflammation following i.t. LPS WT 0 Days TSP-1-/- 0 Days TSP-1-/- 6 Days WT 6 Days

  25. Lack of TSP-1 hinders the ability to resolve lung injury following i.t. LPS

  26. TSP1-/- mice show defective IL-10 production during the resolution phase of injury

  27. CD14+ mononuclear phagocytes in human lung tissue express CD36

  28. Summary • RBC breakdown products • Pro-oxidative, cytotoxic, pro-inflammatory • Counterbalanced by “eat-me” signals • Induction of immunoregulatory pathways? • Disruption of host protective mechanisms, the host is left vulnerable to the harmful effects of RBC transfusion • persistence of inflammation and injury?

  29. Acknowledgements • Lee lab • Zeyu Xiong, M.D. • Yani Zhao, M.D. Ph.D. • Mei Hulver • Liz Lechner, M.D. • Brian Hamburg, M.D. • Anuradha Ray, PhD • Prabir Ray, PhD • Roy Silverstein, M.D. • NIH HL086884 • VMI Hemostasis and Vascular Biology Grant, ITxM

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