1. Plasma Exchange for TAMOF Joseph A Carcillo MD University of Pittsburgh

2. 1) GPSI recommends the use of plasma therapies in children to correct sepsis induced thrombotic disorders including progressive Disseminated Intravascular Coagulation, Secondary Thrombotic Microangiopathy, and Thrombotic Thrombocytopenic Purpura (Grade 2c) 2) ASFA recommends Plasma Exchange for Sepsis induced TAMOF Grade Level III C ‘May be used on an individual basis’

3. THROMBOCYTOPENIA ASSOCIATED MOF ICU PATIENT

4. F Mortality rate on Thr pts vs non-Thr pts F day 4 = 33% vs 16% F day 14 = 66% vs 16% (Akca et al., CCM 2002) Survivors Non-survivors Platelet count rises in survivors

5. Platelet vWF ADAMTS 13 (vWF-CP) tPA PGI Endothelium Platelet ADAMTS 13 (vWF-CP) Platelet vWF Platelet Homeostasis tPA

6. TFPI Heparin ATIII Prot C APC + PGI Thrombomodulin PGI TFPIHomeostasis tPA

7. Platelet Fibrin vWF:Platelet Thrombus PAI-1 tPA Platelet vWF Platelet vWF

8. Fibrin PAI-1 Platelet Fibrin Platelet vWF Platelet Fibrin Platelet vWF Platelet Endothelium PAI-1 tPA Fibrin Thrombus

9. vWF Platelet vWF Shear stress TTP

10. Endothelium Platelet vWF X ADAMTS 13 (vWF-CP) ADAMTS 13 (vWF-CP Ab) TTP

11. Fibrin Platelet vWF Platelet Fibrin vWF TTP

12. Endothelium PAI-1 vWF TF vWF PAI-1 TF PAI-1 VII DIC

13. TF vWF PAI-1 TF VII vWF TF Platelet DIC Consumptive low fibrinogen

14. Endothelium PAI-1 TF PAI-1 vWF TFPI TMA  vWF CP  ADAMTS 13

15. Plasmin Plasminogen PAI-1 X TMA vWF Platelet  ADAMTS 14  vWF CP

16. TF PAI-1 vWF TFPI Platelet vW F Platelet TMA Nonconsumptive normal fibrinogen

17. Brain: 40x with no clots

18. Brain: 40x with clots

19. Kidney: 100x with no clots

20. Kidney: 100x with clot

21. DIAGNOSTIC CRITERIA FOR TAMOF  Thrombocytopenia + AKI  Increased LDH  Normal PT/aPTT or elevated  Multiple organ failure  Remove underlying cause and can respond to TTP like steroid/plasma exchange protocol.

22. PLASMA INFUSION OR EXCHANGE?  Plasma Infusion  Restores clotting factors (VII, VIII, X etc)  Restores vWF cleaving protease  Restores prostacyclin  Restores protein C and antithrombin III  Restores tPA  Plasma Exchange  Removes Abs to vWF cleaving protease  Removes vWF  Removes PAI-1  Removes Tissue Factor

23. PLASMA EXCHANGE MAN

24.  RCT comparing plasma infusion to plasma exchange for TTP showed a significant beneficial treatment effect with plasma exchange therapy  Plasma exchange:  2/51 (4%) deaths  40/51 (80%) responded  Plasma infusion:  8/51 (16%) deaths  25/51 (50%) responded (Rock et al., NEJM 1991)

25. Plasma Exchange Standard Therapy (Busund et al., Intensive Care Med 2002) Plasma Exchange Improved Outcome in Adult Severe Sepsis

30. PELOD decreased from 25.0  2.0 to 0.8  0.6 with plasma exchange at 28 d PELOD increased from 25.4  2.3 to 73.6  18.4 without plasma exchange 73.6  18.4 without plasma exchange at 28 d p < 0.001, power = 1.0, 2F-RM ANOVA

31.  8/14 adults/children survived with 72 h plasmafitration and partial FFP replacement compared to 8/16 without.

32. Use of Therapeutic Plasma Exchange in Children With Thrombocytopenia-Associated Multiple Organ Failure in the Turkish Thrombocytopenia- Associated Multiple Organ Failure Network. Sevketoglu, Esra; Yildizdas, Dincer; Horoz, Ozden; Kihtir, Hasan; Kendirli, Tanil; Bayraktar, Suleyman; Carcillo, Joseph Pediatric Critical Care Medicine. 15(8):e354-e359, October 2014. DOI:10.1097/PCC.0000000000000227

33. 2

34. Blood Purification and Mortality in Sepsis: A Meta-Analysis of Randomized Trials*. Zhou, Feihu; MD, PhD; Peng, Zhiyong; MD, PhD; Murugan, Raghavan; MD, MS; Kellum, John; MD, MCCM Critical Care Medicine. 41(9):2209-2220, September 2013. DOI: 10.1097/CCM.0b013e31828cf412

36.  From 2004-2012 10.8% of Pediatric Severe Sepsis kids received ECMO(4.2%), CRRT (5.3%), and/ or PLEX (4.2%)  1, 162 received PLEX including 196 (11.9% of all ECMO); and 30 on CRRT + ECMO(1.8% of all ECMO).  PLEX and/or ECMO was more commonly used in infants and CRRT in adolescents  2004-2012 Hospital Mortality: PLEX = 20.9%; CRRT = 45%; ECMO = 49.5%

37.  Australian study – 40 + children with severe sepsis randomized to plasmafiltration showed no difference  US TAMOF cohort 81 patients showed sicker patients received plasma exchange with same survival  Turkey TAMOF cohort 46 patients showed improved survival with plasma exchange  My unofficial combination of the USA and Turkey TAMOF cohort studies (n =127) shows reduced mortality with plasma exchange. Mortality decreased from 56% to 30% (p < 0.05) NNT = 4.  Randomized controlled international trial is warranted for TAMOF (NOT severe sepsis without TAMOF) in children and adults.