Vein-to-Vein: Creating New Products to Optimize Patient Outcomes

Transcription

1 Vein-to-Vein: Creating New Products to Optimize Patient Outcomes BETH H. SHAZ, MD CHIEF MEDICAL AND SCIENTIFIC OFFICER EXECUTIVE VICE PRESIDENT NEW YORK BLOOD CENTER N Y B C. O R G S A V E A L I F E N O W. O R G I N N O V A T I V E B L O O D R E S O U R C E S. O R G R I B C. O R G D E L M A R V A B L O O D. O R G

2 CONFLICT OF INTEREST Board of Directors (President-Elect), AABB Board of Directors, Cord Blood Association Employed by New York Blood Center

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5 ADVANCES IN THE PIPELINE Donor Processing Patient Donor recruitment Target recruitment to hospital needs African American and minority Hemoglobin S and Leukoreduction Adverse events Prevention Pre and Post donation care Education Better blood products Improve storage Pathogen inactivation Platelet additive solution Automation Storage bags- DEHP free Testing Personalized products (link donor-patient) Cellular therapy Tissue banking Adverse outcomes Infectious Babesia Bacteria Non infectious TRALI TACO Pediatrics/ Neonates Massive transfusion

6 VEIN-TO-VEIN DATABASES Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) Describing transfused population, blood product use, adverse event rates RBC omic studies- looking at donor demographics and product characteristics (hemolysis) US FDA Center for Biologics Effectiveness and Research (CBER) the Biologics Effectiveness and Safety (BEST) Initiative Electronic health records with ISBT 128 for transfusion rates SCANDAT database Demonstrated no evidence of an association between RBC storage and patient mortality and between donor age and transfused patient outcomes

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8 Comparative evaluation of non-infectious adverse outcomes and their prevalence per 100,000 units transfused based on National Blood Collection and Utilization Surveys,

9 PREPARATION OF BLOOD COMPONENTS FROM WHOLE BLOOD 500 DONATIONS ml 450 +/- 45 ml; AS1,AS3, AS5, SAGM 30 ml for testing; 63 ml anticoag/preservative Whole blood CPD, CP2D Plateletrich plasma Centrifuge-slow AS Buffy coat Centrifuge-fast PAS, Plasma RBC Plateletpoor plasma Platelets 8-24 hrs 25 o Cold C, 5dstore plts Apheresis Washed Leukoreduced Irradiated PF24 plasma FFP -18 o C, 1yr -18 o C, 1yr Cryoprecipitate Cryoreduced plasma Further plasma processing AS- RBC 2-6 o C, 42d

10 PLATELETS Apheresis vs whole blood derived platelets Platelet additive solution vs plasma Leukoreduction Irradiation Pathogen reduction Bacterial mitigation CMV HLA, HPA, crossmatched Washed Cold stored Cryopreserved, lyophilized

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12 BACTERIAL CONTAMINATION MITIGATION STRATEGIES Risk Risk of Septic Transfusion Reaction (Passive Surveillance) Trima Platelets 2/1,000,000 1 Trima Platelets with Large volume culture 0/960,470 2 Amicus Platelets 18/1,000,000 1 Point of Issue Testing 36/1,000,000 3 Incidence rate may be artefact of sample size Pathogen Reduced Platelets <1.6/1,000, Transfusion. 2017;57(12): ; 2 Transfusion. 2017;57(5); 3 Transfusion. 2011;51(12): Transfusion. 2017; 57(12):

13 Recommendations: 1. Prophylactic platelet transfusion for platelet 10,000/µl 2. Prophylactic platelet transfusion for central venous catheter placement for platelet <20,000/µl 3. Prophylactic platelet transfusion for lumbar puncture platelet <50,000/µl 4. Prophylactic platelet transfusion for major nonneuraxial surgery platelet <50.000/µl Guidelines address stable but not Bleeding patients Ann Intern Med. 2015;162(3):

14 UPDATES Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial Demonstrated that platelet transfusion seems inferior to standard care for patients on antiplatelet therapy before intracerebral hemorrhage Thus, platelet transfusions may not recommended for this indication. ASCO Clinical Practice Guideline Update No prophylactic platelet transfusions in adult recipients of autologous hematopoietic stem cell transplantation or patients with chronic, stable, severe thrombocytopenia who are not receiving active treatment Lancet. 2016;387(10038): J Clin Oncol. 2018;36(3):

15 PLATELET ADDITIVE SOLUTION (PAS) Isotonic saline based media with citrate anticoagulant and acetate as a fuel for anaerobic metabolism Potentially improves platelet storage Minimize plasma related AEs Allergic reactions FNTR ABO hemolysis TRALI Greater plasma recovery with collection

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17 AR transfusion rate: 0.29% PASC vs 0.82% PP FNTR transfusion rate: 0.17% PASC vs ).50% PP Transfusion. 2014;54(8):

18 Transfusion 2018;58;

19 P<0.01 P<0.01 P< HLA-antibody screen positive PAS-C (3/50 products) compared to plasma platelets (2/50 products); HLA-antibody screen-positive supernatants of PAS-C platelets had fewer HLA specificities (2 specificities) compared to those of the plasma platelets (18 specificities).

20 REFRIGERATED PLATELETS- FDA APPROVAL To store apheresis platelets at refrigerator temperature (1-6⁰C) without agitation for up to 3 days. The cold stored platelets will only be used in the resuscitation of actively bleeding patients. CS-PLTs have been used for trauma patients at our facility since October As of August 2016, a total of 21 (19.1%) of 119 CS-PLTs have been transfused. The short 3-day storage period combined with the formation of clots in plasma-rich CS-PLTs during storage have been the major causes of a high (80.9%) discard rate. Transfusion. 2017;57(12):

21 Transfusion. 2016;56(1):13-6.

22 Trima-Isoplate and Amicus-Intersol PLTs maintained ph>6.2 Microaggregate formation in Amicus-Intersol PLTs Comparable aggregation responses Clot strength better preserved in Trima-Isoplate PLTs Enhanced adhesion to collagen under flow with Trima-Isoplate PLTs Transfusion 2018;58; Transfusion 2016;56:1320-8

23 METHODS OF PATHOGEN REDUCTION INTERCEPT Amotosalen + UVA light MIRASOL Disruption of nucleic acids via intercalation and crosslinking of pyrimidine bases (C, T, U) Riboflavin + UVA/UVB light Theraflex-UV UVC Disruption of nucleic acids (Guanine) via free oxygen radicals Dimerization of pyrimidines

24 Blood Rev. 2014;28(6):

25 In people with hematological or oncological disorders who are thrombocytopenic: Very uncertain as to whether PR platelets increase the risk of any bleeding No evidence of difference between PR and standard platelets in incidence of clinically significant bleeding complications Probably no difference in risk of developing severe bleeding Probably no difference in incidence of all-cause mortality Probably no difference in incidence of serious adverse events (no bacterial transfusion-transmission) Increased risk of developing platelet refractoriness with PR platelets Received more platelets, shorter time interval between transfusions, and lower corrected count increment with PR platelets Cochrane Database Syst Rev. 2017:CD

26 ADDITIONAL STUDIES Evaluation of the Efficacy of Platelets Treated with Pathogen Reduction Process (Effipap) trial in France In this multicenter, 3-arm RCT that analyzed 790 patients with thrombocytopenia and malignant hematologic diseases, bleeding of grade 2 occurred in 47.9%of patients receiving PR (amotosalen-uv-a) PAS platelets, 43.5%of patients receiving plasma platelets, and 45.3%of patients receiving PAS platelets. With a prespecified margin of 12.5%, noninferiority of PR platelets was not achieved when compared with untreated plasma platelets but was achieved when compared with untreated PAS platelets. No difference with grade 3 or 4 bleeding. RCT evaluating clinical effects of platelet transfusion products: the Pathogen Reduction Evaluation and Predictive Analytical Rating Score (PREPAReS) trial RCT compared Mirasol treated platelets versus standard plasma platelets demonstrated no difference in preventing bleeding or developing HLA class I alloantibodies. PR platelets resulted in 50% lower CCI resulting in more frequent transfusions and increased platelet refractoriness. Mirasol platelets in plasma clinical trial (MIPLATE) RCT of Mirasol platelets versus standard plasma platelets JAMA Oncol. 2018;4(4): Blood. 2018;132(2):

27 PLATELETS SUMMARY PR is now available in the United States Clinical efficacy of INTERCEPT platelets is non-inferior to conventional platelets CCI is lower, platelet refractoriness is more common, increase use of platelets PR represents a new paradigm in addressing transfusion transmitted infections Await future studies and improvements in current technology Ability to match product to patient Platelets in plasma for trauma patient In future cold stored platelets for trauma or massive hemorrhage Platelets in PAS for patients with history of allergic reactions Platelets in PAS for ABO incompatible transfusions

28 AABB PLASMA GUIDELINES 2010 Recommending plasma transfusion to trauma patients requiring massive transfusion (moderate quality evidence). No recommendation for the ratio of plasma:rbc in these patients (low quality evidence). No recommendation for the use of plasma in patients undergoing surgery without massive transfusion (very low quality evidence). Plasma suggested for patients with warfarin related intracranial hemorrhage (low quality evidence). No recommendation for plasma transfusion for warfarin reversal without intracranial hemorrhage (very low quality evidence). No recommendation for plasma transfusion in acute pancreatitis, organophosphate poisoning, coagulopathy associated with acetaminophen overdose, intracranial hemorrhage after severe closed head injury without coagulopathy Use in plasma exchange for thrombotic thrombocytopenic purpura missing Transfusion. 2010;50(6):

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31 TRALI BY YEAR PER 100,000 COMPONENTS

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34 DIFFERENT TYPES OF PLASMA Thawed Plasma Manufactured within 8h, or 24h from donation, then thawed 1-6⁰C Shelf life 5 days Availability within 30 (to thaw), immediate (post thaw) Type specific A, B, AB Compatibility with mobile units: Low PR plasma INTERCEPT Methylene Blue Mirasol S/D Plasma Manufactured from thousands of donors, pathogen inactivated 1-6⁰C Shelf life 24 hours Availability within 30 (to thaw), immediate (post thaw) Type specific/universal A, B, AB Compatibility with mobile units: Low Liquid plasma Lyophylized Plasma Manufactured within 8h, or 24h from donation Stored at room temperature Shelf life 1-2 y Availability <5 Universal A, B, AB Compatibility with mobile units: High Wastage: Low Does not require thawing Spray Dried Plasma Manufactured within 8h, or 24h from donation Stored at room temperature Shelf life 1-2 y Availability <5 Universal A, B, AB Compatibility with mobile units: High Wastage: Low Does not require thawing Unit to unit variability vs pooled more standardized product

35 Octaplas, Pooled Plasma (Human), Solvent/Detergent-Treated (manufactured by OctaPharma) Indications: 1) replacement of coagulation factors in patients with acquired deficiencies due to liver disease, cardiac surgery, or liver transplant, and 2) as a replacement fluid in plasma exchange for patients with thrombotic thrombocytopenic purpura (TTP). Manufactured from 630 to 1,520 single donor units from the same ABO blood group of source plasma and/or recovered plasma. Available in blood group A, B, AB, and O and is administered based on ABO compatibility. Shelf life has been extended to 36 months ( at - < 18 C) and storage of the thawed product is now 24 hours at 1-6 C or 8 hours at room temperature (20-25 C) HLA and HNA antibody testing is performed on each batch and only antibody-negative batches are released.

36 WB vs SD plasma: SD plasma decreased risk of allergic reactions (OR 0.27) and FNTR (OR 0.29) Apheresis vs SD plasma: SD plasma decreased risk of allergic reactions (OR 0.18) and FNTR (OR 0.30) All untreated vs PI plasma: PI plasma decreased allergic reactions (OR 0.54), FNHTR (OR0.35), TACO (OR 0.45) and hypotensive reactions (OR 0.19)

37 Lyophylized Plasma Pooled male, apheresis plasma (A, B, AB) universal plasma No cross match required Pathogen Inactivated or Quarantined Retention of coagulation factors Retention of clot formation (TEG) Retention of thrombin generation Solubilizes in < 6 minutes Two year stability at RT July 10, 2018 FDA News Release FDA takes action to support American military personnel by granting an authorization for freeze-dried plasma product to enable broader access while the agency works toward approval of the product TRANSFUSION 2013;53:65S-71S Anesthesiology. 2012;117(2): Pathogen-reduced, Leukocyte-Depleted Freeze-Dried Plasma (the French FDP) 38

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39 Trauma Massive Transfusion Survival Curve 100% high PL, high PT, high CR 80% high PL, high PT, low CR Percent Alive 60% 40% 20% high PL, low PT, low CR high PL, low PT, high CR low PL, high PT, high CR low PL, high PT, low CR low PL, low PT, high CR 0% Days to Death from Admission low PL, low PT, low CR Shaz et al. Transfusion. 2010;50(2):

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41 6/55 (11%) recipients vs 102/447(23%) non-recipients died at 30 days. 38 received only RBCs, 1 received 1U plasma, 10 1U both. JAMA. 2017;318(16):

42 Pragmatic, multicenter, cluster-randomized, phase 3 superiority trail comparing thawed plasma with standard-care resuscitation during air medical transport 230 patients received plasma, 271 received standard-care Mortality at 30 days significantly lower in plasma group (plasma 23.2% vs control 33.0%, p=0.03) No significant differences in other outcomes N Engl J Med 2018;379: Pragmatic, randomized, single-center (Denver) trial comparing plasma to saline during ambulance transport 65 patients received plasma, 60 received saline No difference in 28-day mortality (plasma 15% vs saline 10%) No significant differences in other outcomes Lancet 2018; 392:

43 KEY DIFFERENCES Average transportation time (Multicenter 52 minutes transfer 28%, 39 minutes direct 72% vs Denver 19 minutes plasma, 16 minutes control) Blunt trauma (Multicenter 81.3% and 83.4% vs Denver 46% and 53%) Average ISS (Multicenter 22 and 21 vs Denver 27 and 27) and other demographic differences (Denver younger, more male)

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45 WHOLE BLOOD Military using fresh whole blood (walking donors) to provide a source of platelets Use of whole blood in civilian trauma patients and pediatric cardiac surgery In the era of 1:1:1 plasma:platelet:rbc transfusion for massive hemorrhage, whole blood provide this balanced resuscitation without the extra fluid Being provided as cold stored, low titer group O whole blood Ease of use for technologists, nurses, and other staff

46 MASSIVE HEMORRHAGE Insufficient basis to recommend the higher transfusion ratio Early use of tranexamic acid, which reduced mortality in bleeding trauma patients Potential use of whole blood versus component therapy Prehospital blood administration Integration of thromboelastography to optimize blood component utilization Use of clotting factor concentrates (e.g., prothrombin complex concentrate and fibrinogen concentrate)

47 PLASMA SUMMARY Group A plasma for emergency use Until lyophilized or spray-dried approved Available for ambulances SD plasma in patients With history of allergic reactions For thrombotic thrombocytopenic purpura patients For patient at risk for TRALI Four factor prothrombin complex concentrates Patients on warfarin needing emergency reversal

48 CONCLUSION Blood is safe and blood saves lives Cool innovation is happening, we need to be able to fund it, pilot it and advance it Blood is not one size fits all- we have the ability to optimize each and every transfusion by matching the product to the patient