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
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
CONFLICT OF
INTEREST
Board of Directors (President-Elect), AABB
Board of Directors, Cord Blood Association
Employed by New York Blood Center
ADVANCES IN THE PIPELINE
Donor Processing Patient
Donor recruitmentTarget recruitment to hospital needs
African American and minorityHemoglobin S and Leukoreduction
Adverse eventsPrevention
Pre and Post donation care
Education
Better blood productsImprove storagePathogen inactivationPlatelet additive solution
AutomationStorage bags- DEHP freeTestingPersonalized products (link
donor-patient)Cellular therapyTissue banking
Adverse outcomesInfectious
BabesiaBacteria
Non infectiousTRALITACO
Pediatrics/ NeonatesMassive transfusion
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
Comparative evaluation of non-infectious adverse outcomes and their prevalence per
100,000 units transfused based on National Blood Collection and Utilization Surveys,
2011-2015
PREPARATION OF BLOOD
COMPONENTS FROM WHOLE
BLOOD DONATIONS
Whole blood
RBC
Platelet-rich
plasma
Centrifuge-slow
AS
Centrifuge-fast
Platelet-poor
plasma
2-6oC, 42dAS-RBC
25oC, 5d
Platelets
-18oC, 1yrPF24
plasma
8-24 hrs
-18oC, 1yrFFP
Further plasmaprocessing
450 +/- 45 mL;
30 mL for testing;
63 mL anticoag/preservative
Apheresis
500 ml
CPD, CP2D
AS1,AS3, AS5,
SAGMBuffy coat
PAS, Plasma
Cryoprecipitate
Cryoreducedplasma
Cold store plts
WashedLeukoreduced
Irradiated
PLATELETS
Apheresis vs whole blood derived plateletsPlatelet additive solution vs plasmaLeukoreductionIrradiationPathogen reductionBacterial mitigationCMVHLA, HPA, crossmatchedWashedCold storedCryopreserved, lyophilized
BACTERIAL CONTAMINATION
MITIGATION STRATEGIES
RiskRisk of Septic Transfusion
Reaction (Passive Surveillance)
Trima Platelets 2/1,000,0001
Trima Platelets with Large volume culture 0/960,4702
Amicus Platelets 18/1,000,0001
Point of Issue Testing 36/1,000,0003
Incidence rate may be artefact of sample size
Pathogen Reduced Platelets <1.6/1,000,0004
1Transfusion. 2017;57(12):2969-2976; 2Transfusion. 2017;57(5); 3Transfusion. 2011;51(12):2573-2582. 4
Transfusion. 2017; 57(12):2946-2957.
Ann Intern Med. 2015;162(3):205-13.
Guidelines address stable but notBleeding patients
Recommendations:1. Prophylactic platelet transfusion for platelet
≤10,000/µl2. Prophylactic platelet transfusion for central venous
catheter placement for platelet <20,000/µl3. Prophylactic platelet transfusion for lumbar
puncture platelet <50,000/µl4. Prophylactic platelet transfusion for major
nonneuraxial surgery platelet <50.000/µl
UPDATES
• Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhageassociated 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
J Clin Oncol. 2018;36(3):283-299.Lancet. 2016;387(10038):2605-2613.
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
Transfusion. 2014;54(8):1927-34.
AR transfusion rate: 0.29% PASC vs 0.82% PPFNTR transfusion rate:0.17% PASC vs ).50% PP
Transfusion 2018;58;891–895
P<0.01
P<0.01 P<0.0001
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).
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 2015. As of August 2016, a total of 21 (19.1%) of 119 CS-PLTs have beentransfused. 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):2836-2844.
Transfusion. 2016;56(1):13-6.
Transfusion 2016;56:1320-8Transfusion 2018;58;1682–1688
Trima-Isoplate and Amicus-Intersol PLTs maintained pH>6.2Microaggregate formation in Amicus-Intersol PLTsComparable aggregation responsesClot strength better preserved in Trima-Isoplate PLTsEnhanced adhesion to collagen under flow with Trima-Isoplate PLTs
METHODS OF PATHOGEN
REDUCTION
INTERCEPT
• Amotosalen + UVA light• Disruption of nucleic acids via intercalation and crosslinking of
pyrimidine bases (C, T, U)MIRASOL
• Riboflavin + UVA/UVB light• Disruption of nucleic acids (Guanine) via free oxygen radicals
Theraflex-UV
• UVC• Dimerization of pyrimidines
Blood Rev. 2014;28(6):235-41.
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:CD009072.
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):468-475. Blood. 2018;132(2):223-231
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
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):1227-39.
TRALI BY YEAR PER 100,000 COMPONENTS
DIFFERENT TYPES OF PLASMA
Thawed PlasmaManufactured within 8h, or 24h from donation, then thawedStored @ 1-6⁰CShelf life 5 daysAvailability within 30’ (to thaw), immediate (post thaw)Type specific
A, B, AB
Compatibility with mobile units: Low
S/D PlasmaManufactured from thousands of donors, pathogen inactivatedStored @ 1-6⁰CShelf life 24 hoursAvailability within 30’(to thaw), immediate (post thaw)Type specific/Universal
A, B, AB
Compatibility with mobile units: Low
Lyophylized Plasma
Manufactured within 8h, or 24h from donationStored at room temperatureShelf life 1-2 y Availability <5’Universal
A, B, AB
Compatibility with mobile units: HighWastage: Low Does not require thawing
Spray Dried Plasma
Manufactured within 8h, or 24h from donationStored at room temperatureShelf life 1-2 y Availability <5’Universal
A, B, AB
Compatibility with mobile units: HighWastage: Low Does not require thawing
PR plasmaINTERCEPTMethylene BlueMirasol Unit to unit variability vs pooled more standardized product
Liquid plasma
• 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.
Octaplas™, Pooled Plasma (Human), Solvent/Detergent-Treated (manufactured by OctaPharma)
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)
Lyophylized Plasma
38
• 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
TRANSFUSION 2013;53:65S-71SAnesthesiology. 2012;117(2): 339-46.
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
Pathogen-reduced, Leukocyte-Depleted Freeze-Dried Plasma (the French FDP)
0%
20%
40%
60%
80%
100%
1 5 9 13 17 21 25 29
high PL, high PT, high CR
high PL, high PT, low CR
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
low PL, low PT, low CR
Trauma Massive Transfusion Survival Curve
Days to Death from Admission
Perc
ent
Aliv
e
Shaz et al. Transfusion. 2010;50(2):493-500.
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):1581-1591.
Pragmatic, multicenter, cluster-randomized, phase 3 superiority trail comparing thawed plasma with standard-care resuscitation during air medical transport230 patients received plasma, 271 received standard-careMortality 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;379:315-26.
Pragmatic, randomized, single-center (Denver) trial comparing plasma to saline during ambulance transport65 patients received plasma, 60 received salineNo difference in 28-day mortality (plasma 15% vs saline 10%)No significant differences in other outcomes Lancet 2018; 392: 283–91
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)
Transfusion 2017;57;1879–1884
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
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)
PLASMA SUMMARY
Group A plasma for emergency use
• Until lyophilized or spray-dried approved
• Available for ambulancesSD 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
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
