BloodNet Newsletter – Spring 2019

Dear BloodNet members,

It was a great pleasure to see you in Snowbird. We were 23participants, which is one more than our previous springmeeting in San Diego.In order to inject fresh blood (although Marisa and Phil havenot yet told us if it is superior to older blood), we would liketo encourage young investigators (fellows or junior faculty)to attend BloodNet meeting and to present their projects atBloodNet. We have therefore offered to create a mentoringprogram, in which young investigators can reach out toBloodNet’s leadership to be paired with senior researchers.We ask all BloodNet members to encourage their youngercolleagues to participate in our group and to attend ourmeetings!Our next meeting will be held on September 4, 2019, inVancouver, BC, Canada.

Note from the Chair

150 members from 9 countries

90 publications in 2018, and 8so far in 2019

5 manuscripts and 1 grant reviewed in the last six months

24 current BloodNet projects

Key Numbers

Oliver Karam, MD, PhDChildren’s Hospital of Richmond

The Thrombosis and Hemostasis groupcontinues to be active, with a wide range ofareas of interest. There are multiple, fundedand unfunded ongoing studies. VinceFaustino leads the ongoing CRETEmulticenter, randomized trial looking at theeffectiveness of enoxaparin in reducing CVC-associated thrombosis. It is expanding to 9sites to complete enrollment of 100 childrenin the next year. Alison Nair, Phil Spinella,Rob Russell, and Barb Gaines are initiating aThrasher grant funded study investigatingpediatric trauma induced coagulopathy.Sheila Hanson has started a single center,pilot study looking at t-PA dwells fordecreasing CVC-associated DVT. If feasible,this will be expanded to a funded multicentertrial. In addition, there are 8 studies ongoing,using the first harvest data from the pediatricECMO data registry, PEDECOR, established incollaboration with BloodNETProposed studies with plans to seek fundingin the near future include: Prophylaxis intrauma or surgical patients (Faustino,Hanson), Prophylaxis in IntubatedAdolescents (Faustino), Cold vs warm platelettransfusion trial (Spinella, Steiner, Zantec),Association of extracellular vesicles withECMO circuit changes (Meyer), TXA for post-tonsillectomy hemorrhage, and Massivetransfusion (Spinella,Wisniewski).Please contact one of the study investigatorsif interested in collaboration.Sheila Hanson and Vince Faustino

Thrombosis subgroup

Ongoing projects include an internationalcollaborative effort to understand immunologiceffects of RBC products produced by differentmanufacture methods (Drs. Spinella, Acker, Norris,Muszynski, and Juffermans). Published resultsfrom our in vitro studies reveal significantdifferences in extracellular vesicle populations andimmunomodulatory potential of RBC productsupernatants by RBC manufacture method - andnot by storage duration alone. An additionalmanuscript is in review, and plans for a fundingapplication to extend these important findings areunderway.

Additional studies by Drs. Acker, Blumberg, andcolleagues are ongoing to evaluate effects of RBCwashing on markers of hemolysis, extracellularvesicles, and immunomodulatory properties in pre-clinical models. Drs. Spinella and D’Alessandro areconducting in vitro studies to evaluate immuneeffects of cold stored platelets, and Dr. Juffermansis evaluating effects of frozen RBC products inanimal and pulmonary epithelial cell stretchmodels. Ongoing observational studies includeRBC-DAMPs, which aims to evaluate relationshipsbetween immune function and heme trafficking incritically ill children with sepsis or traumatic injury(Dr. Remy) and The Transfusion and Organdysfunction in PediatrIC Sepsis (TROPICS) study,which aims to determine the relationshipsbetween RBC transfusion, immune function, andorgan dysfunction in children with septic shock (Dr.Muszynski). Proposed projects include the Red CellEfficacy in Pediatric ARDS (REPAiR) Study (Drs.Muszynski, Spinella) and the TRANSfusionepidemioLogy in pediAtric inTEnsive care units(TRANSLATE) study.Jennifer Muszynski

Immunology subgroup

Marisa Tucci presented a succinctsummary of the challenges incurred sincerecruitment ended for the ABC-PICUstudy.The database has been closed at the endof August 2018. Several issues have arisenthat have resulted in substantial delays.Cleaning the database, obtaining queryresponses, acquisition of missing datahave been very time-consuming.One example of an issue that sloweddown the process was the fact thatmissing data from some sites was due to afinal required step for data entry that didnot take place - missing data from thesesites had to be re-entered.Another example was that patients nottransfused were not all identified in theappropriate place in the CRF whichresulted in additional patients nottransfused for whom determinationsneeded to be made with regard toinclusion in the intent to treat analysis.Some patient population baselinecharacteristics were presented.The manuscript is currently inpreparation. No results could bepresented at the time of the BloodNetmeeting.Marisa Tucci

ABC-PICU: Final

Challenges

The ATHENA Trial is a multi center Bayesianadaptive, Goldilocks design phase 3 RCT that aims todetermine the efficacy of enoxaparin in reducing therisk of lower extremity DVT in mechanicallyventilated adolescents. The trial was designed toenroll a maximum of 400 subjects from 40 ICUs over4 years.

The trial was submitted to NIH but did not receive afundable score. The review panel was concernedabout the clinical significance of the trial despitecommenting that the trial was very strong. Since thelast submission, the American Society ofHematology released their guidelines on VTEidentifying RCTs comparing combined mechanicaland pharmacological thromboprophylaxis overmechanical thromboprophylaxis alone as a highpriority research need. The available evidence froma RCT in adults did not show any reduction in VTEand instead showed a higher risk of bleeding withthe combined strategy. However, the certainty ofthis evidence was very low, thus the need foradditional RCTs. The ATHENA Trial was proposed totest these 2 strategies. Given the new guidelines, weplan to revise the application then submit this June.We look forward to receiving letters of support fromall interested ICUs. Please contactvince.faustino@yale.edu for any questions.Vince Faustino

ATHENA Trial

Emerging evidence, especially in neonates, hasshown potential harm associated with liberalplatelet transfusion thresholds in pediatrics. Verylittle evidence exists regarding optimal platelettransfusion thresholds in critically ill children.Randomized controlled trials may be difficult dueto lack of equipoise from providers. If regionalvariation in practice exists, comparativeeffectiveness studies may be an alternativeapproach.

We conducted a secondary analysis of theprospective, observational data from P3T (pointprevalence of platelet transfusions). Subjectswere grouped according to region (NorthAmerica, Europe, Middle East, Asia and Oceania)and nation. Transfusions were analyzed asprophylactic (given to prevent bleeding) ortherapeutic (given to treat bleeding). Theprimary outcome was the total platelet count(TPC) prior to transfusion. Sub-groups analyseswere performed in children with an underlyingoncologic diagnosis and those supported byextracorporeal life support (ECLS). The dosingand processing of the platelet transfusions wereanalyzed as secondary outcomes. These resultswere paired with an analysis in the variation inplatelet count threshold used throughout anindividual child’s PICU course from a singlecenter.Five hundred and forty nine children from 16

countries were enrolled (67% in North America,17% in Europe, 7% in Oceania, 5% in Asia, and4% in the Middle East) in P3T. Overall, themedian (IQR) TPC prior to prophylactictransfusions (n=360) differed significantly on aregional basis (p=0.04) and ranged from 12 (8-41) x109 cells/L in the Middle East to 45 (20-66)x109 cells/L in Asia. The median TPC prior toprophylactic transfusions did not significantlydiffer between countries (p=0.08), nor did theTPC prior to therapeutic transfusions (n=189)differ on either a regional (p=0.16) or national(p=0.57) basis. For children supported by ECLS(n=90), there were no regional (p=0.06) ornational (p=0.40) differences for prophylactictransfusions. However, significant differences inthe TPC prior to therapeutic transfusions wereobserved on both a regional (p=0.02) andnational (0.04) basis with the Middle East, inparticular Israel, transfusing at the lowestmedian (IQR) TPC [28 (16-81) x109 cells/L]. Forchildren with an underlying oncologic diagnosis(n=233), no differences were seen in the TPC forprophylactic transfusions (n=175) on a regional(p=0.19) or national (p=0.20) basis. Nor weredifferences seen in the TPC prior to therapeutictransfusions on a regional (0.86) or national(p=0.33) basis.In the local analysis of 405 platelet transfusionsgiven to 31 PICU admissions, the goal plateletthreshold was defined in the majority of cases(86%). Each patient received a median (IQR) of 7(2-15) platelet transfusions during the course ofhis/her PICU admission. The goal thresholdchanged frequently [median (IQR) 3 (1-4) times].Though regional and national variation exists inplatelet transfusion practices among critically illchildren, given the frequency of change inplatelet transfusion thresholds on an individualbasis during the course of a child’s PICUadmission, comparative effectiveness studiesmay not be possible.Marianne Nellis

Regional and Local Variability in Platelet Transfusion Practices

BloodNet has grown so much these last fewyears that it was time to have our own bylaws.These bylaws will not only allow us to betterdefine the roles and responsibilities of theexecutive committee and describe theelectoral process, but also help us betransparent. Here is a short summary of ournew bylaws:Membership shall be open to all healthcareand research professionals interested inknowledge development in transfusionmedicine, hemostasis and blood management.Membership is granted after completion andreceipt of a membership application.There are no annual dues. Members are onlyrequired to pay for meeting registration. Therequired meeting registration is in addition toany PALISI registration.Each individual member and individualscovered by institutional membership who haveparticipated (attend in person or call-in) in atleast one third of the meetings in the priorthree years shall be eligible to vote inBloodNet elections and other decisions forwhich voting occurs. In the event of illness orother circumstances whereby an individualmisses the required third of meetings, he/shemay petition the EC to be allowed to vote.Any member or member institution may resignby filing a written resignation with the Chair.The EC shall have the authority to suspend orterminate membership privileges.Periodically, non‐member guests or observersmay request to attend a BloodNet meeting forthe purpose of presenting a proposal, learningabout the organization, or for othereducational, advocacy, or scientific purposes.Prior to the meeting, guests and observers willhave to sign a confidentiality agreement.The Executive Committee is responsible foroverall policy and direction of the Network. Atany given time, the EC shall have 7 members.Ideally, at least one member of the EC shouldbe from a non‐U.S. institution to reflect the

international composition of BloodNet.The Chair work with Vice-Chair to develop theagenda, preside at each meeting, presentupdates to PALISI, is responsible for oversightof significant expenditures (> $250),maintaining a record of active members, and isthe point of contact. The Chair is not elected;after a three-year position as Vice-Chair, theVice-Chair automatically becomes Chair.The Vice-Chair is elected every three years bythe membership at large, must be a currentmember of the EC, and automatically assumesthe Chair position upon completion of theChair’s three‐year term. The Vice-Chair alsoserves as the Scientific Committee Chair, leadsand designs educational initiatives, andoversees BloodNet’s website.The immediate Past-Chair is an advisor to theChair, and will temporarily reassume the Chairposition in the event the Chair must stepdown.

There are four at-large members. Two areappointed by Chair and approved by majorityvote of the Executive Committee, and two arenominated and elected by the membership asa whole. The four EC members at‐large willparticipate in at least half of the semi‐annualmeetings. They may be assigned or acceptadditional responsibilities as needed for theoperation of BloodNet.The four at-large members shall servetwo‐year terms and are eligible for re‐election

BloodNet Bylaws

for a total of two consecutive terms. The Chair,Vice-Chair, and Past-Chair serve three-yearterms. January 1st is the transition date for allEC positions, including Chair and Vice‐Chair. TheExecutive Committee members are eligible forre-election after a 2-year hiatus.The Scientific Committee offers scientific reviewof grant proposals and manuscripts submitted byBloodNet members and is chaired by theExecutive Committee Vice-Chair. The membersare the chair of each approved BloodNet SpecialInterest Groups; and three members electedfrom the membership at-large. They servetwo‐year terms and are eligible for re‐electionfor a total of two consecutive terms.

Special Interest Groups are organized aroundthe research interests of their members and

remain part of the larger BloodNet Network. AllSpecial Interest Group must have a minimum of5 members, meet regularly, and have at leasttwo ongoing research projects approved byBloodNet. Approval of a Special Interest Grouprequires an application to the BloodNet EC and aone‐year probationary period. The Chair of eachapproved Special Interest Group is a member ofthe Scientific Committee.The transition to the new bylaws will be asfollow. The current Chair will remain in office forone year after new election (3-year cycle), afterwhich the Vice-Chair will become Chair. CurrentPast-Chair will remain in office for another year,after which the current Chair will become Past-Chair. We will hold election of a new Vice-Chair(who will serve as chair after a year beforebecoming Chair) and two at-large members. Thetwo other at-large members will be appointedby the current Chair and voted by the currentExecutive Committee.

BloodNet Bylaws (continued)

The 2016 NHLBI Scientific Priorities in PediatricTransfusion Medicine symposium highlighted alack of epidemiologic data on RBC transfusionsin children as a key barrier to progress in thefield. Specific to critically ill children, little isknown about the proportion of patientstransfused by age and diagnosis, the timing oftransfusion, and characteristics of RBC productstransfused. These epidemiologic data areessential to design subsequent RBC transfusiontrials and to optimize transfusion practice. Theproposed TRANSLATE study, led by Dr. JillCholette, would be an international pointprevalence study of RBC transfusion in criticallyill children to identify differences in RBC

transfusion practice in critically ill children acrossmultiple centers and diagnoses. Following thehighly successful models of the PlasmaTV andP3T point prevalence, TRANSLATE promises todeliver vital new information on theepidemiology of RBC transfusion in critically illchildren.Jenn Muszynski

Red Blood Cell Point Prevalence Study

The bylaws were approved by100% of the members withvoting rights, on April 14, 2019.Oliver Karam

The Transfusion and Anemia eXpertise Initiative(TAXI) recommendations, developed to guideRBC transfusion in critically ill children, havebeen published, but additional attention toimplementation of the guidelines is needed tooptimize use. This study uses implementationscience methods to enhance providercompliance with the TAXI recommendations.The integrated Promoting Action on ResearchImplementation in Health Services (i-PARIHS)framework has been used successfully toimplement guidelines, and is being usedcurrently to identify barriers and facilitators tousing the TAXI recommendations.We are completing interviews in 8 PICU/CVICUs

that are focused on assessing contextual factorsthat impact blood transfusion in the ICU.Preliminary findings have highlighted thatdecision making around blood transfusion isimportant to providers and that most are willingto use a guideline around blood transfusion inthe ICU. Contextual challenges related to thebusy and complex ICU environment will informthe next step of the project, developing of atailored implementation plan. A computerizedclinical decision support tool will be created asone part of the implementation strategy. Otherstrategies will focus on provider educationaround the TAXI recommendations, creatingsupport for guideline use, and providingtransfusion practice data back to providers.After implementation in the Stanford PICU andCVICU, we will evaluate the feasibility andacceptability of the implementation strategy aswell as the impact on clinical practice, with agoal to bring implementation strategies to othersites in the future.Kate Steffen

Implementing Transfusion Recommendations

Six months after the publication of theTransfusions and Anemia eXpert Initiative (TAXI)in Pediatric Critical Care Medicine, our mainmanuscript has been viewed more than 2,100times and has been cited in 146 social mediaposts, which ranks it 11th out of 2,743 articles ofa similar age in the journal (99th percentile)!Therefore, we are already thinking about thenext steps. Our objective is to update therecommendations every five years, as newevidence is relatively scarce. We anticipate thatit would take two to three years to update thesystematic review, update therecommendations, and write the newmanuscripts. We are going to explore differentstrategies to increase the dissemination of the

guidelines, working closely with AABB, ISBT, andSCCM. We are also exploring strategies toinvolve young faculty.We have also discussed the opportunity todevelop other guidelines, but the group believeswe should not yet address plasma, platelets, orcryoprecipitate, as there is no solid evidence;the recommendations would only be expertopinions.

TAXI: next steps

Bob Parker was unfortunately not able to attendthe BloodNet meeting, as he was the captain ofthe Long Island Grizzlies, who were competing inLas Vegas for the Las Vegas Hockey Classicchampionship. Most of the games were playedat the City National Arena, the practice rink forthe Las Vegas Golden Knights. Bob was playing

with three of his four sons, one of whom wasthe goalie, who only allowed only 4 goals in 4games. After playing three games in theirdivision, they played the Bay Area Iceman in thedivision finals and won 1:0! Bob’s team hadalready won in 2015 and 2017.Congratulations Bob!!!

Bob Parker and the Long Island Grizzlies

September 4, 2019Vancouver, BC, Canada

Next meeting

Find us on the web:www.bloodnetresearch.org/

Connect on Twitter:@BloodNet_PALISI

Or email Oliver Karam:oliver.karam [at] vcuhealth.org

Connect with us

Executive CommitteeOliver Karam, ChairMarisa Tucci, Vice-ChairPhilip C. SpinellaAllan DoctorJacques LacroixRobert ParkerMarie Steiner

Subgroup leadershipJennifer MuszynskiSheila Hanson

BloodNet Leadership

Scientific CommitteeMarisa Tucci, ChairNeil BlumbergAllan DoctorCassandra JosephsonJacques LacroixNaomi Luban

Phillip NorrisRobert ParkerKenneth RemyChris SillimanPhilip C. SpinellaMarie Steiner