PaulYenson,MDFRCPCVancouver,BritishColumbia

Complement-MediatedThromboticMicroangiopathy:

AnUpdate

DisclosureofCommercialSupport

• Ihavereceivedhonorariafrom:

• AlexionPharmaceuticals• Octapharma Canada• PfizerCanada

Objectives

• Todefinethromboticmicroangiopathy (TMA)andpresentacontemporaryclassificationbasedonourmolecularunderstanding.

• Todiscussthecurrentunderstandingofthepathophysiologyofatypicalhemolyticuremicsyndrome(aHUS),akacomplement-mediatedTMA.

• ToreviewmanagementofatypicalHUS,withafocusonplasmatherapyandeculizumab.

• TohighlightapracticalapproachtodiagnosingandmanagingTMA.

Case

• 41yomale,congenitalfusedhorseshoekidney,noCKD,incarceratedherniarequiringsurgicalrepair2005,otherwisewell.

• 1-weekhistoryoffever,anorexia,leftsidedabdominalpain,non-bloodydiarrhea.

• Noneurologicsymptoms.• Febrile39.3oC,BP190/101.• CRP172mg/L,AST17,ALT34,ALP92,GGT81,amylase174• INR1.1,aPTT 30s,fibrinogen2.4,D-dimer>4000• CTabdomenshowsmildlyenlargedpancreas&appendix,markedmuraldensityc/wcolitis,smallamountintraperitonealfluid.

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LDH 201

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236

261

RenalbiopsyshowingTMA

StoolC&Snegative

Bonemarrowbiopsy“reactive”

Case

Haptoglobin2.30“Afewschistocytes”

Question

• Thispatient’spresumptivediagnosisis:

A. ThromboticthrombocytopenicpurpuraB. ShigatoxinmediatedhemolyticuremicsyndromeC. MalignanthypertensionD. Complement-mediatedTMA(aHUS)E. Ihavenoideabutwhateveritis,heneedsplasmaexchange.

Question

• Thenextbesttest(s)is/are:

A. ADAMTS-13activity/inhibitorB. StoolforShigatoxinELISAorPCRC. Complement-mediateddiseasegenotypingD. Anti-complementfactorHantibodytestingE. AlloftheaboveF. Noneoftheabove

WhatisTMA?

• Aclinicopathological syndromeofmicrovascularstenosiscausingshearingofredbloodcells(andfragmentation)andthrombocytopenia.

• Multiplecauses:• Fibrinclots(e.g.DIC)• VWF-plateletclots(e.g.TTP)• Endothelialinjury• Vasculitis• Microvascularcancer

Loirat &Fremeaux-Bacchi.OJRD(2011).Tsaietal.AmJMed(2013).

ABriefHistoryofTMA

1954FirstdescriptionofHUS(Gasser).

1924Moschcowitz firsttodescribeTTPin16yopatient.

1981ThompsonreportslowC3inyoungboywithHUS.

1982MoakedescribespresenceofULVWFinTTPpatients.

1991CAGdemonstratessuperiorityofPEoverPItotreatTTP.

1977PlasmainfusionssuccessfullyusedtotreatTTP(Byrnes&Khurana).

1975FamilialformofHUS

reportedin41kindreds (Kaplan).

1996-1997ADAMTS13discoveredanditsdeficiencyinTTPpatientsreported.

1998Warwicker identifiesFactorHmutationas

causeofaHUS.

2000-PresentIncreasing#mutationsincomplementsystemreportedinaHUS.

2016rADAMTS13inclinicaltrials.

2013EfficacyofeculizumabtherapyinaHUS inphaseIItrials,leadingtoapprovalbyHealthCanada.

1966Amorosi andUltmanndescribetheclassic“pentad”ofTMA.

“TTP-HUS”

ClassificationofTMAbyMolecularMechanism

ThromboticMicroangiopathy

ThrombocytopeniaMicroangiopathic hemolyticanemia

Endorganimpairment

ShigatoxinmediatedTMA(TypicalHUS) SecondaryTMA

StemcelltransplantPregnancy/HELLP

DrugsMalignantHTNSepsis/DIC

AutoimmuneDzMalignancy

Streptococcalinfxn

TTP(ADAMTS-13deficient)

Complement-mediatedTMA

(aHUS)

CobalaminCdeficiency

Coagulation-mediatedTMA

(THBD)

DGKEdeficientTMA

AtypicalHUS

• Rare,potentiallylife-threateningformofTMA• Annualincidence~3-4/million

• ~50%presentinadulthood• Slightpreponderanceinfemales(adultonset)

• 20%haveextrarenalinvolvement(GI,CNS,CV)• 10-15%mortalityduringacutephase.

Cumulativesurvivalwithout ESRDordeath.

Fremeaux-Bacchi Vetal.Clin JAmSoc Nephrol (2013).Noris Metal.Clin JAmSoc Nephrol (2010).

Teoh CWetal.Transf Apher Sci (2016).

Teoh CWetal.Transf Apher Sci (2016).

MCP

CFH

CFI

-

Teoh CWetal.Transf Apher Sci (2016).

Gainoffunctionoffactor:• C3• FactorB

Lossoffunctionofregulator:• FactorH• FactorI• Membranecofactorprotein

Unknown

MCP

CFH

CFI

-

The2nd HitHypothesis

upon trigger events and ongoing endothelial cell injury inparticular due to continuous amplification of the comple-ment AP. Complement blockade does not alter the geneticpredisposition but increases the threshold for TMA evolve-ment. Therefore, blocking complement activation is the key toarrest the progression of TMA (►Fig. 2).

Pathophysiology within the ThromboticMicroangiopathy Spectrum

Genetic Predisposition and AutoimmunePredispositionSystematic genetic and autoantibody screening has revealed apivotal role for complement dysregulation in patients within

the more and more recognized spectrum of TMAs. Mutationsin complement regulators or activators as well as auto-anti-bodies against CFH-Ab have been found in 34 to 53% and 3 to25% of patients with aHUS, respectively.2,51–55 Of note, in acohort of aHUS patients in India, CFH-Ab HUSwas detected in56%.56 A mutation or CFH antibodies were detected in 71% offamilial and in 66% of sporadic cases.52 Complement alter-ationswere also detected in 29% of patients with de novo HUSpost kidney transplantation,57 in 68% with recurrent HUSafter kidney transplantation58 and in one patient with severeTMA and antibody-mediated rejection (AMR),59 in 86%(18/21) patients with pregnancy-associated HUS,60 in threeof seven patients with cobalamin C deficiency,61–63 in three(CFH-Ab) and six (heterozygous CFHR1 del) of nine patientswith TMA associated with stem cell transplantation(SCT).64,65 Variants in CFH were found in four patients withticlopidine associated TTP66 and one patient suffering fromTMA associated with malignant hypertension.67 An MCPmutation was detected in a child with TMA following treat-ment with cisplatin and carboplatin.68

Several glomerulopathies, such as SLE,69 immunoglobulinA (IgA) nephropathy,70 focal segmental glomerulosclerosis(FSGS),71,72membranous nephropathy (MN),73 andmembra-noproliferative glomerulonephritis (MPGN)74 as well as vas-culitides, especially antineutrophil cytoplasmic antibodies(ANCA)–associated vasculitis (AAV),75 coexist with TMA.

Recent analysis of ADAMTS13 activity and sequencing ofADAMTS13 in patients with aHUS showed a decreasedADAMTS13 activity in 50% patients and variations inADAMTS13 gene in up to 80% (21/29 patients).47 Screening85 genes of the complement and coagulation systems in 36patients with aHUS revealed 42 variants, including 4 variantsin PLG (encoding plasminogen)46 (►Table 1).

While the exact mechanism is still unclear, the link ofdiacylglycerol kinase (DGKE) and complement is so far onlyvaguely identified, suggesting a contribution of noncomple-ment pathways to TMA pathogenesis. DGKE, encoding diac-ylglycerol kinase ε, a protein involved in cell metabolism, wasrecently detected in patients with disease manifestationyounger than 1 year.19 All mutations and risk alleles altering

Fig. 2 Multiple hit hypothesis. TMA disease onset is the consequence of the combination of genetic predisposition and trigger factors/conditions.Predisposition (genetic, autoimmune, or unknown host factors) can be mild or severe, as reviewed by de Cordoba et al.95 Treatment witheculizumab (C5 inhibition) does not alter the predisposition but increases the threshold for TMA onset (indicated by arrow). Trigger factors/conditions range from mild to severe and can occur alone or in combination. Examples for trigger factors include infections, pregnancy,transplantation, metabolic disease, and other glomerulopathies. TMA, thrombotic microangiopathy.

Fig. 1 TMA pathogenesis. The complement, inflammatory, andcoagulation systems interact closely in maintaining the integrity of theendothelial lineage of the microvasculature. Disruption of the physi-ological balance of this immunothrombotic homeostasis leads to TMA.Dashed arrow indicates not well understood interaction. 1. Comple-ment system, 2. Endothelial cells, 3. Inflammation and neutrophils, 4.Coagulation and platelets, 5. Neutrophil extracellular traps, and 6.Microparticles originating from leukocytes, platelets, or endothelialcells. TMA, thrombotic microangiopathy.

Seminars in Thrombosis & Hemostasis Vol. 40 No. 4/2014

Treatment of TMA Spectrum Riedl et al.448

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(URTI,diarrhea,pregnancyarethemostcommon)

Riedl Metal.Semin Thromb Hemost (2016).

ClassificationofTMAbyMolecularMechanism

SecondaryTMA

StemcelltransplantPregnancy/HELLP

DrugsMalignantHTNSepsis/DIC

AutoimmuneDzMalignancy

Streptococcalinfxn

ThromboticMicroangiopathy

ThrombocytopeniaMicroangiopathic hemolyticanemia

Endorganimpairment

ShigatoxinmediatedTMA(TypicalHUS)

TTP(ADAMTS-13deficient)

Complement-mediatedTMA

(aHUS)

CobalaminCdeficiency

Coagulation-mediatedTMA

(THBD)

DGKEdeficientTMA

Jolen Cetal.Blood(2016).

SecondaryTMA:AGeneticSusceptibility?

Noris Metal.Clin JAmSoc Nephrol (2010).

Cause Presence ofComplementGeneVariants

Type ofVariants

Pregnancy 11/36(34%) CFH(7),CFI(2),combined (2)

MalignantHTN 6/34(18%) CFH(3),C3(2),CFB(1)Systemicdisease(SLE,scleroderma)

12/49(24%) CFH(5),CFI(3),C3(1), MCP(1),CFB(1), combined (1)

STEC-HUS 8/18(44%) CFH (2),CFI(1),C3(3),MCP(1) ,combined (1)

Solidorgantransplant 4/23 (17%) CFH(3),CFI(1)

• Noconsensusdiagnosticcriteriaandnodefinitivediagnostictest.

HowdowediagnoseaHUS?

HowdowediagnoseaHUS?

1) ConfirmTMA• MimicsofRBCfragments=irondeficiency,hemoglobinopathies,hyposplenism,oxidativehemolysis,vitaminB12deficiency

• Havehighindexofsuspicionformetastaticmalignancyandinfection(disseminatedfungal,bacterialendocarditis).

2) IdentifysecondarycausesofTMA• STEC-HUS– stoolC&S,ShigatoxinELISAorgenePCRifdiarrhea

HowdowediagnoseaHUS?

I doNOTperformPLEXfor:a) STEC-HUSunlesssevereneurologicpresentationb) Bonemarrowtransplant-associatedTMAc) Gemcitabine-associatedTMAd) Malignancy-associatedTMA(metastatic)

3) “Rulein”TTP

• ADAMTS-13activity/inhibitor(<10%suggestiveofTTP)o Considerbankingsamplespre-PLEX

• Predictivescores1,2,3o Platelets<30,000-35,000+Creatinine<177μmol/LhighlypredictiveofADAMTS13deficiency

o UpfrontsteroidsforsuspectedTTP

• Responsetoplasmaexchange.

1. Bendapudi Petal.Blood (2014).2. BentleyMJetal.Vox Sang(2013).3. Coppo Petal.PLOSOne(2010)

HowdowediagnoseaHUS?

HowdowediagnoseaHUS?

4) aHUS “directed”investigations

• C3andC4levels– ~50%ofpatientswithaHUS presentwithlowC3andnormalC41

• Anti-CFHantibodies– 6-10%ofaHUS patients2

• Complement-mediateddisordersgenotyping- ~50-70%ofaHUSpatients2

1. NorisMetal.Blood(2014).2. NorisM.NEJM(2009)

Enabling Diagnostic and TherapeuticSchedules in Developing Countries

As previously mentioned, the costs of diagnostic testing for asingle case of aHUS (!$10,000), for example, greatly exceedsannual incomes in developing countries. The costs for therecommended therapy (more than $27,000 for the first 4weekly 300 mg doses) merely adds to exacerbate unafford-ability in these regions.

The current recommendations for diagnosis and therapyofaHUS are therefore simply not feasible for patients living indeveloping countries. This would account for nearly 80% of allhuman beings.66 From that perspective, international coop-erations facilitating a proper diagnostic work-up in a strin-gent and cost-efficient manner are indispensable fordiagnosis, and more so with regard to therapy, of manyindividuals suffering from these serious and life-threateningdiseases. This should be embedded in scientifically encour-aged cooperations between developing and so called devel-oped countries.

The first and deciding step in the diagnostic work-up of apatient with HUS is to exclude Stx-induced HUS. Even thiscritical diagnostic step is not possible for most patients indeveloping countries. Together with the exclusion of second-ary HUS forms69 (including cobalamin deficiency and diac-ylglycerol kinase ε [DGKE] HUS which can be suspectedclinically), the next essential diagnostic tests are those forADAMTS13 activity68,69 and testing for CFH-Ab.70

Thus, as a first step of cooperation, the HUS study group,Innsbruck, provided Stx stool ELISA test kits for the Center forPediatric Nephrology and Transplantation, Cairo University,for a project we began in 2011. From all patients presenting

with suspected HUS, serum, ethylenediaminetetraacetic acid(EDTA) plasma and citrate plasma samples were collectedbefore initiating therapy and stored at "80°C. All patientswith a positive stool in the Stx ELISA were excluded fromfurther diagnostic work-up unless they presented as recur-rent cases. From all other patients, the stored samples weresent to the German–Austrian HUS study group center atInnsbruck Medical University for further work-up. As therapid diagnosis of CFH-Ab HUS has a direct impact on furthertreatment strategies, screening for CFH-Ab, and ADAMTS13activity was performed for all included patients as the firststep of complement diagnostics. CFH-Ab patients were notincluded for a further genetic work-up; nevertheless, DNAwas extracted and stored. Altogether, samples from 10 pa-tients with acute D" HUS patients (two males, eight females)seen at the Center for Pediatric Nephrology and Transplanta-tion, Cairo University during the years 2011 to 2012, weresent to InnsbruckMedical University, Austria. In two patients,CFH-Abwas detected. Although 50% of patients showed signsof decreased ADAMTS13 activity, no ADAMTS13 levels below10%, indicating TTP, were detected. In addition, ADAMTS13inhibitors were not detected. The decrease in ADAMTS13activitymight be a secondary phenomenon of the thromboticmicroangiopathy.36 The complement genetic analysis of thesepatients are ongoing and yet not completed.

Although treatment recommendations for patients withCFH-Ab–associated aHUS had been received from InnsbruckMedical University, the delay in sending samples (up to 6months) and receiving results (for CFH-Ab testing !2 weeks,genetics still pending), represented an obstacle toward theirapplication. Thus, all patients received a similar protocol of PE,and symptomatic therapy as required (e.g., antihypertensives,

Fig. 1 HUS/TTP onset in developing countries: a stepwise diagnostic approach. ADAMTS13, a disintegrin and metalloproteinase with athrombospondin type 1 motif, member 13; CFH-Ab, complement factor H antibodies; ELISA, enzyme-linked immunosorbent assay; HUS,hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura. For further explanation, see the text (Section: Enabling Diagnostic andTherapeutic Schedules in Developing Countries).

Seminars in Thrombosis & Hemostasis Vol. 40 No. 4/2014

HUS Disease Spectrum in Developing Regions Hofer et al. 483

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Complement-mediateddiseasegenetictesting

HoferTetal.Semin Thromb Hemost (2014).

HowdowediagnoseaHUS?

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Hemoglobin Platelets Creatinine

DayofAdmission

LDH 201

309

236

261

RenalbiopsyshowingTMA

StoolC&Snegative

Bonemarrowbiopsy“reactive”

Case

Haptoglobin2.30“Afewschistocytes”

Question

• Iwouldtreatthispatientwith:

A. PlasmainfusionB. PlasmaexchangeC. Anti-hypertensivemedicationsD. EculizumabE. SteroidsF. BandE

Plasma

Eculizumab

Complement-MediatedTMA:Treatment

Renal± LiverTransplant

Immunosuppression

PlasmaExchange

PlasmaTherapy

Noris Metal.Clin JAmSoc Nephrol (2010).

• Overallresponse~70%.NodifferencebetweenPIvsPE.• SignificantheterogeneityinPEvolume,frequency,duration,delayedinitiation.

Mutation CFH CFI C3 THBD MCP CFHAb None

ORR 63% 25% 57% 88% 97% 75% 69%

ESRD-death 37% 75% 43% 13% 3% 25% 31%

PlasmaTherapy

Noris Metal.Clin JAmSoc Nephrol (2010).

Mutation CFH CFI C3 THBD MCP CFHAb None

ORR 63% 25% 57% 88% 97% 75% 69%

ESRD-death 37% 75% 43% 13% 3% 25% 31%

• Howtoprescribeplasmatherapy?NOBODYKNOWS!1) Startassoonaspossible.2) Useplasmaexchangeoverplasmainfusion.3) Continuedailyuntilhematologicparametersarenormalandrenal

functionstabilizes.4) Taperdependingonresponse.

Eculizumab

X

Teoh CWetal.Transf Apher Sci (2016).ZuberJetal.NatureRevNephrol (2012)

LichtCetal.KidneyInt (2015).

73x109/L(Mean↑platelets)75x109/L

HematologicImprovement

HematologicNormalization90%

RenalImprovement

Mean↑eGFR 37mL/min/1.73m2 (trial1)8mL/min/1.73m2 (trial2)

4/5ptsstoppeddialysis,2newdialysis

• TMAevent-freestatuso Trial1- 88%(15/17)o Trial2– 95%(19/20)

• AdverseEventsoWelltoleratedo1death– intestinalhemorrhage(?)oNocasesofmeningococcalinfectionoNocasesofneutralizingantibodies

TMAandAdverseEvents

LichtCetal.KidneyInt (2015).

Doeseculizumab work?

SEEMSSAFEANDEFFECTIVE

• ImprovesTMA.• Improvesorstabilizesrenalfunction.• Enablespatientstostopplasmatherapy.• MayormaynotpreventESRD,needfortransplant,ordeath.• Withoutmajortoxicity.

2016-10-08, 10)13 PMNational Post: World's most expensive drug - which costs up to $700,000 per year - too expensive, Canada says

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February 3, 2015

World's most expensive drug - which costs up to $700,000 peryear - too expensive, Canada saysBy Tom Blackwell

Soliris is a potentially lifesaving treatment for two rare blood diseases. But the yearly cost perpatient of as much as $700,000 is even higher than...

Canada's drug-price regulator has taken the rare step of calling a hearing into what is considered the world's mostexpensive prescription medicine, accusing its manufacturer of exceeding the permissible price cap.

The yearly cost per patient of as much as $700,000 is even more than the manufacturer, Alexion Pharmaceutical,charges in the United States, which typically has the steepest prices globally, says the Patented Medicines PriceReview Board (PMPRB).

Soliris is a breakthrough, potentially lifesaving treatment for two rare blood diseases, affecting about 180 patients inCanada.

The board, which has not held an excessive-price hearing since 2012, said it had demanded the U.S.-based firmlower the price and pay back revenue it made above the cap. It refused both requests, according to formal allegationsissued by board staff.

Alexion continues to sell Soliris to Canadians at the highest international price among the comparatorcountries

Federal rules require that drug prices be no more than the median – mid-point – of seven other industrialized nations.

"Alexion continues to sell Soliris to Canadians at the highest international price among the comparator countries,"says the staff document.

If a board adjudication panel finds the price is excessive at a hearing to be held no later than March 6, it could order acost reduction and the repaying of surplus income.

Soliris has caused waves throughout the world in recent years with its eyebrow-raising price tag, but this may be thefirst attempt by a regulator anywhere to force a rollback.

2016-10-08, 10)13 PMNational Post: World's most expensive drug - which costs up to $700,000 per year - too expensive, Canada says

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Photos That Almost Brokethe Internet

Can you reverse high bloodsugar in 3 weeks?

Follow this one secret ruleto lose weight...

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February 3, 2015

World's most expensive drug - which costs up to $700,000 peryear - too expensive, Canada saysBy Tom Blackwell

Soliris is a potentially lifesaving treatment for two rare blood diseases. But the yearly cost perpatient of as much as $700,000 is even higher than...

Canada's drug-price regulator has taken the rare step of calling a hearing into what is considered the world's mostexpensive prescription medicine, accusing its manufacturer of exceeding the permissible price cap.

The yearly cost per patient of as much as $700,000 is even more than the manufacturer, Alexion Pharmaceutical,charges in the United States, which typically has the steepest prices globally, says the Patented Medicines PriceReview Board (PMPRB).

Soliris is a breakthrough, potentially lifesaving treatment for two rare blood diseases, affecting about 180 patients inCanada.

The board, which has not held an excessive-price hearing since 2012, said it had demanded the U.S.-based firmlower the price and pay back revenue it made above the cap. It refused both requests, according to formal allegationsissued by board staff.

Alexion continues to sell Soliris to Canadians at the highest international price among the comparatorcountries

Federal rules require that drug prices be no more than the median – mid-point – of seven other industrialized nations.

"Alexion continues to sell Soliris to Canadians at the highest international price among the comparator countries,"says the staff document.

If a board adjudication panel finds the price is excessive at a hearing to be held no later than March 6, it could order acost reduction and the repaying of surplus income.

Soliris has caused waves throughout the world in recent years with its eyebrow-raising price tag, but this may be thefirst attempt by a regulator anywhere to force a rollback.

Onlyifyoucangetit…

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Hemoglobin Platelets Creatinine

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ADAMTS1339%

Case

Case

• Anti-CFHantibodynegative.• 5monthsafter– Sickkids genotypingshowsheterozygosityforC3mutation(intron18,c.2246-2A>G).

• 6monthsafter- Eculizumab approvedbythirdpartyinsurer• Patientvaccinatedagainstmeningococcus.• Switchedtoeculizumab (900mgIVweeklyx4weekinduction,1200mgIVq2weeksongoing).

Conclusions

• Complement-mediatedTMA(aHUS)isarare,potentiallylife-threateningcondition,oftenresultingfromageneticpredispositioncombinedwithatriggeringevent.o PatientswithsecondaryTMAmayalsoharbour predisposinggeneticvariants,whichisanemergingareaofinterest.

• Complement-mediatedTMAisaclinicaldiagnosis.o ADAMTS-13,ShigatoxinELISAorgenePCRandanti-CFHAbtestinghavethemostvalueindirectingtherapy.

o Platelets <30andserumcreatinine<177arguesstronglyforTTP.

• Thecurrent“standardofcare”iseculizumab therapybutaccessremainsasignificantissue.o PlasmaexchangeremainsthemainstayoftherapyinmanyCanadiancentres.

Acknowledgments

Dr.Gayatri SreenivasanDr.LeslieZypchenDr.KimberleyAmbler

ValBurke,RNMiriamMaphala,RNTraceyHaskins,RNGuin Dorward,RNAliKlepsch,RNMarcelaJiminez,RN

CassandraCheung,RNMatBentley,RNJennPoliszuk,RNVictoriaLeBas,RNChao-YongLeePennyRolls

ThankYouEnjoyCHC-WEST2016!