InternationalJournalofTrichologyIntJTrichology.10(1):1-10

AMeta-analysisOnEvidenceOfPlatelet-richPlasmaforAndrogeneticAlopeciaSalvatoreGiordano,MarcoRomeo1,PietrodiSumma2,Andre'Salval,PetteriLankinen3

DepartmentofPlasticandGeneralSurgery,TurkuUniversityHospital,UniversityofTurku,Turku,Finland1.DepartmentofPlasticSurgery,JiménezDiazFoundation,AutonomousUniversityofMadrid,Madrid,Spain2.DepartmentofPlasticSurgery,CanniesburnPlasticSurgeryUnit,GlasgowRoyalInfirmary,GlasgowG40SF,UnitedKingdom3.DepartmentofOrthopaedicsandTraumatology,TurkuUniversityHospital,UniversityofTurku,Turku,Finland

Addressforcorrespondence:Dr.SalvatoreGiordano,DepartmentofPlasticandGeneralSurgery,TurkuUniversityHospital,OS299,PL52,20521,Turku,Finland.E-mail:salvatore.giordano@gmail.com,salvatore.giordano@tyks.fi

Copyright:©2018InternationalJournalofTrichologyDOI:10.4103/ijt.ijt_74_16Publishedinprint:Jan-Feb2018

Abstract

Background:Platelet-richplasma(PRP)treatmenthasgainedpopularityamongdifferentsurgicalspecialitiesforimprovingvariousconditions.Androgeneticalopecia(AGA)isacommondisorder,withpossiblepsychosocialimplications.PlasticsurgeonshaveincreasedthepracticeofPRPinjectionsforhairrestoration.Ameta-analysisonthistopicwasperformedcomparinglocalinjectionofPRPversuscontroltoinvestigatetheefficacyoflocalPRPinjectionsinAGA.

Methods:Weperformedasystematicliteraturesearch.Theincreaseinnumberofhairswastheprimaryoutcome.Secondaryoutcomesweretheincreaseofhairthicknessandthepercentageincreaseinhairnumberandthickness.

Results:Sevenstudiesinvolving194patientswereretrievedandincludedinthepresentanalysis.Asignificantlylocallyincreasedhairnumberpercm2wasobservedafterPRPinjectionsversuscontrol(meandifference[MD]14.38,95%confidenceinterval[CI]6.38–22.38,P<0.001).Similarly,asignificantlyincreasedhairthicknesscross-sectionper10−4mm2(MD0.22,95%CI0.07–0.38,P=0.005)favoringPRPgroup.Thepooledresultsdidnotshowasignificantpercentageincreaseinhairnumber(MD18.79%,95%CI−8.50–46.08,P=0.18),neitherhairthickness(MD32.63%,95%CI−16.23–81.48,P=0.19)amongpatientstreatedwithPRP.

Conclusion:LocalinjectionofPRPforandrogenicalopeciamightbeassociatedwithanincreasednumberofhairsinthetreatedareaswithminimalmorbidity,butthereisclearlyalackofscientificevidenceonthistreatmentmodality.FurtherstudiesareneededtoevaluatetheefficacyofPRPforAGA.

INTRODUCTIONAndrogeneticalopecia(AGA)alsoknownasmalepatternbaldnessisthemostcommonhairlossdisorderaffectingupto80%ofmenandupto40%ofwomenwithCaucasianheritage.Forpatients,alopeciacausesmajordiscomfortduetoanalteredappearancewithsignificantimplicationsindailylivingandpossibleleadingtodepressionandanxietysymptoms.[1]

Platelet-richplasma(PRP)injectionsforhairrestorationhasemergedtoapopularpracticeamongplasticsurgeonsbecausebothhighlydemandingpatientsandsurgeonsareseekingforminimally-invasiveandcostefficienttreatmentmodalitiesforandrogenicalopecia.[2]ThescientificinterestforPRPwasraisedin2006whenMishraandPavelkomanagedtodemonstratethePRPefficacyinimprovingelbowepicondylitis,reducingthetimeforhealing.[3]Sincethen,PRPlocalinjectionsstartedtobecomeverypopularwhichtransversallyinterestedmanymedicalandsurgicalbranches.[2]

PRPisanautologousproductthatismanufacturedbycentrifugationfrompatientsownvenousbloodlimitingthepotentialriskofdiseasetransmission.ComponentsofPRPincludesseveralgrowthfactors(GF),chemokines,andcytokines,suggestingthatitsbenefitsincludepromotionoftissuehealinginhard-andsoft-tissues.[45]Inanaturalenvironment,plateletsmigrateintotheinflammationsiteandreleaseAlphagranuli,whichareactivatedbyplateletsaggregationwithaconcentrationofGF.[6]Inaddition,localinjectionsofPRPareahighlyappealingtreatmentmodalitybecausetheycaneasilybeadministeredatoutpatientclinicsettings,withlowcosts.Meanwhile,rapidanduncontrolledinterestfrommedicalandnonmedicalprofessionalsmisleadtobelievePRPtobeacarrierofmesenchymal,stemcells,adipocytes,andbonemarrow,whichisobviouslynot.

Althoughthereareseveralrecentreportsandsmallrandomizedcontrolledtrials(RCT)examiningtheuseofPRPforhairlosstreatment,therearenosustainedresultsontheiroverallefficacy,[789]andnoneofthesestudieshavebeensufficientlypoweredtoassesstheriskbenefitofthismodality.[10]Despitetheheterogeneityofthesestudiesandduetothelackofthepreviousmeta-analysisspecificallyforcomparativestudiestoevaluatethisissue,weperformedawholecomprehensiveanalysishypothesizingthatPRPmightprovesignificantbenefits

inimprovingAGA.

METHODSTheobjectiveofthisreviewwastoassesstheliteratureonPRPoutcomesforAGA,withafocusonspecificclinicaloutcomesinacomparativeview,inaccordancewithPRISMAstatementforreportingthismeta-analysis.[11]Thepresentmeta-analysisisregisteredinPROSPERO,aninternationalprospectiveregisterofsystematicreviews,withthereferencecodeCRD42016041811.

Searchstrategy

AllauthorsindividuallycarriedoutafullsystematicliteraturesearchofallrecordsthroughMedline,CochraneLibrary,Embase,Scopus,GoogleScholarandResearchGateforanystudyonPRPuseforhairgrowththerapyinandrogenicalopeciafrominceptiontoAugust2017.

Thetermsemployedinthesearchwere:“androgenicalopecia,”“hairgrowth,”“hairrestoration,”“baldness,”“hairloss”combinedwith“plated-richplasma,”“PRP;”andtheywerecombinedusingBooleanoperators.Eachauthor'ssearchresultsweremerged,andduplicatecitationswerediscarded.ThesearchwasperformedaimingatthosestudiescomparingoutcomesofPRPtreatmentversuscontrolforhairrestoration.Nolanguagerestrictionswereapplied.

Studyselection

Wesearchedfor,andassessedstudiescomparinglocalinjectionsofPRPcomparedtoanycontrolforAGA.StudiestobeincludedinthisreviewhadtomatchpredeterminedcriteriaaccordingtothePICOS(patients,intervention,comparator,outcomes,andstudydesign)approach.CriteriaforinclusionandexclusionarespecifiedinTable1.Nolimitationswereappliedonethnicity,the

ageofpatientsormethodofPRPprocessing.Twoauthors(SGandPL)independentlyreviewedtheabstractsandarticles.Inaddition,thereferencelistsofallrelevantarticleswerescrutinizedaswell.

Seefulltable

Table1.Patients,intervention,comparator,outcomesandstudydesigncriteriaforinclusionandexclusionofstudies

Forthepurposeofthisanalysis,theeligiblestudieswerethosereportingonquantitativeoutcomesonPRPcomparedwithcontroltreatmentforAGA.Eachstudywasindependentlyevaluatedbyallthreeco-authors(SG,MR,PL)forinclusionorexclusionfromthisanalysis[Table1].Tobeincluded,studieshadtoprovidedetailsonbaselinecharacteristics,typeofprocedure,methodofPRPprocessing,andoutcomesonhairregrowthcomparedwithcontrolpatientsorareasinthesamepatient(internalcontrol).

Dataextraction

Datawereindependentlycollectedbytwoinvestigators(SGandPL)andcheckedbyathirdinvestigator(MR)onlyfromtheretrievedarticles.Disagreementoncollecteddatawassettledbyconsensusbetweentheseinvestigators.Noanyattemptwasmadetoobtainspecificormissingdatafromtheauthors.Thefollowingdatawereextracted:firstauthor,yearofpublication,studydesign,numberofpatients,typeofprocedure,andprimaryandsecondarymeasures.

Thequalityoftheincludedstudieswasindependentlyassessedusingthreeinvestigators(SG,MR,PL)usingtheCochraneCollaboration'sRiskofBias

AssessmenttoolforRCT[12]whileusingtheNewcastle–OttawaScaletoevaluatetheindividualnon-randomisedstudies.[13]Theresearchteamconvenedtoresolveanydisagreementontheassessmentandtoreachconsensus.

Outcomemeasures

Theprimaryoutcomewasthedifferenceinnumberofhairspersquarecentimeter.Secondaryoutcomeswerehaircross-sectionincrease,hairregrowth,andthicknesspercentageincrease.

Alloutcomesobtainedfromthestudieswerereportedwiththesamemeasurementsretrievedfromthearticles.Fromonearticle,percentageswerecalculatedfromthepatients'individualdatashowedinthepaper.[14]Thepatient'scontralateralsidewasusedascontrolinsomeoftheincludedstudies;whereaspatientswereallocatedintogroupswherePRPwaseitherusedornotintheotherstudies.Inbothcaseswereaccountedasone.Missingdataweredealtaccordingtopreviouslyvalidatedestimations.[1516]

Statisticalanalysis

StatisticalanalysiswasperformedusingReviewManager5.3software(Copenhagen:TheNordicCochraneCentre,TheCochraneCollaboration,2014).Differencesincontinuousvariableswereexpressedasmeandifference(MD)with95%confidenceinterval(CI).HeterogeneitywasassessedusingI2statistic,whichdescribesthepercentageoftotalvariationacrossstudiesthatisduetoheterogeneityratherthanchance.[17]I2valueswereevaluatedaslow,moderate,orhighat25%,50%,or75%,respectively.Toperformthemeta-analysis,theinversevariancestatisticalmethodwasusedforcontinuousoutcomevariables.Inallcases,weperformedrandom-effectanalysis,whichconsiderthevariationbothwithin-andbetweenstudies[1819]becauseoftheobservationalnatureofsomestudiesincludedinthisanalysis.AvalueofP<0.05wasconsideredtobe

statisticallysignificant.

Finally,weconductedsensitivityanalysesomittingeachstudy,inturn,usingthe“leaveoneout”methodologytodeterminewhethertheresultswereinfluencedexcessivelybyasinglestudy.Publicationbiaswasassessedusingthefunnelplotfortheprimaryoutcome.

RESULTSTheliteraturesearchyieldedsevenarticles[14202122232425]pertinenttothisissueandsourcesofinformationonoutcomesusingPRPinjectionsonscalpforAGA[Table2].TheliteraturesearchflowchartisshowninFigure1.

Seefulltable

Table2.Characteristicsoftheincludedstudies

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Figure1.Flow-chartsummarizingliteraturesearchresults

FivestudieswereRCT,[1422232425]whereastheothertwowereretrospectivestudies.[2021]

IntheRCT,theriskofbiaswaseitherloworunclearusingCochraneCollaboration'stoolforassessingtheriskofbias[

SupplementalTable1

].[12]ThenonRCTswereassessedwiththeNewcastle–OttawaScaleforriskofbiasresultingin0to4starspercategory,indicatingahightolowbias[

SupplementalTable2

].[13]Thedifficultyblindingparticipantsandresearchers,aswellas,thepresenceofinternalcontrolincreasedtheoverallriskofbias.

Theageofthepatientsrangedfrom19to63years,withafollow-upfrom3to24months.Allthestudiesshoweddifferentcentrifugationmethods[Table2].

Sixstudies,[142021232425]involvingatotalof132patients,reportedresultsonMDofnumberofhairspercm2versuscontrolandpooledanalysisshowedasignificantdifferencebetweenthetwotreatmentgroups[MD14.38,95%CI6.38–22.38,P<0.001;Figure2].Similarly,thisoutcomepersistedwhenonlythe4RCTwerepooledtogether[MD3.96,95%CI2.50–5.42,P<0.001;Figure3].

Viewlargerversion

Figure2.Forestplotshowingthesignificantlyincreasednumberofhairspercm2comparedwithco

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Figure3.Forestplotshowingthesignificantlyincreasednumberofhairspercm2comparedwithcontrolamongrandomizedcontrolledtrialstudies

Amongsecondaryoutcomes,wealsoobservedasignificantdifferencebetweenthetwotreatmentgroupsconcerningthehaircrosssectionmeasuredper10−4

mm2[MD0.22,95%CI0.07–0.38,P=0.005;Figure4]favoringPRPgroup,butthesedatawerereportedbyonly2studies.[1421]Wedidnotfoundasignificantdifferencebetweenthetwotreatmentgroupsconcerningthepercentageincreaseofhairnumber[MD18.79%,95%CI−8.50–46.08,P=0.18,Figure5]norhairthickness[MD32.63%,95%−16.23–81.48,P=0.19;Figure6].Althoughnotstatisticallysignificant,thesepooledresultsshowedatrendtowardanincreaseofhairnumber[Figure5]andhairthicknesspercentage[Figure6].

Viewlargerversion

Figure4.Forestplotshowingthesignificantlyincreasedthicknessofhairssectionexpressedas10-4/mm2comparedwithcontrol

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Figure5.Forestplotshowingthepercentageincreaseofhairnumberafterplatelet-richplasmatreatment

comparedwithcontr

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Figure6.Forestplotshowingthepercentageincreaseofhairthicknessafterplatelet-richplasmatreatmentcomparedwithcontrol

Fouroftheincludedstudies[20222324]didnotreportanyadverseeffectsorcomplicationsassociatedwithPRPinjections.Intheothertwopublications,informationaboutpossibleadverseeffectswerenotreported.

Finally,theexclusionofmoststudiesfromtheanalysisdidnotmateriallychangethesummaryestimates,withsensitivityanalysisusingthe“leaveoneout”methodology;however,significantasymmetryinthefunnelplotwasobserved

fortheprimaryoutcome[Figure7].

Viewlargerversion

Figure7.Funnelplotforbiasassessmentinhairnumberincrease

DISCUSSIONThepresentmeta-analysis,includingsixstudiesandencompassingatotalof194patients,providescompellingevidenceaboutPRPtreatmentforhairrestorationinAGA.Asignificantlyincreasednumberofhairspercm2wasobservedaftertreatmentwithPRP[Figures2and3].Furthermore,althoughtheincludedstudieshadarelativelysmalltotalnumberofpatients,wefoundinterestingresultsalsoinhaircross-sectionthicknessandothersecondaryoutcomeswhichshowedatrendtowardbenefitFigure4–Figure6.Thisisthefirstpooledanalysisonthisemergingtopic,showingoverallquantitativeoutcomes.

PRPtherapyisanappealingemergingminimallyinvasivetherapeuticmodalitytoenhancetissuehealing.Although,usedsincethemid-1990sithasrecentlygainedsubstantialincreasinginteresttoprovideacosteffectivemodalitytopromotethehealingprocess.PRPisanautologousproductthatismanufacturedfrompatientsownvenousbloodlimitingthepotentialriskofdiseasetransmission.Bydefinition,PRPcontainsconcentratedtheamountofplateletconcentration,1.000.000/ULplateletcount,3–8foldssuperioramountascomparedtothenormalperipheralblood(range150.000–350.000UL).[242526]Onactivationplateletsundergodegranulation,andrapidly,anarrayofGFsarereleasedfromplateletAlpha-granuli,[26]andGFreleaseiscontinuedinlesserextenduptoseveraldays.[2728]PRPalsocontainsplasmaandover20GFs,whichincludeplatelet-derivedendothelialGF,transformingGF–β,fibroblast

GF–2,vascularendothelialGF,epidermalGF,insulin-likeGF–1,and,inaddition,thrombin,whichhasbiologicalandadhesiveproperties.[29]IthasalsobeenreportedthatPRPinducesoverexpressionendogenousexpressionofGFs.[3031]Throughthecomplexinteractionofgrowthanddifferentiationfactorsandalongwithadhesiveproteinfactors,PRPisbelievedtostimulatehealingbypromotingregenerativechemotaxis,cellproliferation,angiogenesis,extracellularmatrixformation,andcollagensynthesis.[3233]

ThereisnoastandardizedmethodforPRPpreparation,therefore,theremightbedifferencesinproductcomposition.ThisfactmayleadtoanalteredPRPfunction,whichmightexplainthecontroversyfoundintotheliterature.Furthermore,differencesinPRPcompositionresultfromdifferencesinthesamplesretrievedfrompersontoperson.Differencesinthemanufacturingoftheinoculateresult,especiallyfromtheroutineofcentrifugationandwhethereitherbovinethrombinorcalciumchlorideisusedinactivation.[1027]Theusedendproductmayvarybytheusedvolumeandthenumberofinjectionsadministered,aswellasthecolor,plateletcount,thenumberorabsenceofleukocytes,anditsproteincontent.[27]

Recently,anumberofreportshavebeenpublishedshowingpromisingresultsforthetreatmentofAGA.Unfortunately,thesestudiesweregenerallysmall,poorlycontrolled,withoutoutcomes'objectiveandmeasuredquantificationandtherefore,theywerenotincludedinthismeta-analysis.Betsietal.[8]treated42alopeciapatientswithPRP,fivetimesduringover2monthsshowinganimprovementinhairpullingtestandahighoverallpatientsatisfaction.Indeed,theyfoundin31%ofcasessomedrowsinessandsensiblescalp.Schiavoneetal.[9]performedthelargeststudyonthistopic,including64malepatientswithAGAandtheyweretreatedwitharegimenofPRPenrichedwithleukocytesinadditiontoconcentratedplasmaproteins.Twosequentialinjectionswere

performedatinitiationofthestudyandsubsequentlyatthreemonths.Theevaluationwasperformedonthebasisofglobalassessmentofbeforeandafterphotographsbyunblindedassessorsshowinganimprovementinappearancefor62ofthe64patients.[9]Anothernoncontrolled,nonblindedstudyof22patientsfoundanincreaseintotalhairdensityfromameanof143.1atbaselinetoamaximumof170.7hairs/cm2at3monthsfollow-up.[34]Anothernoncontrolled,nonblindedstudyof11patients[35]detectedasignificantreductioninhairlossbetweenfirstandfourthinjection.Particularly,haircountincreasedfromanaveragenumberof71hairfollicularunitsto93hairfollicularunits,withanegativepulltestwasin9patients.[35]

Singhaletal.[36]performedasimilarstudyon10patientsalsoshowingclinicalimprovementinthehaircounts,thicknessandrootstrength.Theyindeedhadthreepatientscomplainingamildheadacheaftertheinitialprocedure.Morerecently,Navarroetal.[9]reportedanoverallincreaseofhairdensityandanincreaseof6.2%anagenhairfollicleswhileadecreaseof5.1%amongtelogenoneson100patientstreatedwithPRP,similarlytoAlvesandGrimalt[24]Wedidnotattempttopoolthedataexistingonhairfolliclecycles,astheywerenotconsistentamongtheincludedstudies.Nonetheless,PRPshowedpromisingresultsalsocombinedwithhairfolliculartransplanttoenhancethepostoperativeoutcomes.[3738]Particularly,UebelstudiedashortseriesofpatientscomparingtwoareasofhairtransplantwithorwithoutPRPintherootofthegrafts.Twoareas(2.5cm2)weremarkedonthescalpandeachplantedwith20grafts/cm2.After1year,theareaimplantedwiththePRP-enrichedgraftsdemonstratedahigherfollicleunitssurvivalrateanddensity.Inamurinemodel,Miaoetal.[39]demonstratedsomeinfluenceofPRPonhairregrowthwhensimultaneouslyinjectedwithtransplantedhairfollicles,withconsistentdata,furtherencouragingclinicalapplications.Again,thedataaboutPRPandhairgrowth,togetherwithasurgicalhairtransplant,aresparseandheterogeneousalthoughpromising.

Nevertheless,theseoutcomescanbeexplainedbythephysiologicalroleofplateletsdegranulationduringinflammation,whichisstimulatedbysurgicalhairtransplantation,atraumaticeventcausinginflammatoryresponseandchemotaxis.[3]Forthisreason,webelievethatsurgicaltransplantationofhairfollicleswithPRPmightbemoreeffectivethatPRPalone.

Theresultsofthismeta-analysisshouldbeviewedinlightofanumberoflimitationsandpotentialbiasinfluencingthesefindings.Onlysixstudieswereusedforthispooledanalysis,onlyfourofthemwererandomizedcontrolledtrial[1422232425]andtwowereobservational[2021]withclearheterogeneityinmethodsandsettings[Table2].WewantedtoincludeonlycomparativestudiestobetterassesstheefficacyofPRP,missingtheoutcomesofone-armstudies.

Thenumberofpatientsconsideredwasextremelysmallandthereweredifferencesinpatients'age,devicesused,centrifugationmethods,control,andareasoftreatment,whichmightbeaconfoundingfactorfortheresults.

Importantstatisticalheterogeneity(I2>75%)wasfoundinallanalysisFigure2–Figure6,showingimportantdifferencesinmethodsandstudysettings.However,theexclusionofanystudyfromtheanalysisdidnotmateriallychangethesummaryestimates,butfunnelplotfortheprimaryoutcomesshowedsignificantasymmetry,whichindicatesthatpublicationbiasmighthavesomehowinfluencedtheresults.

Othermajorlimitationsofthispooledanalysesincludethefactthatmostoftheincludedstudiesusedinternalcontrols,wherethepatient'scontralateralsideorotherareasservedasitsowncontrol,whereasinothers,patientswererandomizedintogroupswherePRPwaseitherusedornotused[Table2].Thereweredifferencesinthetreatedscalpareasandinsomecases,thecontrolgroupwastreatedwithplacentalextract[21]ordalteparinandprotaminecontaining

microparticles[14]withnoplacebocontrol.

CONCLUSIONPRPinjectionforlocalhairrestorationinpatientswithAGAseemstoincreasehairsnumberandthicknesswithminimalornocollateraleffects.However,thecurrentevidencedoesnotsupportthistreatmentsmodalityoverothertreatmentsduetothelackofclinicalevidence,establishedprotocols(i.e.,numberofsessions,centrifugation,zonestobeinjected,etc.),andlong-termfollow-upoutcomes.

Theresultsofthismeta-analysisshouldbeinterpretedwithcautionbecauseitincludespoolingmanysmallstudiesandlargerrandomizedstudiesshouldbeperformedtoverifythisperception.Themedicalliteraturedoesnotconfirmthatthetreatmentisscientificallyrelevant.TheadditionofPRPmightbeusefulinimprovingtheoutcomesofhairtransplantationprocedures,butthereisnoevidencewhetherPRPismoreeffectivethanminoxidilorfinasteridetreatments.Largerstudieswithlong-termfollow-uparewarrantedtovalidatethispromisingtreatmentmodality.

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Table1.Patients,intervention,comparator,outcomesandstudydesigncriteriaforinclusionandexclusionofstudies

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Table2.Characteristicsoftheincludedstudies

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Figure1.Flow-chartsummarizingliteraturesearchresults

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Figure2.Forestplotshowingthesignificantlyincreasednumberofhairspercm2comparedwithco

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Figure3.Forestplotshowingthesignificantlyincreasednumberofhairspercm2comparedwithcontrolamongrandomizedcontrolledtrialstudies

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Figure4.

Forestplotshowingthesignificantlyincreasedthicknessofhairssectionexpressedas10-4/mm2comparedwithcontrol

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Figure5.Forestplotshowingthepercentageincreaseofhairnumberafterplatelet-richplasmatreatmentcomparedwithcontr

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Figure6.Forestplotshowingthepercentageincreaseofhairthicknessafterplatelet-richplasmatreatmentcomparedwithcontrol

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Figure7.Funnelplotforbiasassessmentinhairnumberincrease

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