Hemosta(cOp(onsforHeavyMenstrualBleeding

Vision:Allwomenandgirlswithblooddisordersarecorrectlydiagnosedandoptimallytreatedandmanagedateverylifestage

Peter A. Kouides M.D. Medical and Research Director, Mary M. Gooley Hemophilia Center

Clinical Professor of Medicine, University of Rochester School of Medicine

Attending Hematologist, Rochester General Hospital

OBJECTIVES• Reviewthehemostasisofmenstura1on

•  Iden1fytherapeu1ctargets

• Therapue1cop1onsforheavymensesingeneral

• Therapeu1cop1onsforinheritedbleedingdisorders

• Focusontherapeu1csinvonWillebranddisease

2

Overview of Hemostasis

Reminder…we do not bleed in a vacuum…

Endothelium

SubendothelialCollagen

VonWillebrandFactor

GPIIb/IIIa

Fibrinogen

SubendothelialCollagen

VonWillebrandFactor

Endothelium

IntrinsicPathway

ExtrinsicPathway

Thrombin

SubendothelialCollagen

VonWillebrandFactor

Endothelium

Plasmin

ExcessiveFibrinolysisAKAHeavyMenses

Hemostasis in menstrua7on

•  vWFmediatedplateletaggrega(on

•  Fibrinforma(on•  Vasoconstric(on•  Tissueregenera(on

•  PGinducedplateletinhibi(on

•  Fibrinolysis•  Vasodilata(on

Endothelial cells

Collagen Subendothelium

platelets platelets

platelets

Platelet adhesion Platelet aggregation

GP 1b

GP

11b/

111a

Increasedmenstrualbloodflow>80cc=

MENORRHAGIA(HMB)

INDUCTION: COMPENSATION:INADEQUATE and/or OVER-

PossibleHemosta1cDefectsinMenorrhagia(HMB)

VWF

FIBRIN CLOT FORMATION FACILITATED BY PLATELET AGGREGATION via VWF

endothelial cells VWF FIBRIN STRANDS

Where/why a 22 y/o may present with heavy menses (HMB)

Decreased platelet

number and/or function

Decreased or dysfunctional von Willebrand factor

1.Decreased fibrin generation from the initiation of tissue factor that combines with VIIa→activates X →Xa activates prothrombin → thrombin then generates fibrin clot through cleavage of fibrinogen 2. Decreased fibrin propogation via FXI, FIX and FVIII 3. Decreased fibrin cross-linking d/t FXIII deficiency

Increased plasmin generation due to decreased anti-plasmin

or PAI

In ED with heavy period & blood blisters

in mouth

Dx- ITP

Heavy menses past 2 periods with severe cramps on Motrin 800 qid

Dx- Drug-induced platelet dysfunction

HMB since menarche and freq. epistaxis & bruising; mother same sx

Dx - Inherited Platelet Function Disorder (e.g., dense granule deficiency)

HMB since menarche, epistaxis and easy bruising;

mother same sx

Dx - Von Willebrands,

Type 1

HMB since menarche, history of bleeding at time of umbilical cord separation, easy bruising and epistaxis, history of knee hemearthroses when she fell off skateboard age 11 , mother asymptomatic

Dx - Severe FVII deficiency or could also be any severe rare bleeding disorder like Fibrinogen (FI) deficiency or Prothrombin (FII) deficiency or Factor V deficiency or Factor VII deficiency or FVIII or FIX carrier who is lyonized or Factor XI deficiency or FXIII deficiency

HMB since menarche with easy brusing; mother asymptomatic Dx- Inherited anti-plasmin or

plasminogen activator inhibitor HMB progressively worse past 4-6 cycles, no epistaxis or easy

bruising or family history

Dx - idiopathic HMB- in up to

50% of cases of HMB!

Best Therapy for Heavy Menstrual Bleeding?

Heavy Menstrual Bleeding as a Disorder of Increased fibrinolysis

•  Reportsofincreasedsystemicandlocalizedintrauterinefibrinolysisinheavymenstrualbleedingandinpostpartumhemorrhage

•  Catheterizedsamplesofincreasedfibrinoly1cac1vityinHMBpa1entscomparedtocontrols

WinklerUH.AnnNYAcadSci1992;667:289-90EdlundM,BlombackM,HeL..BloodCoagulFibrinolysis2003;14:593-8

•  12studiesinvolving690women-•  thereduc1oninMBLrangedfrom34%to56%inthosetreatedwith>3mgtranexamicacidfor5days

•  Superiorreduc1oninMBLoverthreecyclescomparedtomefanamicacid(54%versus10%,p<0.001)

• Overall,TAsignificantlyreducesMBLinwomenwithHMB.However,itdoesnotreducethedura1onofmensesorregulatethecycle

BitzerJ,etal.ObstetGynecolSurv.2015;70(2):115–30.MaXesonKA,etal.ObstetGynecol.2013;121(3):632–43.

Tranexamic Acid in HMB: Systema7c Review

ANewandImprovedTranexamicAcid?Lysteda–briefhistory

• Unique formulation that provides a higher per-tablet dose and increases drug absorption

• Designed to maintain efficacy of immediate release TA while minimizing gastrointestinal adverse effects

•  Xanodyne Pharmaceuticals program (2003)

•  FDA approval in November, 2009

FDA Licensure Trial for Lysteda

Lukes, et al. Obstet Gynecol. 2010; 116:865-75

Reduction of MBL*

TA (n=115) 69.6 mL (40.4%)

Placebo (n=67) 12.6 mL (8.2%) *(statistically significant difference, P<.001)

1.3 g tid dosing superior to 650 mg tid dosing

Freeman,etal.AmJObstetGynecol.2011;205:319.e1-7

Risk Profile of Lysteda •  Nosta1s1callysignificantadverseeventscomparedtoplacebo

•  Nothrombo1cevents

•  Thrombosishasnotbeenobservedinmenorwomenreceivingtranexamicacidfor-

•  bleeding2°tocardiacororalsurgery,acuteupperGIbleeding,oroculartrauma

•  Useoftranexamicacidnotassociatedwithanincreasedriskorincidenceofthromboemboliceventscomparedwiththebackgroundrateofthrombo1ceventsinwomenofchildbearingage

Lukes, et al. Obstet Gynecol. 2010; 116:865-75

Outstanding Issues With Lysteda •  Concurrentestrogen-containingcontracep1on

•  Adolescents-aslicensurestudyexcludedage<18yearsage• However,apharmacokine1cstudyin20adolescentfemalesaged12-16yearsofage,nodoseadjustmentwasneeded

•  Recentpilotstudy(n=17)showedoralTAappearedasefficaciousasOCinthemanagementofadolescentHMBbyreducingMBLandimprovingqualityoflife

SrivathsVL,etal.JPediatrAdolescGynecol.2015;28:254e257

Hemosta7c Therapy Beyond Tranexamic Acid DDAVP induces Endothelial cell (EC) via cAMP mediated Weibel- Palade Body secretion increasing membrane- bound and circulating VWF as well as FVIII

DDAVP also induces platelet release and membrane presentation of P-selectin which Mediates platelet rolling on ECs under high shear conditions through PSGL-1/P-selectin Interaction

DDAVP increases EC adhesiveness for platelets and platelet adhesion to collagen probably via VWF P.J.SvenssonBloodReviews28(2014)95–102

DDAVP(1-deamino8-D-arginevasopressin)bindsprimarilytoan1diure1ctype2vasopressinreceptorscomparedtotype1receptors,soreducingundesirablevasoac1vesideeffectsandprolongsitshalf-lifewhencomparedtona1vevasopressin

Physiology of Vasopressin Exploited by DDAVP

Background, DDAVP responsiveness in VWD

•  Type1-UsuallyifFVIII,VWFRCo>10%willhave2-6foldresponsewithimprovedplateletfunc1onbut-

• Whenbaselinelevels10-20%bewareofType1Cwithitsini1alexcellentresponsealbeitshort-lived

•  Type2A-Variable

•  Type2B-UsuallycontraindicatedCastamanG,etal.Blood.2008;111(7):3531–9.

DownsideofINDDAVPforVWD-relatedHMB:•  Quarterofpa1entsexperiencemoderatetoseveresideeffects-

•  Headache•  Flushing•  Nausea/Vomi1ng•  Fa1gue• Weightgain•  Leastcommonbutmostsevere-Hyponatremia>seizure

DunnA,etal.Haemophilia.2000;6:11-14.

CDC Female Data Collec7on pilot study (n=319): Treatments used for menorrhagia in Inherited Bleeding Disorders

Byams V, et al. Haemophilia. 2011; 17 (Suppl. 1): 6–13

Treatment

Oralcontracep(ve 55%

DDAVP 34%

An(-fibrinoly(cs 24%

Bloodorplasmaproducts 7%

Clo_ngfactorproducts 6%

Endometrialabla(on 4%

MIRENA 3%

Uterinearteryemboliza(on 2%

Platelettransfusion 1%

Bleeding Disorder Related Menorrhagia (HMB) Management: TA (Europe, Canada) or DDAVP (U.S.)

Desmopressin(DDAVP)•  Posi1vecaseseriesexperiencebasedonsubjec1veassessment:Ø 80-90%goodtoexcellent

•  Morerecentdata:ControlledstudiesusingPBACorspectrophotometry:Ø RoyalFreeLondon:

•  IntranasalDDAVPwasnotbenerthanplacebo

Ø KarolinskaSweden:•  IntranasalDDAVPincombina1onwithTAmosteffec1ve

Tranexamicacid(TA)•  Innon-VWDmenorrhagia-randomizedstudyØ 54%reduc1oninMBLwithTAalone

•  InVWDmenorrhagiaØ Smallstudies,

Ø Mohri:3g/dosein3pa1ents•  Ong,etal:4g/d(1dose)in4pa1ents

•  Onundarson:4g/d(1dose)in1pa1ent

•  RoyalFreeLondon:15/37(40%)withPBAC<100

KadirR,etal.Haemophilia.2002;8:787-793;EdlundM,etal.BloodCoagFibrinolysis.2002;13:225-231.

MohriH.Thromb&hrombolysis.2002;14:255-257;OngYL,etal.Haemophilia.1998;4:63-65;OnundarsonPT.Haemophilia.1999;5:76.

BonnarJ,SheppardBL.BMJ.1996;313:579-582; RodegherioF,etal.T&H1996;76:692-696;LeissingerC,etal.Haemophilia.2001;7:258-266;

Χεντερ φορ Δισεασε Χοντρολ - �ΥΣΑ Ωοµεν Ωιτη Βλεεδινγ Δισορδερ Μαναγεµεντ Στυδψ

0

10

20

30

40

50

60

70

80

90

No.

of S

ubje

cts

100-199

200-299

300-399

400-499

500-599

600-699

700-799

800-899

900-999

>1000

PBAC

Offered oral contraceptives, but can refuse for any reason and

stay in study

Women with menorrhagia (HMB)

Diagnostic workup

Randomized arm of: tranexamic acid versus intranasal DDAVP

STUDY OUTCOMES Quality of life

Menstrual flow

Coagulation parameters

Kouides, et al. British J Haem.

2009; 145 (2):212-220

PLOT OF MEAN PBAC OVER TIME BY SEQUENCE OF TREATMENT

100

120

140

160

180

200

220

240

260

280

300

0 1 2 3 4

PERIOD

MEA

N P

BA

C

STTS

IN-DDAVPx2cyclesthenTAx2cycle

TAx2cyclesthenIN-DDAVPx2cycles

Kouides, et al. British J Haem. 2009; 145(2):212-220

0

50

100

150

200

250

300

TA 1st DDAVP 2nd DDAVP 1st TA 2nd

PBAC Pre-tx

PBAC Post

The Center for Disease Control Women With Bleeding Disorder Management Study:

Reduction in PBAC - TA vs. DDAVP

PBA

C

Kouides, et al. British J Haem. 2009; 145 (2):212-220

The Center for Disease Control Women With Bleeding Disorder Management Study:

Improvement in QOL - TA vs. DDAVP

0

2

4

6

8

IN-DDAVP first TA first

Unhealthy days baseline

Unhealthy days after rx

n  The number of unhealthy days by SF-36 QOL instrument:

Kouides, et al. British J Haem. 2009; 145 (2):212-220

The Center for Disease Control Women With Bleeding Disorder Management Study:

Improvement in QOL - TA vs. DDAVP, II

Kouides, et al. British J Haem. 2009; 145 (2):212-220

•  TheCenterforEpidemiologicStudiesDepressionScale(CES-D)Ø summaryscoredecreasedfrombaseline,indica1ngfewerdepressivesymptomsinbotharms

• Rutamenorrhagiaques1onnaire-Ø ChangeinmeanscorefrombaselinetoaoerIN-DDAVP,pvalue=0.008

Ø ChangeinmeanscorefrombaselinetoaoerTA,pvalue=0.003

For DDAVP Failures?

•  CombinedtherapywithTA-

EdlundM,etal.BloodCoagulabonandFibrinolysis.2002;13:225-231

VWF concentrates in DDAVP and/or TA refractory cases in VWD-related HMB

VWFformenorrhagia(HMB):Asurveyandliteraturereview•  83surveysdistributedtohemophiliatreatmentcenterMDs

§  20(24.1%)providedsufficientdataforanalysis

•  Of1321womenwithVWDseenduring2011–2014,816(61.8%)hadmenorrhagia(HMB)

•  Combinedoralcontracep1ves,TAanddesmopressinwerethemostcommonfirst-linetherapies

•  VWFreplacementwasathird-linetherapyreportedin13women(1.6%)

•  Togetherwithdatafrom88womenfrom6publishedstudies,VWFreplacementtherapysafelyreducedmenorrhagiain101womenatadoseof33–100IU/kgondays1–6ofmenstrualcycle

Ragni,etal.Haemophilia.2016;22(3):397-402.

FDA Approved VWF products

SingalMandKouidesP:DrugsofToday.2016;52(12):653-666

Plasma-derivedVWFcontainingFVIIIconcentrates

Recombinant

Thankyou!

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