Hemophilia and Von Willebrand Disease: Factor VIII and Von Willebrand Factor (Academic Press) PDF
Preview Hemophilia and Von Willebrand Disease: Factor VIII and Von Willebrand Factor (Academic Press)
AcademicPressisanimprintofElsevier 125LondonWall,LondonEC2Y5AS,UnitedKingdom 525BStreet,Suite1650,SanDiego,CA92101,UnitedStates 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom ©2018ElsevierInc.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans, electronicormechanical,includingphotocopying,recording,oranyinformationstorageand retrievalsystem,withoutpermissioninwritingfromthepublisher.Detailsonhowtoseek permission,furtherinformationaboutthePublisher’spermissionspoliciesandour arrangementswithorganizationssuchastheCopyrightClearanceCenterandtheCopyright LicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions. Thisbookandtheindividualcontributionscontainedinitareprotectedundercopyright bythePublisher(otherthanasmaybenotedherein). Notices Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchand experiencebroadenourunderstanding,changesinresearchmethods,professionalpractices, ormedicaltreatmentmaybecomenecessary. Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgein evaluatingandusinganyinformation,methods,compounds,orexperimentsdescribed herein.Inusingsuchinformationormethodstheyshouldbemindfuloftheirownsafety andthesafetyofothers,includingpartiesforwhomtheyhaveaprofessionalresponsibility. Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors, assumeanyliabilityforanyinjuryand/ordamagetopersonsorpropertyasamatterof productsliability,negligenceorotherwise,orfromanyuseoroperationofany methods,products,instructions,orideascontainedinthematerialherein. LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary ISBN978-0-12-812954-8 ForinformationonallAcademicPresspublications visitourwebsiteathttps://www.elsevier.com/books-and-journals Publisher:JohnFedor AcquisitionEditor:TariK.Broderick EditorialProjectManager:TracyTufaga ProductionProjectManager:SreejithViswanathan CoverDesigner:MilesHitchen TypesetbySPiGlobal,India Acknowledgments The author thanks Anaa Zakarija, MD, for helpful discussions and contributing clinical material, and Sandy Harris, RN, for her long-term commitmenttothecareofpeoplewithbleedingdisorders.Heisgrateful to his wife, Theodora, for her critical review of the manuscript, cogent advice,and unflagging support andencouragement. xiii Author Biography DavidGreen,MD,PhD,isProfessorEmeritusinMedicine,Divisionof Hematology/Oncology, at Northwestern University Feinberg School of Medicine in Chicago, Illinois. He received his medical degree from Jefferson Medical College in Philadelphia, Pennsylvania, and Doctorate in Biochemistry from Northwestern University, Evanston, Illinois. He is a clinician-investigator and author of more than 300 published scientific articles. His most recent book, Linked by Blood: Hemophilia and AIDS, describes the AIDS epidemic in the early 1980s that ravaged the hemo- philiacommunityandledtomajorchangesinthecollectionandproces- singofbloodandbloodproducts.HeisaMasterofAmericanCollegeof Physicians andrecipient of many other awards. ix HEMOPHILIA AND VON WILLEBRAND DISEASE HEMOPHILIA AND VON WILLEBRAND DISEASE Factor VIII and Von Willebrand Factor D G AVID REEN Introduction FVIII/VWF: THE JANUS OF HEMOSTASIS FactorVIII(FVIII)andVonWillebrandFactor(VWF)areproteinsthat aredeficientordefectiveinhemophiliaA(classicalhemophilia)andVon Willebrand Disease (VWD), respectively. They have an impressive his- tory.FVIIIfirstappearedatleast430millionyearsagoandhasbeendis- covered among the coagulation proteins of all jawed vertebrates. Similarly, VWF evolved in ancestral vertebrates some 500 million years ago and has been identified in the Atlantic hagfish (slimy eel), a fish of ancientorigin.Morerecently,therearereferencestoadiseaseresembling hemophiliainthe5thcenturyTalmud,andVWDwasfirstdescribedinthe medicalliteraturein1926.Therelationship betweenFVIIIandVWF baf- fledinvestigatorsforyearsbecauseFVIIIandVWFcirculateintheblood bound together in a single complex. It was not until the early 1970s that FVIIIwasclearlydistinguishedfromVWF.Furthermore,thetwocongen- ital bleeding disorders, hemophilia and VWD, have decreased levels of FVIII, leading to the misdiagnosis of hemophilia in some patients with VWD. TheFVIII/VWFcomplexcanbesymbolicallyrepresentedbyJanus,the double-faced Roman god, who was known as the “God of Beginnings” and “Gatekeeper,” and decreed who and what might pass through his portals.Inlikefashion,VWFinitiateshemostasisbymediatingthebinding ofplateletstotheinjuredvesselwall,andFVIIIopensthedoortocoagu- lationbybindingtothetenasecomplex,anessentialstepinthrombingen- eration. Because of the intimate association of FVIII and VWF in the physiologyofhemostasis,itseemslogicaltoincludethetwoclottingpro- teinsandtheirdisordersinasinglevolume.Thisformatenablesclinicians toconsultonesourcefortheinformationtheymightneedaboutthepatho- physiology, diagnosis,and treatmentof both hemophilia and VWD. FVIIIandVWFaresynthesizedbyendothelialcellsandpackagedintoa specificcellorganelle,theWeibel-PaladeBody(WPB).Uponstimulation by agents such as desmopressin (DDAVP), the WPB releases the FVIII/ VWFcomplexintothecirculation,whichaccountsforthetherapeuticeffi- cacy of desmopressin in selected patients with hemophilia and VWD. However,thosewithseverediseaseusuallyrequireclottingfactorconcen- trates;inHemophiliaandVonWillebrandDisease,thereaderwillfindalist- ingofcommercialproductsapprovedforthetreatmentofhemophiliaand xv xvi INTRODUCTION VWD. The pharmaceutical industry is actively engaged in engineering FVIIIconcentratesthathavealongerhalf-lifeandarelessimmunogenic, because alloantibodies or inhibitors arise in up to 30% of hemophiliacs exposedtoconcentrates.Thisbookdescribescurrentconceptsofantibody formationaswellaspatientmanagementwithbypassingagentsandthe inductionofFVIIItolerance.Anewapproachisthesubcutaneousadmin- istration of drugs that enhance plasma procoagulant activity without requiringFVIII.Theseagentshavebeenshowntodecreaseannualbleed- ing rates in hemophiliacs with inhibitorsand are now in clinical trials. The text explores the genetic landscape of hemophilia and VWD and providesdetaileddescriptionsofthegenesknowntoaffectthesynthesis, release,andclearanceofFVIIIandVWF.Hundredsofmutationsinthese genes result in clinical conditions that vary greatly in their presentation and severity. Gene therapy for serious congenital disorders is rapidly becoming a reality, and hemophilia is no exception; briefly summarized arerecent data from pilotstudiesin patients with severehemophiliaA. Severalacquireddiseasesinduceahemorrhagicdiathesisbyattacking FVIII or VWF. Some of these disorders induce autoantibodies, while othersaffectthereleaseorclearanceoftheclottingfactors.Theclinicalfea- tures,laboratorydiagnosis,andtreatmentofthesedisordersaredescribed indetailinHemophiliaandVonWillebrandDisease.Ahighdegreeofclinical suspicionisrequiredtorecognizetheseconditions,butoncethediagnosis isestablished, mostcan besuccessfully treated. There is considerable evidence that excessive concentrations of FVIII and VWF fuel the formation of pathologic thrombi that obstruct normal blood flow. Increased levels of the factors are inherited in families with specific genetic polymorphisms or are acquired in patients with cancer, diabetes, hyperthyroidism, and other diseases. The book reviews epide- miologic and other evidence that high concentrations of FVIII and VWF contribute to cardiovascular disease, venous thromboembolism, and embolic phenomena in patients with atrial fibrillation. Somecommon misperceptions about hemophilia and VWD are – Affectedmembers of The Royal Familiesof Europe had classical hemophilia A – The female carriers of hemophilia rarely have bleeding problems – Peoplewith hemophiliaarespared from atherosclerosis andcoronary artery disease – FVIII alloantibodies (inhibitors) only affectindividuals with severe hemophilia – Reduced FVIII levels are restrictedto people with hemophilia A – Hemarthroses do notoccur in individuals with VWD – Desmopressinisusedinthesamedosefordiabetesinsipidusandhemophilia – ThelevelsofFVIII&VWFinpeoplewithmildhemophiliaorVWDdonot increase with aging xvii INTRODUCTION Someoftheseerroneousideasmightpotentiallyharmpatientsandare fullydiscussedandcorrectedwithinthepagesofHemophiliaandVonWill- ebrand Disease. Thescienceofhemostasisisrapidlyexpandingandbiomedicalprofes- sionalsarebeingchallengedtoremaincurrentwithvastamountsofpub- lished information. This compact book will be useful for healthcare workers, geneticists, and members of the pharmaceutical industry. It includescontemporarydataonFVIIIandVWFthatwillassistresearchers inhematology,pathology, cellbiology,and those interestedin drug dis- covery.Forclinicians,thebookdescribesthemajorfeaturesofhemophilia A and VWD, indicates the laboratory studies required for a comprehen- sivediagnosis,andincludesadifferentialdiagnosis.Itprovidesdescrip- tions of approved therapeutic concentrates, their indications, recommended doses, and potential adverse effects. Most of the chapters concludewith a list of topics for future investigation. Although the treatment of hemostatic disorders has dramatically improvedinrecentdecades,manypatientshavebeenleftbehindbecause ofthehighcostsofproductsandservices.ThegoalsofPartnersforBetter Care are transparent and comprehensive healthcare, fair and equitable access to medicines, assuring patients’ rights to dignified and culturally competentcare,andstableandreasonablecosts(HFADatelineFederation, Spring2016,p.21).TheirPatientCharterstatesthatpatientsshouldhave an active and formal voice in payment and delivery system reform; rea- sonableandtimelyaccesstoproviderswithintheirnetwork;information aboutcoveredservices,providers,formularies,andout-of-pocketcostsof insurance plans; access to medications, services, devices and other care without discriminationcreated by unreasonable tiering orexcessivecost sharing; not subject to cumbersome preauthorization and renewal pro- cessesthatrestrictaccesstocareandtherapies;andtimelyaccesstoarapid and fair appeals process. Assisting patients in achieving these goals is a shared responsibility of allhealthcare providers. Itisthehopeoftheauthorthatthisbookwillmakeapositivecontribu- tion to the knowledge of everyone involved in the care of people with bleedingdisorders,andwillresultinanimprovedqualityoflifeandbet- terclinical outcome for our patients. Preface My first encounter with factor VIII occurred during my medical resi- dencyintheearly1960s.Traineesweregiventheopportunitytoperform laboratory research, and I elected to work under a famed hematologist, Leandro M. Tocantins (1901–63) [1]. Doctor Tocantins was interested in the role of platelets and clotting factors in blood coagulation. During thecourseofhiswork,heobservedthattheclottingtimeofbloodcontain- ing the anticoagulant, sodium citrate, became shorter with storage. He suggestedthat Iinvestigate this phenomenon. Duringthecourseofthiswork,Iconsideredthepossibilitythatactiva- tion of factor VIII (FVIII) might be responsible for the shortening of the clotting times. FVIII, a protein required for normal blood coagulation, is decreased or absent in people with classical hemophilia. A method for measuring FVIII had been developed by Biggs and Douglas in 1953 [2], but was technically very demanding, available in very few laboratories, andwasbeyondmycapabilitiesatthetime.Fortunately,tworesearchers in Doctor Tocantins’ laboratory, Ruth Holburn and Margaret DeSipin, were very experienced in conducting clotting studies, and performed the FVIII measurements for me. Although the results of these assays did not enlighten my studies, I became intrigued by FVIII and resolved to learn more about this clottingprotein. Duringthecourseofmyclinicaltrainingandinthedecadessince,my interestinFVIIIhasonlygrownmoreintense.Notonlyisthefactorabso- lutelyessentialfortheclottingofbloodofnearlyallvertebratespecies,but itisalsointricatelyrelatedtotheVon WillebrandFactor (VWF), another essential hemostatic protein. In recent years, the relationship between these two factors has finally been clarified, and the treatment of hemo- philiaandVonWillebrandDiseasegreatlyimproved.Ibelievethatabook devoted to these two proteins and their disorders islong overdue. DavidGreen Feinberg School of Medicine of Northwestern University, Chicago, IL, United States References [1] DameshekW.LeandroMTocantins,M.D.Blood1963;22:360–1. [2] BiggsR,DouglasAS.Thethromboplastingenerationtest.JClinPathol1953;6:23–9. xi
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