Ma Cover.indd 1 9/7/2012 8:40:44 PM 9780470659762

ContributorsAnas Alrwas, MDAlice D. Ma, MDResident, Internal MedicineUniversity of Texas Health Science Centerat HoustonHouston, TX, USAAssociate Professor of MedicineDivision of Hematology/OncologyUniversity of North Carolina Schoolof MedicineChapel Hill, NC, USATyler Buckner, MDHematology FellowPediatric Hematology/OncologyAdult HematologyUniversity of North Carolina Schoolof MedicineChapel Hill, NC, USAMarshall Mazepa, MDBenjamin Carcamo, MDTrinh T. Nguyen, DOClinical Assistant ProfessorPediatric Hematology OncologyProvidence Memorial HospitalTexas Tech University, School of MedicineEl Paso, TX, USAAssistant Professor of PediatricsDivision of HematologyUniversity of Texas Health Science Centerat HoustonGulf States Hemophilia and ThrombophiliaCenterHouston, TX, USAMiguel A. Escobar, MDAssociate Professor of Medicine and PediatricsDivision of HematologyUniversity of Texas Health Science Centerat HoustonDirector, Gulf States Hemophilia andThrombophilia CenterHouston, TX, USAMatthew Foster, MDAssistant Professor of MedicineDivision of Hematology/OncologyUniversity of North Carolina Schoolof MedicineChapel Hill, NC, USARaj Sundar Kasthuri, MDAssistant Professor of MedicineDivision of Hematology/OncologyUniversity of North Carolina Schoolof MedicineChapel Hill, NC, USASenior FellowDivision of Hematology/OncologyUniversity of North Carolina Schoolof MedicineChapel Hill, NC, USANidra Rodriguez, MDAssistant Professor of PediatricsDivision of HematologyThe University of Texas Health Science Centerat HoustonMD Anderson Cancer CenterGulf States Hemophilia & Thrombophilia CenterHouston, TX, USAE. Carlos Rodriguez-Merchan,MD, PhDConsultant Orthopaedic Surgeon and AssociateProfessor of OrthopaedicsLa Paz University HospitalUniversidad AutonomaMadrid, SpainJenny M. Splawn, PharmDProvidence Memorial HospitalEl Paso, TX, USAKristy Lee, MS, CGCTzu-Fei Wang, MDClinical Assistant ProfessorDepartment of GeneticsUniversity of North Carolina School of MedicineChapel Hill, NC, USAFellowDivisions of Hematology and OncologyWashington University School of MedicineSaint Louis, MO, USAxiflast.indd xi8/14/2012 3:34:22 PM

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ForewordI am delighted to respond to the invitation to provide a brief introductionto the second edition of Hemophilia and Hemostasis: A Case-Based Approachto Management. The popularity of this text stems from its unique case-basedapproach. Drs Roberts, Ma, and Escobar are renowned and frequentlyconsulted experts in the management of patients with bleeding disorders.Although the hemophilias and other inherited bleeding disorders havebeen the focus of a comparatively large body of literature, there areremarkably few randomized-controlled clinical trials on which to base firmevidence-based recommendations. This fact was most recently broughthome to me as a member of the team charged with revising the WorldFederation of Hemophilia’s Treatment Guidelines; our goal was to provideappropriately graded recommendations of the literature and generallyaccepted practices for the practicing clinician. Unfortunately, the paucity ofhigh-quality level 1 evidence does not obviate the need to make clinicaldecisions on a daily basis when caring for patients with bleeding disorders.The authors address these management dilemmas in a comprehensiveseries of “mini-chapters” that provide an easy reference format for thereader. In this day and age of electronic fingertip access to state-of-the-artreviews on PubMed, it is sometimes said that textbooks are obsolete beforethey are even published. While there may be some truth to this viewpointin the case of standard texts, no amount of electronic searching can providethe ready access to the august consensus opinions of these seasonedexperts, who have “been down that same road” before. As such, this bookis a must for every hematologist or nurse who is charged with taking careof patients with bleeding disorders.Nigel S. Key MB ChB FRCPHarold R. Roberts Distinguished Professor of Medicineand Pathology and Laboratory MedicineChief, Section of HematologyDirector, UNC Hemophilia and Thrombosis CenterChapel Hill, NCxiiiflast.indd xiii8/14/2012 3:34:22 PM

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PART IHemophilia Aand Hemophilia BPartTitle-I.indd 18/14/2012 3:43:27 PM

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SECTION IGeneral OverviewSections1.indd 38/14/2012 3:52:30 PM

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INTR ODU C TIO N 1The Hemophilic Ankle:An UpdateE. Carlos Rodriguez-MerchanLa Paz University Hospital and Universidad Autonoma, Madrid, SpainQWhat is the latest information regarding the treatment of hemophilic arthropathy inthe ankle?It is well known that the ankles in hemophilic patients tend to bleed,beginning at an early age of 2–5 years. The synovium is only able to reabsorb a small amount of intra-articular blood; if the amount of blood isexcessive, the synovium will hypertrophy as a compensating mechanism,so that eventually the affected joint will show an increase in size of thesynovium, leading to hypertrophic chronic hemophilic synovitis. Thehypertrophic synovium is very richly vascularized, so that small injurieswill easily make the joint rebleed. The final result will be the vicious cycleof hemarthrosis–synovitis–hemarthrosis, which eventually will result inhemophilic arthropathy (Figure I1.1).Pathogenesis of synovitis and cartilage damagein hemophilia: experimental studiesHooiveld et al. (2004) investigated the effect of a limited number of jointbleedings, combined with loading of the affected joint, in the developmentof progressive degenerative joint damage. They concluded that experimental joint bleedings, when combined with loading (weight-bearing) ofthe involved joint, result in features of progressive degenerative jointdamage, whereas similar joint hemorrhages without joint loading do not.The authors suggest that this might reflect a possible mechanism of jointdamage in hemophilia. In two other papers (Hakobyan et al. 2004;Hemophilia and Hemostasis: A Case-Based Approach to Management, Second Edition.Edited by Alice D. Ma, Harold R. Roberts, Miguel A. Escobar. 2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd.5Introduction 1.indd 58/14/2012 3:37:36 PM

6   The hemophilic ankle: an updateFigure I1.1 Severe hemophilicarthropathy of the ankle in an adulthemophilia patient.Valentino et al. 2004), hemophilic arthropathy was studied in animalmodels. Despite these interesting papers, the pathogenesis of hemophilicarthropathy remains poorly understood.The best way to protect against hemophilic arthropathy (cartilagedamage) is primary prophylaxis beginning at a very early age. Starting prophylaxis gradually with once-weekly injections has the presumed advantageof avoiding the use of a central venous access device, such as a PortaCath,which is otherwise often necessary for frequent injections in very youngboys. The decision to institute early full prophylaxis by means of a port hasto be balanced against the child’s bleeding tendency, the family’s socialsituation, and the experience of the specific hemophilia center. The reportedcomplication rates for infection and thrombosis have varied considerablyfrom center to center. Risk of infection can be reduced by repeated education of patients and staff, effective surveillance routines and limitations onthe number of individuals allowed to use the device. In discussing optionsfor early therapy, the risks and benefits should be thoroughly discussedwith the parents. For children with inhibitors needing daily infusions forimmune tolerance induction, a central venous line is often unavoidableand is associated with an increased incidence of infections.From a practical point of view, radiosynovectomy, together with primary prophylaxis to avoid joint bleeding, can help to halt hemophilicsynovitis. Ideally, however, radiosynovectomy should be performed beforethe articular cartilage has eroded. Radiosynovectomy is a relatively simple, virtually painless, and inexpensive treatment for chronic hemophilic

The hemophilic ankle: an update   7Figure I1.2 Radiosynovectomy of theankle with 186 rhenium.synovitis, even in patients with inhibitors, and is the best choice forpatients with persistent synovitis.RadiosynovectomyRadiosynovectomy is the intra-articular injection of a radioactive materialto diminish the degree of synovial hypertrophy and to decrease the numberand frequency of hemarthroses (Figure I1.2). Radioactive substances havebeen used for the treatment of chronic hemophilic synovitis for manyyears. Radiation causes fibrosis within the subsynovial connective tissue ofthe joint capsule and synovium. It also affects the complex vascular system,in that some vessels become obstructed; however, articular cartilage is notaffected by radiation.The indication for radiosynovectomy is chronic hemophilic synovitiscausing recurrent hemarthroses, unresponsive to treatment. There arethree basic types of synovectomies: chemical synovectomy, radiosynovectomy, and arthroscopic synovectomy. On average, the efficacy of theprocedure ranges from 76 to 80%, and can be performed at any age. Theprocedure slows the cartilaginous damage which intra-articular bloodtends to produce in the long term.Radiosynovectomy (Yttrium-90, Phosphorus-32, and Rhenium-186)can be repeated up to three times at 6-month intervals. Chemicalsynovectomy can be repeated weekly up to 10–15 times if rifampicin isused. After 35 years of using radiosynovectomy world wide, no damage hasbeen reported in relation to the radioactive materials. Radio synovectomyis currently the preferred procedure when radioactive materials areavailable; however, rifampicin is an effective alternative method if

8The hemophilic ankle: an updateradioactive materials are not available. Several joints can be injected in asingle session, but it is best to limit injections to two joints at the same time.There are two interesting papers that focus on the treatment of chronichemophilic synovitis. Corrigan et al. (2003) have used oral D-penicillaminefor the treatment of 16 patients. The drug was given as a single dose in themorning before breakfast. The dose was 5–10 mg/kg bodyweight, not toexceed 10 mg/kg in children, or 750 mg/day in adults. The duration oftreatment was 2 months to 1 year (median 3 months). Ten patients had anunequivocal response, 3 had a reduction in palpable synovium and 3 hadno response. Minor reversible drug side effects occurred in 2 patients(proteinuria in one and a rash in the other).Radossi et al. (2003) have used intra-articular injections of rifamycin.Among a large cohort of nearly 500 patients, they treated 28 patients during a 2-year period. The patients followed an on-demand replacementtherapy program and developed single or multiple joint chronic synovitis.The indications for chemical synovectomy were symptoms of chronicsynovitis referred by patients reported in a questionnaire. In Radossi’sseries there were 5 patients with inhibitors to factor VIII. Their average agewas 34 years. Rifamycin (250 mg) was diluted in 10 mL of saline solutionand 1–5 mL was then injected into the joint. The follow-up ranged from 6to 24 months. Thirty-five joints were treated with 169 infiltrations in total.Rifamycin was injected once a week for 5 weeks, i.e. the patient had tocome to hospital at weekly intervals. Twenty-four procedures were considered effective in 19 patients according to the evaluation scale, while 6treatments were considered fair to poor. Five patients (six joints) with antifactor VIII inhibitors were treated. In four joints the results were good,while in the two remaining joints the results were poor.There are two main limitations for the use of antibiotics in synovectomy: the procedure is painful, and it should be repeated weekly for manyweeks to be effective. In fact, Radossi’s schedule included injection of rifamycin into the joints once a week for 5 weeks (Radossi et al. 2003).However, they make no mention of the pain associated with the injections.They also state that rifamycin may be indicated when radiosynovectomy isnot available, contraindicated for medical reasons, or not accepted bypatients. To the best of my knowledge I do not know of any medical contraindications to radiosynovectomy, or why patients should reject such anefficient and safe procedure. The Italian authors state that, to date, theycannot say if their program is able to delay long-term functional impairment because of the lack of a longer follow-up. However, according to theirpreliminary experience, they consider that rifamycin synovectomy appearsto be effective in reducing joint pain and in improving the range of motion.The study of Corrigan et al. (2003), which used D-penicillamine, hastwo main limitations: the small number of patients and the lack of use ofIntroduction 1.indd 88/14/2012 3:37:36 PM

CASE STUDY 10: Mild Hemophilia and Intraocular Injections 57 . Alice D. Ma . CASE STUDY 11: Endoscopy/Colonoscopy and Hemophilia 59 . Alice D. Ma . CASE STUDY 12: Dialysis and Hemophilia 61 . Alice D. Ma . CASE STUDY 13: Circumcision 65 . Nidra Rodriguez . CASE STUDY 14: Pharmacokinetic Studies for Surgery 67 . Miguel A. Escobar . CASE STUDY 15: