Management of Hemophilia under Limited Resources Ampaiwan Chuansumrit, M.D. ISTH Advanced Training Course International Hemophilia Training Center-Bangkok Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Disclosures for In compliance with COI policy, ISTH requires the following disclosures to the session audience: Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare Novo Nordisk, Shire, Roche Novo Nordisk, Shire, Roche Novo Nordisk, Shire, Roche Presentation includes discussion of the following off-label use of a drug or medical device: <N/A>
Integration of Hemophilia into the Existing Infrastructure University hospital Regional hospital Provincial hospital District hospital Health station Super specialized care Complicated cases 3 o medical care 3 o hemophilia care 2 o medical care 2 o hemophilia care 1 o medical care 1 o hemophilia care 1 o health care home care treatment
Replacement Therapy for Thai Hemophilia Western Countries Thailand Whole blood 1930 1939-1964 Plasma 1943-1965 1964-1978 Cryoprecipitate & FFP 1965-1970 1965 Intermediate purity factor concentrate 1970-1980 Virus inactivated high purity factor concentrate 1990 1996 First generation recombinant factor concentrate 1990 2003 Second to third generation recombinant factor concentrate 2000 + 2003 +
Laboratory Diagnosis of Hemophilia A & B Prolonged APTT Low level of FVIII:C or FIX:C Bedside diagnostic kit - First version published in Haemophilia 2009;15:361-364. WB WB +FVIII WB +FIX - Second version published in Haemophilia 2013;19:e48-e49.
Important Issues Provide knowledge to patients and parents Effective bleeding prevention through daily life-style should be emphasized
First Aid Management for Bleeding Episode R = Rest I = Ice C = Compression E = Elevation
Healthy Diet Healthy diet is important, not to gain too much weight that will burden the joint function and create difficulty in venipuncture
Hereditary Bleeding Disorder ว1 2373 on 3 Jan 2007
Replacement Therapy Heat-Treated Lyophilized Cryoppt
Replacement Therapy Episodic bleeding treated in the hospital Early bleeding treated at home, nearby health stations or hospitals Prophylactic treatment
Treatment Guideline Type of bleeding Initial Level of factor (%) Maintenance 1. Bleeding at muscle, suture wound, dental procedure* 20-30 2. Deep hematoma, hemarthrosis, large wound 40-60 20-30 (3-7 days) 3. Bleeding in vital organs, CNS, GI, ileopsoas muscle, and general surgery e.g. appendectomy 80-100 40-50 (1 week) 4. Major surgery of musculoskeletal, brain surgery 80-100 40-50 (1-3 weeks) *In case of using fibrin splint, replacement therapy may not be needed
Continuous Infusion Chuansumrit A, et al. Thai J Hematol Transf Med 1998;8:25-31.
Dental Splint
Fibrinogen + Thrombin Fibrin Glue - to treat superficial wound - to prevent bleeding in - dental extraction, surgery
Replacement Therapy Episodic bleeding treated in the hospital Early bleeding treated at home, nearby health stations or hospitals Prophylactic treatment
Early Treatment At the first sign of tingling sensation associated with early bleeding into muscles or joints Immediate after trauma When treatment is given early, less blood product was used and less further bleeding occurs compared to delayed treatment
Process Mapping of Treating Early Bleeding Intervention Morbidity Suffering from pain Transfusiontransmitted diseases IPD 10-24 h before receiving blood components Significant bleeding Transport to hospital ER / OPD Receiving blood component: cryoppt, FFP 3-7d 3-12 h 1-3 h 6-12 h Register at Hemophilia Comprehensive Care Center Early bleeding episode Infusing factor concentrate at home/nearby hospital 15-60 min Hospitalized 3-7 d - Absence from work &school - Direct cost: IPD - Indirect cost
Case Study from Ramathibodi Hospital Parents provide proper care to prevent bleeding episodes Provide early bleeding treatment at home, nearby health stations or hospitals 1-10 years 250 units every 7 days 11-15 years 500 units every 10 days 16-20 years 500 units every 15 days Hospitalization 1-15 years 3 hospitalizations per year 16-20 years 2 hospitalizations per year
Patients and Parents Exercise to have prominent vein Select the venipuncture site and remove the needle while hospitalized Practice venipuncture on a model and real vein
Exercise to Have Prominent Vein
Simple Tool for Practicing Venipuncture
Practice Venipuncture in the Hospital
Benefit of Early Treatment among Thai Hemophilia First decade 1971-1980 Second decade 1981-1990 Third decade 1991-2000 Number of patients 47 58 59 Number of patients receiving home treatment Number of patients with unaided proper walking 15 (31.9%) 30 (51.7%) 40 (67.8%) 27 (62.8%) 43 (75.4%) 49 (84.5%) Proportion of deaths 14 (29.8%) 8 (13.8%) 3 (5.1%) Chuansumrit A, et al. Haemophilia 2004;10:542-9.
Nationwide Coverage of Hemophilia Starting 2009 Set up a hemophilia / hematology clinic A limited budget to purchase factor concentrate for treating early bleeding episode A limited budget to treat life-threatening bleeding episodes or emergency surgery Patient has to conduct self-care to avoid bleeding
Dose of Factor VIII / Factor IX Children less than 10 years of age received 250 units of factor VIII concentrate weekly Age 1 yr, BW 10 kg, 25 units/kg Age 3 yr, BW 14 kg, 18 units/kg Age 5 yr, BW 18 kg, 14 units/kg Age 7 yr, BW 22 kg, 11 units/kg Age 9 yr, BW 26 kg, 10 units/kg
Nationwide Coverage of Hemophilia Starting 2009 49 hospitals participate to the registration with a total of 1,519 patients Empty bottle of factor concentrate Provided factor concentrate
24-Hour Hotline Consultation 089-4413100 International Hemophilia Training Center-Bangkok
Hemophilia Day Started April, 1995
Short Course Training for Medical Personnel 12-13 Nov, 2009 Chiang Rai Regional Hospital 28-29 Jul, 2006 Chiang Mai University Hospital 26-27 Apr, 2007 Khon Kaen University Hospital 25-26 Aug, 2011 Sawanpracharak Regional Hospital 24-25 Nov, 2011 Sappasitprasong Regional Hospital 17-18 Jan, 2008 Ratchaburi Regional Hospital 25-26 Feb, 2010 - Saraburi Regional Hospital - Thammasat University Hospital - Srinakarinviroj University Hospital 22-23 May, 2008 Nakhon Si Thammarat Regional Hospital
Comparison between Before and After Receiving Factor Concentrate for Treating Early Bleeding Before After Total episodes of hospitalization 681 445* Episodes of hospitalization/case 2.7 + 3.1 1.8* +2.4 Total days of hospitalization 3,230 1,724* Days of hospitalization/case 12.8 + 14.3 6.8* + 10.7 Days of hospitalization/bleed 4.7 3.9* *P < 0.001 Sooksriwong C, et al. Haemophilia 2012;18:e347-e363.
Comparison between Two Policies Severity Policy Life time cost of QALY Cost per ICER treatment (THB) QALY Mild No home base care 4,998,017 23.29 214,595 Home base care 5,225,394 26.11 200,103 80,542 Moderate No home base care 13,659,490 16.47 829,504 Home base care 11,198,618 22.44 499,157 Cost saving Severe No home base care 25,908,099 12.21 2,122,085 Home base care 20,189,367 20.61 979,557 Cost saving Pattanaprateep O, et al. VIHRI 2014;3C:37-38.
Replacement Therapy Episodic bleeding treated in the hospital Early bleeding treated at home, nearby health stations or hospitals Prophylactic treatment - single dose prophylaxis - secondary prophylaxis for 1-3 months - long term prophylaxis
Prophylactic Treatment Standard dose of prophylaxis 25-40 units/kg three times per week for hemophilia A and twice a week for hemophilia B Escalated regimen of 50 units/kg once a week, 30 units/kg twice a week and 25 units/kg three times per week Low dose prophylaxis of 8-10 units/kg twice weekly* or daily 5 units/kg *Chuansumrit A, et al. Southeast Asian J Trop Med Public Health 1995;26(2):243-246.
Adult Hemophilia with Morbidity Chronic synovitis induces frequent bleeding and pain Deformity of the musculoskeletal requiring corrective orthopedic surgeries and rehabilitation - Large amount of virus-inactivated factor concentrate - Prosthesis: hip, knee - 3-6 month prophylaxis for preserving the replaced joint and act as low dose immune tolerance
Teaching Material for Genetic Counseling
Carrier Detection & Prenatal Diagnosis 1988 Carrier detection by assaying FVIII:C, FIX:C, VWF:Ag 1991 Addition of DNA analysis 1994 Prenatal diagnosis for females at risk of having a hemophiliac son with severe and moderate degrees - Chorionic villus sampling for 11-14 weeks of gestation - Amniocentesis for 16-20 weeks of gestation - Cordocentesis for 20-24 weeks of gestation Chuansumrit A, et al. Haemophilia 2016;880-5.
Hemophilia with Inhibitor The most problematic complication Difficulty in effective bleeding control Higher treatment costs Increased morbidity and mortality Prevalence of factor VIII inhibitor 25-30% of patients with severe hemophilia A Prevalence of factor IX inhibitor 2-3% of patients with hemophilia B
Bonn Protocol of ITI Factor VIII concentrate 100 u/kg bid FEIBA 40-60 u/kg bid when inhibitor <1 BU Factor VIII concentrate 150 u/kg bid Brackmann HH, et al. Vox Sang 1996;70(Suppl):30-5.
Important Predictors of Successful ITI Low pre ITI inhibitor titer <10 BU Low peak historical inhibitor titer <200 BU Low peak inhibitor during ITI <50-100 BU Short duration between the onset of inhibitor and start of ITI <1-2 years Low risk factor VIII gene: small insertion, small deletion, missense mutations
Immune Tolerance Induction Lyophilized cryoprecipitate 13 units/kg 3 times/week Inhibitor (BU/mL) 600 500 400 300 200 100 0 0 2 4 9 10 12 14 16 24 36 Weeks Heat treated lyophilized cryoprecipitate Chuansumrit A, et al. Haemophilia 2000;6:523-5.
Dose of Factor VIII Plasma-derived factor VIII concentrate 100 units/kg 3 times/wk for 6 months 50 units/kg 3 times/wk for 6 months 50 units/kg 1-2 times/wk for 1 year
FVIII:C (BU) Immune Tolerance Induction 10 3.1 4.4 3.8 1.7 2.4 0.46 0.24 0 0 0 0 0 0 87 Factor VIII conc 50 u/kg x 2/wk PCC 50 u/kg x 2/wk 100 u/kg x 3/wk 50 u/kg x 3/wk 70 u/kg x 2/wk Week
Successful ITI Negative inhibitor (<0.6 BU) Normalized FVIII recovery >66% FVIII:C half life >6 h after 72 h washout period
Inhibitor to Factor VIII Clotting Activity 4500 Episodic treatment Immune tolerance 2 nd Prophylaxis 4000 3500 Inhibitors (BU) 3000 2500 2000 1500 1000 500 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Age (Years)
46
Plasma Fractionation Centre National Blood Centre, Thai Red Cross Society
Plasma Fractionation Centre National Blood Centre, Thai Red Cross Society
Thank You for Your Attention