European Haemophilia Consortium Round Table of Stakeholders Orthopaedic Aspects in Haemophilia Care What are the goals of treatment? A Haematologist’s perspective Professor Cedric HERMANS MD PhD FRCP (Edin, Lon) Haemostasis and Thrombosis Unit Haemophilia Clinic Division of Haematology Cliniques Universitaires Saint-Luc Catholic University of Louvain 1200 Brussels, Belgium 1 cedric.hermans@uclouvain.be
Speaker disclosures Shareholder No relevant conflicts of interest to declare Grant / Research No relevant conflicts of interest to declare Support Pfizer, Bayer, Shire, Novo Nordisk, CSL Behring, Consultant Octapharma, Sobi, LFB, CAF-CDF, OctaPharma Employee No relevant conflicts of interest to declare Paid Instructor No relevant conflicts of interest to declare Speaker bureau No relevant conflicts of interest to declare Other
THE MOST FAMOUS HAEMOPHILIA PATIENT T SARÉVITCH A LEXIS (1904-1918) 10 year-old 4 year-old 8 year-old 3
HAEMOPHILIA TODAY : NOT LONGER A ROYAL DISEASE BUT A DISEASE THAT CAN BE TREATED This young boy with severe haemophilia can now be treated safely and have a normal life. 4
H AEMOPHILIA Blood Coagulation Defect Debilitating Arthropathy
Bleeding complications in patients with haemophilia Hip Intra-Cranial Ilio-psoas Muscle 6
Factor Level Phenotype (%) Annual bleeding rate (ABR) without Replacement >150% 0 50 – 150% 0 25 – 49% 0 6 – 24% 0 – 1 Mild 1 – 5% 1 – 5 Moderate <1% 52 Severe 7
The Most Affected Joints in Haemophilia • 90% of bleeding episodes affect MSK system • Up to 80% in ankles, knees and elbows • 10% of hematomas • Begin by age 2
Why do patients with haemophilia bleed in their joints ? Haemotological reason • Nonvital tissues express low levels of TF. • These tissues appear to rely more on the intrinsic pathway of coagulation to maintain hemostasis. • This may explain why hemophilia A and B patients exhibit spontaneous hemorrhages into skeletal muscle and joints. Mackman N . Arterioscler Thromb Vasc Biol. 2004 Jun;24(6):1015-22.
Why do patients with haemophilia bleed in their joints ? Anatomical reason Elbows, knees and ankles are the Shoulders and hips are less most susceptibe to acute susceptible to acute haemarthrosis haemarthrosis « hinge joint » synovium gets stuck in the joint
Consequence of hemarthrosis: Inflammation and hypertrophy of the Synovium Interleukin-1 Interleukin-6 TNF-alpha Source: S. Lobet Source: Novo Nordisk
Musculoskeletal bleeding episodes in patients with haemophilia Features Location Joint Muscle Reason Spontaneous Induced (trauma, physical activity) Presentation Clinically patent Suclinical
Clinical haemarthrosis Symptomatic Large amount of blood Clinically patent Subclinical haemarthrosis Small amount of blood Clinically silent Asymptomatic
Injection of missing Treatment of haemophilia Factor VIII or IX Replacement or substitutive therapy by regular intravenous infusions of exogenous clotting F8 or F9 to correct clotting factor deficiency in order to treat or prevent bleeding episodes
Treatment of haemarthrosis should not be delayed
WITH A JOINT BLEED, TIME LOST IS JOINT AND CARTILAGE LOST Visit our Website: http://www.hemophilie-ucl.be and discover our computer-generated movie on blood coagulation and haemophilia
The benefits of early treatment : a well-known concept in various therapeutic areas CARDIOLOGY Saves cardiac muscle Acute myocardial infarction NEUROLOGY Saves neurones Acute ischemic stroke HAEMOPHILIA Saves cartilage Acute haemarthrosis
Requirements for early treatment of bleeding episodes in patients with haemophilia PATIENT TREATMENT Replacement or Education Bypassing Good understanding Haemostatic efficacy Rapid recognition Convenience of use Good venous access HEALTH CARE SYSTEM Home-treatment Education
Better than early treatment, PREVENTION of haemarthrosis is the optimal option
Ideal treatment of Severe Haemophilia : Prevention of bleeding episodes by regular infusions FVIII 1% Time Regular self-administration of F8 or F9 concentrate in order to prevent bleeding episodes F8 correction by regular infusion (20-40 units/kg – 3x/week or 1x/2days) 20
The Concept of Prophylaxis >150% • Patients with moderate hemophilia 50 – 150% (FVIII / FIX 2 – 5%) have much less frequent haemarthrosis than 25 – 49% patients with severe disease (<1%) • The rationale for prophylaxis is to 6 – 24% maintain FVIII / FIX >1% in order to prevent spontaneous bleeding episodes, especially haemarthrosis 1 – 5% <1% 21
Prophylactic Treatment of Haemophilia A: Basic Principles Infusions of concentrate • Regular infusions of FVIII 60 % concentrates aim to convert Factor VIII measured in blood severe into moderate 50 % • No consensus on optimal 40 % prophylaxis regimen 30 % • Considering a recovery of 2, and 20 % a half-life of 9-13 hours for currently available FVIII 10 % concentrates, 2-3 infusions per 1 % week are needed Monday Tuesday Wednesday Thursday Friday Saturday Sunday
Choices of Treatment Regimens and Different Ages at Which They Are Implemented Prevention of On-demand Treatment Life- threatening Bleeding Short-term Prophylaxis Reduction of Progression of Secondary Prophylaxis in Arthropathy Adolescents and Adults and Disability Enable Normal Activities of Late Secondary Prophylaxis Daily Life and Physical Exercise Early Secondary Prophylaxis Enable Practically Normal Psychosocial Primary Prophylaxis Development without Overprotection 0 5 10 15 20 25 30 35 40 Age (years) A. Coppola. Blood transfusion, 2008. 23
How should prohylaxis be started in 2017 ? • To all boys with severe haemophilia A/B • Around the age of one year • At a low dose , i.e. usually 25 U/kg • Frequency of every 2 nd day/trough guided • Avoiding “immunological danger signals” first 20 ED • As “prophylaxis” during first 20 ED instead of “on demand”
D ATA S UPPORTING P ROPHYLAXIS : R ETROSPECTIVE AND P ROSPECTIVE S TUDIES Author Outcome Prophylaxis On-Demand Liesner et al. 1996 1 All bleeds/year (median) 1.5 14.7 Joint bleeds/6 mos Szucs et al. 1998 2 3.1 8.8 (mean) Joint bleeds/year Yee et al. 2002 3 0.5 3.5 (median) Panicker et al. 2003 4 Major bleeds/year (mean) 1.9 15.5 Feldman et al. 2006 5 (Interim results: Joint bleeds/year (mean) 1.2 N/A prophylaxis only) N/A = not available. 1. Liesner et al. Br J Haematol. 1996;92(4):973-978 2. Szucs et al. Haemophilia. 1998;4(4):498-501 3. Yee et al. Haemophilia. 2002;8(2):76-82. 4. Panicker et al. Haemophilia. 2003;9(3):272-278 5. Feldman et al. J Thromb Haemost. 2006;4(6):1228-1236.
Prophylaxis Reduces the Occurrence of Bleedings On-demand Prophylaxis (n=33) (n=32) Total Bleeds/year (90% less) 18 1.9 Joint Bleeds/year (90% less) 5 0.5 Manco-Johnson M. et al, NEJM , 2007; 357:535-44. 26
PK of FVIII and the risk of haemarthrosis Reduced bleeding risk zone Peak FVIII level ( %) Trough time Monday Friday Wednesday Peak / time spent in reduced Important to prevent activity related and traumatic bleeds bleeding risk zone: Trough Important to prevent spontaneous break through bleeds AUC Important to prevent subclinical bleeds, maximizing the window of protection Collins PW: Plenary lecture „Personalized Prophylaxis“ WFH congress July, 10 2012
R ISKS OF STOPPING PROPHYLAXIS IN ADULTS • Haemophiliacs do not lose the risk of joint bleeding at the age of 18 • Switching to “on - demand” will lead to haemarthroses – how many before haemophilic arthropathy develops ? • Risk of losing the benefits of the financial and human resource invested in childhood
S ECONDARY P ROPHYLAXIS • Introducing prophylaxis in adulthood is effective in reducing joint bleeding and improving joint function
N UMBER OF BLEEDS ON SECONDARY PROPHYLAXIS On-demand Prophylactic Median treatment † treatment* (interquartile P value ‡ range) number Months 1 – 6 Months 7 – 13 of bleeds per ( n = 20) ( n = 19) patient Joint bleeds 15.0 (11 – 26) 0 (0 – 3) < 0.001 All bleeds 20.5 (14 – 37) 0 (0 – 3) < 0.001 Spontaneous 13.5 (7 – 29) 0 (0 – 1) < 0.001 bleeds Trauma bleeds 2.5 (0 – 9) 0 (0) < 0.001 Median observation period was 192 days. † Median observation period was 177 days. ‡ Wilcoxon test. Collins et al JTH 2009 8, 83-89
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