日期：112年12月29日（星期五） 演講主題：高雄地區第494次小兒科聯合病例討論會：淺談血友病 主持醫院：高雄長庚兒童醫院

1. 淺談血友病
市立鳳山醫院/高雄長庚紀念醫院兒童內科
羅婉珊醫師
2023/12/29

2. Before we start…
• The 3 most common hereditary
bleeding disorders:
1. Hemophilia A (factor VIII
deficiency)
2. Hemophilia B (factor IX
deficiency)
3. von Willebrand disease (VWD)
• Hemophilia C: factor XI deficiency
Hemophilia A and
hemophilia B are the most
common severe inherited
bleeding disorders
The clinical features and
many of the diagnostic
considerations for
hemophilia A and B are
similar

3. Outline
INTRODUCTION DIAGNOSIS AND
TREATMENT
COMPREHENSIVE CARE
OF HEMOPHILIA

4. Introduction

5. The first case of hemophilia
Dates from ancient Egypt • The first registered reference
comes from Hebrew texts from
the 2nd century A.D
• The writings explicitly banned
circumcision for those children
with a previous family history of
at least 2 deceased brothers due
to hemorrhage after this
procedure

6. The royal disease
• Affected the royal families of England,
Germany, Russia and Spain in the
19th and 20th centuries
• Queen Victoria from England
‘‘transmitted’’ the hemophilia B
genetic inheritance to several royal
houses in Europe
• Her latest son Leopold who died at the
age of 30, after a bleeding episode due
to a mild knee trauma

7. • Use of the term hemophilia was ascribed to Schönlein in the 1820s
• The prolonged clotting time of hemophilic blood was first noted in 1893
• Decrease in factor VIII levels in hemophilia A was initially identified in
1947
• In 1952 levels of factor IX were found to be decreased in Christmas
disease, which was the early term used to denote hemophilia B
Use of the term hemophilia

8. Hemophilia
• X-linked, recessively inherited coagulation disorder
• Lack of coagulation factor VIII, FVIII (hemophilia A)
• Lack of coagulation factor IX, FIX (hemophilia B)

12. • Hemophilia occurs in approximately 1 in 5000~10000 males
• Of all patients with hemophilia, 80% to 85% have hemophilia A, and 10% to 15%
have hemophilia B
• No apparent racial predilection
• World Federation of Hemophilia (WFH) states that worldwide 196706 patients
are recorded as having hemophilia
• In Taiwan, around 1000 hemophilia A patients and 200 hemophilia B patients

13. Hemophilia - severity
• The severity of hemophilia and of its clinical symptoms is determined
by residual FVIII or FIX activity compared to the activity of normal
pooled plasma
1. Severe (factor level < 1%)
2. Moderate (factor level 1~5%)
3. Mild (factor level 5~40%)

14. Severity of
hemophilia
Mild Moderate Severe
Factor level 5~40% 1~5% < 1%
Spontaneous
bleeding
Rare Occasional Often
Bleeding
manifestations
Severe bleeding only
with major trauma or
surgery
Gross bleeding following
mild to moderate trauma;
some hemarthrosis; seldom
spontaneous hemorrhage
Bleeding after minimal or
unknown trauma;
unprovoked muscle and
joint bleeding
• Clinical phenotype usually corresponds to the factor level
• Annualized bleeding rates (ABR):
1. Untreated severe hemophilia: 60 hemorrhages per year
2. Mild hemophilia: less than 1 hemorrhage per year
3. Often no clinical difference between moderate and severe hemophilia

15. LANZKOWSKY’S manual of pediatric hematology and oncology 6 edition

16. Common sites of hemorrhage in hemophilia
Hemarthrosis Mucous membrane
hemorrhage:
Mouth
Dental
Epistaxis
Gastrointestinal
High-risk hemorrhage
Central nervous system:
Intracranial
Intraspinal
Retropharyngeal
Retroperitoneal
Hemorrhage causing compartment
syndrome/nerve compression:
Femoral (iliopsoas muscle)
Sciatic (buttock)
Tibial (calf muscle)
Perineal (anterior compartment of leg)
Median and ulnar nerve (flexor muscles of
forearm)
Intramuscular hematoma
Hematuria

17. Musculoskeletal bleeding in
severe hemophilia
• Although patients with hemophilia may bleed in
any area of the body, the hallmark of hemophilia
is deep bleeding into joints and muscles
• Bleeding episode as often as 1-2 times/week
without prophylactic factor treatment
• Bleeding into the joint space, a condition referred
to as hemarthrosis
• Usually begin when the child reaches the toddler
age

18. Fig. Schematic
representation of a healthy
joint(left) and hemophilic
arthropathy (right)
• A condition in which the
synovium, cartilage and
subchondral bone are
damaged
• Pathological changes include
synovial hyperplasia,
hemosiderin deposition,
immune cell infiltration
neo-angiogenesis
cartilage degradation
bone erosion and formation
of osteophytes
• Similar to OA (degenerative
joint disease) and RA
(inflammatory joint disease)
Pulles et al. Pathophysiology of hemophilic arthropathy and potential
targets for therapy. Pharmacol Res. 2017 Jan;115:192-199.
Hemophilic arthropathy

19. ROM limitation
Warmth, swelling,
and tenderness
• Patients who sustain hemarthrosis:
an aura of tingling or warmth →
increasing pain → decreased ROM
of the joint as the joint capsule
becomes progressively distended
• For young children who are unable
to verbalize symptoms, severe
pain and distention of the joint
space often occur before the
location of the hemorrhage can be
easily determined
• Older children are often able to
tell their parents when a
hemorrhage is beginning to occur,
even in the absence of significant
signs on PE

20. Musculoskeletal bleeding in severe hemophilia
• The clinical diagnosis of intramuscular hematoma is often
elusive
• Such hemorrhage occurs deep within the muscle
• Vague feeling of pain on motion
• Because the bleeding is not in a closed space, the mass may
be difficult to palpate
• The circumference of the affected limb is generally increased
• Should be considered to be as severe as hemarthrosis
because it may result in severe muscular contractures as a
result of fibrosis and atrophy or even pseudotumor formation
• Muscle weakness also predisposes patients to joint
hemorrhage
Haemophilia foundation Australia

21. Diagnosis and treatment

22. LANZKOWSKY’S manual of pediatric hematology
and oncology 6 edition

23. Coagulopathy PT aPTT Platelet count
Hemophilia A or B Normal Prolonged Normal
von Willebrand
disease (VWD)
Normal Normal or
prolonged
Normal or
reduced
Platelet defect Normal Normal Normal or
reduced
Screening test
• Hemophilia should be suspected when unusual bleeding is
encountered in a male patient

24. Treatment of hemophilia – general concepts
• The gold standard for hemophilia treatment has for many years been
regular, long-term treatment to prevent hemorrhage
• Infusions of plasma-derived or recombinant factor drugs
• Minimize spontaneous hemarthroses
• Additional infusions are performed in cases of breakthrough bleeding:
1. Following traumatic injuries
2. Before sporting activities
3. Before surgeries

25. Current clotting factor replacement strategies
Severity of
hemophilia
Mild Moderate Severe
Factor level 5~40% 1~5% < 1%
On demand
Prophylaxis

26. • After the observation in the 1930s that administration of plasma
corrected the clotting time of hemophilic blood
• The modern era of treatment began in 1964 with the discovery of
cryoprecipitate and plasma fractions containing factor IX
• More purified products were introduced in 1965 and were referred to
as factor VIII concentrates (containing both factor VIII and VWF)

27. • The attempts to limit transfusion-
related viral infections during the
1980s
1. improved donor selection
2. heat treatment of the product
3. further refined purification
schemes
• In 1984 and 1985 the genes for factor
VIII and factor IX were cloned
• In 1989, recombinant factor VIII was
first used clinically

28. Recombinant clotting factors
• Patients could more readily and safely be treated with primary and
secondary prophylactic therapy
• Markedly reduce the likelihood of spontaneous bleeding episodes and
the progression of hemophilic arthropathy

29. Current treatment – severe hemophilia
• Regularly administered prophylaxis with factor concentrates
• Maintain a factor level above 1 % of normal FVIII or FIX activity
• Regular prophylaxis started in early childhood largely prevents
arthropathy
• Continued through out life, prophylaxis leads to near normalization of
life expectancy

30. Current treatment – severe hemophilia
• The relatively short half-life of FVIII and FIX in the circulation
necessitates frequent intravenous administration of factor
concentrates (BIW or TIW)
1. Demanding and expensive
2. “sawtooth” pattern of factor levels in plasma
3. Need to carefully plan periods of increased physical activities, such
as sport
breakthrough
bleeding can occur

31. New progress has been made based on the prolongation of the half-life
of factors VIII and IX

32. Extended-half-life (EHL) clotting factors
• Half-life of factor VIII in the
plasma: 8 ~12 hours
• Half-life of factor IX in the
plasma: 12 ~24 hours
• Extended half-lives (EHL) factor:
1. Reduce injection frequency
2. Increase trough levels
• Various techniques are used to
delay clearance:
1.Fusion techniques (Fc domain
of immunoglobulin or
albumin)
2.Pegylation (covalent binding
of polyethylene glycol at
particular points on the factor)

33. Inhibitors to FVIII and FIX
• The development of
alloantibodies to FVIII and FIX
compromised replacement
therapy
• More widespread in severe
hemophilia A than in severe
hemophilia B (30% & 5%)
• Particularly common during the
initial treatment (within the first
50 exposure days to FVIII) period
in early childhood
• The risk of developing inhibitors
is affected by multiple factors
1. Early age at exposure
2. Presence of the common
inversion mutation
3. Large deletions of the FVIII
gene
4. African-American ethnicity
5. A sibling with hemophilia and
an inhibitor

34. Immune tolerance therapy (ITI)
• Regular, high dose coagulation factor infusions administered over a
long period
• Eliminates inhibitors in approximately 80% of patients

35. Bleeding in hemophilia patients with inhibitors
• In such cases coagulation factor replacement has limited effect
• Bypass agents (BPA) are thus use such as:
1. Activated prothrombin complex concentrate (APCC, Feiba®)
2. Recombinant activated coagulation factor FVII (rFVIIa, NovoSeven®)

36. Extended half life clotting factors
• IX fused to proteins with long half-life such as albumin, Peg or Fc
• Particularly effective in hemophilia B
• Reduce treatment burden
• Maintain higher factor trough levels for improved bleed prevention
• Non–coagulation factor–based treatment for hemophilia
→ Factor VIII analog: Emicizumab (Hemlibra®), SC administration
Once weekly Once every 2 weeks Once every 4 weeks
1.5 mg/kg 3 mg/kg loading dose 6 mg/kg
per week for 4 weeks in
all cases → 6 mg/kg

38. • A 型血友病且有抗體病人; 若發生突破性出血時，第一線藥物
為 rVIIa或第八凝血因子；除非沒有其他選擇，儘量避免使用
Feiba
• 嚴重且未帶有抗體 A 型血友病病人之預防性治療：< 12 y.o.

40. Castaman G, Di Minno G, De Cristofaro R, Peyvandi F. The Arrival of Gene Therapy for Patients with
Hemophilia A. Int J Mol Sci. 2022 Sep 6;23(18):10228.

41. Why gene therapy ?
• Hemophilia is a good candidates for gene therapy, since :
1. The clinical manifestations are due to lack of a single protein
2. A small increase in circulating levels of the deficient clotting factor to 5%
of normal significantly modifies the bleeding diathesis
3. The levels of these proteins in circulation can be assessed readily
4. Tight regulation of transgene expression is not necessary since a wide
range of FIX or FVIII is expected to be beneficial and nontoxic
5. Animal models such as FVIII- and FIX-knockout mice and dogs with
hemophilia A or B have facilitated extensive preclinical evaluation of
gene therapy strategies
6. The efficiency of therapy can be assessed easily

42. Comprehensive care of
hemophilia

44. Other supports
• Liver disease management (Non-
alcohol fatty liver disease (NAFLD),
liver cancer, cirrhosis)
• Dental care
• Quality-of-life assessments and
psychosocial support
• Ongoing patient/family caregiver
education and support
• Emergency care should be available at
all times
• 血友病中心

47. Pharmacokinetic (PK) monitoring
• Dosing must be individually tailored and may vary according to the
patient’s hemorrhage type and frequency, joint status, activity level,
and pharmacokinetic profile
• For people with hemophilia receiving FVIII/FIX concentrates who
would benefit from optimization of prophylaxis, the WFH
recommends individualized PK monitoring especially when bleeding
occurs during daily life

49. Reference
• 台灣血友病治療建議 2023
• LANZKOWSKY’S manual of pediatric hematology and oncology 6 & 7 edition
• Nathan and Oski's Hematology and Oncology of Infancy and Childhood 8th edition
• Miesbach W, Schwäble J, Müller MM, Seifried E. Treatment Options in Hemophilia.
Dtsch Arztebl Int. 2019 Nov 22;116(47):791-798.
• Weyand AC, Pipe SW. New therapies for hemophilia. Blood. 2019 Jan
31;133(5):389-398.
• Castro HE, Briceño MF, Casas CP, Rueda JD. The history and evolution of the
clinical effectiveness of haemophilia type a treatment: a systematic review. Indian
J Hematol Blood Transfus. 2014 Mar;30(1):1-11.
• Amit C. Nathwani: Gene therapy for hemophilia. Hematology 2022, ASH
education program
• Haemophilia foundation Australia

50. Thank you very much
for your attention
F1 羅婉珊