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HEMOPHILIA & OTHER
HEREDITARY BLEEDING DISORDERS
Djajadiman Gatot
Novie Amelia C
Hematology-Oncology Division
Department of Child Health
Faculty of Medicine University of Indonesia/
Dr Cipto Mangunkusumo Hospital
Hereditary Bleeding Disorders

Hereditary clotting factor deficiencies
 Single clotting factor deficiency
 Factor
I, II, V, VII, X, XI, XIII deficiency (autosomal)
 Factor VIII/IX deficiency (X-linked recessive)
 Factor XII deficiency (non-bleeding disorder)
 Multiple
clotting factor deficiencies
F
V + F VIII (autosomal recessive)
 Vitamin K dependent factors (F II, VII, IX, X)

Von Willebrand Disease

Inherited platelet disorders
Wintrobe’s Clinical Hematology, 11th ed, 2004
WFH Global Survey 2012
WFH, 2013
Pathophysiology
http://accessmedicine.net/
Diagnosis
Beck N. Diagnostic hematology. 2009
Clinical distinctions
Finding
Disorders of Coagulation
Disorders of Platelets or Vessel
Petechiae
Rare
Characteristic
Deep dissecting hematoma
Characteristic
Rare
Superficial ecchymoses
Common, usually large &
solitary
Characteristic, usually small &
multiple
Hemarthrosis
Characteristic
Rare
Delayed bleeding
Common
Rare
Bleeding from superficial cuts
& scratches
Minimal
Persistent, often profuse
Sex of patient
80-90% male
Relatively more common in
females
Positive family history
Common
Rare
Wintrobe’s Clinical Hematology, 11th ed, 2004
Clinical manifestation & treatment
Defect
Bleeding
manifestation
Fibrinogen
variable
N/
Prothrombin variable
N
Factor V
Mild-moderate
Factor VII
Moderate-severe
Factor VIII
variable
Factor IX
variable
Factor X
variable
Factor XI
variable
Factor XII
Factor XIII
PT
PTT
BT
Treatment
Cryoprecipitate
PCC
FFP
N
N
rF.VIIa
N
N
F.VIII or DDAVP(mild)
N
N
F.IX
N
Plasma/PCC
N
N
Plasma/PCC
Non-bleeding
N
N
No need
severe
N
N
cryoprecipitate
N
Colman RW, et al. Hemostasis & thrombosis : basic rinciples & clinical practice. 2006
Hemophilia
Definition


Hemophilias comprise a category of hereditary
bleeding disorders resulting from congenital
deficiencies of proteins involving in blood
coagulation
X-linked recessive disorder
 Hemophilia
A : factor VIII (antihemophilic factor)
deficiency
 Hemophilia B : factor IX (Christmas factor)deficiency
Hemostasis & Thrombosis : Basic Principals & Clinical Practice. 4th ed, 2006
Epidemiology

Hemophilia A
 80-85%
of hemophilia cases
 1 in 5000 male births

Hemophilia B
1
in 30,000 male births
Am J Hematol.1998;59:288-294.
Jumlah Pasien Hemofilia, 2014
1585
1270 1280
1210
1136
1084 1103
757
1706 1737
1388
850
530
180
230
Data : Himpunan Masyarakat Hemofilia Indonesia, Februari 2014
Pattern of inheritance
Hemophilia in Pictures. WFH, 2005
Genetics



Genes of factor VIII/IX are located on the distal
part of the long arm (q) of X chromosome
Female (women) are carriers
F VIII & F IX gene defects :
 Gross
gene rearrangements
 Insertions/deletions
 Single-base substitutions

Approximately 30% cases have no family history
(occur as a result of spontaneous novel mutations)
Carrier state


Normal women phenotype, usually no clinical
symptoms.
Obligate carriers are:
 daughters
of a person with hemophilia
 mothers of one son with hemophilia and who have at least
one other family member with hemophilia
 mothers of one son with hemophilia and who have a
family member who is a known carrier of the hemophilia
gene
 mothers of two or more sons with hemophilia
Guidelines for the Management of Hemophilia, WFH 2012
Degrees of Severity
Hemophilia in Pictures. WFH, 2005
Clinical Classification*
Severe
Coagulation factor level
< 1%
Moderate
1 - 5%
Mild
> 5%
Bleeding
spontaneous
Episodes
1-2 x/wk
1 x/mo
none
Hemarthrosis
common
occasionally
rare
* Hemophilia A or B
mild trauma moderate trauma
Clinical manifestation
 Bleeding:
• usually deep (hematoma, hemarthrosis)
• spontaneous or following mild trauma
 Type:
 hemarthrosis
 hematoma
 intracranial hemorrhage
 hematuria
 epistaxis
 bleeding of the frenulum (baby)
Clinical manifestation
3%
30%
2%
3%
45%
15%
Hemarthrosis
2%
Muscle bleed
Hemophilia in Pictures. WFH, 2005
Sites of bleeding
Guidelines for the Management of Hemophilia, WFH 2012
Hemarthrosis
Hemophilia in Pictures. WFH, 2005
Frequency of bleeding at different sites
Guidelines for the Management of Hemophilia, WFH 2012
Diagnosis

Presenting history : (boy)
 Easy
bruising in early childhood
 Spontaneous bleeding (particularly into the
joints & soft tissue)
 Excessive bleeding following trauma or
surgery
 History of abnormal bleeding in family
Guidelines for the Management of Hemophilia, WFH 2012
Physical examination
Hemostasis screening tests
Guidelines for the Management of Hemophilia, WFH 2012
Definitive diagnosis

Factor VIII and/or IX assay

Genetic testing
 Establish
diagnosis in prenatal testing of male fetuses
 Predict severity of disease
 Estimate risk of developing inhibitor
 To differentiate mild hemophilia A from vWD type 2N.
 Cost-effective carrier testing of at-risk female family
members
Guidelines for the Management of Hemophilia, WFH 2005
Mayo Clin Proc. 2005;80(11):1485-1499
Management of bleeding episode




Stop bleeding with clotting factor within 2
hours of onset
Veins should be well reserved
Avoid the use of anti-aggregation drugs
Home therapy
Followed by comprehensive treatment
First aid : RICE
REST: The arm or leg should rest on pillows or be
put in a sling or bandage. The person should not
move the bleeding joint or walk on it.
ICE: Wrap an ice pack in a damp towel and put it
over the bleed. After 5 minutes, remove the ice for at
least 10 minutes. Keep alternating: 5 minutes on, 10
minutes off, for as long as the joint feels hot. This may
help decrease pain and limit bleeding.
COMPRESSION: Joints can be wrapped in a tensor
bandage or elastic stocking. This gentle pressure may
help to limit bleeding and support the joint. Use
compression carefully with muscle bleeds if a nerve
injury is suspected.
ELEVATION: Raise the area that is bleeding above
the level of the heart. This may slow blood loss by
lowering pressure in the area.
Hemophilia in Pictures. WFH, 2005
Blood component replacement therapy
factor-VIII
Fresh-frozen plasma
Cryoprecipitate
Factor-VIII concentrate
Factor-IX concentrate
(unit/ml)
~ 0,5
~ 4,0
25 - 100
-
factor-IX
(unit/ml)
~ 0,6
25 - 35
(ml)
200
20
10
20
Replacement therapy
Dose calculation :
F VIII (unit):
BW (kg) x % (plasma target –patient F VIII ) x 0,5
F IX (unit):
BW (kg) x % (plasma target –patient F IX )
Comprehensive care
To be governed through multidiscipline approach
involving experts in the field of:
 hematology
 orthopedics
 infectious disease
 nutrition
 dentistry
 occupational therapy
 vocational therapy
 psychology
 nursing
 genetics
Bleeding
Joint
Muscle
(excl.iliopsoas)
Iliopsoas
-initial
-maintenance
CNS
-initial
-maintenance
Resp. tract
-initial
-maintenance
Gastrointestinal
-initial
-maintenance
Ginjal
Deep laceration
Operasi mayor
-pre-op
-post-op
Tooth extraction
-before procedure
-after procedure
Hemofilia A
Plasma Target (%)
Duration (day)
Hemofilia B
Plasma Target (%)
10-20
10-20
1-2*
2-3*
10-20
10-20
Duration
(day)
1-2*
2-3*
20-40
10-20
1-2
3-5#
15-30
10-20
1-2
3-5#
50-80
30-50
20-40
1-3
4-7
8-14^
50-80
30-50
20-40
1-3
4-7
8-14^
30-50
10-20
1-3
4-7
30-50
10-20
1-3
4-7
30-50
10-20
20-40
20-40
1-3
4-7
3-5
5-7
30-50
10-20
15-30
15-30
1-3
4-7
3-5
5-7
60-80
30-40
20-30
10-20
1-3
4-6
7-14
50-70
30-40
20-30
10-20
1-3
4-6
7-14
50
20-40
1-3*
40
20-30
1-3*
Other treatment

DDAVP

Genetic engineering

Supportive: • antifibrinolytic agent
• analgesics

Physiotherapy (rehabilitation)
On demand vs Prophylaxis
Complications
Inhibitor
 Development of factor-VIII inhibitor (20-30%
in severe hemophilia A)
 Treatment of inhibitor:
 increase dose of F-VIII
 shortcut coagulation pathway : by-passing
agent (F VIIa, prothrombin complex
concentrate/PCC)
 use of F-VIII from other species
………Complications

Transfusion transmitted disease
In
the past there were several diseases transmitted by
transfusion such as:
Malaria
Syphilis
Hepatitis
HIV/AIDS
With
adequate screening and storage the TTD can be
diminished
There are still risk of transmission with:
Parvovirus B 19
Creutzfeld-Jacob disease
…….Complications

Musculoskeletal :
 Synovitis
 Chronic
hemophilic arthropathy
 Pseudotumors
 Fractures
Von Willebrand Disease
Introduction



Estimated prevalence varied from 1% of general
population to 125 cases per million population
All ethnic background; severe disease have been
documented in Israel, Sweden and Iran
Typical symptoms : mucocutaneous bleeding
Role of VWF
in primary hemostasis
N Engl J Med 2004;351:683-94.
VWF – F VIII complex
N Engl J Med 2004;351:683-94.
Classification
Type of VWD
Definition
Type 1 (≈80%)
Partial quantitative deficiency of VWF
Type 2 (≈20%)
Qualitative defects of VWF
2A
Qualitative variants with decreased platelet function (high molecular
weight multimer)
2B
Qualitative variants with increased binding affinity for platelet
glycoprotein 1b
2M
Qualitative variants with decreased platelet function (normal
molecular weight multimer)
2N
Qualitative variants with reduced binding of F VIII
Type 3 (<1%)
Complete absence of VWF
Hemostasis & Thrombosis : Basic Principals & Clinical Practice. 4th ed, 2006
Pattern of inheritance

Type 1 & 2 : autosomal dominant

Type 3 : autosomal recessive
Diagnosis

Focused on 3 factors :
 Personal
history of excessive mucocutaneous bleeding
 Evidence of family history of the condition
 Laboratory demonstration of VWF deficiency :
 Complete
Blood Count, Bleeding Time
 Platelet aggregation test
 APTT
 Factor VIII:C
 VWF:Ag
 VWF:Rco
 VWF multimers
Hemostasis & Thrombosis : Basic Principals & Clinical Practice. 4
th
ed, 2006
Clinical definition of a significant bleeding trait






Recurrent nosebleeds requiring medical treatment (packing,
cautery, etc) or leading to anemia
Oral cavity bleeding/bleeding from skin laceration
lasting for at least 1 hour, restarting over the next 7 days or
requiring medical treatment
Prolonged bleeding associated with or following dental
extraction/other oral surgery
Menorrhagia requiring medical attention or leading to anemia
Spontaneous GI bleeding requiring medical attention or
leading to anemia, unexplained by local causes
Prolonged bleeding from other skin/mucous membrane
surfaces requiring medical treatment
Pediatric Hematology, 3rd ed, 2006.
Treatment


Desmopressin (DDAVP)
Blood component therapy :
 Cryoprecipitate
 Plasma
derived F VIII concentrate (intermediate purity)
 Recombinant VWF concentrate

Adjunctive therapy :
 Antifibrinolytic
agents : tranexamic acid, aminocaproic
acid
 Estrogen (reducing menstrual bleeding)
Hemostasis & Thrombosis : Basic Principals & Clinical Practice. 4th ed, 2006
Thank you