hemophilia & other hereditary bleeding disorders djajadiman gatot novie amelia c...
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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
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Hereditary Bleeding Disorders Hereditary clotting factor deficiencies
Single clotting factor deficiencyFactor 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 disordersWintrobe’s Clinical Hematology, 11th ed, 2004
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WFH Global Survey 2012
WFH, 2013
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http://accessmedicine.net/
Pathophysiology
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Diagnosis
Beck N. Diagnostic hematology. 2009
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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 RareWintrobe’s Clinical Hematology, 11th ed, 2004
Clinical distinctions
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Defect Bleeding manifestation
PT PTT BT Treatment
Fibrinogen
variable N/ Cryoprecipitate
Prothrombin
variable N PCC
Factor V Mild-moderate
FFP
Factor VII
Moderate-severe
N N rF.VIIa
Factor VIII
variable N N F.VIII or DDAVP(mild)
Factor IX
variable N N F.IX
Factor X variable N Plasma/PCC
Factor XI
variable N N Plasma/PCC
Factor XII
Non-bleeding N N No need
Factor XIII
severe N N N cryoprecipitate
Clinical manifestation & treatment
Colman RW, et al. Hemostasis & thrombosis : basic rinciples & clinical practice. 2006
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Hemophilia
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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
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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.
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Jumlah Pasien Hemofilia, 2014
Data : Himpunan Masyarakat Hemofilia Indonesia, Februari 2014
180230
530
757850
1084 1103 1136121012701280
1388
15851706 1737
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Pattern of inheritance
Hemophilia in Pictures. WFH, 2005
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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)
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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
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Degrees of Severity
Hemophilia in Pictures. WFH, 2005
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Clinical Classification*Clinical Classification*
Severe Moderate MildSevere Moderate Mild
Coagulation factor level Coagulation factor level < 1% 1 - 5% > 5%
Bleeding spontaneous mild trauma moderate trauma Bleeding spontaneous mild trauma moderate trauma
Episodes 1-2 x/wk 1 x/mo noneEpisodes 1-2 x/wk 1 x/mo none
Hemarthrosis common occasionallyHemarthrosis common occasionally rarerare
** Hemophilia A or B Hemophilia A or B
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Clinical manifestationClinical manifestation
Bleeding: Bleeding:
• • usually deep (hematoma, hemarthrosis)usually deep (hematoma, hemarthrosis)
• • spontaneous or following mild trauma spontaneous or following mild trauma
Type:Type: hemarthrosishemarthrosis
hematomahematoma
intracranial hemorrhageintracranial hemorrhage
hematuriahematuria
epistaxisepistaxis
bleeding of the frenulum (baby)bleeding of the frenulum (baby)
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Hemarthrosis Muscle bleed
Clinical manifestation
Hemophilia in Pictures. WFH, 2005
45%
30%
15%
3%
3%2%
2%
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Sites of bleeding
Guidelines for the Management of Hemophilia, WFH 2012
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HemarthrosisHemarthrosis
Hemophilia in Pictures. WFH, 2005
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Frequency of bleeding at different sites
Guidelines for the Management of Hemophilia, WFH 2012
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DiagnosisDiagnosisPresenting 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
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Physical examination
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Hemostasis screening tests
Guidelines for the Management of Hemophilia, WFH 2012
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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 2005Mayo Clin Proc. 2005;80(11):1485-1499
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Management of bleeding episode 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
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First aid : RICEREST: 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
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Blood component replacement therapyBlood component replacement therapy
factor-VIII factor-IXfactor-VIII factor-IX (unit/ml) (unit/ml) (ml)(unit/ml) (unit/ml) (ml)
FFresh-frozen plasmaresh-frozen plasma ~ ~ 0,5 0,5 ~~ 0,6 200 0,6 200 CCryoprecipitate ryoprecipitate ~~ 4,0 - 204,0 - 20 FFactor-VIII concentrateactor-VIII concentrate 25 - 100 - 1025 - 100 - 10 FFactor-IXactor-IX concentrate concentrate - 25 - 35 20- 25 - 35 20
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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 )
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 )
Replacement therapy
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Comprehensive careComprehensive care
To be governed through multidiscipline approach To be governed through multidiscipline approach involving experts in the field of:involving experts in the field of:
hematology hematology occupational therapy occupational therapy
orthopedics orthopedics vocational therapy vocational therapy
infectious disease infectious disease psychology psychology
nutrition nutrition nursing nursing
dentistry dentistry genetics genetics
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BleedingHemofilia A Hemofilia B
Plasma Target (%) Duration (day) Plasma Target (%) Duration (day)
Joint 10-20 1-2* 10-20 1-2*Muscle (excl.iliopsoas)
10-20 2-3* 10-20 2-3*
Iliopsoas-initial-maintenance
20-4010-20
1-23-5#
15-3010-20
1-23-5#
CNS-initial-maintenance
50-8030-5020-40
1-34-7
8-14^
50-8030-5020-40
1-34-7
8-14^
Resp. tract-initial-maintenance
30-5010-20
1-34-7
30-5010-20
1-34-7
Gastrointestinal-initial-maintenance
30-5010-20
1-34-7
30-5010-20
1-34-7
Ginjal 20-40 3-5 15-30 3-5Deep laceration 20-40 5-7 15-30 5-7Operasi mayor-pre-op-post-op
60-8030-4020-3010-20
1-34-6
7-14
50-7030-4020-3010-20
1-34-67-14
Tooth extraction-before procedure-after procedure
5020-40
1-3* 4020-30
1-3*
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Other treatment
DDAVP
Genetic engineering
Supportive: • antifibrinolytic agent
• analgesics
Physiotherapy (rehabilitation)
On demand vs Prophylaxis
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ComplicationsComplications
InhibitorInhibitor
DDevelopment of factor-VIII inhibitor (20-evelopment of factor-VIII inhibitor (20-30% 30%
in severe hemophilia A)in severe hemophilia A)
Treatment of inhibitor:Treatment of inhibitor:
increase dose of F-VIII increase dose of F-VIII
shortcut coagulation pathway : by-passing shortcut coagulation pathway : by-passing
agent (F VIIa, prothrombin complex agent (F VIIa, prothrombin complex
concentrate/PCC)concentrate/PCC)
use of F-VIII from other species use of F-VIII from other species
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………………ComplicationsComplications
Transfusion transmitted diseaseTransfusion transmitted diseaseIn 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 diminishedThere are still risk of transmission with:
Parvovirus B 19 Creutzfeld-Jacob disease
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………….Complications.Complications
Musculoskeletal : Synovitis Chronic hemophilic arthropathy
Pseudotumors Fractures
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Von Willebrand Disease
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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
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Role of VWF in primary hemostasis
N Engl J Med 2004;351:683-94.
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VWF – F VIII complex
N Engl J Med 2004;351:683-94.
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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
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Pattern of inheritance
Type 1 & 2 : autosomal dominant
Type 3 : autosomal recessive
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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. 4th ed, 2006
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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.
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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
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Thank you