HEMOPHILIA & OTHER HEREDITARY BLEEDING DISORDERS Djajadiman Gatot Novie Amelia C Hematology-Oncology Division Department of Child Health Faculty of Medicine

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 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

WFH Global Survey 2012

WFH, 2013

http://accessmedicine.net/

Pathophysiology

Diagnosis

Beck N. Diagnostic hematology. 2009

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

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

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

Data : Himpunan Masyarakat Hemofilia Indonesia, Februari 2014

180230

530

757850

1084 1103 1136121012701280

1388

15851706 1737

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


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

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)

Hemarthrosis Muscle bleed

Clinical manifestation


45%

30%

15%

3%

3%2%

2%

Sites of bleeding


HemarthrosisHemarthrosis


Frequency of bleeding at different sites


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


Physical examination

Hemostasis screening tests


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

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

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.


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

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

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

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*

Other treatment

DDAVP

Genetic engineering

Supportive: • antifibrinolytic agent

• analgesics

Physiotherapy (rehabilitation)

On demand vs Prophylaxis

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

………………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

………….Complications.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


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


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)


Thank you

Documents

HEMOPHILIA & OTHER HEREDITARY BLEEDING DISORDERS Djajadiman Gatot Novie Amelia C Hematology-Oncology Division Department of Child Health Faculty of Medicine