BLEEDING DISORDERS

HEMATOLOGY ONCOLOGY DIVISION

CHILD HEALTH DEPARTMENT
UNIVERSITY OF SUMATERA UTARA

HISTORY & EXAMINATION

History in suspected bleeding :
- Type of bleeding : mucocutaneous, hemarthroses /
muscle haematomas
- Severity of bleeding : blood transfusions, anemia
- Previous tests of the haemostatic system : operations,
dental extractions, trauma, childbirth
- Age of onset
- Family history
- Other medical problems
- Drugs : aspirin, NSAID
David M Keeling. Bleeding disorder. In : ABC of hematology. 3rd ed.2007

 History suggestive of mucocutaneous bleeding :

- Prolonged epistaxis
- Cutaneous haemorrhage and bruising with minimal or no
apparent trauma
- Prolonged bleeding from trivial wounds
- Oral cavity bleeding
- Spontaneous gastrointestinal bleeding
- Menorrhagia not associated with structural lesions of the
uterus
David M Keeling. Bleeding disorder. In : ABC of hematology. 3rd ed.2007

Conditions which may be mistaken for coagulopathy :

- Henoch Schonlein Vasculitis
- VKDB
- Steroid purpura / Cushings disease
- Amyloid in the skin vessels
- Ehlers Danlos / Pseudoxanthoma elasticum
- Cryoglobulinemia

David M Keeling. Bleeding disorder. In : ABC of hematology. 3rd ed.2007

LABORATORY INVESTIGATIONS

Investigations in suspected abnormal bleeding :

- Screening tests : FBC, PT / aPTT / TT, PFA 100 Closure
or Bleeding time
- Other first line investigations : Factor VIII, Factor Von
Willebrand Activity, VWD Antigen, Platelet Agregation,
Platelet Nucleotides
- Second line investigations : Factor XIII, 2 - antitripsin

David M Keeling. Bleeding disorder. In : ABC of hematology. 3rd ed.2007

Interpretation of coagulation
screening test
Result

Cause

PT >>, aPTT Normal

Def. F VII, early stage of VKDB or liver disease

PT Normal, aPTT >>

Def. F VIII, F IX, XI, Lupus anticoagulant

PT >>, aPTT >> :

TT Normal

Def. F II, V, X, VKDB, Liver disease

TT >>

Afibrinogenemia, Heparin, DIC

David M Keeling. Bleeding disorder. In : ABC of hematology. 3rd ed.2007

INHERITED BLEEDING DISORDER

10
Hoffbrand V,dkk. Postgraduate Haemotology.5th ed. 2005

History Of Hemophilia
Talmud (2nd century AD): if a women had two sons
that died from circumcision her third son would not
be required to be circumcised

Albucasis (10th century AD) : there were families

whose males died of bleeding after only minor
traumas

Dr. John Conrad Otto (1803) : "a hemorrhagic

disposition existing in certain families"

http://en.wikipedia.org/wiki/Haemophilia
http://www.hemophilia-information.com/history-of-hemophilia.html
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http://dujs.dartmouth.edu/spring-2009/a-royal-shame-prince-leopolds-hemophilia-and-its-effect-on-medicalresearch

John Hay (1813) : Tranmission of hemorrhagic disease

from affected males into their unaffected daughters

Friedrich Hopff (1828) : The term "haemophilia" is derived

from the term "haemorrhaphilia"

Patek and Taylor (1937) : Discovered anti-hemophilic

globulin

Dr. Pavlosky (1947): Haemophilia A and haemophilia B to

be separate diseases by doing a lab test

http://en.wikipedia.org/wiki/Haemophilia
http://www.hemophilia-information.com/history-of-hemophilia.html
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http://dujs.dartmouth.edu/spring-2009/a-royal-shame-prince-leopolds-hemophilia-and-its-effect-on-medicalresearch

Royal Family

http://en.wikipedia.org/wiki/Haemophilia
http://www.hemophilia-information.com/history-of-hemophilia.html
13
http://dujs.dartmouth.edu/spring-2009/a-royal-shame-prince-leopolds-hemophilia-and-its-effect-on-medicalresearch

Pedigree of Royal Family

14

In the 1880s, the decade of Leopolds death, there was a peak in the
number of articles published about hemophilia in Great Britain.
http://dujs.dartmouth.edu/spring-2009/a-royal-shame-prince-leopolds-hemophilia-and-its-effect-on-medical-research

15

DEFINITION & INCIDENCY

Hemophilia is an X-linked congenital bleeding disorder
caused by a deficiency of coagulation factor VIII in
hemophilia A or factor IX in hemophilia B
Hemophilia has an estimated frequency of approximately
one in 10.000 births
World : 400.000 people with hemophilia
2

Guidelines for the management of hemophilia.2nd edition.Canada:Blackwell Publishing Ltd:2012

16

From total of hemophilia population, Hemophilia A =

80% - 85%, Hemophilia B = 10% - 15%
Hemophilia affects males on the maternal side but,
1/3 of all cases are spontaneous mutation
Hemophilia C is the bleeding disorder associated with
reduced level of factor IX

Guidelines for the management of hemophilia.2nd edition.Canada:Blackwell Publishing Ltd:2012

AAP. Textbook of pediatric care. 2009

17

SIGNS & SYMPTOMS

Clinical manifestations :
* Early bruising in early childhood
* Spontaneous bleeding esp. joint, muscle, soft tissue
* Excessive bleeding following trauma or surgery
Bleeding manifestations :
* Hemarthrosis
* Mouth bleeding
* Soft tissue bleeding * Hematuria
* Life threatening building : ICH, airway compromise,
retroperitoneal bleeding
Guidelines for the management of hemophilia.2nd edition.Canada:Blackwell Publishing Ltd:2012
AAP. Textbook of pediatric care. 2009

18

Sites of Bleeding in Hemophilia

19

20

HEMOPHILIA CARIER
Asymptomatis
Lab : F VIII <<<, Lyionisasi x factor normal
Obligat Carier :
Daughter from father with hemophilia
Mother with two hemophilias sons
Mother with one hemophilias son and one hemophilias
brother

21

LABORATORY FINDINGS

Full Blood Count : Normal

HST : aPTT >>, PT & TT Normal
F VIII <<
Genetic analysis

Lanszowsky. Manual of Pediatric Hematology Oncology. 5th ed. 2011

22

Relationship of Bleeding Severity to

Clotting Factor Level
Severity

Clotting Factor Level

Bleeding Episodes

Severe

< 1 U/dL (<0.01 IU/mL)

or < 1% of normal

Spontaneous bleeding into joints or

muscles, predominantly in the absence
of identifiable hemostatic challenge

Moderate

1-5 IU/dL (0.01 005

IU/mL) or 1-5% of
normal

Occasional spontaneous bleeding;

prolonged bleeding with minor trauma
or surgery

Mild

5-40 IU/dL (0.05 0.40

IU/mL) or 5 - < 40% of
normal

Severe bleeding with major trauma or

surgery. Spontaneous bleeding is rare

Guidelines for the management of hemophilia.2nd edition.Canada:Blackwell Publishing Ltd:2012

23

Severe

Moderate

Mild

Hemophilia A

70%

15%

15%

Hemophilia B

50%

30%

20%

Onset of age

< 1 years old

1 2 years old

2 years old

ICH Neonates

Sometimes

Rare

Rare

Bleeding after
circumcision

Common

Common

Rare

Muscle / joint
bleeding

Spontan

Post minor trauma

Post major trauma

CNS Bleeding

High risk

Medium risk

Low risk

Post surgery
bleeding

Common

Common

Rare

Oral bleeding

Common

Common

Rare

Lanszowsky. Manual of Pediatric Hematology Oncology. 5th ed. 2011

24

Treatment History of
Hemophilia
1970s : Factor
Concentrate

1965 : Cryoprecipitate

1950s :
FFP

1900s :
WB

1980s : Factor Concentrate

infects 80% patients with
HIV
1985 : First viral inactivated
factor products
1992 : First non plasma
derived factor

http://en.wikipedia.org/wiki/Haemophilia
http://www.hemophilia-information.com/history-of-hemophilia.html
25
http://dujs.dartmouth.edu/spring-2009/a-royal-shame-prince-leopolds-hemophilia-and-its-effect-on-medicalresearch

Product

Content

Dose,
concentration, size
of units

Indications,
comments

FFP

Whole plasma

5-15 mL/kg, 1
U/coagulation factor

Multiple factor
deficiency

Cryoprecipitate

F VIII, F VW, F
XIII, Fibrinogen

1 U/kg >> F VIII 2%,

75 100 u F VIII &
VWF

F XIII def,
hypofibronogenemia

F VIII

F VIII

1 u/kg >> F VIII 2%

Hemophilia A

Humate P

F VIII, VWF

F VIII 20-40 U/mL,

VWF 50-100 U/mL

Severe VWD

F IX

F IX

1 U/kg >> F IX 2%

Hemophilia B

Prothrombin
complex

F II, VII, IX, X

Preassayed for F IX

Hemophilia B

Activated
Prothrombin
Complex

F II, VII, IX, X,

VIII by passing
activity

Preassayed for ability Hemophilia A or B with

to shorten aPTT
inhibitor

Novoseven

Recombinant F
VIIa

Preassayed

Hemophilia A or B with
inhibitor, F VII def 26

TREATMENT
Factor replacement therapy
- F VIII : % desired (rise in F VIII) x BW (kg) x 0.5
- F IX : % desired (rise in F IX) x BW (kg) x 1.4
F VIII replacement therapy: 1 iu/kg will rise 2% of F VIII
F IX replacement therapy : 1 iu/kg will rise 1% of F IX
T of F VIII : 12 hours
T of F IX : 24 hours
Nelson Pediatrics. 18th ed. 2011

27

28
Lanszowsky. Manual of Pediatric Hematology Oncology. 5th ed. 2011

OTHER TREATMENTS

DDAVP (1-Deamino-8D-arginine Vasopresin)

Increase FVIII levels 2 -6 fold.
Dose :
IV = 0.3 ug/kg in 25 50 ml NS over 15 20 minutes
SC = IV = effective
Intranasal = BW < 50 kg = 150 ug (one metered dose)
BW > 50 kg = 300 ug (two metered dose)
- Side effects = asymptomatic facial flushing, thrombosis,
hyponatremia
- Contraindicated = children < 2 years of age
Lanszowsky. Manual of Pediatric Hematology Oncology. 5th ed. 2011

29

 Antifibrinolytic theraphy
Epsilon aminocaproic acid (EACA) : orally : 50 100
mg/kg every 6 hours (max. 24 gr/day)
Tranexamic acid : 20 25 mg/kg orally or 10 mg/kg/IV
every 8 hours
CI : patient with urinary tract bleeding

Lanszowsky. Manual of Pediatric Hematology Oncology. 5th ed. 2011

30

PROPHYLAXIS
Aim : to prevent spontaneous joint bleeding
Treatment provided 2 3 days to maintain
measurable plasma level of clotting (1% - 2%)
Young children need insertion of central catheter to
ensure venous access
Primary prophylaxis : since early diagnosis
Secondary prophylaxis : given if there is bleeding
Nelson Pediatrics. 18th ed. 2011

31

SUPPORTIVE CARE
Psychosocial intervention to patient and family
Anticipatory guidance : use of car seats, seatbelts, bike
helmets
Avoid aspirin and other NSAID
Complete immunizations ,esp. Hepatitis B, with subcutan
injection to all immunizations

Nelson Pediatrics. 18th ed. 2011

32

COMPLICATIONS
Chronic arthropathy
Inhibitor to factor VIII or factor IX
Transfusion transmitted infectious diseases
Anemia
Muscle atrofi
Compartment syndrome
Neurologic disorder
Nelson Pediatrics. 18th ed. 2011

33

INHIBITOR

30% Hemophilia A inhibitor

Inhibitor morbidity & mortality >>
Risk factors :
Early age at exposure
Presence of the common inversion mutation
Large deletion of the FVIII gene
African American ethnicity
A hemophiliac sibling with an inhibitor
Lanszowsky. Manual of Pediatric Hematology Oncology. 5th ed. 2011
Luther JM. Textbook of hemophilia. 2nd ed. 2010

34

Low responder :
Titer : < 5 Bethesda Units (BU)
Treatment : FVIII replacement : 100 unit/kg / 12 hours
High responder : > 5 BU
Treatment : bypassing agents and recombinant factor
VIIa

Lanszowsky. Manual of Pediatric Hematology Oncology. 5th ed. 2011

35

VON WILEBRAND DISEASE

VWD is an autosomally inheritted congenital bleeding
disorder caused by a deficiency (type 1), dysfunction
(type 2) or complete absence (type 3) of VWF
VWF has two function :
* plays an integral role in mediating adherence of
platelets at sites of endothelial damage, promoting
formation of platelet plug
* binds and transport F VIII, protecting it from
degradation by plasma proteases

Lanszowsky. Manual of Pediatric Hematology Oncology. 5th ed. 2011

36

Type 1

Type 2A

Type 2B

Type 2M

Type 2N

Type 3

Pseudo

VWF: Ag

<

<

<

</N

</N

<

VWF R:CO

<

<<<

<<

<<

</N

<<

F VIII

</N

</N

</N

<<

1% - 6%

</N

LD-RIPA

>>>

>

PFA-100

>/N

>

>

>

>>>

>

BT

>/N

>

>

>

>>>

>

Platelet

<

<

VWF
Multimer

</N

Abnormal

Abnormal

</N

</N

Abnormal

Frequency

1% - 2%

Rare

Rare

Rare

Rare

1 : 250000

Rare

Nathan & Oski. Hematology of infancy and childhood. 7th ed. 2009

37

38

BLOOD TYPE AND VWD

Blood type

Lower VWF; Ag Limit

35.6 U/dL (mean 74.8 U/dL)

48.0 U/dL (mean 105.9 U/dL)

56.8 U/dL (mean 116.9 U/dL)

AB

63.8 U/dL (mean 123.3 U/dL)

Gill JC et al. Blood. 1987;69:1691-5

39

SIGNS & SYMPTOMS

Mucocutaneous bleeding :
Excessive bruising
Epistaxis
Menorrhagia
Postoperative hemorrhage
GI Bleeding
Symptoms can change

Lanszowsky. Manual of Pediatric Hematology Oncology. 5th ed. 2011

40

LABORATORY FINDINGS
Bleeding time & aPTT prolonged (aPTT may be normal if
F VIII is greater than 30% - 40%)
F VIII & VWF normal or prolonged
BT & PFA 100 : sensitive but not spesific
Genetic : chromosome 12 contains gene of VWF

Lanszowsky. Manual of Pediatric Hematology Oncology. 5th ed. 2011

41

TREATMENT
Desmopresin for type 1 VWD, but CI for type IIB
(because it may cause platelet aggregation and DIC)
Severe bleeding or dont respond to desmopresin
treatment : Humate P
Mild epistaxis treatment : EACA or tranexamic acid

Lanszowsky. Manual of Pediatric Hematology Oncology. 5th ed. 2011

42

Type 1 Type 2A

Type 2B

Type 2M

Type 2N

Type 3

Pseudo

Severe
Hemorr.
Major
surgical

DDAVP

F VIII; VWF
Concentrate

F VIII; VWF
Concentrate

F VIII; VWF
Concentrate

F VIII; VWF
Concentrate

F VIII; VWF
Concentrate

Platelet
transfusion

Mild
Hemorr.
Minor
surgical

DDAVP

F VIII; VWF
Concentrate

F VIII; VWF
Concentrate

F VIII; VWF
Concentrate

F VIII; VWF
Concentrate

F VIII; VWF
Concentrate

Platelet
transfusion

Oral
surgical
procedure

DDAVP
& EACA

F VIII; VWF
Concentrate
& EACA

F VIII; VWF
Concentrate
& EACA

F VIII; VWF
Concentrate
& EACA

F VIII; VWF
Concentrate
& EACA

F VIII; VWF
Concentrate
& EACA

Platelet
transfusion
& EACA

Lanszowsky. Manual of Pediatric Hematology Oncology. 5th ed. 2011

43

Von Willebrand Dis.

Hemophilia A

Symptoms

Bruising, epistaxis,
menorrhagia,mucosal bleeding

Joint / muscle bleeding

Sexual

Male = Female

Male >>

Frequency

1:200, 1:500

1:6000

Abnormal protein

VWF

F VIII

Molecular Weight

0.5 20 x 106 DA

280 kDA

Function

Platelet adhesion

Clotting cofactor

Site of synthesis

Endothelial cell or megacariocyte

??

Chromosome

Chromosome 12

X chromosome

Inhibitory frequency

Rare

14% - 25% of patients

History

Abnormal

Abnormal

aPTT

Normal or >>

>>

Factor VIII

Borderline or decreased

Decreased or absent

VWF Ag

Decreased or absent

Normal or decreased

VWF R:CO

Decreased or absent

Normal or decreased

VWF Mutimers

Normal or abnormal

Normal

Lab test

Lanszowsky. Manual of Pediatric Hematology Oncology. 5th ed. 2011

44

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