gives an overview of congenital bleeding disorders especially the more common ones - hemophilia and von willebrand disease

1. Congenital Bleeding
Disorders
Ma. Ysabel Lesaca-Medina, MD
Pediatric Hematology-Oncology

3. Prince
Leopold
Born
1853

4. Princess beatrice,
9th
child
Princess
louise
Prince leopold,
8th
child

5. Married to Princess Helene: 1882

6. Princess Alice
Hemophilia carrier

7. London news:
Death of the duke
of albany
March 27, 1884
Villa Nevada
Morphine side
effects

8. Prince
charles
Princess alice

10. Outline
 What is and how does hemostasis occur?
 How does one evaluate a patient presenting with
bleeding?
 What are the features of the Congenital Bleeding
Disorders?
 Hemophilia A, Hemophilia B
 Von Willebrand Disease
 Platelet function disorders
 Rare Coagulation Factor Deficiencies

11. What is Hemostasis ?
 Maintenance of fluid
blood flow
 Prevention of bleeding

12. Hemostasis – 3 stages
1. Vascular
– vasoconstriction
1. Platelet (PRIMARY HEMOSTASIS)
– Platelet plug formation
1. Coagulation (SECONDARYHEMOSTASIS)
– Fibrin thrombus formation
– Clotting factors

13. Intact vessel

14. Platelet Phase

15. platelet phase

16. Resting  activated
platelets

17. Coagulation phase

18. Fibrin Clot

19. PTT

20. APTT

21. PT

22. TT

24. Factor XIII
cross links fibrin

26. Clinical Evaluation
of Bleeding patient

27. Clinical History

28. Detailed History
 Symptoms:
 Epistaxis
gum bleeding, easy bruising, menorrhagia,
hematuria, GI bleeding
(platelet problem)
 hemarthrosis, intramuscular bleed
(coagulation problem)
 Delayed onset bleeding
(factor XIII problem)

29. Detailed History
Response to hemostatic challenge: circumcision,
surgery, phlebotomy, immunization, suture
placement/removal
Underlying medical conditions :
 liver disease, renal failure, vitamin K deficiency
Medications:
 antiplatelet drugs, anticoagulants, antimetabolites,
antibiotics

30. Detailed History
 Family history:
 similar symptoms
 response to hemostatic challenge,
 consanguinity
 Menorrhagia
 > 3 soaked pads /day
 Flooding
 Hb < 10g/L

31. Physical Examination

32. Physical Examination
Petechiae < 2mm
Purpura 2mm – 1 cm
Hematoma
Ecchymoses > 1 cm

33. Physical Examination
HEMARTHROSIS

34. Physical Examination
INTRAMUSCULAR BLEED, PSOAS

35. Laboratory evaluation

36. Laboratory Evaluation
 Initial lab tests
 CBC with platelet
 PT (extrinsic)- VII, X, V, II, I
 PTT (intrinsic)- XII, XI, IX, VIII, X, V,II, I
 Further work up:
 Thrombin time
 PFA, platelet aggregation
 Mixing Studies, clotting factor assays, VW antigen
tests, urea clot lysis assay

37. DDX, based on initial
screen
↑ PT
Normal plt,
Normal PTT
↑ PTT
Normal plt,
Normal PT
↑ PT,PTT
Normal plt
•Early Liver
Disease
•Early Vit K
Def
•F VII Def
•F VIII def
(hemophilia or VWD)
•F IX, XI, XII def
•Inhibitors
•Late Liver
Disease
•Late Vit K
deficiency
•Massive
Transfusion

38. ↑ PTT, TT
Normal PT,
Normal plt
All normal Platelet dec
Heparin
- activates AT III 
AT III inactivates
thrombin
- PTT more sensitive
to heparin
VWD
Platelet fxn d/o
Mild factor def (VIII, IX, XI, XIII )
Collagen Disorder
Vitamin C def
CAMT,
TAR,BSS
WAS, GPS
ITP
Infection
CAMT = Congenital Amegakaryocytic Thrombocytopenia BSS = Bernard Soulier Syndrome
TAR = Thrombocytopenia with Absent Radius
GPS = Gray Platelet Syndrome WAS = Wiskott Aldrich Syndrome

39. Out Patient Clinic Time

40. 6 year/ M
 Needs dental extraction; sent for hematologic clearance
 History of easy bruisability
 Mother and aunts report easy bruisability and strong
menses
 2 cousins died during delivery of unknown cause

41.  Labs
 CBC Normal
 PT Normal
 PTT 39.3 (23 – 33 secs)

42. DDX, Normal plt, Normal PT
prolonged PTT,
 Dec Factor
VIII due to
 Hemophilia A
 VWD
 Dec Factor IX,
XI, XII
 Lupus
anticoagulant or
other coagulation
factor inhibitors

43.  Factor VIII : 0.29 u/ml (0.5 – 1.5 u/ml)
 VWF : 1.2 u/ml (0.5 – 1.5 u/ml)

44. Hemophilia A, mild
Diagnosis

45. HEMOPHILIA
 Essentials
 Factor VIII (or IX ) deficiency
 X-linked (2/3) or
spontaneous mutation (1/3)
 Sxs: Bruising, soft tissue bleeding,
hemarthrosis
 Labs: Prolonged PTT + dec factor
VIII (or IX) levels

46. HEMOPHILIA
 Most common severe congenital
bleeding disorder
 Prevalence
 Hemophilia A (Factor VIII)
 1 / 10,000 males
 Hemophilia B (Factor IX)
 1 / 50,000 males

47. HEMOPHILIA –
severity classification
 Factor VIII
– reported in units / ml ( 1 unit/ml = 100% factor
activity)
- Normal range: 0.5 – 1.5 IU/ml (50 – 150%)
Classification
- Severe (60% of cases) : < 1% factor VIII
(spontaneous bleeding)
- Moderate : 1 to < 5%
- Mild : 5 – 50 % ( only with trauma and surgery)

48. HEMOPHILIA- Lab
findings
 PTT (normal plt; normal PT)
 Dx is confirmed by Factor Assay
 F VIII ( with normal VWF ) =
Hemophilia A
 Dec F IX = Hemophilia B

49. HEMOPHILIA- S/Sx
 Severe Hemophiliacs
 Usually initial presentation in 1st
2 years of life
( severe bruising and joint bleeds)
 40 – 50% present in the 1st
month of life
 1- 4% present in the neonatal period (birth trauma)

50. HEMOPHILIA
 Mild or Moderate
 Boys
 Trauma related bruising or bleeding
 Excessive bleeding following surgery or dental
extraction
 Girls ( carriers )
~ Often with Factor VIII < normal
 Mild bruising or bleeding
 Heavy menstrual periods

51. HEMOPHILIA-Cxs
 Hemarthroses
 If recurrent  joint destruction
 Intracranial hemorrhage
 Leading cause of death among
hemophilliacs
 Intramuscular hematomas
 Compartment syndrome  muscle and
nerve death ( anterior forearm, anterior
tibial compartment)

52. HEMOPHILIA-Cxs
• Infection
• HIV, Hep B, Hep C
• Not at risk, With current donor screening and viral
inactivation of factor concentrates,
• But still at risk for:
• Hepatitis A
• Creutzfeld-Jakob Disease
• Parvovirus B-19
• Recommend Hep A and Hep B vaccines for all pxs

53. HEMOPHILIA-Cxs
• Acquired antibody to Factor VIII
• Antibody that inactivates F VIII function
• Develops in
• 30% of pxs with severe hemophilia
• < 5% of Hemophilia B

54. Antibody to factor VIII
• Quantified by Bethesda units
• 1 Bethesda unit – inactivates 50% of F VIII function
• TREATMENT:
• < 5 B.U.
• Increase dose of F VIII
• > 5 BU
• Bypass agents: prothrombin complex conc ; FVII
• ITI (immune tolerance induction)

55. HEMOPHILIA-
Tx
General aim of Mx:
correct factor VIII to w/in normal
limits  prevent or stop bleeding
Mild
May respond to desmopressin (ADH)
- Releases endothelial stores of
VWF
Most still need exogenous F VIII
after

56. HEMOPHILIA-Tx
• Factor VIII dose
• Non-life/limb threatening bleed
• 20 to 30 u/kg  40 – 60% F VIII activity
• Large hemarthrosis and life/limb threatening bleed
• 50 u/KG  100% F VIII activity
• Cryoprecipitate
• 100 u F VIII / unit
• e.g. 10 kg child –> 20 u/kg =
• 200 u F VIII -> 2 u cryoppt)
• (FFP (contains factor IX) – used for Hemophilia B)

57. HEMOPHILIA-Tx
 Prophylaxis
 Preventive F VIII infusions
 2 to 3x, weekly
 To achieve F VIII level >1%
 Expensive
 Initiate after 1st
joint bleed
 Do not start before 6 months of age –
increases risk of inhibitor devlpt

58. HEMOPHILIA
TREATMENT
in the pipe line
GENE
THERAPY

59.  NEXT PATIENT please…

60. 13 / female
Cc: menometrorhagia
 Easy bruising and occasional epistaxis since childhood
 Gum bleeding on toothbrushing
 No previous BT
 Iron supplement in the past

61.  Family History
 Maternal grandmother and mother with
epistaxis and heavy menses
 3 brothers and 2 sisters normal

62.  Hb 114
 Platelet 300 (150 – 450)
 PT : normal; 12.9 sec INR 1.1
 PTT : normal; 32.5 (23.5 – 33.5)

63. ↑ PTT, TT
Normal PT,
platelet
All normal Platelet dec
Heparin
VWD
Platelet fxn d/o
Mild factor def (VIII, IX, XI,
XIII )
Collagen Disorder
Vitamin C def
CAMT, TAR,BSS
WAS, GPS
ITP
2 Infection

64.  VIII
 0.48 u /ml (0.5 – 1.5 u/ml)
 VWF Ag
 0.20 u /ml (0.5 – 1.5 u/ml)

65. VonWillebrand Disease,
type 1
DIAGNOSIS

66. Von Willebrand
Disease
 Most common inherited
bleeding disorder
(Prevalence: 1% - by lab def’n;
only 10% symptomatic)
 Quantitative or
Qualitative deficiency
of vWF
 Easy bruising /
epistaxis from
childhood /
menorrhagia Dr. Erik Von Willebrand, 1926

67. Diagnosis
 Criteria
 VWF Ag < 30%
 Or VWF Ag 30-50% , in patient
with clinical symptoms supportive
of VWF

68. The Von Willebrand
Factor
 Protein in plasma
 Function
1. Tethers platelets to
damaged
endothelium
2. Binds and protects
Factor VIII
Endothelial cells
w/stored VWF

69. vWD

70. vWD- Classification
 Type 1
 Classic ; 80% of patients
 Partial quantitative deficiency
 Type 2
 Dysfunctional VWF- qualitative
 Type 3
 Nearly COMPLETE deficiency

71. vWD-Inheritance
 Mostly AD ; can be AR
 Theoretically, equal males and females
 But more females dxd (menorrhagia)
 Can be acquired
 rare
 Hypothyroidism, Wilms tumor, Cardiac
disease, Renal disease or SLE / Valproic
acid
 Most often caused by Ab to VWF

72. vWD- S/Sx
 Increased bruising and excessive epistaxis
 Prolonged bleeding with trauma or surgery
 Menorrhagia
 Significant menorrhagia from menarche 
prompt investigation for congenital bleeding d/o

73. vWD-Labs
 Initial screen:
- PT normal
- PTT sometimes prolonged
> in type 3 (factor VIII dec)
- Platelet sometimes dec
> in types 2 and 3
 Most of the time: PT, PTT, platelet --- NORMAL
 Blood type ‘O’ – normally lower vWF

74. VWD
 Bleeding time
- prolonged
 Platelet function analyzer
– prolonged closure time
 vWF assay
- Definitive test

75. vWD -Treatment
 VWD types 1 and 2
 Desmopressin
 Releases vWF from endothelial stores
 IV or intranasal ( high concentration spray )
 Variable response  measure VIII and vWF 60
minutes after
 May cause fluid shifts (hyponatremia seizures )
 Tachyphylaxis occurs (stored VWF limited)
 Further therapy with VWF concentrate or
cryoprecipitate

76. VWD -treatment
 Intermediate purity F VIII
concentrates
 Cryoprecipitate

77. AdjunctiveTreatment
 Antifibrinolytic agents
(Tranexamic acid / E-aminocaproic acid )
 Prevents plasminogen  plasmin
 For mucosal bleeding
 Topical thrombin and fibrin glue
 Estrogen containing contraceptive tx
 For menorrhagia

78. Rare Coagulation Disorders

79. Rare coagulation disorders
 Other congenital coagulation factor
deficiencies
 Afibrinogenemia /hypofibrinogenemia
 Deficiencies of factor V, VII, X, XI, XIII
 Combined, occur in 1-500,000 to 1:2,000,000
 Autosomal recessive
 Most common : Factor VII def
 Causes most bleeding sxs: Factor X and Factor XIII
def

80. Rare coagulation disorders
 S/Sx
 Umbilical stump bleeding
 Delayed cord separation
 Intracranial or intestinal hemorrhage
 Muscle hematomas
 Easy bruising
 Prolonged bleeding ff heelprick

81. Inherited platelet
Disorders

82. Inherited platelet disorders
 Decreased number and abn function
 Bernard Soulier Syndrome (BSS)
 Wiskott Aldrich Syndrome (WAS)
 Gray Platelet Syndrome (GPS)
 Normal number but abn function
 Glanzman Thrombasthenia (GT)
 Storage Pool Disorder (SPD)

83. Dec # and abn platelet fxn
Defect S/Sx Labs
BSS No GPIb/IX plt
receptor ->
defective
binding to
VWF
ARecessive
Bruising/
bleeding from
infancy
Moderate
thrombocytopenia
Large platelets
GPS Alpha granule
deficiency
Severe bruising
bleeding from
early age
Mild
thrombocytopenia
Large
gray/Agranular
platelets

84. GLANZMANN
THROMBASTHENIA
Defect S/Sx Labs
Normal number
Normal morph
Platelet GP
IIb/IIIA
(fibrinogen
receptor) –
FAILS TO
AGGREGATE
ARecessive
Severe spont’
mucosal
bleeding
Presents in
infancy
BT
Flow
cytometry
Plt
aggregation

85. SUMMARY

86. Summary
 Hemostasis
 3 stages
 Vasoconstriction
 Platelet phase
 Coagulation phase
 Congenital bleeding disorders
 Hemophilia A, B
 VWD
 Rarer coagulation disorders
 Inherited platelet disorders

87. Summary
 Suspect a congenital bleeding disorder
 Symptoms presenting in early infancy/childhood
 Similar symptoms in family members
 Consanguinity
 Most common disorders
 Hemophilia
 VWD

88. Summary
 Do coagulation screen
 Deranged PTT only
 Think…
 Hemophilia – hemarthrosis/intramuscular
bleed
 VWD – bruising / petechiae, epistaxis
 Platelet, PT, PTT all normal
 Think…
 VWD
 Platelet function disorder
 Mild coagulation disorders

89. Hemophilia A or B
(factor VIII /IX def)
VWD
(VWF def or abn)
Inheritance X linked
De novo (1/3)
AD
(few AR)
S/Sx Easy bruisability
Hemarthrosis
Soft tissue bleed
Menorrhagia
Easy bruisability
Epistaxis
Menorrhagia
Labs Prolonged PTT Normal plt, PT, PTT
< Prolonged PTT (few) >
Confirmatory
test
Factor VIII /IX assay VWF assay
Treatment Desmopressin (for mild
Hemophilia A)
Recomb Factor VIII /IX
Cryoprecipitate /FFP
Desmopressin
Intermediate purity FVIII
Cryoprecipitate