Hemophilia

1
Hemophilia

• Galila Zaher
• Consultant Hematologist
• MRCPath
• KAUH

2
Prevalence

• World-wide occurs in all racial groups.
• Few decades ago, children with haemophilia had a
  significantly reduced life expectancy.
• Crippled with arthritis joint deformity
• Recent studies increased life-expectancy
• Now face few limitations.
• Normal schools, most jobs are open with full
  employment and marriage.

3
Hemophilia Statistics By Country

• Country-specific prevalence statistics
• Extrapolations of various prevalence rates
  against the populations
• Calculation is automated and does not take into
  account differences across various countries
• May be highly inaccurate and only give a general
  indication to actual prevalence
• CureResearch.com

4
Hemophilia In The Middle East (Extrapolated
Statistics)
Country/Region Extrapolated Prevalence Population Estimated Used
Afghanistan 2,096 28,513,6772
Egypt 5,596 76,117,4212
Gaza strip 97 1,324,9912
Iran 4,963 67,503,2052
Iraq 1,865 25,374,6912
Israel 455 6,199,0082
Jordan 412 5,611,2022
Kuwait 165 2,257,5492
Lebanon 277 3,777,2182
Libya 414 5,631,5852
Saudi Arabia 1,896 25,795,9382
Syria 1,324 18,016,8742
West Bank 169 2,311,2042
Yemen 1,472 20,024,8672
U Arab Emirates 185 2,523,9152
Turkey 5,065 68,893,9182
5
Hemophilia Prevalence

• Saudi Arabia 1,896 patients with Hemophilia
• KFSH Riyadh gt150 Patients
• Department of Hematology Dammam 54patients
• KAUH 40 patients
• Lack of public awareness
• Absence of national registry
• Under- diagnosis

6
Hereditary Coagulation Factor Deficiencies In
KFSH Riyadh

• Patient number gt159
• Hemophilia A122 patients Hemophilia B37
  patients

7
Hereditary Coagulation Factor Deficiencies In
Eastern Province

• In a retrospective analysis 1991-97
• 54 patients
• 42 hemophiliacs, 39 hemophilia A , 2 hemophilia B
  
• 5 Saudi patients factor XIII deficiency
• 7 patients von Willebrand disease.
• Hemophilia B and von Willebrand disease was lower
  than expected
• East Mediterr Health J. 1999
  Nov5(6)1188-95.

8
Hereditary Coagulation Factor Deficiencies In KAUH

• In a 5-year retrospective analysis
  (2000-2005)KAUH
• 47 patients age 4-26 years
• 40 inherited factor deficiency 7 have platelets
  defect
• 21 hemophilia A , 9 hemophilia B
• 2 patients factor V deficiency, one FVII, FXI,
  FX FXII deficiency
• 4 patients von Willebrand disease.
• von Willebrand disease was lower than expected
• Haemophilia B was higher than expected

9
Hereditary Coagulation Factor Deficiencies In KAUH
10
Hemophilia Patient Registry In KAUH
MRN Nationality FVIII level vWF level FIX level Bethesda Virology Diagnosis Severity
460497 Yemeni 1 82 2 Negative Haemophilia A Severe
466795 Yemeni 1 ND   Negative Negative Haemophilia A Severe
504823 Sudanese 5 ND   ND Negative Haemophilia A Moderate
555810 Saudi 5 ND   ND Negative Haemophilia A Moderate
297426 Saudi         Negative Haemophilia A  
506610 Saudi 10 ND     Negative Haemophilia A Mild
298966 Saudi 5 ND     Negative Haemophilia A Moderate
269095 Saudi 0.30 ND     ND Haemophilia A Severe
465375 Yemeni 5       Negative Haemophilia A  
527413 Saudi         Negative Haemophilia A  
527142 Saudi           Haemophilia A  
496784 Saudi 10         Haemophilia A Mild
318666 Saudi           Haemophilia A  
395720 Palestinian 3   100     Haemophilia A Moderate
465375 Saudi           Haemophilia A  
564518 Saudi           Haemophilia A  
537778 Saudi 5 51 62   Negative Haemophilia A  
438217 Indian 32         Haemophilia Moderate 
581455 Saudi 5 62 100 Negative Negative Haemophilia A Moderate
582141             Haemophilia A  
472359 Indonesian 1         Acquired haemophilia Severe
11
Hemophilia Patient Registry In KAUH
509898 Yemeni Normal Normal       Haemophilia B Mild
501241 Saudi   Normal     Negative Haemophilia B Moderate
492428 Afghan           Haemophilia B Mild
423667 Saudi           Haemophilia B  
363660 Saudi     5   Negative Haemophilia B Moderate
509898 Yemeni Normal Normal 10     Haemophilia B Moderate


574140 Egyptian     52     Haemophilia B  

440433 Saudi Normal Normal   Reg. Negative Haemophilia B Moderate
5452394             Haemophilia Moderate
390282 Saudi Normal         Von Willebrand Disease Mild
429172 Saudi           Von Willebrand Disease  
544348 Yemeni 10 6     Negative VWD
561922 Saudi 5 3       Von Willebrand Disease Severity
518075 Sudanese Normal   Normal     Factor VII Def.  
258546 Syrian         Negative Factor V Def.  
232283 Syrian         HCV Ab Factor V Def.  
440647 Saudi Normal Normal Normal     Prolonged PT  
282904 Saudi           Factor XI Def.  
501201 Pakistani Normal Normal Normal     Factor XII Def. Mild
568488             Factor X Def. Mild
12
Prevalence Of VWD

• VWD commonest inherited bleeding disorder
• Dammam 7/54 KAUH 4/40
• Female patients presenting to gynecologist
• Under- diagnosis lack of lab support
• VWF is an acute phase reactant

13
Diagnosis and Management

• Base line coagulation screen
• Mixing studies
• Factor Assay
• Inhibitor quantitation
• Factor Concentrate
• DDAVP Tranexamic acid
• FFPs Cryoprecipetate

14
Report On The Universal DataCollection System
Infectious Disease Complications Hemophilia (n835) vWD (n94)
H B V infection 19.2 3.2
HC V infection 48.4 10.6

Centers for Disease Control and Prevention
National Center for Infectious Diseases Atlanta,
Georgia
15
Prevalence Of Hepatitis B Virus Exposure and
Vaccination Status
16
Hepatitis B Virus Infection

• The rate of exposure to HBV in congenital
  bleeding disorders 11.1
• Trans R Soc Trop Med Hyg.
  1989 Mar-Apr83(2)256-7
• 22/40 not tested reflecting lack of written
  protocols
• 18/40 tested and were negative reflecting the
  routine neonatal immunization program started
  1990 in SA including HB vaccine

17
Hepatitis B Virus
18
HCV Transmission

• HCV major cause of virus-induced liver diseases
• 1990, anti-HCV of blood donors became mandatory
• Incidence of post-transfusion HCV lt 1
• Improvements in HCV antibody assays 1/106
• Hemophilia generated new susceptible populations

19
Prevalence Of HCV Infection Among Persons With
Hemophilia
20
Hepatitis C Virus Antibodies Saudi Population

• HCV is endemic in the Saudi population
• Overall frequency of 5.3
• 5 X gt reported from Western Europe and USA
• Hemophiliacs. Seropositivity rate 78.6
• 
  Vox Sang. 199160(3)162-4

21
Hepatitis C Virus
22
Case 1

• Patient name M T
• Sex Male 2 years
• Diagnosis Hemophilia A at age of 7 m
• Admission date 3-11-2002
• Lethargy , vomiting fever for 1 D
• Tonic-clonic convulsions for 2 D

23
History Examination

• On/off painful joint swelling after minor
  injuries.
• Not on regular treatment
• Circumcision 6 m ago (FVIII).
• Family history of hemophilia A ,thalassemia SCA
  
• Vitals normal
• Neck rigidity
• Neurological examination normal
• Other systems examination

24
Investigations 

•  Hb 9.2g/dl WBC 16.5X109 plt509X109
• PT 1.2 sec PTT 69.2 sec
• 50/50 immediate mix PTT 40.2 sec
• 50/50 post- incubation mix PTT 80 sec
• Factor VIII level 2
• Inhibitor level 50 Bethesda units
• CT scan brain subdural hematoma

25
Management

• Patient was started on factor VIII concentrate 8
  hourly
• Aiming x 100 x10 D
• Neurosurgery consult observe
• Patient was improving clinically 

26
Management

• Patient was started on Malom Protocol
• Cyclophosphamide 2 mg/kg/d
• Prednisolone 1 mg/kg/d
• Factor VIII stat 100 IU/kg Infusion
  10 IU/kg/hr x3D

27
Hospital Course

• Repeat  CT scan resolution of subdural hematoma
  
•  Patient was discharged on
• - Tegretol 50 mg PO BID
• - Cyclophosphamid 25 mg PO OD
• - Prednisolone 5 mg PO BID
• - F VIII conc 250 IU IV weekly

28
 Follow-Up

•  Follow-up in OPD
• Inhibitor screen at Nov 2003. No evidence of
  inhibitors.

29
Case 2

• 15 y old girl
• Referred with history of PR bleeding .
• History of salmonella infection.
• PMH of ? 2 attacks of DVT (clinical suspicion).

30
Case History cont

• CBC Hb 3.5 g/dl PLT 159X109/L.
• Isolated prolonged APTT.
• Mixing studies NC.
• Factor VIII level 2.
• PRBCs TX , FFP FVIII concentrate.

31
Transfer To KAUH

• Fresh PR bleeding heavy menstrual period .
• Febrile .
• Bruises on anti-cubital fossa .

32
Investigations

• Hb 7.5 g/dl APTT 118 sec.
• Mixing study immediate post incubation NC
• Factor VIII level 2 VWF level 80
• Bethesda assaygt 500 IU.
• LA screen ACL Ab negative .
• Septic screen negative.
• Serology HBSAg R,HBEAg positive
• Family study FVIII level normal

33
Admission Course

• Upper GIT endoscopy Hiatus Hernia.
• No blood TX.
• Hb level 7.5? 9.5 g/dl on iron supplementation.

34
Incidence

• 1/1,000,000 annually.
• Males females.
• 5th decade.
• IgG 1-4 K or mixed .
• Against A2 domain in 48.
• Or C2 domain FVIII binding to VWF.
• 
  Haemophilia 1998 Jul4(4)558-63

35
Green D Lechner K Thrombosis and Haemostasis
45 200-203 (1981)
36
Management

• Clinical presentation.
• Titer of the inhibitor.
• Associated medical condition.
• Likelihood of spontaneous remission .
• Risk of toxicities of therapy .
• Cost .

37
Management

• Prednisolone alone without cyclophosphamide
• Regular F/U in OPD
• Continuous search for underlying cause
• CT chest ,abdomen pelvis every year
• Autoimmune profile every 6m
• 3 years since diagnosis Idiopathic Acquired
  Hemophilia

38
Dental Extraction

• During F/U patient had fractured wisdom tooth for
  extraction
• Patient was admitted prior to extraction
• FVII level gt1
• Bethesda assay gt500IU
• Trial of FVIII conc under IVIG, no improvement in
  FVIII level
• Recombinant FVII 90 micg No intra-operative nor
  post-operative bleed
• Local fibrin glue to maintain local hemostasis

39
Case 3

• Patient name H K
• Known sever HA bloody diarrhea Oct 2001
• Post circumcision bleed
• Lf knee swelling post trauma
• Family history HA brother

40
Follow Up

• Intra-muscular hematoma
• Wasting of the Rt hand muscles post wrist bleed
• Age 3 years Inhibitor 50 B IU
• Rt knee hemarthrosis limited extension flexion
  
• Sever tongue bleed which required ICU admission
• Inhibitor assay 2BU Low responder

41

• LA is a 35-y male with severe hemophilia
• Left knee joint bleed.
• Inhibitor titer of 35 BU
• known high responder
• Failed immune tolerance.
• Hepatitis C positive
• Difficult venous access.

42
Available treatment options

• High responder
• APCCs every 12 to 24 hours
• APCCs is a plasma-derived product (Hep C)
• An anamnestic response is not a concern since LA
  has already failed immune tolerance.
• Low risk of thromboembolic complications
• Recombinant factor VIIa

43

• Its short half-life
• Frequent dosing is needed
• Difficult venous access catheter
• Higher cost than APCCs.
• Porcine factor VIII may be an option.

44
Porcine factor VIII

• Porcine titer to check for x-reactivity
• Titer less than 10 BU, porcine factor VIII may
  be effective.
• Mild infusion reactions in 10 of patients.
• Inhibitors may develop to the porcine factor.
• Porcine factor must be stored frozen.

45

• 2-year-old child with severe HA.
• Spontaneous bleed in the right elbow
• 2X rFVIII in the last 36 hours.
• However, swelling has worsened
• rFVIII had been effective for past bleeds.

46

• Inhibitor titer
• rFVIIa while waiting for titer results
• High doses of rFVIII would be ineffective and may
  result in higher inhibitor levels.
• X-sensitivity to porcine FVIII is unknown.
• Early control of bleeding is essential to prevent
  permanent damage to the joint.

47

• High inhibitor titer (BU25).
• Control bleeding
• Immune Tolerance Induction
• Early initiation of ITI and a young age are two
  factors associated with successful ITI.
• Daily factor infusions for a prolonged period of
  time.
• rFVIIa for bleeding episodes (to avoid an
  anamnestic response).
• Inhibitor titers monitored every 2 weeks.
• ITI may be started when inhibitor titers are less
  than 5 BU.

48
Genetic Disorders Impact On Health Care Delivery

• No agreed-upon definitive cure with acceptable
  risk
• Chronic nature requires lifelong medical
  attention
• Expensive supportive and symptomatic therapy
• Significant burden on the health care delivery
  system.
• el-Hazmi MA East Mediterr Health J.
  1999 Nov5(6)1104-13.

49
Thank you
50
Hemophilia working Group in KAUH

• Blood bank specialist
• Pediatrician
• Infectious disease specialist
• Orthopedic surgeon
• Dentist
• Pharmacist
• Hemophilia nurse
• Social worker
• Hematologist

51
Prevalence of hepatitis A virus exposure
vaccination status among persons with
hemophilia.
52
FACTOR VIII MOLECULE
A2
A3
B
A1
C1
C2
53
Diagnosis Management

• Diagnosis of acquired hemophilia
• Quantification of inhibitors Bethesda assay.
• Search for an underlying disorder
• No correlation between inhibitor titres and
  severity or the pattern of bleeding.
• Treat the bleeding
• Eliminate the inhibitor by Imunnosupression
• Diagnose underlying conditions

54
Recombinant FVIIa

• Retrospective 74 bleeding episodes in 38
  patients
• Good efficacy in 75 of bleeds
• Partial response in 17 of cases
• Response usually within 8-24 hours
• Hay C et al. Thromb. Haemostas. 78
  1463-1467 (1997)

55
The Malmo protocol
immunoadsorption
factor replacement
suppression of inhibitor
56
MALMÖ TREATMENT MODEL

• Inhibitor titre levels gt 10 Bethesda Units
• Plasmapheresis with immunoadsorption initially
  to lower inhibitor levels as much as possible.
• IV cyclophosphamide 12 -15 mg / kg x 2 days then
  3 mg / kg orally x 8-10 days
• D4 IGg 0.4 g / kg x 5 days
• Daily FVIII to maintain FVIII level 40 - 100
  for 2 - 3 ws
• Once inhibitors are not detectable, factor VIII
  is 2-3x/W.

57
IMMUNE TOLERANCE PROTOCOLS IN HEMOPHILIA WITH
INHIBITORS
Protocol of cases Successfully Average
Duration Tolerized of Induction Therapy
Malmö ( 1 ) 16 10 ( 62.5
) 20 days Bonn ( 2 ) 60 52 ( 86.7 ) 14
months
(1) Freiburghaus C et al Hemophilia 5 32 - 30
1999 (2) Oldenberg J et al Vox Sanguinis 77 (
1 ) 49 - 54 1999
58
Prevalence Of HIV Infection Among Persons With
Hemophilia