Hemophilia Galila Zaher

Hemophilia

• Galila Zaher

• Consultant Hematologist

• MRCPath

• KAUH

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.

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

Hemophilia In The Middle East (Extrapolated Statistics)

Hemophilia Prevalence

• Saudi Arabia :1,896 patients with Hemophilia

• KFSH Riyadh >150 Patients

• Department of Hematology Dammam :54patients

• KAUH :40 patients

• Lack of public awareness

• Absence of national registry

• Under- diagnosis

Hereditary Coagulation Factor Deficiencies In KFSH Riyadh

• Patient number >159

• Hemophilia A:122 patients Hemophilia B:37 patients

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 Nov;5(6):1188-95.

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

Hereditary Coagulation Factor Deficiencies In KAUH

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

Diagnosis and Management

• Base line coagulation screen

• Mixing studies

• Factor Assay

• Inhibitor quantitation

• Factor Concentrate

• DDAVP & Tranexamic acid

• FFPs & Cryoprecipetate

Report On The Universal Data Collection System

Prevalence Of Hepatitis B Virus Exposure and Vaccination Status

Hepatitis B Virus Infection

• The rate of exposure to HBV in congenital bleeding disorders 11.1%

• Trans R Soc Trop Med Hyg. 1989 Mar-Apr;83(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

Hepatitis B Virus

HCV Transmission

• HCV major cause of virus-induced liver diseases

• 1990, anti-HCV of blood donors became mandatory

• Incidence of post-transfusion HCV < 1%

• Improvements in HCV antibody assays: 1/106

• Hemophilia generated new susceptible populations

Prevalence Of HCV Infection Among Persons With Hemophilia

Hepatitis C Virus Antibodies Saudi Population

• HCV is endemic in the Saudi population

• Overall frequency of 5.3%

• 5 X > reported from Western Europe and USA

• Hemophiliacs. Seropositivity rate :78.6%

• Vox Sang. 1991;60(3):162-4

Hepatitis C Virus

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

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

Investigations 

•  Hb: 9.2g/dl WBC: 16.5X109 plt:509X109

• 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

Management

• Patient was started on factor VIII concentrate 8 hourly

• Aiming x 100% x10 D

• Neurosurgery consult : observe

• Patient was improving clinically 

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

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

 Follow-Up

•  Follow-up in OPD

• Inhibitor screen at Nov 2003. No evidence of inhibitors.

Case 2

• 15 y old girl

• Referred with history of PR bleeding .

• History of salmonella infection.

• PMH of ? 2 attacks of DVT (clinical suspicion).

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.

Transfer To KAUH

• Fresh PR bleeding & heavy menstrual period .

• Febrile .

• Bruises on anti-cubital fossa .

Investigations

• Hb 7.5 g/dl & APTT 118 sec.

• Mixing study :immediate & post incubation NC

• Factor VIII level 2% & VWF level 80%

• Bethesda assay> 500 IU.

• LA screen &ACL Ab :negative .

• Septic screen : negative.

• Serology: HBSAg “R”,HBEAg positive

• Family study FVIII level :normal

Admission Course

• Upper GIT endoscopy “Hiatus Hernia”.

• No blood TX.

• Hb level 7.5 9.5 g/dl on iron supplementation.

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 Jul;4(4):558-63

Management

• Clinical presentation.

• Titer of the inhibitor.

• Associated medical condition.

• Likelihood of spontaneous remission .

• Risk of toxicities of therapy .

• Cost .

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

Dental Extraction

• During F/U patient had fractured wisdom tooth for extraction

• Patient was admitted prior to extraction

• FVII level >1%

• Bethesda assay >500IU

• 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

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

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

• 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.

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

• Its short half-life

• Frequent dosing is needed

• Difficult venous access :catheter

• Higher cost than APCCs.

• Porcine factor VIII may be an option.

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.

• 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.

• 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.

• High inhibitor titer (BU=25).

• 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.

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 Nov;5(6):1104-13.

Thank you

Hemophilia working Group in KAUH

• Blood bank specialist

• Pediatrician

• Infectious disease specialist

• Orthopedic surgeon

• Dentist

• Pharmacist

• Hemophilia nurse

• Social worker

• Hematologist

Prevalence of hepatitis A virus exposure &vaccination status among persons with hemophilia.

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

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)

The Malmo protocol

MALMÖ TREATMENT MODEL

• Inhibitor titre levels > 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

• D+4 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.

Prevalence Of HIV Infection Among Persons With Hemophilia