Hemophilia Galila Zaher

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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




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