Hemophilia

Galila Zaher Consultant HematologistMRCPathKAUH

PrevalenceWorld-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 statisticsExtrapolations 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)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

Hemophilia PrevalenceSaudi Arabia :1,896 patients with Hemophilia KFSH Riyadh >150 PatientsDepartment of Hematology Dammam :54patientsKAUH :40 patients Lack of public awareness Absence of national registryUnder- 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 1991-9754 patients 42 hemophiliacs, 39 hemophilia A , 2 hemophilia B 5 Saudi patients factor XIII deficiency7 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)KAUH47 patients age 4-26 years40 inherited factor deficiency & 7 have platelets defect 21 hemophilia A , 9 hemophilia B 2 patients factor V deficiency, one FVII, FXI, FX & FXII deficiency4 patients von Willebrand disease. von Willebrand disease was lower than expected Haemophilia B was higher than expected

Hereditary Coagulation Factor Deficiencies In KAUH

Inherited bleeding disorders

HA

HB

VWD

FV Def

FVII Def

FX Def

FXI Def

FXII Def

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

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

Hemophilia Patient Registry In KAUH

Prevalence Of VWDVWD commonest inherited bleeding disorderDammam 7/54 & KAUH 4/40Female patients presenting to gynecologistUnder- diagnosis : lack of lab supportVWF is an acute phase reactant

Diagnosis and Management

Base line coagulation screenMixing studies Factor AssayInhibitor quantitation Factor ConcentrateDDAVP & Tranexamic acidFFPs & Cryoprecipetate

Report On The Universal DataCollection System Infectious

Disease Complications

Hemophilia (n=835)

vWD (n=94)

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 DiseasesAtlanta, Georgia

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 protocols18/40 tested and were negative reflecting the routine neonatal immunization program started 1990 in SA including HB vaccine

Hepatitis B Virus

Hepatitis B SAg negative

Hepatitis B S AgPositive

Not tested

HCV TransmissionHCV 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 populationOverall frequency of 5.3%5 X > reported from Western Europe and USAHemophiliacs. Seropositivity rate :78.6%

Vox Sang. 1991;60(3):162-4

Hepatitis C Virus

Hepatitis C negative

Hepatitis C Positive

Not tested

Case 1Patient name: M T Sex: Male 2 yearsDiagnosis: Hemophilia A at age of 7 m Admission date: 3-11-2002 Lethargy , vomiting & fever for 1 DTonic-clonic convulsions for 2 D

History & ExaminationOn/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 rigidityNeurological examination normalOther systems examination

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

PT: 1.2 sec PTT: 69.2 sec50/50 immediate mix PTT 40.2 sec50/50 post- incubation mix :PTT 80 secFactor 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 : observePatient was improving clinically 

ManagementPatient was started on Malom ProtocolCyclophosphamide 2 mg/kg/dPrednisolone 1 mg/kg/dFactor 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 .

InvestigationsHb 7.5 g/dl & APTT 118 sec. Mixing study :immediate & post incubation NCFactor VIII level 2% & VWF level 80%Bethesda assay> 500 IU.LA screen &ACL Ab :negative . Septic screen : negative.Serology: HBSAg “R”,HBEAg positiveFamily 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

idiopathicpregnancymalignancydrugsautoimmune

Green D & Lechner K: Thrombosis and Haemostasis 45: 200-203 (1981)

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

ManagementPrednisolone alone without cyclophosphamideRegular F/U in OPDContinuous search for underlying cause CT chest ,abdomen & pelvis every yearAutoimmune profile every 6m3 years since diagnosis: Idiopathic Acquired Hemophilia

Dental ExtractionDuring F/U patient had fractured wisdom tooth for extractionPatient was admitted prior to extractionFVII level >1%Bethesda assay >500IUTrial of FVIII conc under IVIG, no improvement in FVIII levelRecombinant FVII 90 micg ; No intra-operative nor post-operative bleedLocal fibrin glue to maintain local hemostasis

Case 3Patient name : H K Known sever HA :bloody diarrhea Oct 2001Post circumcision bleedLf knee swelling post trauma Family history :HA brother

Follow UpIntra-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 riskChronic nature requires lifelong medical attentionExpensive 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 specialistPediatricianInfectious disease specialistOrthopedic surgeonDentistPharmacistHemophilia nurseSocial workerHematologist

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

A1

A3A2

B

C1C2

FACTOR VIII MOLECULE

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 patientsGood efficacy in 75% of bleedsPartial response in 17% of casesResponse usually within 8-24 hours

Hay C et al. Thromb. Haemostas. 78: 1463-1467 (1997)

The Malmo protocol factor replacementimmunoadsorption

suppression of inhibitor

MALMÖ TREATMENT MODELInhibitor titre levels > 10 Bethesda UnitsPlasmapheresis 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 daysD+4 IGg 0.4 g / kg x 5 daysDaily FVIII to maintain FVIII level 40 - 100 % for 2 - 3 ws

Once inhibitors are not detectable, factor VIII is 2-3x/W.

IMMUNE TOLERANCE PROTOCOLS IN HEMOPHILIA WITH INHIBITORS

ProtocolProtocol # of cases# of cases # Successfully # Successfully Average Average DurationDuration

TolerizedTolerized of Induction of Induction TherapyTherapy

%%Malmö Malmö ( 1 ) ( 1 ) 1616 10 ( 62.5 ) 10 ( 62.5 ) 20 days20 days

Bonn Bonn ( 2 )( 2 ) 6060 52 ( 86.7 ) 52 ( 86.7 ) 14 months14 months

(1) Freiburghaus C et al Hemophilia 5 : 32 - 30 ; 1999(2) Oldenberg J et al Vox Sanguinis 77 ( 1 ) : 49 - 54 ; 1999

Prevalence Of HIV Infection Among Persons With Hemophilia