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Hemophilia

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

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Hemophilia

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  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)

  5. 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

  6. Hereditary Coagulation Factor Deficiencies In KFSH Riyadh • Patient number >159 • Hemophilia A:122 patients Hemophilia B:37 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 Nov;5(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

  11. Hemophilia Patient Registry In KAUH

  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 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-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

  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 < 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 > reported from Western Europe and USA • Hemophiliacs. Seropositivity rate :78.6% Vox Sang. 1991;60(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 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

  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 Historycont • 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 assay> 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 Jul;4(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 >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

  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 (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.

  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 Nov;5(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

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