Hemophilia & von willibrand disease

1. Hemophilia & von willibrand disease Dr.Padmashini

2. objectives History Introduction Definition Clinical Features Diagnosis Available treatment modalities

3. Best known of the hereditary bleeding disorders. First coined by Schonleinin 1820s. Originally termed “Haemorraphilia” i.e. love for haemorrhages but over time contracted to Hemophilia. History

5. Hemophilia is often called the disease of kings because it was carried by many members of Europe’s royal family. • Queen Victoria of England was a carrier of hemophilia

6. Introduction • Hemophilia are bleeding disorders due to deficiency or defect in one of the factor present in clotting cascade, • X – linked recessive disorder, • Disease of men with women being asymtomatic carrier

9. Definition • Hemophilia A (classic) :deficiency or dysfunction of factor VIII • It is a large single chain protein that regulates the activation of factor X by proteases generated in intrinsic coagulation pathway • Incidence : 1 in 10,000males

10. Hemophilia B (Christmas) : deficiency or dysfunction of factor IX • Incidence : 1 in 25,000-35,000 males • Von willibrand disease : It is a hereditary deficiency a defect in portion of factor VIII complex

11. Types • Factor level < 1% - severe disease • Factor level 1-5% - moderate disease • Factor level 5-20 % - mild disease • Factor level 20-50% - unaware that they have hemophilia

12. Easy bruising & recurrent bleeding in to joints & muscles Bleeding occurs hrs or days after injury if untreated continue for days or weeks Clinical features

13. Large collection of clotted blood putting pressure on adjacent normal tissue-necrosis of muscle – compartment syndrome

14. Pseudophlebitis : venous congestion Pseudotumour : bone cysts result from unresolved hematoma

15. CNS : SDH occur spontaneously or with minimal trauma Hematuria : common usually not serious Femoral neuropathy due to pressure from unsuspected retroperitoneal hematoma

16. Mucocutaneous bleeding: spontaneous bleeding in to orophraynx , GI tract, epistaxsis ,hemoptysis, delayed bleeding after dental extraction

17. Hemophilic Arthropathy: • chronic inflammation. • Chronic proliferative synovitis • characterised by progressive and erosive destruction of joint cartilage, narrowing of joint space

18. scenario • A one yr old male baby brought to ER at around 4 pm with bleeding continously after a small cut in the knee joint while playing at around 11am on the same day

19. Lab Investigation COAGULATION PROFILE • PT – normal • aPTT – prolonged • Factor assay factor VIII deficiency – hemophilia A factor IX deficiency – hemophilia B • Bleeding time - normal

20. Prenatal diagnosis • Obtain chorionic villi samples in 10th-11th gestational week and perform direct genotype testing.

21. Initial assesment • Early & complete factor replacement before or at the same time as other resuscitative & diagnostic maneuvers • Bleeding in to neck,tongue,retropharynx – airway compromise – intubation • Bleeding in to CNS – immediate factor replacement fallowed by CT scan

22. Cont.. • Neurologic defecit localize to region with in spinal cord – MRI • Hemophilic pt with back, thigh, groin, abdominal pain-factor replacement with imaging • Hemarthrosis – consult orthopedist for splinting & rehabilitation

23. Special attention • Adequate pain relief with opiods • Avoid aspirin & NSAID DONTS • Central lines should not be placed with out factor replacement • ABG/ arterial line • IM injections

24. Treatment • Factor replacement therapy Two different options : • Plasma derived & purified factor • Recombinant factor replacement

25. Hemophilia A • Human plasma derived factor VIII products • Human plasma derived factor VII • Recombinant factor VIII products • Porcine factor VIII products

26. Hemophilia B • Factor IX complex product • Activated factor IX complex product • Purified factor IX product • Recombinant factor IX product

27. DOSAGE • Dosing regimen based on clotting factor volumeof distribution, half life of factor & hemostatic level of factor required to control the bleeding

28. Hemophilia A • One unit of factor VIII per Kg of body weight raises plasma level by approximately0.02U/ml • Half life – 8-12 hrs • Dose of FVIII (units) = (percent desired rise in plasma FVIII) x (body wt) x 0.5

29. Hemophilia B • One unit of factor IX per Kg of body weight raise the plasma level by0.01u/ml • Half life – 16 hrs • Dose of factor IX(units)=(percent desired rise in factor IX) X body weight

30. FACTOR REPLACEMENT GUIDELINES

31. Minimum initial factor levels 40-50% 80-100% 50% 100% 30-50% 100%

32. FFP or cryoprecipitate Each bag cryoprecipitate: 100 units of factor VIII FFP – all plasma clotting factor ,concentration of 1u/ml One unit FFP – raise factor level 3-5 % Undiagnosed bleeding disorder

33. Cryoprecipitate • Prepared by slowly thawing fresh frozen plasma at 2-4`C, then harvesting the precipitate by centrifugation. • Cryo prepared from 200ml of FFP contains 80-100 U of FVIII, ~250mg fibrinogen and useful amounts of FXIII and vWF per 10-15ml of precipitate. • Use thawed cryo within 4hr. • Can be stored at -18`C for 1yr.

34. scenario • A 10 yr old girl weighing 20kg a known case of haemophilia B came to ER with complaints of profuse gum bleeding after brushing her teeth

35. Oral & mucosal bleeding : Area identified, cleaned of inadequate clot & dry topical thrombin placed at bleeding site Factor replacement should be 80-100 % Specific problems

36. Antifibrinolytic agent( epsolin aminocarporic acid & tranexamic acid) • Dose of EACA – 75-100 mg/kg q 6 h (children) • 1-6 g q 6 h for adults • Given PO /IV

37. Tranexamic acid oral- 25 mg/kg/dose every 6-8hr. iv - 10 mg/kg/dose every 6-8hr Topical hemostatic agent – microfibrillar collagen hemostat,thrombin & absorbable gelatin sponges

38. scenario • A 25 yr old gentleman who is diagnosed as having haemophilic A 10 yrs ago, with factor level of 25% admited in the hospital for severe AGE,while securing I.V cannula pt had continous bleeding from the vene puncture site

39. Treated with desmopressin Desmopressin cause release of Vwf from endothelial site Inc amount of Vwf capable of carrying additional amount of factor VIII in plasma Mild hemophilia A

40. Dose • Intravenous: 0.3 ug/kg ( max 20 ug) over 30 min • Intra nasal : children > 5 yrs single spray in single nostril (150 ug total dose) • Adults & adolescent 300 ug total dose

41. Third dose – inc factor by 2-3 times • Repeated 8-12 hrs • Pts stores of factor VIII will be depleted & subsequently effect will be less

42. Scenario • A 7yr old boy who is an haemophilic came to ER with complains of tooth ache O/E pt was having caries tooth,for which dentist has adviced tooth extraction

43. Filling carries tooth : single infusion of factor VIII with administration of 4-6 g of EACA q6h for 3-4 days Major oral & periodontal surgery , extraction of permanent teeth – factor replacement begin before surgery & continue for 2-3 days Dental procedure

44. Inhibitors • Usually IgG antibodies that rapidly neutralize factor VIII activity Two types : • Type 1 – raise their antibody fallowing exposure to factor VIII • Type 2 – low antibody titre not stimulated by factor VIII infusion

45. Type 1 – should not receive factor VIII • Control of bleeding – porcine factor VIII -prothrombin complex concentrate • Type 2 – respond to higher doses of factor VIII

47. Gene therapy –Involves transfer of genes that express a particular gene product into human cells • studies in human under trial

48. Complication • Multiple episodes of hepatitis • Elevated hepatocellular enzyme level • Hepatospleenomegaly • End stage liver disease • Iv drug abusers & long term hemophilia – high risk for AIDS

49. Von willibrand disease • It is a hereditary deficiency a defect in portion of factor VIII complex • vWF is a glycoprotien ,synthesized, stored & then secreted by vascular endothelial cells • Co factor for platelet adhesion & carrier protien for factor VIII

50. Major three groups • Type 1 : common & partial quantitiative disease • Type 2 : qualitative ( abnormal function) • Type 3 : severe & almost compelete defeciency of vWF