Hemophila

an overview about hemophilia

1. HEMOPHILIA – AN OVERVIEW

2. OBJECTIVES To know the basic concepts about Hemophilia How to approach a case of Hemophilia? How to Calculate Factor requirement? Management in special situations Lifestyle modifications of the hemophiliacs

3. COAGULATION FACTORS Factor I – Fibrinogen Factor II - Prothrombin Factor III – Tissue factor (Tissue Thromboplastin ) Factor IV – Calcium Factor V – Labile factor ( Proaccelerin ) Factor VII – Serum Prothrombin Conversion Accelerator (SPCA) Factor VIII – Anti-Hemophilic Factor Factor IX – Partial Thromboplastin Component (PTC); Christmas Factor Factor X – Stuart- Prower Factor Factor XI – Plasma Thromboplastin Antecedent (PTA) Factor XII – Hagemann factor Factor XIII – Fibrin stabilizing Factor

4. What is Hemophilia ? Hemophilia is an X linked recessive hemorrhagic disorder due to mutations in F8 gene and the most common being inversion of intron 22 sequence (Hemophilia A or Classic Hemophilia) or F9 gene (Hemophilia B). Males are usually affected and women who carry a single mutated gene are generally asymptomatic. Family history of the disease is absent in about 30% cases (for whom the mothers carry a de novo single mutated allele).

5. Degrees of Severity of Hemophilia Hemophilia A and Hemophilia B are clinically indistinguishable. The disease phenotype co-relates with residual activity of Factor VIII & IX and can be classified as: Severe (< 1 %) Moderate (1 – 5 %) Mild (6 – 30 %)

6. CLINICAL HIGHLIGHTS

7. Hemophilia clinically manifests when a child begins to walk or crawl. In severe and Moderate forms: * Bleeding into joints ( hemarthrosis ), soft tissues and muscles. * After Trivial trauma or even spontaneously In milder forms: * Infrequent bleeding usually secondary to trauma.

8. FORMS OF BLEEDING Acute hemarthroses are painful erythematous swelling which have the tendency to recur. Chronic hemarthroses are debilitating with synovial thickening and synovitis in response to intrarticular bleed.

9. COMPLICATIONS OF BLEEDING

10. Muscle contractures on adapting a posture to relieve pain Muscle atrophy JOINT CONTRACTURES

11. Hemophilic arthropathy “Target joint” = irreversibly damaged joint with vicious cycle of injury and repeated bleeding

12. Joint destruction

13. Hematomas into muscles of distal parts of limbs may lead on to Compartment syndrome

14. OTHER FORMS OF BLEEDING Life threatening bleeding in form of bleeding into oropharyngeal spaces, CNS or retroperitoneum . Retroperitoneal hemorrhages accumalate large quantities of blood Formation of masses with calcification and inflammatory tissue reaction. Pseudotumor syndrome with damage to the femoral nerve Hematuria a frequent among hemophilia patients, even in the absence of genitourinary pathology

15. LABS Prolongation of aPTT Normal Bleeding Time and platelet Count FVIII and FIX clotting activity determination

16. TREATMENT

17. HISTORY OF CLOTTING FACTOR CONCENTRATES: Prior to 1950: whole blood 1952: Hemophilia A distinguished from B 1950-1960: FFP and Cryoprecipitate Early 1970s: Commercial plasma-derived factor concentrates Mid-late 1970’s: Home infusion practices 1981: First AIDS death in the Hemophilia community Mid-1983: Factor concentrates heat treated for hepatitis 1985: All products heat treated for viral inactivation 1987: Monoclonal factor concentrates 1992: Recombinant factor VIII 1994: Recombinant factor IX-albumin free 2001: 2nd generation recombinant factor VIII

18. HOME THERAPHY Advantages: Immediate access to the treatment It is achieved with clotting factor concentrates or other lyophilised products that are safe and can be stored in a domestic fridge that can be reconstituted easily Cryoprecipite can also be kept in fridge but it should not be frozen.

19. Monitoring of home therapy 1. It should be supervised by a comprehensive care centre with adequate education and training to the pt. Teaching should include recognising a bleed and its complications, dosage calculation, preparation and storage. 2. Administration of clotting factor with aseptic techniques, performing venipuncture , record keeping, as well as proper storage and disposal of needles and handling of blood spills 3. Patients or parents should keep bleeding records that include date and site of bleeding, dosage and lot no. of product used, as well as any adverse effects. 4. Home care can be instituted for young children having adequate venous access and motivated family members undergone adequate training. Self infusion can be encouraged to older children and teenagers. 5. Implanted venous access device (PORT-A-CATH) can also be used but this will be associated with complications like infection and thrombosis.

20. FACTOR REPLACEMENT THERAPY It can be started in response to a bleeding episode or as a prophylactic treatment. Primary Prophylaxis: a tool for maintaining the missing clotting factor at levels >1% or higher on a regular basis in order to prevent bleeds, especially at the onset of hemarthroses . Hemophiliac boys receiving regular infusions of FVIII of 25-40 IU/kg (3 days /week) or FIX( 2 days/week) can reach puberty without detectable joint abnormalities

21. How to calculate Factor requirement? Factor VIII concentrate increases factor VIII activity approximately 2% for every 1 IU/kg infused. A 50 IU/kg IV bolus raises factor VIII activity approximately 100% over baseline. Extended treatment should follow with 25-IU/kg IV bolus q12h to maintain sufficient levels. FVIII dose (IU) = (Target FVIII levels – FVIII baseline levels) x Body weight ( kgs ) x 0.5 unit/kg Half life of FVIII is 8 to 12 hours, hence requires BD dose to maintain therapautic range

22. FACTOR IX REQUIREMENT FIX dose (IU) = (Target FIX levels – FIX baseline levels) x Body weight ( kgs ) x 1 unit/kg FIX recovery postinfusion is usually only 50% of predicted value half life of FIX is 24 hours and hence given an OD dose.

23. TREATMENT OF BLEEDS GOAL OF TREATMENT Mild Bleeds Uncomplicated Hemarthroses or superficial hematomas Maintain factor level at 30 -50% Severe hemarthroses On Target joint Same as mild bleeds with additional doses to maintain levels of 15 -25% for 2 – 3 days. Large hematomas Maintain factor level at 50% and factor replacement required for a period of 1 week or longer Severe bleeds Oropharyngeal spaces CNS or retroperitoneum Maintain factor level at 30 -100% for 7 days Prophylactic replacement for surgery Maintain factor level at 100% for 7 days

24. MANAGEMENT OF BLEEDING WITH INHIBITORS Patients with inhibitors must be in consultation with centers experienced in management of such patients before and all serious bleeds should be managed in such centres Choice of product should be based on the titre of the inhibitor, records of clinical response to products, site & nature of bleeding. Patient with a low responding inhibitor should be treated with a high dose of specific factor replacement at a much higher dose, if possible to neutralize the inhibitor with excess factor activity

25. NON TRANSFUSION THERAPHY IN HEMOPHILIA Mild-to-moderate hemophilia A with minor bleeding: * DDAVP (0.3 mg/kg IV in 50 to 100 mL NS infused over 30 minutes, or 300 mg intranasally [ Stimate , 1.5 mg/ mL ] dosed every 12 hours). Increases factor VIII activity threefold to fivefold and has a half-life of 8 to 12 hours. Tachyphylaxis may occur after several doses ANTI-FIBRINOLYTIC AGENTS: EACA or Tranexemic acid. Bleeding in gums, GIT or during oral surgery. EACA – loading dose of 200mg/kg followed by 100 mg/kg per dose every 6 th hourly. Tranexemic Acid – 25 mg/kg 3 to 5 times a day. Not indicated to control hematuria because of the risk of formation of occlusive clot in the lumen of genitoruinary tract structues

26. COMPLICATIONS DUE TO FACTOR REPLACEMENT

27. Inhibitor formation Formation of alloantibodies to the factor, that is the leading complication of Hemophilia treatment. High risk groups: Severe deficiency of factor Family history of inhibitor Mutation in FVIII or FIX Gene derangements Need for intensive replacement therapy ( major surgeries, intracranial bleeding or trauma) Clinically, hemophilia is diagnosed when patients do not respond to factor replacement at therapeutic levels

28. LABS The laboratory test to conform the presence of an inhibitor is an aPTT with a mix ( with normal Plasma). A 1:1mix with normal plasma normally corrects the aPTT but in patients with inhibitor the aPTT is abnormally prolonged. Bethedsa assay – to define the specificity of the inhibitor and its titer.

29. Bethesda Assay for Inhibitors Serial dilutions of patient plasma in normal plasma Incubate 2 hours Assay residual factor activity 1 Bethesda Unit neutralizes 50% of factor in an equivalent volume of normal plasma Example: 1:100 dilution of patient plasma + normal plasma → 50% residual factor activity, so inhibitor titer is 100 BU

30. Bethesda Assay Residual factor activity dilution pt plasma 50% 1:1 1:10 1:100 1:1000 100 BU

31. Inhibitor patients High responders Initial inhibitor titer >10 BU, do Not respond to FVIII or FIX conc - entrates Low responders Initial inhibitor titer <10 BU responds Well to human or Porcine FVIII with Minimal/no increase in inhibitor titres

32. TREATMENT OF HEMOPHILIACS WITH INHIBITORS Recombinant factor VIIa Enhances TF-driven thrombin formation FEIBA ( F actor E ight I nhibitor B ypassing A ctivity) Mixture of partially activated vitamin K-dependent clotting proteases including VIIa High dose factor VIII (if low titer inhibitor) Induction of tolerance with daily factor VIII infusions Optimal dose not established Role for concomitant immunosuppression ? Patients with severe hemophilia A and inhibitors resistant to ITI: use of anti CD20 monoclonal Antibody with FVIII is effective but transitional.

33. INFECTIOUS DISEASES HCV infection – major cause of morbidity and 2 nd leading cause of death in hemophilia patients exposed to older clotting factor concentrates. Co-morbidity of underlying liver diseases is clear in these individuals. Response to HCV antiviral therapy is also restricted with even more proportion among co-infected with HIV. End stage liver disease requiring liver transplantation may be curative for both liver disease and for hemophilia.

34. Cardiovascular diseases & malignancy Though the early assumption that hemophilia would protect against occlusive vascular disease because of the underlying hypocoagulablility but Physical inactivity, hypertension, CKD and HIV co-infection on ART (commonly observed in hemophiliacs) points more in favor of cardiovascular risk. At risk for HIV and HCV related malignancies. Hepatocellular cancer (HCC) – most prevalant among HIV negative hemophiliacs.

35. LIFE STYLE MODIFICATIONS OF HEMOPHILIACS

36. Goal is to avoid excessive bleeding to protect joints Avoid contact sports – football, hockey or wrestling Can indulge in activities like swimming, bicycle riding Avoid medications – aspirin, ibuprofen, use alternatives like acetaminophen Heparin, warfarin, clopidogrel should also be avoided PRACTICE GOOD DENTAL HYGIENE Goal is to prevent excessive bleeding

37. PROTECT FROM INJURIES : Knee pads, elbow pads, helmets safety belts all may help in preventing injuries. Keep your home free of furniture with sharp corners. CARRY IDENTIFICATION AT ALL TIMES: Always carry a card mentioning the fact that the person is suffering from hemophilia , the type of treatment & the drugs prescribed etc. TRAVEL WITH CARE : While on travel carry all medications and store information about hemophilia clinics around the place.

38. MANAGEMENT OF HEMOPHILIA IN SPECIAL SITUATIONS

39. 1. Surgical intervention may be elective or emergency. Whenever possible pt. is shifted to the hemophilic treatment center. 2. Surgery is undertaken in a place(OT) where reliable and adequate laboratory facilities should be available for monitoring clotting factor level. 3. Pre-operative assessment of inhibitor screen 4. Surgery to be scheduled early in the week and early in the day for optimal laboratory and blood bank support. 5. Availability of sufficient quantities of clotting factor concentrates.. 6. Dosage and duration of clotting factor concentrate coverage depends on type of surgery performed. PLANNING FOR SURGERY : Adequate coagulation factor should be available. If bleeding is very high elective surgery should be postponed. Antiplatelet should be avoided peri -operatively. Adult – 70kg – with severe hemophilia A – taken for major surgery – factor 8 requirement is 50,000 – 80,000 units SURGERY Major Minor Abdominal Removal of skin lesions Intracranial Dental problems Spinal Arthroscopy Joint replacement

40. Coagulation factor replacement for surgery is based on Through factor level : minimum factor level measured immediately before next bolus Peak factor level – maximum factor level measured in 1hr of bolus injection ADULT - MAJOR SURGERY - CONTINOUS INFUSION Minor procedures – continuous infusion of factor is enough Day Factor 8 level Dose( IUKg ) 1 - 6 More than 50% 2.5 – 3.0 IU/Kg/ hr More than 7 Often change to bolus Pre-op : 80 – 100IU/Kg

41. ADULTS – MAJOR SURGERY – BOLUS DOSING MINOR SURGERY Day Factor 8 Factor 9 Pre-op 40-50 1-3 80 - 100 80 - 100 4-6 60- 80 60- 80 More than 7 40- 60 40- 60 Day Factor 8 Factor 9 Pre-op 20 - 30 1-3 40-50 40-50 More than 4 20- 30 20- 30

42. LIVER BIOPSY : Transjugular liver biopsy is necessary for hemophiliac & the factor replacement should be done as explained above, Pt should be hospitalised for 48 hrs DENTAL PROCEDURE : After factor 8 replacement for pt. undergoing dental procedures, antifibrinolytic agent is also strongly recommeded due to alteration of mucosa in these procedures TRANEXEMIC ACID – ANTIFIBRINOLYTIC OF CHOICE Dose- 15- 20mg/kg DELIVERY : Deliver the baby by the least traumatic method Avoid ventouse Avoid mid cavity forceps Avoid prolonged labour Replace factor if necessary for the mother during labour Check CBC, aPTT ,, Factor level & X-matching

43. POSTPARTUM : Keep more than 50% for 3 days Prophylactic OCP should be started from delivery continued for 1 month FOR BABIES : Vit . K – to prevent HDN Hep B vaccination mandatory All newborns delivered by hemophiliac should be screened by cord blood HEMOPHILIAC WOMEN PRESENTED WITH MENORRHAGIA Antifibrinolytic agent – Tranexamic acid – 1g Q6H during menstrual bleed DDAVP – Desmopressin – intranasal(1.5mg/ml) or SC (0.3microgram/Kg) Should begin with DDAVP when menstrual bleeding starts & can be repeated every 12-24hrs S/E – facial flushing ADH effect (+) hence avoid excess fluid intake

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