BASIC CONCEPTS IN HEMOPHILIA

1. BASIC CONCEPTS IN HEMOPHILIA Regina B. Butler, R.N. The Children�s Hospital of Philadelphia

2. HEMOPHILIA Hemophilia is a sex-linked, genetic disorder characterized by the deficiency or absence of one of the clotting proteins in plasma. The result is delayed bleeding (spontaneous or traumatic). FVIII Deficiency: Hemophilia A FIX Deficiency: Hemophilia B

3. Normal Coagulation Constriction of injured vessels Platelet plug formation Platelets adhere to damaged vessel Platelets aggregate , forming a primary clot Fibrin clot formation

4. Fibrin Clot Formation Clotting proteins circulate in inactive form. The intrinsic and extrinsic pathways function to activate clotting factors in sequence. Both pathways trigger the final, common pathway to convert fibrinogen to fibrin.

5. Fibrin Clot Formation The intrinsic pathway is activated by contact of blood with damaged vessel wall conversion of Factor XII to XIIa. Subsequent factors, including VIII and IX, are activated to convert X to Xa,

6. Fibrin Clot Formation Xa activates prothrombin, which forms thrombin. Thrombin converts fibrinogen into fibrin strands, which stabilize the clot.

7. Defect in Hemophilia First steps in clotting function well: immature platelet plug forms bleeding stops

8. Defect in Hemophilia First two steps occur If clotting protein decreased or absent, fibrin formation disrupted Platelet plug breaks up Repeated cycle of bleeding, stopping

9. Patterns of Inheritance Sex-linked, recessive Abnormal gene carried on X chromosome

10. Affected Males Males have one X chromosome Presence of affected X chromosome = hemophilia Cannot transmit affected genes to sons All daughters of affected men are obligate carriers.

11. Carrier State Females have 2 X chromosomes Normal gene codes for factor production May pass gene to son (hemophilia) May pass gene to daughter (carrier) Rarely have bleeding symptoms

12. Obligate Carriers Two or more sons with hemophilia One son and another relative with hemophilia Daughter of a man with hemophilia

13. Family History Approximately 1/3 of new cases have no family history Possible reasons for lack of family history: inadequately reported or unknown history mutation originating in mother�s ovum mutation originating in maternal grandparent (most common: maternal grandfather)

14. Diagnosis of Hemophilia Presentation Bleeding from circumcision ( in North America) Multiple raised bruises Testing due to family history History Patient history Family history

15. Diagnosis of Hemophilia Laboratory Studies Screening studies: PT (normal) PTT (prolonged) BT (usually normal) Specific Assays Factor VIIIc Factor IX assay

16. Severity of Hemophilia Severity correlates with amount of factor in plasma: Normal levels = 50%-150% Severe : < 1% (spontaneous bleeding) Moderate: 1-5% (bleeding after trauma) Mild: >5% (bleeding after serious trauma or surgery)

17. Sites of Bleeding LIFE-THREATENING BLEEDS CNS Bleeding intracranial hemorrhage - leading cause of death from bleeding spontaneous after mild or major trauma

18. Sites of Bleeding LIFE-THREATENING BLEEDS Airway Obstruction neck swelling bleeding under tongue GI hemorrhage common in severe hemophilia absence of demonstrable lesions

19. Sites of Bleeding Common Sites in Young Children Head trauma immediate treatment and evaluation Mouth bleeding frenulum tears exfoliation and eruption of teeth usually not problematic

20. Common Sites of Bleeding Hemarthrosis most common site of bleeding knees, ankles and elbows most frequent target joints hemophilic arthropathy

21. Common Sites of Bleeding Muscle Bleeding Second most frequent site Any area of body (frequently extremities) Large muscles: significant blood loss thigh iliopsoas Closed spaces: nerve compression

22. Management of Hemophilia TRADITIONAL GOAL OF THERAPY The goal of therapy in hemophilia is to replace the deficient factor at the first sign of bleeding to stop the bleeding and prevent resulting complications.

23. Management of Hemophilia PROPHYLAXIS Prophylaxis is treatment on a regular basis to prevent bleeding. GOAL: Maintain factor level > 1% Primary prophylaxis : regular treatment, starting at an early age, to prevent bleeding Secondary prophylaxis: regular treatment to stop the cycle of bleeding in a chronic joint

24. Prophylaxis Advantages: decreased joint bleeding decreased bleeding into other areas increased participation in activities predictable schedule of treatment

25. Prophylaxis Disadvantages: Cost Availability of factor Venous access Adherence to schedule False sense of security Lack of family assessment skills /appropriate interventions

26. Factor Replacement Products Infused I.V. to raise factor VIII or IX levels Derived from human plasma prior to 1992 Safety concerns: viral transmission All donors, products screened All products have viral inactivation steps No transmission of HIV, HBV, HCV reported in U.S. since 1987

27. Factor Replacement Products Plasma Derived: Factor VIII Factor VIII with vWF Prothrombin Complex Concentrates Coagulation Factor IX Recombinant: Factor VIII Factor IX

28. Treatment of Bleeding Goal: raise factor level from baseline to a hemostatic level. Stated as �desired correction� (%) Dose depends on individual response and type and severity of bleeding

29. Dose of Factor Replacement Products Factor VIII: 1 i.u./kg raises factor level 2%. ( % correction X wt (kg) X .5 = i.u.) PD FIX: 1 i.u./kg raises factor level 1 % rFactor IX: 1.2 i.u./kg raises factor level 1% ( % correction X wt (kg) X 1.2 = i.u.)

30. Factor ReplacementBiologic Half Life Factor VIII: 8-12 hours 8-12 hours Factor IX: 18-24 hours

31. Treatment of Bleeding Episodes Early and appropriate treatment of each episode is critical to minimizing the complications of bleeding in patients with hemophilia. Replacement of the deficient clotting factor is the single most important step in any intervention.

32. Treatment of Serious Bleeding Factor VIII or IX to reach high level Treat ASAP, before diagnostic evaluation Maintain factor VIII or IX levels above 30% until hemostasis achieved.

33. Treatment of Joint and Muscle Bleeding Factor replacement at first sign of bleeding Repeated dosing may be indicated R.I.C.E.

34. Treatment of Muscle Bleeding Check hb if large muscle involved Rest observe for parasthesias

35. Treatment of Mouth Bleeding Factor Replacement Antifibrinolytics Soft diet Avoid straws, bottles, pacifiers Topical agents

36. Complications of Hemophilia Complications of Bleeding: Hemophilic arthropathy: result of repeated bleeding into joint space Anemia CNS/ organ damage Complications of Treatment: Inhibitors Hepatitis HIV

37. Hepatitis A Rarely transfusion related Few cases reported in factor recipients Vaccination recommended

38. Complications of TreatmentHepatitis B Often transfusion related Can become chronic Vaccination recommended

39. Complications of TreatmentHepatitis C Most common cause of liver disease in hemophilia Transmitted through blood (factor concentrates before 1987) Risk: chronic liver disease liver carcinoma

40. Complications of TreatmentHIV Infected blood supply in late 1970�s and early 1980�s 80% of treated patients with severe hemophilia infected in U.S. by 1985 Testing and viral inactivation steps since 1985 No documented case in U.S. in factor supply since 1987

41. Future Directions Increased use of prophylaxis ? Increased access to care worldwide Increasing purity of products Prolonged half-life Affordable, available treatment products Gene therapy

42. Patiently Waiting for a Cure