BASIC CONCEPTS IN HEMOPHILIA

1
BASIC CONCEPTS IN HEMOPHILIA

• Regina B. Butler, R.N.
• The Childrens 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 mothers 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 lt 1 (spontaneous bleeding)
• Moderate 1-5 (bleeding after trauma)
• Mild gt5 (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 gt 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 1970s and early
  1980s
• 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