Transcript 3.85 MB

Principles of Factor
Replacement Therapy
Lisa N Boggio, MS, MD
Rush University Medical Center
Coagulation: The Process that Controls
Bleeding
Normal
Bleeding begins
Bleeding Disorder
Bleeding begins
Vessels constrict
Vessels constrict
Incomplete platelet plug
leads to continued bleeding
Platelet plug forms
Fibrin clot stops bleeding
Incomplete and/or delayed
formation of fibrin clot results in
continued bleeding
Hemophilia
 Factor VIII or IX deficiency 10:100,000
– Can be others, FXI, FX, FVII, FV, etc.
 Recurrent musculoskeletal bleeding
– resulting arthritis and joint contractures
– more bleeding, severe pain, and disability
 Management goals
– symptom relief
– prevention of progression of joint damage
– preservation of joint function
Relationship of Bleeding severity
to Clotting Factor Level
SEVERITY
CLOTTING
FACTOR LEVEL
BLEEDING EPISODES
Severe
< 1 IU/dl
(< 0.01 IU/ml) or
< 1 % of normal
Spontaneous bleeding into joints or
muscles, predominantly in the
absence of identifiable hemostatic
challenge
Moderate
1-5 IU/dl
(0.01-0.05 IU/ml) or
1-5% of normal
Occasional spontaneous bleeding;
prolonged bleeding with minor
trauma or surgery
Mild
5-40 IU/dl
(0.05-0.40 IU/ml) or
5-<40% of normal
Severe bleeding with major trauma
or surgery.
Spontaneous bleeding is rare
WFH Guidelines for Treatment of Hemophilia, 2nd Ed. Haemophilia 2012
Localization of Bleeding
:
Brain
Ear, nose, and throat
Muscles
Belly
Urinary tract
Skin
Joints
Nerves
Bleeding into the Joint Spaces
Elbows
Wrists/fingers
Hips
Knees
Ankles/toes
Treatment
 1940s FFP
 1950-60s Cryoprecipitate
 1970s purified FVIII +vWF
 1980s highly purified FVIII and IX
 1990s recombinant FVIII and IX
 2000s recombinant FVIII with little or no
human proteins
 2010s prolonged half life
Hambleton J. Curr Opin Hematol. 2001;8:306-311.
http://reddymed.com/vwd/treatment_pp.html
Complications
 From Blood/Factor
– HIV
– Hepatitis C
– Hepatitis A
– Hepatitis B
– Liver failure
 From Bleeding
– Arthritis
– Stroke
Forbes CD et al, eds. Hemophilia. London. Chapman and Hall,1997.
Principles of Care
 Prevent and treat bleeding with the deficient
clotting factor
 Life threatening bleeding (head, neck, chest,
GI tract) give factor immediately
 DDAVP can raise FVIII levels (3-6 times
baseline) to control bleeding in mild hemophilia
– Test prior for response prior to use
 Avoid anti-platelet agents
– Aspirin, NSAIDS
Definition of a Target Joint
 4 bleeds/joint over 6 months
 20 bleeds/joint in a lifetime
Uniform Data Collection, CDC.
Palliative Therapies
 RICE
– Rest
– Ice
– Compression
– Elevation
 Aspiration of a tense joint space for comfort
 Corticosteroids
 Pain medications
DDAVP
 A synthetic version of vasopressin
 Increases plasma VWF & factor VIII
concentrations by stimulating its release from
intracellular stores in endothelial cells
 Ineffective in severe hemophilia and type 3 von
Willebrand disease
 Contraindicated in individuals with known
hypersensitivity or significant side effects
Hambleton J. Curr Opin Hematol. 2001;8:306-311.
DDAVP
 Dosing
– Nasal spray 150mcg/spray
 1 spray for children, 2 for adults
– 0.3 mcg/kg (max 21 mcg) IVPB over 20 min
 Side effects include
– Flushing, Headache
– Hyponatremia, seizures
– Abdominal cramps, BP changes
 Tachyphylaxis may occur with repeat dosing
Factor Concentrates
 Virally inactivated
 Factor IX
– ∆Factor level desired x weight (kg)
 Factor VIII
– [∆Factor level desired x weight (kg)]/2
 Plasma pooled from up to 30,000 plasma
donations
 Recombinant – cells lines Chinese hamster
ovaries, baby hamster kidney, human
Suggested Factor Treatment
Hemophilia A
Hemophilia B
TYPE OF
DESIRED
HEMORRHAGE LEVEL
(IU/DL)
DURATION
(DAYS)
DESIRED
LEVEL
(IU/DL)
DURATION
(DAYS)
Joint
10-20
1-2
10-20
1-2
Deep Muscle
Iliopsoas
20-40
10-20
1-2
Day 3-5
15-30
10-20
1-2
Day 3-5
CNS
50-80
30-50
20-40
1-3
4-7
8-14
50-80
30-50
20-40
1-3
4-7
8-14
Throat, neck
renal
30-50
10-20
1-3
4-7
30-50
10-20
1-3
4-7
Minor Surgery
40-80
20-50
Pre-op
1-5 post op
40-80
20-50
Pre-op
1-5 post-op
WFH Guidelines for Treatment of Hemophilia, 2nd Ed. Haemophilia 2012
Antifibrinolytics
 Prevents breakdown of clot by plasmin
 Tranexamic Acid & Epsilon Aminocaproic Acid
 No value in the prevention of hemarthroses
 Mucosal bleeding
 Dosing
– EACA – 100 mg/kg po every 6 hours or may
use liquid mouthwash (max 5g/dose)
– TXA – 10 mg/kg IV, 25 mg/kg po every 8
hours (max 1300 mg/dose)
Cryoprecipitate and Fresh Frozen
Plasma
 Hemophilia A
– Cryoprecipitate is preferable to FFP
– 100 mL to start
 Hemophilia B
– FFP and cryo-poor plasma contain FIX
– starting dose is 15−20 ml/kg
 Major concerns as to the safety and quality of
FFP & cryoprecipitate
– Not recommended unless no other option
WFH Guidelines for Treatment of Hemophilia, 2nd Ed. Haemophilia 2012
Inhibitors
 Catastrophic complication of severe
hemophilia
 Antibodies render the patient resistant to
replacement factor concentrates
 Increased bleeding, increased risk of death
and disability
 Occurs in ~30% of Hemophilia A and 3% of
hemophilia B
Clinical Manifestations
 Does not increase bleeding
– Unless mild/mod -> severe
 Normal therapy fails
 Difficult to control hemostasis
 Increased morbidity/mortality
Treatment Strategies
Dual Objectives
Acute
Management
Stop the
Bleeding
Long-term
Strategy
Eradicate
Inhibitor
Treatment
Strategies
Overview of Treatment
Life- or Limb-Threatening Hemorrhage
<10 BU
FVIII or FIX
Porcine
FVIII
>10 BU
Porcine FVIII
PCCs/APCCs
rFVIIa
Plasmapheresis
Immunoadsorption
Treatment in Inhibitors
 Bypassing agents
– Prothrombin complex concentrates
– Activated prothrombin complex
concentrates (80-100 units/kg)
– Recombinant factor VIIa (90-120 mcg/kg)
 Hemophilia B – special considerations
– Monitor for first 10-20 exposures for
anaphylaxis when starting factor IX
replacement therapy
– Anaphylaxis and renal failure may occur