Transcript Hemophilia A

The Basics of Hemophilia
Hemostatic System
• Blood vessels
• Platelets
• Plasma coagulation system
• Proteolytic or Fibrinolytic system
How Bleeding Stops
• Vasoconstriction
• Platelet plug formation
• Clotting cascade activated to form fibrin
clot
3. FACTOR DEFICIENCIES
• Disorders of coagulation I: Inherited
• Excessive bleeding may occur as a result of an inherited
defect of one of the coagulation factors or other protein
involved in coagulation.
Types of Bleeding Disorders Caused By
Coagulation Factor Deficiencies
• Hemophilia A (factor VIII deficiency)
• Hemophilia B (factor IX deficiency)
• Hemophilia C (factor XI deficiency)
• von Willebrand Disease (vWD)
• Other
What is Hemophilia?
• Hemophilia is an inherited bleeding
disorder in which there is a deficiency
or lack of factor VIII (hemophilia A),
factor IX (hemophilia B) or factor XI
(hemophilia C)
Inheritance of Hemophilia
• Hemophilia A and B are X-linked recessive disorders
• Hemophilia is typically expressed in males and carried
by females
• Severity level is consistent between family members
• ~30 % of cases of hemophilia are new mutations
Detection of Hemophilia
• Family history
• Symptoms
– Bruising
– Bleeding with circumcision
– Muscle, joint, or soft tissue bleeding
• Hemostatic challenges
– Surgery
– Dental work
– Trauma, accidents
• Laboratory testing
Degrees of Severity of Hemophilia
• Normal factor VIII or IX level = 50-150%
• Mild hemophilia
– factor VIII or IX level = 6-50%
• Moderate hemophilia
– factor VIII or IX level = 1-5%
• Severe hemophilia
– factor VIII or IX level = <1%
U. S. Incidence of Hemophilia
• Hemophilia A: 20.6 per 100,000 males
– Severe: 50-60%
• Hemophilia B: 5.3 per 100,000 males
– Severe: 44%
Types of Bleeds
• Joint bleeding - hemarthrosis
• Muscle hemorrhage
• Soft tissue
• Life threatening-bleeding
• Other
Joint or Muscle Bleeding
• Symptoms
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Tingling or bubbling sensation
Stiffness
Warmth
Pain
Unusual limb position
Life-Threatening Bleeding
• Head / Intracranial
– Nausea, vomiting, headache, drowsiness, confusion, visual
changes, loss of consciousness
• Neck and Throat
• Abdominal / GI
Other Bleeding Episodes
• Mouth bleeding
• Nose bleeding
• Scrapes and/or minor cuts
• Menorrhagia
Complications of Bleeding
• Flexion contractures
• Muscle atrophy
• Joint arthritis / arthropathy
• Chronic pain
• Neurologic impairment
Treatment of Hemophilia
• Replacement of missing clotting
protein
– On demand
– Prophylaxis
• Antifibrinolytic Agents
• Others
Factor VIII Concentrate
• Intravenous infusion
– IV push
– Continuous infusion
• Dose varies depending on type of bleeding
• Half-life 8-12 hours
• Each unit infused raises serum factor VIII level by 2 %
Factor IX Concentrate
• Intravenous infusion
– IV push
– Continuous infusion
• Dose varies depending on type of bleeding
• Half-life 12-24 hours
• Each unit infused raises serum factor IX level by 1%
History of Clotting Factor Concentrates
Prior to 1950: whole blood
1952: Hemophilia A distinguished from B
1950-1960: FFP and Cryoprecipitate (IIIV, IIIX, I, VWF)
Early 1970s: Commercial plasma-derived factor
concentrates
Mid-late 1970’s: Home infusion practices
1981: First AIDS death in the Hemophilia community
Complications of Treatment
• Inhibitors/Antibody development
• Hepatitis A
• Hepatitis B
• Hepatitis C
• HIV
Inhibitors
• Definition
– IgG antibody to infused factor VIII or IX concentrates,
which occurs after exposure to the extraneous VIII or
IX protein.
• Prevalence
– 20-30% of patients with severe hemophilia A
– 1-4% of patients with severe hemophilia B
Hepatitis
• Hepatitis A- small risk of transmission
– Vaccination recommended
• Hepatitis B - no transmissions since 1985
– Vaccination recommended
• Hepatitis C - no transmissions since 1990
– ~90% of patients receiving factor concentrates prior to 1985 are HCV
antibody positive
Human Immunodeficiency Virus
• No transmissions of HIV through factor
concentrates since 1985 due to viral inactivation
procedures
General points:
• Also known as Christmas disease.
• Females are almost exclusively asymptomatic carriers of
the disorder, and may have inherited it from either their
mother or father.
• When a blood vessel is injured, a temporary clot does
form, but the missing coagulation factors prevent fibrin
formation which is necessary to maintain the blood clot.
Thus a haemophiliac does not bleed more intensely than
a normal person, but for a much longer amount of time.
• In severe haemophiliacs even a minor injury could result
in blood loss lasting days, weeks, or not ever healing
completely.
• The critical risk here is with normally small bleeds which
due to missing factor VIII take long times to heal.
Laboratory features:
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Prolonged activated partial thromboplastin lime (APTT).
Normal prothrombin time (PT).
Normal bleeding time (BT).
Plasma factor VIII or IX reduced
Carriers have factor VIII or IX approximately 50% of
normal. DNA analysis is helpful in carrier detection and
counselling.
• Von Willebrand factor level is normal.
• A family history is frequently present, although not
essential.
• Recently, genetic testing has been made available to
determine an individual's risk of attaining or passing on
Haemophilia.
• A very small minority of patients have antibodies against
factor VIII and XI that impair its functioning. Management
of these patients is more complicated.
Haemophilia C
• Hemophaelia C was first discovered in a young
Ashkenazic Jewish American in the 1950s.
• Haemophilia C is a mild form of haemophilia affecting
both sexes.
• However, it predominantly occurs in Jews of Ashkenazi
descent.
• It is the fourth most common coagulation disorder after
von Willebrand's disease and haemophilia A and B.
Von Willebrand disease
• Family of bleeding disorders
• Caused by a deficiency or an abnormality of von
Willebrand Factor
• It arises from a qualitative or quantitative deficiency
of von Willebrand factor
• It is known to affect humans and dogs.
• There are four types of hereditary vWD.
• The disease is more frequent than haemophilia A.
• Males and females are affected equally.
vWF Production
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Vascular endothelial cells
Megakaryocytes
Most vWF is secreted
Some vWF is stored
– Endothelial cells
– Alpha granules of platelets
• Release stimuli (EC)
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Thrombin
Histamine
Fibrin
C5b-9 (complement membrane attack complex)
• Release stimuli (platelets)
– Thrombin
– ADP
– Collagen
vWF Function
• Adhesion
– Mediates the adhesion of platelets to sites of vascular injury
(subendothelium)
– Mediates platelet to platelet interaction
• Binds GPIb and GPIIb-IIIa on activated platelets
• Stabilizes the hemostatic plug against shear forces
• vW Factor Functions in Hemostasis
• Carrier protein for Factor VIII (FVIII)
– Protects FVIII from proteolytic degradation
– Localizes FVIII to the site of vascular injury
vWD History
• 1931: Erik von Willebrand described novel bleeding
disorder
– Prolonged BT and normal platelet count
– Mucosal bleeding
– Both sexes affected
• 1950s: Prolonged BT associated with reduced FVIII
• 1970s: Discovery of vWF
• 1980s: vWF gene cloned
• Most frequent inherited bleeding disorder
• Autosomal inheritance pattern
– Males and females are affected equally
Clinical Manifestations
• Most with the disease have few or no symptoms
• For most with symptoms, it is a mild manageable
bleeding disorder with clinically severe hemorrhage only
with trauma or surgery
• The various types of vWD present with varying degrees
of bleeding tendency (typically from mucous membranes
(mouth. nose bleeds, bruising, menorrhagia which is
heavy menstrual periods (in women) and blood loss
during childbirth (rare) may occur).
• Excess blood loss following trauma or surgery.
• Death may occur.