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HEMOPHILIA
Curs an IV - limba engleza
2012-2013
Coagulation factor disorders
• Inherited bleeding
disorders
– Hemophilia A and B
– vonWillebrands disease
– Other factor deficiencies
• Acquired bleeding
disorders
– Liver disease
– Vitamin K
deficiency/warfarin
overdose
– DIC
Factor Deficiencies
(CONGENITAL)

HEMOPHILIAS
Caused by lack of coagulation factors

VON WILLEBRAND’S DISEASE
Caused by lack of von willebrand´s factor
History
• First references are mentioned in Jewish texts in second
century AD by Rabbi Ben Gamaliel who correctly
deduced that sons of mother- that he did not know at
that time- was an hemophilic carrier bled to death after
circumcision. Hence he made a ruling that excepted
newborn Jewish boys of this ritual if two previous
brothers had had bleeding problems with it.
• Then Rabbi and physician Maimonides in the XII
century noted that the mothers were the carriers, hence
the second ruling that if she married twice the newborns
from the second marriage were also excepted.
• In 1800 John Otto a physician in Philadelphia wrote a
description of the disease where he clearly appreciated
the cardinal features: an inherited tendency of males to
bleed
• In 1928 the word Hemophilia was defined.
Types of Hemophilia
• Hemophilia A
Absence or deficiency of Factor VIII
• Hemophilia B (Christmas Disease)
Absence or deficiency of Factor IX
• Hemophilia C
Absence or deficiency of Factor XI
Very rare and mild
Background
• Inherited deficiency of factor VIII (hemophilia A) or
factor IX (hemophilia B)
• Sex-linked inheritance; almost all patients male
– Female carriers may have mild symptoms
• Most bleeding into joints, muscles; mucosal and CNS
bleeding uncommon
• Severity inversely proportional to factor level
< 1%: severe, bleeding after minimal injury
1-5%: moderate, bleeding after mild injury
> 5%: mild, bleeding after significant trauma or surgery
Etiology - Genetics of
Hemophilia
• Hemophilia is due to mutation of the gene
situated on X chromosome
• About half of cases of hemophilia A due to an
inversion mutation in intron 1 or 22
• Remainder genetically heterogeneous
– Nonsense/stop mutations prevent factor production
– Missense mutations may affect factor activity
rather than production
• 15-20% of cases due to new mutations
Etiology - Hemophilia Inheritance
•
Hemophilia is an X-linked gene disease.
o
A father with the X-linked gene will pass it to all his
daughters resulting in heterozygous carriers.
o
A mother who is a carrier of the mutant gene will pass
the gene on to half her sons and half her daughters. All
her sons will have hemophilia and all her daughters will
be heterozygous carriers.


Females are carriers
Males have the disease
Etiology - Genetics
• Transmitted by females, suffered by males
• The female carrier transmits the disorder to half their sons
and the carrier state to half her dtrs
• The affected male does not transmit the disease to his sons
(Y is nl) but all his dtrs are all carriers (transmission of
defected X)
Etiology - Genetics
• Hemophilia in females
If a carrier female mates with an affected
male there’s the possibility that half their
daughters are homozygous for the disease
Other possibility: Turner syndrome (45,X0)
with a defective X
Epidemiology Hemophilia A & B
• It is the second most common inherited clotting factor
abnormality (after von Willebrand disease)
• 1 in 5000-10000 live male births
• No difference between racial groups
•
Hemophilia A is 90-80% of all Hemophiliacs
•
Hemophilia B is10-15% of all Hemophiliacs
•
Factor VIII …1:10,000 males
•
Both X-linked recessive
•
Rare females…, inherited from both parents.
•
One-third - spontaneous genetic mutation.
Clinic - Hemophilia A & B
Clinical manifestations are indistinguishable
• Hemarthrosis (most common)
Fixed joints
• Soft tissue hematomas (e.g., muscle)
Muscle atrophy
Shortened tendons
• Other sites of bleeding
Urinary tract
CNS, neck (may be life-threatening)
• Prolonged bleeding after surgery or dental
extractions
Clinical manifestations
• Frequency and severity of bleeding are related to F VIII levels
Severity
F VIII activity
Clinical manifestations
Severe
<1%
Spontaneous hemorrhage from early
infancy
Freq sp hemarthrosis
Moderate
2-5%
Hemorrhage sec to trauma or surgery
Occ sp hemarthrosis
Mild
>5%
Hemorrhage sec to trauma or surgery
Rare sp bleeding

Coinheritance of prothrombotic mutations (i.e. Factor V Leiden)
can decrease the risk of bleeding
Clinical Manifestations:
Hemarthrosis
• The most common, painful and most physically,
economically and psychologically debilitating
manifestation.
• Clinically:
 Aura: tingling warm sensation
 Excruciating pain
 Generally affects one joint at the time
 Most commonly: knee; but there are others as elbows, wrists
and ankles.
 Edema, erythema, warmth and LOM
 If treated early it can subside in 6 to 8 hs and disappear in 12 to
24 hs.
 Complications: Chronic involvement with joint deformity
complicated by muscle atrophy and soft tissue contractures
Clinical Manifestations:
Hemarthrosis
• Pathophysiology:
 Bleeding probably starts from synovial vessels into the
synovial space.
 Reabsorption of this blood is often incomplete leading to
chronic proliferative synovitis, where the synovium is more
thickened and vascular, creating a “target joint” with
recurrence of bleeding.
 There is destruction of surrounding structures as well-bone
necrosis and cyst formations, osteophytes
 Terminal stage: Chronic Hemophiliac arthropathy: fibrous or
bony ankilosing of the joint.
Hemophilia – Hemarthrosis
Hemophilia – Hemarthrosis
Hemophilia – Hemarthrosis
Hemophilia – Hemarthrosis
Clinical Manifestations
Hematomas
• Subcutaneous and muscular hematomas spread within
fascial spaces, dissecting deeper structures
• Subcutaneous bleeding spreads in characteristic mannerin the site of origin the tissue is indurated purplish black
and when it extends the origin starts to fade
• May compress vital structures: such as the airway if it is
bleeding into the tongue throat or neck; it can
compromise arteries causing gangrene and ischemic
contractures are common sequelae, especially of calves
and forearms
Clinical Manifestations
Hematomas
• Muscle hematomas:
1. calf,
2. thigh,
3. buttocks,
4. forearms
• Psoas hematoma- if right sided may mimic
acute appendicitis
• Retroperitoneal hematoma: can dissect through
the diaphragm into the chest compromising the
airway. It can also compromise the renal
function if it compresses the ureter
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Clinical Manifestations
Hematomas
Clinical Manifestations
Hematomas
Clinical Manifestations
Hematomas
Clinical Manifestations
Hematomas
Clinical Manifestations
Hematomas
Clinical Manifestations
Hematomas
•Leading cause of death of
hemophiliacs
•Spontaneous or following
trauma
•May be subdural, epidural or
intracerebral
•Suspect always in hemophilic
patient that presents with
unusual headache
•If suspected- FIRST TREAT,
then pursue diagnostic workup
•LP only when fVIII has been
replaced to more than 50%
Laboratory diagnosis
• Nomenclature:
– FVIII protein that is lacking or aberrant
– FVIIIc functional FVIII measured by clotting assays
– FVIIIag Antigenic protein that can be detected with
immunoassays
• Deficit can be quantitative or qualitative
• General Lab: prolonged aPTT, nl PT and BT
• Mixing studies: aPTT corrects with normal plasma –if there
are no factor VIII antibodies present
• Clotting assays: F VIII activity, expressed in % of normal
DecreasedQUANTITATIVE
• Immunoassays: “Cross Reactive Material” Positive- there is an
antigen similar to the F VIII protein- QUALITATIVE
Differential diagnosis - Clinical Features of
Bleeding Disorders
Platelet
disorders
Coagulation
factor disorders
Site of bleeding
Skin
Mucous membranes
(epistaxis, gum,
vaginal, GI tract)
Deep in soft tissues
(joints, muscles)
Petechiae
Yes
No
Ecchymoses (“bruises”)
deep
Small, superficial
Large (hematomas),
Hemarthrosis / muscle bleeding
Extremely rare
Common
Bleeding after cuts & scratches
Yes
No
Bleeding after surgery or trauma
Immediate,
usually mild
Delayed (1-2 days),
often severe
Differential diagnosis - Clinical
Features of Bleeding Disorders
 Remember the basic differences between bleeding associated
with coagulation factor deficiencies and bleeding associated
with platelet problems.
 Deep bleeding such as in joints and hematomas generally arise
as the result of a coagulation deficiency.
 Superficial bleeding such as petechiae, bruises, epistaxis, and
hematuria generally reflect a quantitative or qualitative
deficiency of platelets.
Hemophilia
Treatment of bleeding episodes
• Unexplained pain in a hemophilia should be
considered due to bleeding unless proven
otherwise
• External signs of bleeding may be absent
• Treatment: factor replacement, pain control,
rest or immobilize joint
• Test for inhibitor if unexpectedly low response
to factor replacement
Treatment
Factor replacement
• Choice of treatment: is based on
Purity of the factor (how concentrated or
“purified” the factor is)
Safety
Cost
 Nowadays most used therapies are believed to
be effective and relatively safe
Treatment of hemophilia A
• Intermediate purity plasma products
– Virucidally treated
– May contain von Willebrand factor
• High purity (monoclonal) plasma products
– Virucidally treated
– No functional von Willebrand factor
• Recombinant factor VIII
– Virus free/No apparent risk
– No functional von Willebrand factor
Treatment
Factor replacement
•
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



Replacement of F VIII is the cardinal step to prevent or reverse
acute bleeding episodes
Dosing: Replacement products can be given on the basis of
body weight or plasma volume ( aprox 5% of body weight)
1 U/ml = 100% factor activity
Practically 1 unit of F VIII/kg increases F VIII about 0.02
U/ml
In a severe hemophiliac, to raise F VIII to 100% activity or 1
U/ml, we need 50 U/kg
Redosing is based on half life: 8-12 hs
Monitoring of Factor activity is crucial during therapy
Dosing clotting factor
concentrate
• 1 U/kg of factor VIII should
increase plasma level by about
2% (vs 1% for factor IX)
• Half-life of factor VIII 8-12
hours, factor IX 18-24 hours
• Volume of distribution of factor
IX about twice as high as for
factor VIII
• Steady state dosing about the
same for both factors – initial
dose of factor IX should be
higher
FACTOR VIII CONCENTRATE
• Recombinant
– Virus-free, most expensive replacement
– Treatment of choice for younger/newly diagnosed hemophiliacs
– Somewhat lower plasma recovery than with plasma-derived
concentrate
• Highly purified
– Solvent/detergent treated, no reports of HIV or hepatitis
transmission
• Intermediate purity (Humate-P™)
– Contains both factor VIII and von Willebrand factor
– Solvent/detergent treated, no reports of HIV or hepatitis
transmission
– Mainly used to treat von Willebrand disease
DDAVP
• Releases vWF/fVIII from endothelial cells
• Factor VIII levels typically rise 2-4 fold after 30-60 min
(IV form) or 60-90 min (intranasal)
• Enhanced platelet adhesion due to ↑ vWF
• Useful for mild hemophilia (VIII activity > 5%) prior to
dental work, minor surgery etc
• Trial dose needed to ensure adequate response
• Cardiovascular complications possible in older patients
Dosing guidelines for
hemophilia A
• Mild bleeding
– Target: 30% dosing q8-12h; 1-2 days (15U/kg)
– Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria
• Major bleeding
– Target: 80-100% q8-12h; 7-14 days (50U/kg)
– CNS trauma, hemorrhage, lumbar puncture
– Surgery
– Retroperitoneal hemorrhage
– GI bleeding
• Adjunctive therapy
– alfa amino caproic acid (Amicar) or DDAVP (for mild disease
only)
Factor replacement in severe hemophilia A
Site of bleed
Desired factor level
Dose
Other
Joint
40-50%
20-40 U/kg/day
Rest, immobilization, PT
Muscle
40-50%
20-40 U/kg/day
Risk of compartment
syndrome or neuro
compromise
Oral mucosa
50% initially
25 U/kg x 1
Follow w ith
antifibrinolytic therapy
Epistaxis
GI
GU
CNS
Trauma or surgery
Initially 80-100%, then 30% 40-50 U/kg then 30-40
until healed
U/kg daily
Pressure, packing,
cautery
Initially 100%, then 30%
until healed
Initially100%, then 30%
until healed
Initially100%, then 50%
until healed
40-50 U/kg then 30-40
U/kg daily
40-50 U/kg then 30-40
U/kg daily
50 U/kg then 25 U/kg q
12h infusion
Endoscopy to find
lesion
Initially100%, then 50%
until healed
50 U/kg then 25 U/kg q Test for inhibitor before
12h infusion
surgery!
R/O stones, UTI
•Give factor q 12 hours for 2-3 days after major surgery, continue with daily infusions for 7-10 days
•Trough factor levels with q 12 h dosing after major surgery should be at least 50-75%
•Most joint and muscle bleeds can be treated with “minor” (50%) doses for 1-3 days without
monitoring
Complications of therapy
• Formation of inhibitors (antibodies)
– 10-15% of severe hemophilia A patients
– 1-2% of severe hemophilia B patients
• Viral infections
– Hepatitis B
– Hepatitis C
– HIV
Human parvovirus
Hepatitis A
Other
Complications of therapy
Development of Antibodies
• Specific inhibitor antibodies that neutralize FVIII
activity
• Most frequently in severe affected patients- affecting
25%
• Predisposing factors: severe disease, type of genetic
mutation (inversion, nonsense mutation, deletions),
family history of inhibitors development
• Seen aprox 9-11 days post factor VIII exposure
Complications of therapy
Development of Antibodies
• Diagnosis: mixing study does not correct aPTT.
Bethesda assay: which consists of serial
dilutions of plasma is pooled with normal
plasma and incubated for 2 hs, then the activity
level is measured by coagulation assays. The
higher inhibitor titer, the greater the dilution
required to demonstrate residual FVIII activity.
It is expressed on Bethesda Units: High
responders: >5 Bethesda units, low responders
<5.
5/23/2017
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Course and prognosis
Development of Antibodies
 Treatment: of active bleeding and inhibitor ablation via immune
tolerance induction.
• High purity FVIII: treatment of life threatening hemorrhages
in pts that are low responders
• Porcine FVIII: high responders with high inhibitors levels that
have life threatening hemorrhages
• Prothrombin complex concentrates and activated prothrombin
complex concentrates: bypassing agents for thrombosis
(prothrombin, fVII, fIX, f X and Prot S and C). Carries high
risk of thrombosis and it is difficult to monitor.
• rFVIIa: Effective response in 90% of patients. Gets activated
by tissue factor, so thrombosis response is more modulated
than that of APCCs, however there are no studies comparing
them both
Treatment of hemophilia B
• Agent
– High purity factor IX
– Recombinant human factor IX
– Highly purified (solvent/detergent treated, no reports
of virus transmission)
– Prothrombin complex concentrate
• Mixture of IX, X, II, VII
• Low risk of virus transmission
• Some risk of thrombosis
• Dose
– Initial dose: 100U/kg
– Subsequent: 50 U/kg every 24 hours
Treatment - Prophylaxis
• Prophylactic treatment should be considered in all
patients with severe hemophilia
• In 1997 was recommended by the Medical and Scientific
Advisory Council of the National Hemophilia Foundation.
• Candidate should be reliable to manage a central
venous catheter device
• Administration is three times a week to make a severe
hemophiliac a moderate phenotype
• There is significant improvement in the clinical condition
and quality of life.
Carrier detection and Antenatal
diagnosis
 Family history: if we follow the inheritance pattern a
female is a carrier if she:
 Has an hemophilic father
 Has two hemophilic sons
 Has one hemophilic son and has a family history
 Has a son but no family history, there is a 67%
chance that she is.
Carrier detection and Antenatal
diagnosis
 Coagulation based assays:
 Generally heterozygous females have <50% f VIII levels but if
normal it can’t be excluded
 vWF is usually normal or elevated in female carriers, so F
VIII:FvW ratio is low which adds sensitivity to these tests
 DNA based assays:
 Southern blot can detect the inversion in intron 22
 If negative for that, there is the need for DNA sequencing
 For prenatal diagnosis: DNA testing on choronic villi samples
obtained by biopsy at week 12