Transcript 14-hemophiliax

Bleeding Disorders
Hemophilia
Hemostasis
* The intimal surface of blood vessels throughout
the body is lined by monolayer of endothelial cells.
These express anticoagulant properties that
promote blood fluidity normally.
At the site of vascular injury endothelial cells are
activated and converted from antithrombotic to
prothrombotic state or become detached exposing
circulating blood to thrombogenic constituents of
subendothelium.
Coagulation Cascade
This results in platelet adhesion that is mediated by
vWF that anchors platelets to blood vessel wall by
binding to platelet GPIb receptors. Then adherent
platelets undergo "release" reaction discharging
constituents of their storage granules such as ADP,
TXA2 which causes further platelets adhesion &
platelet activation.
Activated platelets expose binding sites for fibrin (GP
IIb-IIIa), and then fibrin is formed from plasma
fibrinogen by the action of thrombin. This results
from the activation of coagulation factors cascade
b y either the intrinsic or extrinsic pathways.
Hemophilias
Hemophilia A (HA), considered the classic form of the disease,
results from a congenital deficiency of factor VIII (FVIII).
Hemophilia B (HB), also called Christmas disease, is a
consequence of a congenital deficiency of factor IX (FIX)
Hemophilia C (deficiency of factor XI)can be distinguished from
hemophilia A (deficiency of factor VIII) and hemophilia B
(deficiency of factor IX) by the absence of bleeding into
joints and muscles and by its occurrence in individuals of
either sex.
autosomal but not completely recessive because
heterozygotes may have bleeding.
Epidemiology
1: 5000 male births
--- All races & ethnic groups are affected
--- Peak in 2nd & 3rd decades of life
The annual incidence of hemophilia A in Europe and North
America is approximately 1 case per 5000 male births. It is
the most common X-linked genetic disease, and the second
most common factor deficiency after von Willebrand
disease (VWD).
The incidence of hemophilia B is estimated to be
approximately 1 case per 30,000 male births. In the United
States, the prevalence of hemophilia A is 20.6 cases per
100,000 male individuals, with 60% of those having severe
disease. The prevalence of hemophilia B is 5.3 cases per
100,000 male individuals, with 44% of those having severe
disease.
Genetics
X-linked recessive
--- Genes located on long arm of X-chromosome
--- Usually affects males
--- Females are carriers transmitting disease to
sons
--- Female hemophiliacs may be seen in:
* X-chromosome lyonization
* mating between hemophiliac male & female
carrier
* Carrier female with Turner's syndrome
* Carrier with testicular feminization
S&S
--- Severity of bleeding related to level of plasma FVIII
* < 1% activity --- severe disease
* 1-5% activity --- moderate clinical course
--- bleeding in severe cases in early infancy during circumcision
or even during intrauterine life
--- Spontaneous bleeding
--- Acute hemarthroses causing burning or tingling sensation
followed by intense pain & swelling. The joint is swollen, hot &
tender with erythema of the overlying skin. Joint stiffness &
compromised mobility & maintained in a flexed position
* Joint aspiration is not recommended because it may
introduce infection
* FVIII replacement rapidly stops bleeding, resolves
hematoma & improves symptoms
* Recurrent hemarthroses result in chronic synovial
hypertrophy, damage to cartilage, subchondral bone
cyst formation, bony erosion & flexion contractures.
Later OA changes
* Dx by MRI & ultrasound since x-ray may
underestimate the extent of bone & cartilage damage
* Analgesics, rest, avoidance of wt bearing, avoid
NSAIDs
* Synovectomy surgical & non-surgical
* Non-weight bearing exercises
* Joint prosthesis or arthrodesis
* Prevention – planned administration of FVIII 3 times
per week at levels to maintain factor activity at 1-2%
normal
--- Intramuscular hematomas
* follow trauma or IM injection or vaccination
* may compress vital structures
--- Retroperitoneal hematomas
* should be treated aggressively & immediately
--- Mucosal hemorrhage may be seen nose, GIT,
GUT
--- Intracranial bleeding 2nd cause of death after
AIDS
Ask about the patient's family history and bleeding
symptoms.
Male patients with severe hemophilia present at
circumcision.
Easy bruising may occur at the start of ambulation or primary
dentition.
The patient may have a history of hemarthroses and
prolonged bleeding with surgical procedures, trauma,
dental extraction, and he or she may have spontaneous
bleeding in soft tissues.
A traumatic challenge relatively late in life may have to occur
before mild or moderate hemophilia is diagnosed. Factors
that elevate FVIII levels (e.g. stress, exercise) may mask
mild hemophilia. Physiologically low levels of all vitamin K–
dependent procoagulant factors may complicate the early
diagnosis of hemophilia B.
The principal sites of bleeding in patients with
hemophilia are as follows:
For joints, weight-bearing joints and other joints are
affected.
Regarding muscles, those most commonly affected are
the flexor groups of the arms and gastrocnemius of the
legs. Iliopsoas bleeding is dangerous because of the
large volumes of blood loss and because of
compression of the femoral nerve.
In the genitourinary tract, gross hematuria may occur in
as many as 90% of patients.
In the GI tract, bleeding may complicate common GI
disorders.
Bleeding in the CNS is the leading cause of hemorrhagic
death among patients with hemophilia
Physical Exam
Direct the examination to identify signs related to
spontaneous or, with minimal challenge, bleeding
in the joints, muscles, and other soft tissues.
Observe the patient's stature.
Examine the weight-bearing joints, especially the
knees and ankles, and, in general, the large joints
for deformities or ankylosis.
Look for jaundice, other signs of liver failure (eg,
cirrhosis from viral infection), and signs of
opportunistic infections in patients who are HIV
seroconverted
Differential Diagnoses
Ehlers-Danlos Syndrome
Platelet Disorders
Factor V
von Willebrand Disease
Factor VII
Factor XI Deficiency
Glanzmann Thrombasthenia
Other Problems to Be Considered
Other congenital bleeding disorders must be excluded. These
may include the following:
von Willebrand disease (autosomal dominant transmission)
Platelet disorders (eg, Glanzmann thrombasthenia)
Deficiency of other coagulation factors, ie, FV, FVII, FX, FXI, or
fibrinogen
Acquired hemophilia
Laboratory Studies
The plasma concentration of FVIII or FIX determines the
severity of hemophilia.
Levels of these factors are assayed against a normal pooled-plasma
standard, which is designated as having 100% activity or the
equivalent of FVIII or FIX 1 U/mL. Patients' tested values ranging
from 50-150% are considered in the normal range of variance.
Aging, pregnancy, contraceptives, and estrogen replacement
therapies are associated with increased levels.
In term and healthy premature neonates, FIX values are lowered
(20-50% of the normal level) and rise to normal levels after 6
months (hepatic immaturity). FVIII levels are normal during that
period of life.
Spontaneous bleeding complications are severe in individuals with
undetectable activity (<0.01 U/mL), moderate in individuals with
activity (2-5% normal), and mild in individuals with factor levels
greater than 5%.
).
Hemophilia A and hemophilia B protein deficiencies
of the intrinsic pathway result in abnormal
whole-blood clotting times, prothrombin times (PTs),
and activated partial thromboplastin times
(aPTTs).
FVIII and FIX activities are usually determined by using
the 1-stage assay based on the aPTT.
Differentiation of hemophilia A from von Willebrand disease is
possible by observing normal or elevated levels of von
Willebrand factor antigen and ristocetin cofactor activity.
Bleeding time is prolonged in patients with von Willebrand
disease but normal in patients with hemophilia.
Laboratory confirmation of a FVIII or FIX inhibitor is clinically
important when bleeding is not controlled after adequate
amounts of factor concentrate are infused during a bleeding
episode.
For autoantibody and alloantibody inhibitors, obtain a repeat
measurement of the patient's prolonged aPTT after incubating
the patient's plasma with normal plasma at 37°C for 1-2 hours.
If the prolonged aPTT is not corrected, use the Bethesda method to
titrate the inhibitor biologic concentration. By convention, more
than 0.6 BU is considered a positive result for an inhibitor, less
than 5 BU is considered a low titer of inhibitor, and more than 10
BU is a high titer (neutralizing effectiveness of factor concentrate
therapy to control bleeding )
℞
--- FVIII replacement
* Severe cases need 50000-80000 IU per year
Level 80-100% for surgery & life threatening bleeds
50% for serious bleeds
25-30% for minor bleeds (hemarthroses & hematuria)
1 IU FVIII / kg body wt = 2% activity increase
3500 IU for 70 kg adult with severe disease needs 100% level
Subsequent dosing every 8-12 hours up to 10-14 days
--- Cryoppt is a rich source of FVIII
--- FFP
--- HB vaccination at an early age
--- HA vaccination
--- Ancillary ttt
* Anti fibrinolytic agents – EACA, tranexamic acid
* DDAVP intravenously or intra nasally
FVIII inhibitors --- Allo-Abs arise spontaneously in pt
with severe def
--- suspected when replacement not produce
the immediate relief desired in bleeding
symptoms
--- IgG4 type measured in Bethesda unit (BU)
1 BU = 50% activity
--- ttt – porcine FVIII concentrate 50-100 U/kg
-- Immune tolerance induction regimen
(desensitization)
FIX deficiency: Christmas disease
Same as hemophilia (hemophilia B)
Less severe disease & less prevalent
Prevention
Prophylactic replacement of FVIII or FIX is used to maintain a
measurable level at all times, with the goal of avoiding
hemarthrosis and breaking the vicious cycle of repetitive
bleeding and inflammation that results in destructive arthritis.
This goal is achieved by administering factor 2-3 times a week.
The National Hemophilia Foundation has recommended the
administration of primary prophylaxis, beginning at the age of 1-2
years.
Carrier testing may prevent births of individuals with major
hemophilia. This testing can be offered to women interested in
childbearing who have a family history of hemophilia.
Carrier testing is valuable for women who are related to obligate carrier
females or males with hemophilia.
Prenatal diagnosis is important even if termination of the pregnancy is
not desired because a cesarean delivery may be planned or
replacement therapy can be scheduled for the perinatal period.
Preimplantation genetic diagnosis has been used as a possible
alternative to prenatal diagnosis in combination with in
vitro fertilization to help patients avoid having children with
hemophilia or other serious inherited diseases.
The genetic diagnosis is made by using single cells obtained during
biopsy from embryos before implantation. For this, fluorescence
in situ hybridization (FISH) is used.
This technique circumvents pregnancy termination.
In summary, data suggest that genetic correction of the
hemophilias is feasible.
Future prospects for RNA repair, use of gene-modified endothelial
progenitors, and gene-modified stem-cell therapy are being
investigated.
Patients report decreasing bleeding episodes; this observation
suggests that reasonable factor levels can be reached and
encourage further research in this type of hemophilia
treatment.
Gene transfer for the treatment of hemophilia requires a
combination of vector delivery systems, animal models, and
clinical models and/or studies to prove its practical utility.
Complications
Infection is the most important complication of hemophilia therapy.
As many as 20,000 donors may contribute to a single lot of plasma-derived FVIII
concentrate.
The preferred source of factor are recombinant preparations, which do not show a risk of
transmitting infectious disease, which is still theoretically possible with plasmaderived concentrates.
Virally attenuated products have reduced the risk of hepatitis observed in most patients
receiving early-developed products.
Products that are not heat treated result in 90% positivity rates for hepatitis B surface
antibody and hepatitis C virus. Therefore, their use is not recommended (or generally
available) for routine management.
More than 50% of patients with severe hemophilia who have used older products have
elevations in liver enzyme levels.
Outbreaks of hepatitis A infection in Europe and the United States have prompted more
vigorous monitoring of product safety than before.
HIV infection has been the most serious complication of hemophilia to date. In the United
States, as many as 90% of adults with severe hemophilia are HIV-positive. HIVassociated immune thrombocytic purpura is an exceedingly serious complication in
patients with hemophilia because it may result in lethal intracranial bleeding. Correct
platelet counts to less than 50,000/mL. Steroids are of limited effectiveness, and
intravenous immunoglobulin or anti-Rh(D) generally induces transient remissions.
Anti-HIV medications and splenectomies may result in long-term improvement of
thrombocytopenia.
Allergic reactions are occasionally reported with the use
of cryoprecipitate, fresh-frozen plasma (FFP), and
factor concentrates. Premedication or adjustment of
the rate of infusion may resolve the problem.
Thrombosis or even acute myocardial infarctions have
been encountered in patients especially those with
concurrent liver disease or those taking multiple
doses, as during surgery. A highly purified FIX product
that is preferred.
The cost of treatment of an average adult patient is
more than $100,000 per year.
Costs are increased for the treatment of patients with
inhibitors.
The use of prophylactic factor has resulted in short-term
increases in cost, though the long-term economic benefit of
reducing the incidence of joint disease is expected to
outweigh the initial expense.
Prognosis
Prophylactic use of antihemophilic factors and early treatment with replacement
therapy with factors that are safe from infections have dramatically improved the
prognosis of patients regarding morbidity and mortality due to severe
hemophilia.
Factor concentrates have made home-replacement therapy possible, improving
patients' quality of life.
In addition, dramatic gains in life expectancy occurred during the era of replacement
therapy.
The life expectancy rose from 11 years or less for patients with severe hemophilia before
the 1960s to more than 50-60 years by the early 1980s.
Viral complications occurred during the factor replacement era.
Intracranial hemorrhages and hemorrhages of the soft tissue around vital areas, such
as the airway or internal organs, remain the most important life-threatening
complications.
The lifetime risk of intracranial bleeding is 2-8% and accounts for one third of deaths due
to hemorrhage, even in the era of factor replacement.
The life expectancy of patients having inhibitors may be slightly shorter than that of
patients not having inhibitors.
Approximately one quarter of children and adolescents with severe hemophilia aged 6-18
years have below-normal motor skills and academic performance and have more
emotional and behavioral problems than others