Transcript Platelet Disorders

Platelet Disorders
Majid vafaie MD
• Platelets playa critical role in hemostasis.
• When the vascular endothelium is disrupted,
platelets adhere to the subendothelium and
initiate primary hemostasis.
• Excessive bleeding occurs if primary
hemostasis is abnormal because platelets are
either deficient in number or defective in
function
• The normal circulating platelet count for all
ages ranges from 150,000 to 400,000/microL.
• Circulating platelets constitute two thirds of
total body platelets; the remaining platelets
are located within the spleen.
• The average life span of platelets is 7 to 10
days, although survival of transfused
platelets in a thrombocytopenic recipient is
reduced proportionately to the severity of the
thrombocytopenia
Platelet characteristics
• Size: 1–4 μm (younger platelets are larger).
• Mean platelet volume (MPV): 8.9 6 1.5 μm3
• Distribution: one-third in the spleen, twothirds in circulation
• Average lifespan: 9–10 days.
Idiopathic (Autoimmune)
Thrombocytopenic Purpura
• The most common cause of acute onset of
thrombocytopenia in an otherwise well child
is (autoimmune) idiopathic thrombocytopenic
purpura (ITP)
Epidemiology
• estimated about 1 in 20,000,1-4 wk after
exposure to a common viral infection, an
autoantibody directed against the platelet
surface develops with resultant sudden onset
of thrombocytopenia
• A recent history of viral illness is described in
50-65% of cases of childhood ITP
• The peak age is 1-4 yr, although the age
ranges from early in infancy to the elderly
In childhood, males and females are equally
affected
• ITP seems to occur more often in late winter
and spring after the peak season of viral
respiratory illness
Pathogenesis
• Why some children develop the acute
presentation of an autoimmune disease is
unknown
• The exact antigenic target for most such
antibodies in most cases of childhood acute
ITP remains undetermined
• in chronic ITP most patients demonstrate
antibodies against the platelet glycoprotein
complexes, a11 b-B3 and GPIb
• After binding of the antibody to the platelet
surface, circulating antibody-coated platelets
are recognized by the Fc receptor on splenic
macrophages, ingesed, and destroyed.
• Most common viruses have been described in
association withITP, including Epstein-Barr
virus and HIV
• Epstein-Barr virus-related ITP is usually of
short duration and follows the course of
infectious mononucleosis
• HIVassociated ITP is usually chronic
• Helicobacter pylori or rarely following the
MMR vaccine
Clinical Manifestations
• The classic presentation of ITP is a previously
healthy 1-4 yr old child who has sudden onset
of generalized petechiae and purpura
• The parents often state that the child was fine
yesterday and now is covered with bruises and
purple dots
• Often there is bleeding from the gums and
mucous membranes, particularly with
profound thrombocytopenia (platelet count
<10 x 109/L)
• There is a history of a preceding viral infection
1-4 wk before the onset of thrombocytopenia
• Findings on physical examination are normal,
• other than the finding of petechiae and
purpura
• Splenomegaly,lymphadenopathy, bone pain,
and pallor are rare
classification system
• 1. No symptoms
• 2. Mild symptoms: bruising and petechiae,
occasional minor epistaxis,very little interference
with daily living
• 3. Moderate: more severe skin and mucosal lesions,
more troublesome epistaxis and menorrhagia
• 4. Severe: bleeding episodes-menorrhagia, epistaxis,
melena requiring transfusion or hospitalization,
symptoms interfering seriously with the quality of life
• The presence of abnormal findings such as
hepatosplenomegaly,bone or joint pain, or
remarkable lymphadenopathy suggests other
diagnoses (leukemia).
• When the onset is insidious, especially in an
adolescent, chronic ITP or the possibility of a
systemic illness, such as systemic lupus
erythematosus (SLE), is more likely
Outcome
• Severe bleeding is rare (<3% of cases in 1 large
international study).
• In 70-80% of children who present with acute
ITP, spontaneous resolution occurs within 6
mo.
• Therapy does not appear to affect the natural
history of the illness
• Fewer than 1% of patients develop an
intracranial hemorrhage.
• Those who favor interventional therapy argue
that the objective of early therapy is to raise
the platelet count to >20 x 109/L and prevent
the rare development of intracranial
hemorrhage.
• There is no evidence that therapy prevents
serious bleeding
• Approximately 20% of children who present
with acute ITP go on to have chronic ITP.
• The outcome/prognosis may be related more
to age, as ITP in younger children is more likely
to resolve whereas the development of
chronic ITP in adolescents approaches 50%.
Laboratory Findings
• Severe thrombocytopenia (platelet count <20
x 109/L) is common,
• platelet size is normal or increased
• In acute ITP, the hemoglobin value,white
blood cell (WBC) count, and differential count
should be normal.
• Hemoglobin may be decreased if there have
been profuse nosebleeds or menorrhagia
• Bone marrow examination shows normal
granulocytic and erythrocytic series, with
characteristically normal or increased
numbers of megakaryocytes
• Some of the megakaryocytes may appear to
be immature and are reflective of increased
platelet turnover
Indications for bone marrow
aspiration/biopsy
• an abnormal WBC count or differential
• unexplained anemia
• findings on history and physical examination
suggestive of a bone marrow failure syndrome
or malignancy
• In adolescents with new-onset ITP, an ANA
should be done to evaluate for SLE
• HIV studies should be done in at-risk
populations,especially sexually active teens
• Platelet antibody testing is seldom useful in
acute ITP
• A direct antiglobulin test (Coombs) should be
done if there is unexplained anemia to rule
out Evans syndrome (autoimmune hemolytic
anemia and thrombocytopenia) or before
instituting therapy with IV anti-D
Differential Diagnosis
• The well-appearing child with moderate to
severe thrombocytopenia,an otherwise
normal complete blood cell count (CBC),and
normal findings on physical examination has a
limited differential diagnosis that includes
exposure to medication that induces drugdependent antibodies, splenic sequestration
due to previously unappreciated portal
hypertension, and rarely, early aplastic
processes, such as Fanconi anemia
• Other than congenital thrombocytopenia
syndromes such as thrombocytopenia-absent
radius (TAR) syndrome and MYH9-related
thrombocytopenia, most marrow processes
that interfere with platelet production
eventually cause abnormal synthesis of red
blood cells (RBCs) and WBCs and therefore
manifest diverse abnormalities on the CBC
• Disorders that cause increased platelet
destruction on a nonimmune basis are usually
serious systemic illnesses with obvious clinical
findings (e.g., hemolyticuremic syndrome
[HUS], disseminated intravascular coagulation
[D1C))
• Isolated enlargement of the spleen suggests
the potential for hypersplenism owing to
either liver disease or portal vein thrombosis
• Autoimmune thrombocytopenia may be an
initial manifestation of SLE, HIV infection,
common variable immunodeficiency, or rarely
lymphoma
• .
• Wiskott-Aldrich syndrome (WAS must be
considered in young males found to have
thrombocytopenia with small platelets,
particularly if there is a history of eczema and
recurrent infection
Treatment
• There are no data showing that treatment
affects either short- or long-term clinical
outcome of ITP
• Many patients with new-onset ITP have mild
symptoms, with findings limited to petechiae
and purpura on the skin, despite severe
thrombocytopenia
• Compared with untreated control subjects,
treatment appears to be capable of inducing a
more rapid rise in platelet count to the
theoretically safe level of >20 x 109/L,
although there are no data indicating that
early therapy prevents intracranial
hemorrhage.
• Antiplatelet antibodies bind to transfused
platelets as well as they do to autologous
platelets.
• Thus, platelet transfusion in ITP is usually
contraindicated unless life-threatening
bleeding is present
Initial approaches
• 1. No therapy other than education and
counseling of the family and patient for
patients with minimal, mild, and moderate
symptoms, as defined earlier
• This approach emphasizes the usually benign
nature of ITP a coaster that ensues once
interventional therapy is begun
• This approach is far less costly, and side effects
are minimal
• IVIG at a dose of 0.8-1.0 g/kg/day for 1-2 days
induces a rapid rise in platelet count(usually
>20 x 109/L) in 95% of patients within 48 hr
• IVIGappears to induce a response by
downregulating Fc-mediated phagocytosis of
antibody-coated platelets
• IVIG therapy is both expensive and timeconsuming to administer
• after infusion, there is a high frequency of
headaches and vomiting, suggestive of IVIGinduced aseptic meningitis
• For Rh positive patients, IV anti-D at a dose of
50-75 mcg/kg causes a rise in platelet count
to >20 x 109/L in 80-90% of patients within 4872 hr When given to Rh positive individuals, IV
anti-D induces mild hemolytic anemia RBCantibody complexes bind to macrophage Fc
receptors and interfere with platelet
destruction, thereby causing a rise in platelet
count
• IV anti-D is ineffective in Rh
negative patients
Rare life-threatening episodes of intravascular
hemolysis have occurred in children and
adults following infusion of IV anti-D
• Corticosteroid therapy has been used for
many years to treat acute and chronic ITP in
adults and children.
• Doses of prednisone of 1-4 mglkg/24 hr
appear to induce a more rapid rise in platelet
count than in untreated patients with ITP
• Whether bone marrow examination should be
performed to rule out other causes of
thrombocytopenia, especially acute
lymphoblastic leukemia, before institution of
prednisone therapy in acute ITP is
controversial.
• Corticosteroid therapy is usually continued for
2-3 wk or until a rise in platelet count to >20 x
109/L has been achieved, with a rapid taper to
avoid the long-term side effects of
corticosteroid therapy, especially growth
failure, diabetes mellitus, and osteoporosis.
• Each of these medications may be used to
treat ITP exacerbations,which commonly
occur several weeks after an initial course of
therapy.
• In the special case of intracranial
hemorrhage, multiple modalities should be
used, including platelet transfusion,IVIG, highdose corticosteroids, and prompt consultation
by neurosurgery and surgery
• There is no consensus regarding the
management of acute childhood ITP, except
that patients who are bleeding significantly
should be treated, representing less than 5%
of children with ITP.
• Intracranial hemorrhage remains rare, and
there are no data showing that treatment
actually reduces its incidence
• The role of splenectomy in ITP should be
reserved for 1 of 2 circumstances.
• The older child (>4 yr) with severe ITP that
has lasted >1 yr (chronic lTP) and whose
symptoms are not easily controlled with
therapy is a candidate for splenectomy
• Splenectomy must also be considered when
life-threatening hemorrhage (intracranial
hemorrhage) complicates acute lTP, if the
platelet count cannot be corrected rapidly
with transfusion of platelets and
administration of lVIG and corticosteroids.
• Splenectomy is associated with a lifelong risk
of overwhelming postsplenectomy infection
caused by encapsulated organisms and the
potential development of pulmonary
hypertension in adulthood
Chronic Idiopathic
Thrombocytopenic Purpura
• Approximately 20% of patients who present
with acute ITP have persistent
thrombocytopenia for >12 mo and are said to
have chronic ITP
• a careful re-evaluation should be performed,
especially for autoimmune disease, such as
SLE; chronic infectious disorders, such as HIV;
and non immune causes of chronic
thrombocytopenia, such as type 2B and
platelet-type von Willebrand disease, X-linked
thrombocytopenia, autoimmune
Iymphoproliferative syndrome,CVIDS,
autosomal macrothrombocytopenia, and WAS
(also X-linked)
• The presence of co-existing H. pylori infection
should be explored and, if found, treated.
• Therapy should be aimed at controlling
symptoms and preventing serious bleeding.
• In lTP, the spleen is the primary site of both
anti platelet antibody synthesis and platelet
destruction.
• Splenectomy is successful in inducing
complete remission in 64-88% of children with
chronic ITP.
• This effect must be balanced against the
lifelong risk of overwhelming postsplenectomy
• infection
• This decision is often affected by lifestyle
issues as well as the ease with which the child
can be managed using medical therapy, such
as lVlG, corticosteroids, IV anti-D
• Rituximab, a chimeric monoclonal anti-B cell
antibody, effectively induces a remission in 3050% of children with chronic lTP
• Two new effective agents that act to stimulate
thrombopoiesis, romiplastin and eltrombopag
have been approved by the Federal Drug
Administration to treat adults with chronic lTP.
• There are no data regarding either drug's
safety or efficacy in children.
THROMBOCYTOPENIA IN THE
NEWBORN
• Neonatal Alloimmune Thrombocytopenia
(NAIT)
• Neonatal Autoimmune Thrombocytopenia
• Neonatal thrombocytopenia is relatively
common, occurring in 1–3% of healthy term
infants and in 20–30% of sick neonates
• Thrombocytopenia in sick neonates is often
due to underlying illness such as sepsis, DIC or
respiratory distress syndrome or due to
maternal factors such as pregnancy-induced
hypertension and gestational diabetes and
intrauterine growth retardation (IUGR)
NAIT
• NAITis the most common cause of severe
thrombocytopenia in the newborn
• It occurs in approximately 1 in 1,000 births.
• NAIT typically resolves in 2–4 weeks
• First-born infants are often affected and
subsequent affected pregnancies are more
severe and therefore require antenatal
treatment
• Neonatal alloimmune thrombocytopenia can
be thought of as a platelet analog of Rh
incompatibility
• It differs from Rh incompatibility because 50%
of cases are first-born infants, suggesting the
antigenic exposure occurs early in pregnancy
unlike in Rh which occurs primarily at the time
of delivery
• The most common antigen involved is P1A1
(HPA-1a) which accounts for approximately
75% of cases
• A further 10–20% of cases are due to maternal
sensitization to HPA-5b
Clinical Features
• Typically infants are otherwise-healthy fullterm babies, generalized petechiae within
minutes of birth ,ecchymosis
cephalhematomata
• Bleeding from the umbilicus, skin puncture
site, or gastrointestinal or renal tract
• ICH (up to 10–20%)
• Death in utero may occur
• Early jaundice occurs in 20% of cases.
• Platelet count is very low at birth, usually
,50,000/mm3
Treatment
• random donor platelet transfusion 10–20
ml/kg
• IVIG 1 g/kg/day for 1–3 days depending on
response with the goal platelet count being
above 30–50,000/mm3
• Methylprednisolone (1 mg IV) every 8 hours
with IVIG until the IVIG is stopped.
• No tapering of the steroid is necessary
• Head ultrasound is mandatory for the
thrombocytopenic neonate
• If there are any abnormal neurological
findings, a CT or MRI should be done
• If ICH is present in NAIT on ultrasound, the
target platelet count should be greater than
100,000/mm3 and a head CT or MRI should
be performed to better define the
hemorrhage. Ultrasound should be repeated
at one month to identify early hydrocephaly
Management of Subsequent
Pregnancies
• If a previous sibling has been identified, the
likelihood of the next fetus being affected
depends on the father’s platelet typing.
• If the father is homozygous for the antigen
responsible (as is the case in 75% of men with
HPA-1A) then essentially all later fetuses
will be affected
• If the father is heterozygous, or if typing is
unavailable or uncertain,amniocentesis or (if
necessary) fetal blood sampling could
determine fetal platelet type
• due to the invasive nature and potential to
cause fetal bleeding, it is recommended to
avoid fetal blood sampling to evaluate platelet
count whenever possible
• Instead mothers with a previously affected
neonate without ICH should be started on a
combination of weekly IVIG at 1 gram per
kilogram per week and prednisone at 0.5 mg
per kilogram per day starting at 20 weeks
gestation until birth
• Previous child with ICH in the secon trimester:
• Start treatment at 12 weeks gestation with
IVIG 2 g/kg/week with or without prednisone
0.5–1 mg/kg/day (added at 20–26 weeks)
• Previous child with ICH during third trimester:
• Start treatment at 12 weeks gestation with
IVIG 1 g/kg/week; with or without increasing
dose of IVIG to 2 g/kg at week 20; with or
without prednisone at 0.5–1 mg/kg/day (at 28
weeks).
Neonatal Autoimmune
Thrombocytopenia
• Neonatal autoimmune thrombocytopenia is
due to a passive transfer of autoantibodies
from mothers with isolated ITP (it may be
seen in association with other conditions such
as maternal SLE, hypothyroidism and
lymphoproliferative states).
• Neonates born to mothers who have
autoimmune thrombocytopenia are typically
well after an uncomplicated delivery.
• To distinguish this entity from neonatal
alloimmune thrombocytopenia,maternal
history must be obtained and the maternal
platelet count determined.
GTP
• Gestational thrombocytopenia (GTP) occurs in
5–10% of pregnancies, but maternal
thrombocytopenia by definition is mild (70–
100,000/mm3) in GTP
• GTP is not associated with neonatal
thrombocytopenia
• The platelet count in the mother swiftly
returns to normal after delivery
• Neonatal thrombocytopenia in infants born to
mothers with autoimmune thrombocytopenia
is usually less severe than that seen in
alloimmune thrombocytopenia
• only 10–15% of newborns have a platelet
count less that 50,000/mm
• Neonatal passive ITP is also associated with a
lower bleeding rate than in NAIT
• ICH only occurs rarely
• The platelet count may often be near-normal
at delivery, but then falls to a clinically
significant nadir over the next 1–3 days
Treatment
• Treatment is required when the infant’s
platelet count falls below 30,000/mm3 or if
significant bleeding is present.
• The regimen is the same as for NAIT, using
IVIG, IV methylprednisolone and random
donor platelet transfusion if indicated.
• The duration of neonatal thrombocytopenia is
usually about 3 weeks
• Unlike NAIT, there is no benefit to the fetus
from maternal treatment during pregnancy