GANGGUAN PEMBEKUAN

DARAH PADA ANAK

BLOK VIII HEMATOLOGI DAN LIMFATIK

As a result of injury to the blood vessel
endothelium, three events take place
simultaneously:
1.Vasoconstriction (vascular phase)
2. Platelet plug formation (primary
hemostatic mechanism—platelet phase)
3. Fibrin thrombus formation (initiation,
amplification, and propagation phases).
 Endothelial cells secrete substances that
repel platelets (prostaglandin I2 [PGI2],
and nitric oxide)
 Initiate coagulation (collagen, fibronectin)
 Promote platelet adhesion (von
Willebrand’s factor [vWF]) platelet
aggregation (adenosine diphosphate
[ADP] and fibrin dissolution (tissue
plasminogen activator)
 Catalyze the inhibition of thrombin
(heparin and thrombomodulin)
 Inhibit the initiation of fibrin dissolution
(tissue plasminogen activator inhibitor)
 Participation of platelets in hemostasis is a
fundamental component of the physiologic
process of coagulation
 Platelets provide surfaces for the assembly
of coagulation factors
 The platelets aggregate and increase the
mass of the hemostatic plug
 They also mediate blood vessel constriction
(by releasing serotonin) and neutralize
heparin
 All of the plasma coagulation factors are
produced in the liver; factor VIII is also
produced by endothelial cells
 The plasma coagulation factors work in
an interdependent manner to generate
thrombin (factor IIa) from prothrombin
(factor II); thrombin then digests
fibrinogen to form fibrin monomers
The common disease
 ITP ( Immune Thrombocytopenia
Purpura)

 VWD (Von Willebrand Disease)

 Hemophilia
ITP
 The most frequent cause of
thrombocytopenia is immune-mediated
platelet destruction due to
autoantibodies, drug-dependent
antibodies, or alloantibodies
Immune thrombocytopenic purpura (ITP) is
a syndrome characterized by:
 Thrombocytopenia (platelet count less
than 100,000/mm3)
 Shortened platelet survival
 Presence of antiplatelet antibody in the
plasma
 Increased megakaryocytes in the bone
marrow
 This condition may be acute, chronic, or
recurrent.
 In the acute form, the platelet count returns
to normal (>150,000/mm3) within 6 months
after diagnosis, and relapse does not occur.
 In the chronic form, the platelet count remains
low beyond 6 months
 In the recurrent form, the platelet count
decreases after having returned to normal
levels.
Incidence
The true incidence of ITP is unknown
because the disease is often transient. The
estimated incidence is about 1 in 10,000
children per year.
 Clinical Features
1. Age: The greatest frequency of occurrence is
between ages 2 and 8 years.
Infants less than 2 years old (infantile ITP)
have the following clinical features:
a. Higher male/female ratio
b. Less frequent occurrence of infection before
ITP
c. Less frequent occurrence of chronic ITP
d. Poor response to treatment
e. More severe clinical course.
2. Sex: Both sexes are equally affected.
3. Predisposing factors: A history of preceding
infection, usually viral, is noted within the
preceding 3 weeks in 50–80% of cases.
Nonspecific upper respiratory infections
are the most common cause in post
infectious cases
Symptoms
Petechiae, purpura, ecchymoses, and mucous
membrane bleeding are the symptoms
associated with ITP
 Skin: Ecchymoses or purpura are usually
found on the anterior surface of the lower
extremities and over bony prominences,
such as the ribs, scapula, shoulders, legs, and
pubic area. Symptoms are mild in 50% of
cases, with few bruises on the legs or trunk
 Mucous Membranes
Petechiae may be found in the
subconjunctival, buccal mucosa, soft
palate, and skin.
Bleeding from the nose, gums, mucous
membranes, gastrointestinal tract, or
kidneys
Menorrhagia may occur and may be severe.
Hematemesis and melena are infrequent
Internal Organs
Central nervous system: a serious
complication, usually preceded by headache
and dizziness and acute bleeding
manifestations elsewhere
Retinal hemorrhage
Middle ear: uncommon; leads to hearing
impairment
Deep muscle hematomata and hemarthrosis:
rare
Signs
 Pallor is usually absent unless there has
been significant bleeding.
 The tip of the spleen is palpable in fewer
than 10% of patients.
 Cervical lymphadenopathy is not present
unless the precipitating factor is a viral
illness.
Laboratory Findings
1. Platelet count:
a. Always less than 150,000/mm3.
b. Often less than 20,000/mm3 in patients
with severe generalized hemorrhagic
manifestations.
c. MPV increased; normal MPV, 8.9±1.5 μm3.
II. Blood smear: conditions.
a. Blood smear normal, apart from
thrombocytopenia (if active infection,
increased neutrophils, lymphocytes, or
atypical mononuclear cells may be
present).
b. Anemia present only in proportion to
amount of blood loss.
III. Bone marrow:
a. Increased megakaryocytes, often
immature and with absence of budding
b. Normal erythroid and myeloid cells
c. Increased eosinophils occasionally seen
d. Erythroid hyperplasia if significant blood
loss.
IV. Coagulation profile:
a. Bleeding time—usually abnormal
b. Prothrombin time (PT), activated partial
thromboplastin time (APTT), and
fibrinogen level—normal
Diagnosis
Criteria for the diagnosis are as follows:
1. Clinical examination: purpura with an otherwise essentially normal
physical examination, with no significant splenomegaly and no
lymphadenopathy
2. Platelet count and blood smears: thrombocytopenia only, with no evidence
of red cell or white blood cell abnormalities
3. Bone marrow: normal to increased number of megakaryocytes with
normal myeloid and erythroid elements
4. Exclusion of secondary causes of thrombocytopenia, such as
hypersplenism, microangiopathic hemolytic anemia, disseminated
intravascular coagulation (DIC), drug-induced thrombocytopenia
Treatment
 No treatment is required when the platelet count
is greater than 20,000/mm3 and the patient is
asymptomatic or has mild bruising but no
evidence of mucous membrane bleeding.
 Competitive contact sports should be avoided.
 Depo-Provera or any other long-acting
progesterone is useful in suspending menstruation
 Aspirin, nonsteroidal antiinflammatory agents, and
any other drugs that interfere with platelet
function should not be given.
 Treatment is indicated for children with
platelet counts less than 20,000/mm3 and
significant mucous membrane bleeding,
and those with platelet counts less than
10,000/mm3 and minor purpura. The
treatment choices are steroids, IVIG, or
anti-D.
 Steroid Therapy
a. A course of prednisone, 2 mg/kg/day
(maximum 60 mg/day), is given in divided
doses. Prednisone is reduced in a
stepwise fashion at 5- to 7-day intervals,
irrespective of the platelet count, and is
stopped at the end of 21–28 days,
regardless of the response.
b. In severe cases, methylprednisolone
(Solu-Medrol) 30 mg/kg/day (500
mg/m2/day; maximum 1 g/day) for 3 days
c. Prolonged use of steroids in ITP is
undesirable.
 High-Dose Intravenous Gammaglobulin
Indications in acute ITP:
a. Neonatal symptomatic immune
thrombocytopenia and infants less than 2
years of age who are generally more
refractory to steroid treatment
b. Alternative therapy to corticosteroid
therapy but is much more expensive, has
significant side effects, is not significantly
clinically better than steroid therapy to
justify expense and side effects of its use
Dosage:
a. Acute ITP: a total dose of 2 g/kg body
weight given as follows:
(1) 0.4 g/kg IVGG per day for 5 days OR
(2) 1 g/kg per day for 2 days.
Lower doses of 800 mg/kg/day as a single
dose or 250 mg/kg/day for 2 days have
been used with success
 Chronic ITP:
(1) Initial IVGG dose of 1 g/kg body weight
daily for 2 days, followed by periodic
single infusions (0.4–1 g/kg depending on
response) to maintain platelet count at a
safe level (>20,000/mm3)
(2) Alternate-day corticosteroids is useful
adjunctive therapy when IVGG is used.
Rituximab
Rituximab is a humanized mouse
monoclonal antibody against the B-cell
surface antigen CD-20. The rationale for
its use in ITP is to eliminate autoreactive
B cells.
Dose
375 mg/m2 IV weekly for 4 weeks.
 Plasmapheresis
In patients who manifest thrombocytopenia
and life-threatening bleeding despite medical
intervention and splenectomy, protein A
column treatment of plasma and reinfusion
can be used for rapid removal of platelet
antibodies. By accelerating the clearance
of circulating antiplatelet factors, this may be
useful in patients with severe ITP
 Platelet Transfusions
Platelet transfusions are indicated when
there are neurologic signs suggestive of
intracranial bleeding, signs of internal
bleeding, or if an emergency surgery is
indicated.
Although platelet survival is short, a platelet
transfusion may have a temporary
beneficial hemostatic effect.
 Splenectomy
Indications
Splenectomy is indicated for severe acute ITP
with acute life-threatening bleeding, which is
nonresponsive to medical treatment.
Splenectomy is also indicated for chronic
purpura with bleeding symptoms or platelet
count persistently below 30,000/mm3, which
is nonresponsive to medical treatment for
several years
Prognosis
Up to 70% of patients have a complete and
long-lasting recovery after splenectomy.
Response to steroids and IVGG is a good
indication of the likelihood of response to
splenectomy (about 80–90%). Forty
percent of patients with persistent
thrombocytopenia after splenectomy have
an accessory spleen.
 Treatment of Children with Life-
Threatening Hemorrhage
1. Platelet transfusion
2. methylprednisolone 500 mg/m2 IV per
day for 3 days
3. IVGG 2 g/kg
4. Emergency splenectomy.
Hemophilia
 The most common coagulation disorders
are hemophilia A and B.
 Hemophilia A is an X-linked recessive
bleeding disorder attributable to decreased
blood levels of functional procoagulant
factor VIII (FVIII, VIII:C, antihemophilic
factor).
 Hemophilia B is also an X-linked recessive
disorder and is indistinguishable from
hemophilia A with respect to its clinical
manifestations.
 In hemophilia B, the defect is a decreased
level of functional procoagulant factor IX
(FIX, IX:C, plasma thromboplastin
component, or Christmas factor).
 The incidence of hemophilia is probably 1
per 6,000 live male births. Factor VIII
deficiency accounts for 80–85% of cases of
hemophilia, with factor IX deficiency
accounting for the remainder.
 Both types occur with similar incidence
among all races and in all parts of the world
 Hemophilia A Carrier Detection
Excessive lyonization may result in reduced
FVIII levels in female carriers of hemophilia;
hence, a reduced FVIII level can have utility
in diagnosing the carrier state.
 Hemophilia B Carrier Detection
Hemophilia B carriers have a wide range of
FIX levels but, in a subset of cases, can be
detected by the measurement of reduced
plasma factor IX activity (in 60–70% of
cases).
 Prenatal Diagnosis
Prenatal diagnosis of hemophilia can be
performed by either chorionic villus
sampling (CVS) at 10–12 weeks’ gestation or
by amniocentesis after 15 weeks’ gestation.
If DNA analysis is not available or if a woman’s
carrier status cannot be determined, fetal
blood sampling can be performed at 18–20
weeks’ gestation for direct fetal factor VIII
plasma activity level measurement.
Clinical Course of Hemophilia
 Hemophilia should be suspected when
unusual bleeding is encountered in a male
patient.
 Clinical presentations of hemophilia A and
hemophilia B are indistinguishable.
 The frequency and severity of bleeding in
hemophilia are usually related to the plasma
levels of factor VIII or IX.
 The median age for first bleeding episode is
10 months, corresponding to the age at
which the infant becomes mobile
Treatment (Factor Replacement
Therapy)
 Factor replacement therapy is the
mainstay of hemophilia treatment.
 The degree of factor correction required
to achieve hemostasis is largely
determined by the site and nature of the
particular bleeding episode.
 Commercially available FVIII products
include high-purity recombinant
preparations, highly purified plasma-derived
concentrates (monoclonal/immunoaffinity
purified), and intermediate-purity
plasmaderived preparations.
 Available FIX products include recombinant
FIX and plasma-derived high-purity FIX
concentrate (coagulation FIX concentrate).
von Willebrand Disease
 Von Willebrand disease (vWD) is an
autosomally inherited congenital bleeding
disorder caused by a deficiency (type 1),
dysfunction (type 2), or complete absence
(type 3) of von Willebrand factor.
 vWF has two functions:
1. It plays an integral role in mediating
adherence of platelets at sites of
endothelial damage, promoting formation
of the platelet plug.
2. It binds and transports FVIII, protecting it
from degradation by plasma proteases
 Deficiency of vWF results in
mucocutaneous bleeding and prolonged
oozing following trauma or surgery.
 vWD is the most common hereditary
bleeding disorder, with biochemical
evidence present in 1–2% of the
population and biochemical evidence
combined with a bleeding history of 0.1%
of the population.
Type 1 vWD
 This is the most common form of the disorder
and is characterized by a mild to moderate
decrease in the plasma levels of vWF.
 DDAVP can be used to manage most hemostatic
problems in patients with type I vWD.
 DDAVP treatment generally normalizes FVIII,
vWF, and the bleeding time.
 The standard dose may be repeated daily as
necessary.
 Response to DDAVP should be assessed for each
individual patient.
Type 2A vWD
 This variant is associated with decreased platelet-
dependent vWF function and a lack of large HMW
multimers in plasma and platelets.
 DDAVP treatment usually increases the FVIII level in
type 2A, and the bleeding time may improve in some
patients.
 DDAVP may suffice to control some types of bleeding
in patients with this variant.
 Other patients will require treatment with clotting
factor concentrates containing both FVIII and vWF.
 Use of cryoprecipitate for vWF replacement therapy
should not be utilized because this product does not
undergo viral inactivation treatment
Type 2B vWD
 This variant is a rare form of vWD
 There may be mild thrombocytopenia due to
spontaneous agglutination of the platelets.
 DDAVP is contraindicated in type 2B vWD
because of transient thrombocytopenia
resulting from release and clearance of
abnormal vWF.
 Clotting factor concentrates containing both
FVIII and vWF are the mainstay of
treatment for this vWD variant.
Type 2N vWD
 Type 2N vWD is a result of an abnormal vWF
molecule that does not bind factor VIII
 The unbound factor VIII is rapidly cleared from
circulation, resulting in reduction of plasma factor VIII
as compared with the level of vWF.
 Some of these patients may be misdiagnosed as
having hemophilia A.
 In type 2N vWD FVIII levels increase following
DDAVP infusion but the released FVIII circulates only
for a short time because of impaired binding to vWF..
 For major bleeding or surgery, the recommended
treatment is a factor VIII concentrate containing high
levels of vWF.
Type 2M vWD
 The vWF protein is released by DDAVP so
that patients heterozygous for this variant
may respond clinically to standard doses
of DDAVP.
 For homozygotes the vWF released by
DDAVP is defective and a poor clinical
response occurs.
 Major bleeding episodes or surgery should
be managed with vWF replacement therapy.
Type 3 vWD
 The clinical phenotype is a severe bleeding disorder with
major deficits in both primary and secondary hemostasis.
 The plasma level of FVIII and vWF is virtually undetectable.
 Patients are unresponsive to DDAVP (no releasable vWF
stores) and require episodic treatment with vWF containing
FVIII concentrates.
 Administration of FVIII concentrates containing vWF to
these patients is contraindicated because life-threatening
anaphylactic reactions may result.
 In the absence of vWF the half-life of the infused FVIII will be
short (1–2 hours) and administration of high doses, at short
intervals or by continuous infusion, will be required.
 Administration of rFVIIa at a dose of 90 μg/kg every 2 hours
has produced hemostasis for some of these patients.
Selamat Belajar