Immune thrombocytopenic purpura (ITP)

• The most common cause of

thrombocytopenia in childhood.
• It occurs at any age, but most children
present between the ages of 2 years and 10
years.
• A recent history of viral illness is seen in 50-
65% of cases, more often in winter and
spring.
Age and sex distribution of ITP
 Pathogenesis
• ITP is caused by antiplatelet IgG
autoantibodies, produced by the spleen and
lead to increased platelet destruction in the
spleen where antibody-coated platelets are
removed by mononuclear phagocytes →
thrombocytopenia.
• The thrombocytopenia may be accompanied by
a compensatory increase of megakaryocytes in
the bone marrow.
 Clinical manifestations of ITP
• A previously healthy child with abrupt
onset of generalized petechiae, purpura
and epistaxis,1-4 weeks after a viral
infection.
• Severe bleeding such as intracranial
hemorrhage is rare.
• No anemia (unless there is severe
bleeding) and no organomegaly.
Petechiae and purpura Glass test
 Diagnosis of ITP
• CBC → isolated thrombocytopenia. Mild
anemia may be present due to significant
bleeding.
• The diagnosis is based on clinical presentation
and the isolated thrombocytopenia on CBC.
• Bone marrow examination is not routinely
required in the presence of typical clinical
findings and CBC, but when performed, it
demonstrates an increased number of
megakaryocytes.
 Diagnosis of ITP
Indications for BME:
• Atypical findings (anemia, neutropenia, HSM
or marked LAP). BME is indicated to rule out
leukemia or aplastic anemia.
• If the child is going to be treated with steroids,
since steroids may temporarily mask the
diagnosis of ALL.
Bone marrow examination is controversial (the aim to do it to exclude leukemia and aplastic anemia) but the point against this is neither
leukemia nor aplastic anemia will present with thrombocytopenia alone
But if the presentation is atypical (reduction in more than one element, significant anemia, change in WBC or if pt has hepatosplenomegaly or
lymphadenopathy –> bone marrow examination should be done
- If you decide to treat pt with steroid before do BM examination because if u gave steroid to pt and thrombocytopenia is due to leukemia the
 DDx of ITP
• Acute leukemia
• Aplastic anemia
• HSP
• Meningococcemia
 HSP
• Vasculitis of unknown etiology.
• Preschool and school age children.
• The hallmark is non-thrombocytopenic palpable purpura,
which predominantly occurs on the lower extremities and
buttocks.
• Other features of HSP include arthritis, gastrointestinal, and
renal involvement.
• Dx is clinical. IgA is often present in skin and renal lesions.
• Treatment: Self-limiting in most cases. NSAIDs for arthritis,
steroids for GI or renal involvement.
• The prognosis is excellent, most cases resolve within 3-4
weeks. Rarely, patients develop chronic renal disease.
Distribution is
very
important for
differentiating
b/t HSP and
ITP
 Meningococcemia
• Due to Neisseria meningitidis
(meningococcus).
• Presentation: Septic shock, purpura,
hypotension, seizures, and multiple organ
dysfunction.
 Treatment of ITP
• In 80% of children, the disease is acute, benign,
and self-limiting, remitting spontaneously
within 6 months after diagnosis.
• Most children do not need any therapy if their
platelet count is > 20 × 10⁹/L with mild bleeding.
• The child should avoid trauma and contact
sports.
• Platelet counts should be checked weekly.
 Indications for treatment of ITP
• Moderate and severe bleeding (ICH, GI
hemorrhage).
• Severe thrombocytopenia (platelet count
<10,000/mm3).
• Persistent minor bleeding that affects daily life
such as excessive epistaxis or menstrual bleeding.
The treatment options: oral prednisolone, IVIG or
IV anti-D immune globulin.
 Treatment of ITP
Treatment of ICH: platelet transfusion, IVIG, high-dose
steroid, and surgical consultation. Platelet transfusion
raise the platelet count only for a few hours, because
antiplatelet antibodies bind to transfused platelets.
Indications for Splenectomy:
• Acute ITP with life-threatening bleeding, if the platelet
count cannot be corrected rapidly with platelet
transfusion, IVIG and steroids.
• Chronic ITP in a child > 4 years of age with severe ITP,
whose symptoms are not easily controlled with therapy.
 Chronic ITP
Persistent thrombocytopenia >12 months. It occurs in
20% of patients. Adolescents >> young children.
Treatment of chronic ITP
• Repeated treatments with IVIG, IV anti-D, or high-dose
pulse steroids are effective in delaying the need for
splenectomy.
• Rituximab (monoclonal antibody) induce partial or
complete remission in 1/3 of cases.
• Thrombopoietic growth factors is a new treatment.
• Splenectomy induces a remission in 70-80%.
 Vitamin K deficiency bleeding (VKDB) beyond neonatal
period
Risk factors:
• Exclusive BF.
• Prolonged antibiotic administration which result
in alterations in the gut flora.
• Pancreatic diseases with fat malabsorption.
• Liver disease.
• Use of vit. K antagonists
(warfarin)
 VKDB
• Presentation: Bruising, mucous
membrane bleeding, excessive
bleeding associated with trauma or
invasive procedures.
• PT and aPTT are prolonged.
• Treatment: IM vitamin K.
• Prevention: Prophylactic vitamin K.
 Liver diseases
• The liver is the synthetic site for most
of the procoagulant and anticoagulant
proteins.
• Bleeding in chronic liver diseases is due to
reduced synthesis of coagulation proteins,
activation of fibrinolytic system,
thrombocytopenia, platelet dysfunction,
and vitamin K deficiency.
 Liver diseases
• The clinical manifestations are similar to
those of vitamin K deficiency.
• Lab findings: prolonged PT and aPTT.
• Management of coagulopathy in liver
disease: FFP contains all clotting factors,
but large volumes are required.
 DIC
• Consumption of procoagulants, anticoagulants,
fibrinolytic proteins and platelets.
• DIC is always caused by an underlying disorder; in
children, the most common etiology is sepsis. Other
causes include: malignancy (AML), trauma, major
hemorrhage, severe hemolysis and major surgeries.
• Patients develop hemorrhagic and/or thrombotic
complications. In some patients, hemorrhage may
predominant, and in others thrombosis is the main
feature.
 Presentation and diagnosis of DIC
• A critically ill child + bleeding from many sites
+ signs of thrombosis (skin necrosis, renal or
hepatic insufficiency).
• DIC is suggested by elevated PT, aPTT and D-
dimers, low fibrinogen levels,
microangiopathic hemolysis, and the
presence of an underlying condition known
to be associated with DIC.
 Microangiopathic HA
• Anemia that results from physical damage to the
red cells following the occlusion of arterioles and
capillaries as a result of fibrin deposition or
platelet aggregation.
• Causes: infection (DIC or HUS), physical trauma
(mechanical heart valves) and autoimmune
(TTP).
• The blood film contains numerous fragmented
cells (schistocytes).
 D-dimers
• D-dimer is the fibrin degradation product
(FDP). It reflects ongoing activation of the
hemostatic system.
• Used in the diagnosis of DVT, PE and DIC.
• A negative D-dimer test exclude VTE.
• The negative test is < 250 ng/mL.
 Treatment of DIC
• Specific treatment of the underlying cause.
• FFP which contain all coagulation proteins.
• Platelet transfusion, if there is significant
thrombocytopenia.
Prognosis and outcome:
• Mortality is high due to the underlying cause or
complications of bleeding or thrombosis.
• Those who survive may recover completely or have
permanent sequelae.
 von Willebrand Disease (vWD)
• Von Willebrand factor (vWF) is a plasma glycoprotein synthesized and
stored in endothelial cells and megakaryocytes.
• Functions of vWF:
1-It facilitates platelet adhesion to sites of vascular
injury.
2-It acts as the carrier protein for FVIII, protecting it
from inactivation and clearance.
• In vWD there is ↓ or dysfunction of vWF, resulting in defective
platelet plug formation.
• It is the most common inherited bleeding disorder, approaching an
incidence of 1%.
 Classification
• Type 1: partial↓of vWF (mild to moderate ↓)
, 75-80% of cases, AD, mild, may not be
diagnosed until puberty or adulthood.
• Type 2: defect in vWF function, most cases
are AD, few cases are AR, 15-20% of cases of
vWD.
• Type 3: total (complete) ↓, extremely rare,
AR, severe.
 Clinical presentation
Depends on the subtype and severity:
• Mucocutaneous bleeding, epistaxis,
gingival bleeding, cutaneous bruising,
and menorrhagia.
• Type 3 may have manifestations similar
to hemophilia A (hemarthrosis).
 Diagnosis of vWD
Specific tests for vWD:
• vWF antigen
• Ristocetin cofactor (vWF: RCo).
• FVIII activity
• vWF multimers test.
 Treatment of vWD
• Type 1: Minor bleeding is treated by
desmopressin (DDAVP) and/or
antifibrinolytic agents (aminocaproic acid
or tranexamic acid). Major bleeding or
surgery is treated by FVIII/vWF-containing
concentrates. DDAVP is synthetic form of
the hormone vasopressin (ADH). It
increases the endogenous vWF.
 Treatment of vWD
• Type 2 and type 3: FVIII/vWF-containing
concentrates.
• FFP is not used because it do not contain
enough vWF.
• Cryoprecipitate is not be used because it
cannot be virally inactivated.
• Aspirin and NSAID should be avoided.
 THE HEMOPHILIAS
• Hemophilia A (classical hemophilia), XLR, ↓FVIII,
incidence 1:5000 male births. Def factor 8 , more common 80%
• Hemophilia B (Christmas disease), XLR, ↓FIX,
incidence 1:25,000 male births. Def factor 9
• Hemophilia C, AR, ↓ XI, 1 in 100,000 people.
• In hemophilia clot formation is delayed and is not
strong (soft friable clot).
• Clinically, hemophilia A and B are indistinguishable
other than by their therapy.
 Hemophilia A
• Factor VIII is a plasma glycoprotein, synthesized in liver
endothelial cells (not in the hepatocytes). In the
circulation, it is immediately linked to vWF. This
prevents enzymatic degradation of FVIII until it is
needed during coagulation.
• Two-thirds have a family history of hemophilia, whereas
one-third are sporadic (mutation).
• Females can be affected in cases of extreme X
chromosome lyonization or Turner syndrome also if father is
affected and mother carrier
 Classification of hemophilia A
• Severe hemophilia (60% of cases): FVIII activity is
<1% of normal, bleeding is spontaneous, manifests in
infancy. Severe bleeding after circumcision.
• Moderate (10% of cases): factor activity is 1-5% of
normal and require minor trauma to induce bleeding
(rarely spontaneous).
• Mild (30% of cases): factor activity is >5-30% of
normal, no spontaneous bleeding, may go
undiagnosed for many years until the patient is
exposed to major trauma or surgery.
 Clinical manifestations
• FVIII does not cross the placenta; bleeding
symptoms may present in the neonatal
period.
• Easy bruising and severe mucosal bleeding
in infants.
• Most children present towards the end of
the first year of life, when they start to crawl
or walk (and fall over).
 Clinical manifestations
• The hallmark is bleeding into joints
(hemarthroses) and muscles, which may be
induced by minor trauma or spontaneous in
severe cases.
• The hemarthroses occur mostly in ankle,
knee and elbow joints.
• Petichiae and purpura are not features of
hemophilia.
Hemarthroses
 LABORATORY FINDINGS AND DIAGNOSIS
• Prolonged aPTT.
• Other tests are normal.
• The diagnosis is confirmed by specific
factor assay (analysis of FVIII
activity).
• But nowadays by DNA analysis (most accurate)
 Treatment
Factor replacement therapy:
• Recombinant FVIII concentrate is given by IV infusion
whenever there is any bleeding, and before and after
any operation.
• In severe hemophilia, prophylactic FVIII is given every 2-
3 days (To convert severe to moderate) to prevent spontaneous
bleeding and chronic arthropathy. this will increase the incidence of
hemarthrosis because reccurent hemarthrosis will lead to chronic arthropathy.

• FVIII is also present in FFP (but large volume is required),

and in cryoprecipitate (but not virally inactivated).
 Treatment
• In mild and moderate hemophilia A, the
endogenous FVIII and vWF can be released
from the storage sites by the administration of
desmopressin acetate (DDAVP). Stimulate release endogenouse
FVIII from endothelium

• Aminocaproic acid (inhibitor of fibrinolysis)

may be useful for bleeding symptoms in
locations with prominent fibrinolytic activity,
such as the mouth, GIT, and uterus.
 SUPPORTIVE CARE
• Avoidance of aspirin and other NSAID
that affect platelet function.
• Avoidance of IM injection and violent
contact sports.
• Vaccinations against hepatitis B.
• Periodic screening for hepatitis B and C,
HIV, and abnormalities in liver function.
 Chronic complications
• Development of inhibitory antibodies (IgG
antibodies) against infused F VIII or 9 (25-35% of cases),
leading to failure of a bleeding episode to respond to
appropriate replacement therapy.
How to eradicate the antibodies? by Immune tolerance
therapy (desensitization) with repeated exposure to FVIII
concentrate over a period of months to years.
How to treat bleeding in the presence of a high titer
inhibitor? bypassing therapy with either high doses of
recombinant FVIIa or a prothrombin complex concentrate. (factor 8 or 9 bypassing
agents) We have two (recombinant activated factor 7 or a prothrombin complex concentrate)
 Chronic complications
• Chronic arthropathy (degenerative joint
disease) due to recurrent hemorrhage.
Prophylactic FVIII may reduce the incidence.
• Transmission of blood-borne viruses (HB, C,
HIV) due to the use of non-virally inactivated
clotting factor concentrates derived from
plasma. Recombinant products are safe from
transfusion-transmitted diseases.
Chronic arthropathy due to repeated hemarthrosis
in the knee joint → widening of the intercondylar
notch and cortical irregularity Hemophilia
Normal
 Hemophilia A
Detection of carriers:
• Direct gene mutation analysis: the most accurate test
• F VIII is carried in plasma by vWF (when mother is carrier):
FVIII / vWF = 1 →normal
FVIII / vWF = < 1 →carrier
Prenatal diagnosis:
• DNA analysis: using cells from Chorionic Villus Sampling
or by amniocentesis.
• Fetal blood sampling for direct FVIII plasma activity level
measurement.
• Thrombosis; formation of blood clots it occur in the veins and arteries
• In the vein will cause swelling of involved part
• In the artery will cause ischemia and necrosis
• And sometimes will lead to thromboembolism
• The first peak occur in infant and second peak in adolescent
• Most cases of thrombosis in children are acquired
• Only 5% is due to hereditary (congenital thrombophilia) most common due to factor 5 leiden mutation
• The most common predisposing factor is central venous catheter as (TPN, chemotherapy, hemodialysis, prolong administration of
antibiotic as cystic fibrosis) all for these we use central line
• Other diseases as malignancy infection cyanotic CHD (PCV is high), nephrotic syndrome, immobilization, severe dehydration, obesity…
• Clinical presentation (DVT, stroke, PE, cerebral thrombosis, renal vein thrombosis, in neonate may present with purpura fulminans)
• protein C deficiency can occur in severe septicaemia here purpura fulminans is not due to thrombocytopenia is due to acquired
protein C deficiency

• Dx:-
• D-dimer
• Radiology - Look for site of location of thrombosis (US,venograph for DVT), (CT- pulmonary E), (MRI for stroke and cerebral sinovenous
thrombosis)
• Also by signs and symptoms
• Also screening (assay for protein C&S) PCR for mutation of factor 5

• Tx
• Anticoagulant like heparin and warfarin
• Thrombolytic agents
• Streptokinase
• In neonate replacement therapy with factors
 Case presentation 1
HISTORY
A 4-year-old male child presented with acute history of
bleeding from multiple sites for 2 days.
Initially, few red spots appeared on both the lower legs
which the parents thought were mosquito bites. By the next
morning, the rash spread all over the body with red spots of
multiple sizes including the face. He also had mild bleeding
from the gums and epistaxis. There was no history of fever or
any other symptoms. The child was playful and eating well. No
history of bleeding from any other site. He did not have any
similar past history.
 Case presentation 1
ANALYSIS OF HISTORY
Acute bleeding in 4 years old child, without
previous history, suggests that the condition is
acquired and not congenital.
 Case presentation 1
EXAMINATION
The child was well, alert and active. He was
afebrile and not pale. He had generalized
petechiae and purpura. There were conjunctival
hemorrhages in both eyes and mild ooze from
the gums. He did not have bone tenderness.
There was no HSM and no LAP. Systemic
examination was completely normal.
 Case presentation 1
ANALYSIS OF PHYSICAL EXAMINATION
• Petechiae and purpura indicate that the defect is in the
primary hemostasis.
• The purpura is diffuse and not confined to legs and
buttocks. This exclude HSP.
• The child is well, not anemic, no LAP and no HSM. This
makes leukemia and aplastic anemia unlikely.
• Presence of skin and mucous membrane hemorrhages
without any other clinical manifestations suggests an
isolated platelet type coagulation defect.
 Case presentation 1
INVESTIGATIONS
• CBC: Hb 10.5 g/dL, total WBC count 9,800/cmm, with normal
differential count, platelet count 6,000/cmm.
• PT: 15 second (control 14 second)
• PTT: 32 second (control 30 second)
ANALYSIS
• No defect in the secondary hemostasis.
• Normal CBC, except for severe thrombocytopenia. This means
isolated thrombocytopenia.
• Neither leukemia nor aplastic anemia presents with
thrombocytopenia alone.
 Case presentation 1
A bone marrow aspirate (BMA): increased
megakaryocytes were noted on BMA with
normal myelopoiesis and erythropoiesis.
The above investigations confirmed the
diagnosis of ‘Acute ITP’.
 Case presentation 1
TREATMENT AND FOLLOW-UP
This child received a single dose of IV IG after
admission to the hospital. The platelet count
increased to 55,000/cmm on the next day and
gradually normalized to above 150,000/cmm by
4 weeks. He is well on a follow-up of 6 months.
 Case presentation 1
DISCUSSION
Acute onset of petechiae or purpura in a young child with
mucosal hemorrhages suggests acute ITP, in the absence
of other manifestations like fever, infections, lymph
nodes, and HSM. The hemogram in such cases would
reveal ‘isolated’ thrombocytopenia. Any abnormalities
other than low platelets on the hemogram suggest an
alternative diagnosis. Acute ITP is a diagnosis of
exclusion. Bone marrow examination helps to exclude
conditions like leukemia and aplastic anemia.
 Case presentation 1
DISCUSSION
Treatment is indicated when the child has mucosal bleeding and
platelet counts below 20,000/cmm. There are three options: (1)
IVIgG, (2) Steroids and (3) Anti-RhD. All three modalities are
equally effective, but cost of treatment is considerably different.
Therapy with IVIg is the costliest while steroids are the cheapest.
Children without mucosal bleeds and platelet counts more than
20,000/cmm may not require any treatment. All children must
avoid injuries to prevent serious hemorrhage especially in the
CNS. Platelet transfusions are not useful in ITP. More than 95%
children recover in 3-6 months with or without treatment.
 Case presentation 1
LEARNING POINTS
• Acute ITP is a diagnosis of exclusion
• Isolated thrombocytopenia is the hallmark
• All children do not require treatment
• Treatment is required if the child has mucosal
bleeds and a platelet count less than 20,000/cmm
• Most children recover in 3-6 months
• Platelet transfusions are not useful in ITP.
 Case presentation 2
HISTORY
A 14-month-old male child, start walking unsupported one
month ago, presented with a painful swelling of the right
knee without any apparent injury, since the last 4 days. There
was no history of fever or any other associated symptoms. On
direct questioning, an isolated ecchymotic spot was noticed at
about the same time on the elbow. No history of any other
joint swellings, now or in the past, no history of excessive
bleeding from the umbilical cord at birth, no history of
epistaxis and no family history of similar disorder (including
siblings).
 Case presentation 2
ANALYSIS OF HISTORY
• An acute painful swelling of a single large joint suggests
arthritis.
• In the absence of any fever, an acute infective pathology
is unlikely.
• An injury could explain both the ecchymoses and the
joint swelling (traumatic arthritis).
• If there is definitely no injury, then in this afebrile child
one may consider a coagulation disorder resulting in both
hemarthroses and ecchymoses.
 Case presentation 2
PHYSICAL EXAMINATION
• Well nourished, comfortable, not sick looking.
• Weight 10.7 kg.
• Temp/pulse/respiration: normal.
• No pallor.
• Tense tender swelling of the right knee.
• A single ecchymotic patch on the right elbow.
• Liver just palpable (soft), spleen not palpable.
• Other systems normal.
 Case presentation 2
ANALYSIS OF PHYSICAL EXAMINATION
• The only positive findings are a tense tender knee joint
swelling with an ecchymotic spot on the elbow.
• Spontaneous swelling in the absence of any other findings
means hemarthrosis, which suggest a bleeding disorder due
to a coagulation factor deficiency (congenital or acquired).
• Spontaneous hemarthrosis is not a feature of acquired
disorders.
• Hemophilia is the commonest inherited coagulation disorder.
 Case presentation 2
ANALYSIS OF PHYSICAL EXAMINATION
• Prothrombin complex factor deficiency (II, V, VII and X) are
usually acquired and rarely inherited.
• Factor XII deficiency does not present clinically as a
bleeding disorder.
• Factor XIII deficiency commonly has its onset in infancy,
with bleeding after separation of the umbilical cord stump.
• Factor XI deficiency (hemophilia C) can occur in both sexes
as it has an autosomal recessive inheritance and
spontaneous hemorrhage is rare.
 Case presentation 2
ANALYSIS OF PHYSICAL EXAMINATION
• In vWD, spontaneous hemarthrosis is
very rare.
• So, this child must be suffering from
either factor VIII (hemophilia A) or IX
deficiency (hemophilia B). Clinically, they
are indistinguishable from one another.
 Case presentation 2
INVESTIGATIONS
• Hb 9.8 g/dL.
• WBC normal.
• Platelet count normal
• PTT 87 seconds.
• PT normal.
• Factor VIII activity: less than 1%
• Factor IX activity: normal.
FINAL DIAGNOSIS: severe Hemophilia A.