Hemophilia, thrombocytopenia and
The American Society of Hematology 2011 evidence-based practice
GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA
depending on the type and cause of hemorrhagic syndrome: vasopathies,
IMMUNE THROMBOCYTOPENIC PURPURA (ITP)
Autoantibodies against platelet surface
o Typically 1–4 weeks after a nonspecific viral infection
o Most 1–4 years of age → sudden onset of petechiae and purpura with
o Most resolve within 6 months
o <1% with intracranial hemorrhage
o Platelet size normal to increased
o Other cell lines normal
o Bone marrow—normal to increased megakaryocytes
o Transfusion contraindicated unless life-threatening bleeding (platelet
antibodies will bind to transfused platelets as well)
o No specific treatment if platelets >20,000 and no ongoing bleeding
o If very low platelets, ongoing bleeding that is difficult to stop or life-
o If inadequate response, then prednisone
o Splenectomy reserved for older child with severe disease
Immune Thrombocytopenic Purpura (idiopathic thrombocytopenic
purpura, autoimmune thrombocytopenic purpura, primary thrombocytopenic
Background: Immune thrombocytopenic purpura (ITP) is a clinical
(thrombocytopenia) present as a bleeding tendency, easy bruising (purpura), or
extravasation of blood from capillaries into skin and mucous membranes
Pathophysiology: An abnormal autoantibody, usually immunoglobulin G
(IgG) with specificity for one or more platelet membrane glycoproteins, binds to
circulating platelet membranes.
Immunoglobulin-coated platelets induce receptor–mediated phagocytosis
by mononuclear macrophages, primarily but not exclusively in the spleen. The
spleen is the key organ in the pathophysiology of ITP, not only because platelet
autoantibodies are formed in the white pulp, but also because the
the red pulp.
If bone marrow megakaryocytes are not able to increase production and
maintain a normal number of circulating platelets, thrombocytopenia and purpura
Frequency: The annual incidence of chronic ITP has been estimated to be
1 in 10,000
spontaneous or accidental, trauma-induced intracranial bleeding in patients whose
platelet counts are less than 10,000 per µL. This situation occurs in 1-2% of cases.
Sex: In children, the incidence is the same among males and females.
Age: Children may be affected at any age, but the peak incidence occurs in
children aged 3-5 years.
seems to occur within a few weeks of recovery from a viral illness.
Thrombocytopenia is a recognized complication following Ebstein-Barr virus
infection; varicella virus; cytomegalovirus; rubella virus; hepatitis A, B or C; or
more typically, a vaguely defined, viral, upper respiratory infection or
gastroenteritis. Transient thrombocytopenia often follows recent immunization
with attenuated live-virus vaccines.
occur during the acute retroviral syndrome coincident with fever, rash, and sore
(by prior exposure) to quinidine or quinine may develop immune-mediated drug
purpura within hours to days of subsequent exposure. ther drugs that have been
associated with drug purpura include antibiotics (eg, cephalothins, rifampicin),
gold salts, analgesics, neuroleptics, diuretics, antihypertensives, eptifibatide
(Integrilin), and, more recently, abciximab (ReoPro), a chimeric monoclonal
and ecchymoses, oozing from a venepuncture site, gingival bleeding, or
hemorrhagic bullae indicates that the patient is at risk for a serious bleeding
complication (Fig. 1). If the patient's blood pressure was taken recently, petechiae
may be observed under and distal to the area where the cuff was placed and
inflated (Fig. 2). Similarly, suction-type ECG leads may induce petechiae.
Abdomen. The spleen is palpable in less than 10% of children with
Complete blood count. The hallmark of ITP is isolated thrombocytopenia.
Peripheral blood smear
The morphology of red cells and leukocytes is normal.
The morphology of platelets is typically normal, with varying
numbers of large platelets.
ethylenediaminetetraacetic acid (EDTA)-anticoagulated blood are evidence of
Antiplatelet antibody. Assays for platelet antigen-specific antibodies,
platelet-associated immunoglobulin, or other antiplatelet antibodies are available
in some medical centers and certain mail-in reference laboratories.
Computer-assisted tomographic (CT) scanning or magnetic resonance
imaging (MRI) Use them promptly when the medical history or physical
examination suggests serious internal bleeding.
and biopsy. In ITP, a normal-to-increased number of megakaryocytes exist in the
absence of other significant abnormalities.
Spleen. No specific findings exist in the spleen.
level, permitting patients with ITP to live normal lives while awaiting
spontaneous or treatment-induced remission. After 6 months, if the platelet count
cannot be maintained at a safe level or it cannot be maintained at a safe level with
medication without serious treatment-related toxicity, consider splenectomy.
drugs of choice for initial management of ITP.
Intravenous immune globulin (IVIG) has been the drug of second
Rh(D) positive with ITP, intravenous Rho immune globulin (RhIG) offers
comparable efficacy, less toxicity, greater ease of administration, and a lower cost
The limitation of using IV RhIG is the lack of efficacy in patients
hemolysis in persons who are Rh(D) positive and should not be used when the
hemoglobin concentration is less than 8.0 g/dL.
Medical care in children
The initial treatment of ITP depends on whether the risk of severe
Children whose platelet count is greater than 30,000/ L typically
only have mild purpura, and the risk of a severe hemorrhage is low. They may be
managed as outpatients without specific treatment.
Children whose platelet count is less than 20,000/ L may have more
IVIG for patients who are Rh(D) negative is a more aggressive treatment.
Children whose platelet count is less than 10,000/ L are likely to
treatment with IV methylprednisolone and either IV RhIG or IVIG is appropriate.
Platelet transfusions may be required for overt bleeding but are not
Chronic or treatment-resistant ITP
For those patients whose platelet counts do not or no longer respond
splenectomy, other treatments are available.
Data supporting these options are based on relatively few case studies
and splenectomy, necessitating treatment with alternative options, perform an
imaging study to ensure that the problem is not associated with the presence of an
Among the medical treatment options in these circumstances are
ascorbic acid, colchicine, or interferon-alpha, for which conflicting reports of
efficacy in the medical literature exist.
Surgical Care: In acute ITP, splenectomy usually results in a rapid,
complete, and lifelong clinical remission. In chronic ITP, the results of
splenectomy typically are less predictable. Platelet counts may not revert to fully
normal values, and relapses are not uncommon. Splenectomy results in a lifelong
increased risk of sepsis from infection by encapsulated bacteria. In children, the
risk of bacterial sepsis after splenectomy is estimated to be 1-2%. Many
pediatricians recommend delaying splenectomy until children are aged 5 years.
1.5-2.0 mg/kg/d may be adequate for management of nonurgent situations or
when risk of adverse effects is high because of predisposing factor, such as
diabetes or psychiatric illness
of a severe bleeding tendency in ITP. IV methylprednisolone recommended when
most rapid and reliable treatment of ITP is required. In this situation, combine
methylprednisolone with IV RhIG in qualified patients who are Rh(D) positive or
IVIG in patients who are Rh(D) negative or unqualified patients who are Rh(D)
immunoglobulin product manufactured from pools of plasma from persons who
are Rh(D) negative and have been alloimmunized to the D blood group antigen. A
single infusion of 50 µg/kg, followed by a second dose, if required, of 20-40
µg/kg, is recommended; an off-label dose of 75 µg/kg in patients whose
hemoglobin concentration is at least 8.0 g/dL may increase efficacy without
adverse effect Not recommended for persons whose Rh blood type is Rh(D)-
negative or who have had a splenectomy; IV RhIG should not be used for persons
whose hemoglobin concentration is <8.0g/dL; persons with known IgA deficiency
and anti-IgA are at risk of an anaphylactic/anaphylactoid reaction to all plasma-
containing biologicals, including IV RhIG
Immune globulin intravenous (IVIG, Gamimune, Gammagard,
Sandoglobulin) Begin with 1.0 g/kg infused IV at starting rate of 0.5 mL/kg/h
(5% solution) to a maximum rate of 4.0 mL/kg/h; repeat dose at 3-4 wk intervals
when indicated by decreasing platelet count
production of abnormal autoantibody. Azathioprine (Imuran) -- May be
effective in some patients with ITP who do not or no longer respond to
corticosteroids, IV RhIG, or IVIG. May be used in conjunction with prednisone to
splenectomy. Adult Dose 2 mg/kg/d PO/IV Pediatric Dose 50mg/daily
Inhibit cell growth and proliferation. Cyclophosphamide (Cytoxan) -- May be
useful in some patients who do not or no longer respond to corticosteroids, IV
RhIG, IVIG, or splenectomy. Induces less of a decrease in platelet count
compared to other immunosuppressive alkylating agents. 2 mg/kg/d PO or 1.0-1.5
q2-4mo as a bolus IV infusion; occasionally, patients require more frequent
Prognosis: More than 80% of children with untreated ITP had a
spontaneous recovery with completely normal platelet counts in 2-8 weeks. Fatal
bleeding occurred in 0.9% on initial presentation. Fatal intracerebral hemorrhage
occurs rarely in children who have been treated with prednisone and IV RhIG or
IVIG for at least 2 days.
Thrombasthenia Glanzmann thromboasthenia, Glanzmann disease,
constitutional thrombopathy, hereditary hemorrhagic thrombopathy
he noted purpuric bleeding in patients with platelet counts within the reference
range. Glanzmann thrombasthenia is one of several inherited disorders of platelet
athophysiology: Glanzmann thrombasthenia is an autosomal recessive trait
whereby the production and assembly of the platelet membrane glycoprotein (GP)
IIb-IIIa is altered, preventing the aggregation of platelets and subsequent clot
estimated at approximately 5%. ]
Age: Patients with Glanzmann thrombasthenia are typically diagnosed in
infancy; all individuals with the disorder are recognized by age 5 years.
The diagnosis is made in patients with refractory hemorrhage and
appropriate findings on the diagnostic laboratory studies
in persons with thrombasthenia.
failure of platelets to aggregate in response to any of the usual agonists are
diagnostic of thrombasthenia.
thrombasthenic have platelet counts within the reference range and, on blood
smear, normal platelet morphology.
(aPTT) are within reference ranges.
A urinalysis may demonstrate proteinuria and microscopic hematuria.
The diagnosis is confirmed by documenting the absence of GP IIb-
IIIa via sodium dodecyl sulfate-polyacrylamide gel electrophoresis of
radiolabeled platelet proteins.
transfusion of normal platelets.
E-aminocaproic acid may be useful in controlling bleeding after
recombinant factor VIIa.
diseases that results in inflammation of blood vessels. Arteries and veins of any
size in any organ may be affected, leading to ischemic damage to organs. The
pattern of vessel involvement is highly variable, leading to innumerable clinical
presentations. The most common vasculitides of childhood are Henoch-Schцnlein
purpura and Kawasaki disease. See articles on Kawasaki Disease, Infantile
Polyarteritis Nodosa, Polyarteritis Nodosa, and Takayasu Arteritis.
For the clinician, diagnosing the cause of vasculitis is a difficult task that
involves distinguishing disease entities with possibly overlapping clinical
presentations. Classification criteria have been established for a number of
distinct clinical syndromes, but these are less useful in making a diagnosis in
patients who do not meet all the criteria of any one disease. While groups of
patients with unifying features can be identified, a patient with vasculitis often
presents initially with nonspecific constitutional findings. Various classification
schemes for vasculitis have been proposed, most recently by an international
consensus conference in Chapel Hill, North Carolina in 1994. This classification
is as follows:
Large-sized vessel vasculitis
Temporal arteritis - Granulomatous arteritis of the aorta and major
occurs in patients older than 50 years
Takayasu arteritis - Granulomatous arteritis of the aorta and major
Medium-sized vessel vasculitis
Polyarteritis nodosa - Necrotizing vasculitis of medium- or small-
involvement without glomerulonephritis
Kawasaki disease - Medium- and small-sized arteritis of childhood
have been found on autopsy.)
Small-sized vessel vasculitis
inflammation involving the respiratory tract and necrotizing vasculitis of small- to
medium-sized vessels; associated with asthma and eosinophilia (Under the
classification of the American College of Rheumatology and traditional
classifications, Wegener granulomatosis and Churg-Strauss syndrome are grouped
together with polyarteritis nodosa under medium-sized vessel vasculitis.)
Microscopic polyangiitis (MPA) - Pauci-immune necrotizing
glomerulonephritis common; pulmonary capillaritis frequent
glomeruli typical; associated with arthritis or arthralgia
Essential cryoglobulinemic vasculitis - Vasculitis with cryoglobulin
cryoglobulins; skin and glomeruli often involved
Cutaneous leukocytoclastic vasculitis - Isolated cutaneous vasculitis
Resulting from vasculitic lesions with endothelial activation; in children, more
often due to hypercoagulable states or catheter instrumentation
Idiopathic thrombocytopenic purpura (ITP), also known as primary immune
thrombocytopenic purpura and autoimmune thrombocytopenic purpura, is defined
causes of thrombocytopenia. The 2 distinct clinical syndromes manifest as an acute
condition in children and a chronic condition in adults.
ITP is a decrease in the number of circulating platelets in the absence of toxic
exposure or a disease associated with a low platelet count.
ITP is primarily a disease of increased peripheral platelet destruction, with most
patients having antibodies to specific platelet membrane glycoproteins. Relative
marrow failure may contribute to this condition, since studies show that most
patients have either normal or diminished platelet production.
Acute ITP often follows an acute infection and has a spontaneous resolution within
2 months. Chronic ITP persists longer than 6 months without a specific cause.