Idiopathic thrombocytopenic purpura

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Idiopathic thrombocytopenic purpura

Classification and external resources

Purpura, or small bruise-like markings, may occur in

ITP
ICD-10
D69.3
ICD-9
287.31
OMIM
188030
DiseasesDB
6673
MedlinePlus
000535
eMedicine
emerg/282
MeSH
D016553
Idiopathic thrombocytopenic purpura (ITP) is the condition of having an abnormally low
platelet count (thrombocytopenia) of unknown cause (idiopathic).[1] As most incidents of ITP
appear to be related to the production of antibodies against platelets, immune
thrombocytopenic purpura or immune thrombocytopenia are terms also used to describe
this condition. Often ITP is asymptomatic (devoid of obvious symptoms) and can be
discovered incidentally, but a very low platelet count can lead to an increased risk of bleeding
and purpura.
ITP is diagnosed with a complete blood count (a common blood test). In some situations,
additional investigations (such as a bone marrow biopsy) may be necessary to ensure that the
platelet count is not decreased due to other reasons. Treatment may not be necessary in mild
cases, but very low counts or significant bleeding might prompt treatment with steroids,
intravenous immunoglobulin, anti-D immunoglobulin, or stronger immunosuppressive drugs.
Refractory ITP (ITP not responsive to conventional treatment) may require splenectomy, the
surgical removal of the spleen. Platelet transfusions may be used in severe bleeding together
with a very low count. Sometimes the body may compensate by making abnormally large
platelets.

Contents

1 Signs and symptoms

2 Pathogenesis

3 Diagnosis

4 Treatment
o

4.1 Steroids

4.2 Anti-D

4.3 Steroid-sparing agents

4.4 Thrombopoietin receptor agonists

4.5 Surgery

4.6 Platelet transfusion

4.7 H. pylori eradication

4.8 Experimental and novel agents

5 Epidemiology

6 History

7 Synonyms

8 References

9 External links

Signs and symptoms

Petechiae on the lower extremities.

Visible symptoms of ITP include the spontaneous formation of bruises (purpura) and
petechiae (tiny bruises), especially on the extremities, bleeding from the nostrils, bleeding at
the gums, and menorrhagia (excessive menstrual bleeding), any of which may occur if the
platelet count is below 20,000 per l.[2] A very low count (<10,000 per l) may result in the

spontaneous formation of hematomas (blood masses) in the mouth or on other mucous

membranes. Bleeding time from minor lacerations or abrasions is usually prolonged.
Serious and possibly fatal complications due to an extremely low count (<5,000 per l) may
include subarachnoid or intracerebral hemorrhage (bleeding inside the skull or brain), lower
gastrointestinal bleeding or other internal bleeding. An ITP patient with an extremely low
count is vulnerable to internal bleeding caused by blunt abdominal trauma, as might be
experienced in a motor vehicle crash. These complications are not likely in a patient whose
platelet count is above 20,000 per l.

Pathogenesis
In many cases, ITP's cause is not idiopathic but autoimmune,[3] with antibodies against
platelets being detected in approximately 60 percent of patients. Most often these antibodies
are against platelet membrane glycoproteins IIb-IIIa or Ib-IX, and are of the immunoglobulin
G (IgG) type. The famous HarringtonHollingsworth experiment established the immune
pathogenesis of ITP.[4]
The coating of platelets with IgG renders them susceptible to opsonization and phagocytosis
by splenic macrophages, as well by Kupffer cells in the liver. The IgG autoantibodies are
also thought to damage megakaryocytes, the precursor cells to platelets, but this is thought to
contribute only slightly to the decrease in platelet numbers. Recent research now indicates
that impaired production of the glycoprotein hormone thrombopoietin, which is the stimulant
for platelet production, may be a contributing factor to the reduction in circulating platelets.
This observation has led to the development of a class of ITP-targeted drugs referred to as
thrombopoietin receptor agonists.
The stimulus for auto-antibody production in ITP is probably abnormal T cell activity.[5][6][7]
Preliminary findings suggest that these T cells can be influenced by drugs that target B cells,
such as rituximab.[8]

Diagnosis
The diagnosis of ITP is a process of exclusion. First, the clinician has to determine that there
are no blood abnormalities other than low platelet count, and no physical signs except for
signs of bleeding. Then, the secondary causes (usually 510 percent of suspected ITP cases)
should be excluded. Secondary causes could be leukemia, medications (e.g., quinine,
heparin), lupus erythematosus, cirrhosis, HIV, hepatitis C, congenital causes,
antiphospholipid syndrome, von Willebrand factor deficiency, onyalai and others.[2][9] In
approximately one percent of cases, autoimmune hemolytic anemia and ITP coexist, a
condition referred to as Evans syndrome.[9]
Despite the destruction of platelets by splenic macrophages, the spleen is normally not
enlarged. In fact, an enlarged spleen should lead a clinician to investigate other possible
causes for the thrombocytopenia. Bleeding time is usually prolonged in ITP patients.
However, the use of bleeding time in diagnosis is discouraged by the American Society of
Hematology practice guidelines.[10] A normal bleeding time does not exclude a platelet
disorder.[11]

A bone marrow examination may be performed on patients over the age of 60 and those who
do not respond to treatment, or when the diagnosis is in doubt.[9] On examination of the bone
marrow, an increase in the production of megakaryocytes may be observed and may help in
establishing a diagnosis of ITP. An analysis for anti-platelet antibodies is a matter of
clinician's preference, as there is disagreement on whether the 80 percent specificity of this
test is sufficient.[9]

Treatment
A platelet count below 20,000 per l is generally an indication for treatment. Patients with a
count between 20,000 and 50,000 per l are usually evaluated on a case-by-case basis, and,
with rare exceptions, there is usually no need to treat patients with a count above 50,000 per
l.[9] Hospitalization may be recommended in cases of very low counts, and is highly
advisable if significant internal or mucocutaneous bleeding has developed. A count below
10,000 per l is potentially a medical emergency, as the individual may be vulnerable to
subarachnoid or intracerebral hemorrhage as a result of moderate head trauma.[citation needed]
Treatment is typically administered under the direction of a hematologist and treatment
recommendations sometimes differ for adult and pediatric ITP.[12]

Steroids
The first line of treatment usually consists of steroids, a group of medications that suppresses
the immune system. The dose and mode of administration is determined by the platelet count
and whether there is active bleeding: in emergencies, infusions of dexamethasone or
methylprednisolone may be used, while in milder forms the treatment may consist of oral
prednisone or prednisolone. Once the platelet count has improved, the dose of steroid is
gradually reduced while monitoring for relapses. 6090% percent of people will experience a
relapse during dose reduction or cessation.[9][13] Long-term steroids are usually avoided, as
they can cause numerous side-effects such as osteoporosis, diabetes and cataracts.[citation needed]

Anti-D
Another strategy that is suitable for Rh-positive patients is treatment with Rho(D) immune
globulin (Anti-D), which is intravenously administered. Anti-D is normally administered to
Rh-negative women during pregnancy and after the birth of an Rh-positive infant to prevent
sensitization to the Rh factor in the newborn. Anti-D has been demonstrated effective on
some ITP patients, but is costly, produces a short-term improvement and is not recommended
for post-splenectomy patients.[14]

Steroid-sparing agents
Immunosuppresants such as mycophenolate mofetil and azathioprine are becoming more
popular for their effectiveness. In chronic refractory cases where the immune pathogenesis
has been confirmed, the off-label use of vincristine, a chemotherapy agent, may be
attempted. However, vincristine, a vinca alkaloid, has significant side-effects and its use in
treating ITP must be approached with caution, especially in children.
Intravenous immunoglobulin (IVIg) may be infused in some cases. IVIg, while sometimes
effective, is costly and produces a short-term improvement that generally lasts less than a

month. However, in the case of an ITP patient scheduled for surgery who has a dangerously
low platelet count and has experienced a poor response to other treatments, IVIg can increase
the count and reduce bleeding risk.

Thrombopoietin receptor agonists

Thrombopoietin receptor agonists are pharmaceutical agents that treat ITP by stimulating
platelet production instead of attempting to curtail platelet destruction. As of 2011, two such
products are available:

Romiplostim (trade name Nplate) is a thrombopoiesis stimulating Fc-peptide fusion

protein (peptibody) that is administered by subcutaneous injection. Designated an
orphan drug in 2003 under USA law, clinical trials demonstrated romiplostim to be
effective in treating chronic ITP, especially in relapsed post-splenectomy patients.[15]
[16]
Romiplostim was approved by the United States Food and Drug Administration
(FDA) for long-term treatment of adult chronic ITP on August 22, 2008.[17]

Eltrombopag (trade name Promacta) is an orally-administered agent with an effect

similar to that of romiplostim. It too has been demonstrated to increase platelet
counts and decrease bleeding in a dose-dependent manner.[18] Developed by
GlaxoSmithKline and also designated an orphan drug by the FDA, Promacta was
approved by the FDA on November 20, 2008.[19]

Medicare in the USA will cover most of the cost of romiplostim or eltrombopag treatment
under Part-A.

Surgery
Splenectomy (removal of the spleen) may be considered, as platelets targeted for destruction
will usually meet their fate in the spleen. The procedure is potentially risky in ITP cases due
to the increased possibility of significant bleeding during surgery. Durable remission
following splenectomy is achieved in 60 to 65 percent of ITP cases, less so in older subjects.
[20]
As noted in the introduction, the use of splenectomy to treat ITP has diminished since the
development of steroid therapy and other pharmaceutical remedies.

Platelet transfusion
Platelet transfusion alone is normally not recommended except in an emergency, and is
usually unsuccessful in producing a long-term platelet count increase. This is because the
underlying autoimmune mechanism that is destroying the patient's platelets will also destroy
donor platelets.

H. pylori eradication
In adults, particularly those living in areas with a high prevalence of Helicobacter pylori
(which normally inhabits the stomach wall and has been associated with peptic ulcers),
identification and treatment of this infection has been shown to improve platelet counts in a
third of patients. In a fifth, the platelet count normalized completely; this response rate is
similar to that found in treatment with rituximab, which is more expensive and less safe.[21] In

children, this approach is not supported by evidence, except in high prevalence areas. Urea
breath testing and stool antigen testing perform better than serology-based tests; moreover,
serology may be false-positive after treatment with IVIG.[22]

Experimental and novel agents

Dapsone (also called diphenylsulfone, DDS, or avlosulfon) is an anti-infective sulfone

drug. In recent years, Dapsone has also proved helpful in treating lupus, rheumatoid
arthritis and has had some application as a second-line treatment for ITP. The exact
mechanism by which Dapsone assists in ITP is unclear. However, limited studies
report successful increases in platelet counts in 4050 percent of patients administered
the drug.[23][24]
The off-label use of rituximab, a chimeric monoclonal antibody against the B cell
surface antigen CD20, has been shown in preliminary studies to be an effective
alternative to splenectomy in some patients.[8][25][26] However, many patients
experience significant side-effects, there is a small risk of fatality due to progressive
multifocal leukoencephalopathy caused by a reactivated JC virus, and randomized
controlled trials have yet to be conducted.[27]
Promising results have been reported in a small phase II study of the experimental
kinase inhibitor tamatinib fosdium (R788). In a population of 14 patients refractory to
other treatments (ten of them having relapsed following splenectomy), nine responded
to tamatinib and six achieved platelet counts greater than 100,000.[28]

Epidemiology
A normal platelet count is considered to be in the range of 150,000450,000 per microlitre
(l) of blood for most healthy individuals. Hence one may be considered thrombocytopenic
below that range, although the threshold for a diagnosis of ITP is not tied to any specific
number.
The incidence of ITP is estimated at 50100 new cases per million per year, with children
accounting for half of that amount. At least 70 percent of childhood cases will end up in
remission within six months, even without treatment.[29][30][31] Moreover, a third of the
remaining chronic cases will usually remit during follow-up observation, and another third
will end up with only mild thrombocytopenia (defined as a platelet count above 50,000).[29]
ITP is usually chronic in adults[32] and the probability of durable remission is 2040 percent.
[13]
The male to female ratio in the adult group varies from 1:1.2 to 1.7 in most age ranges
(childhood cases are roughly equal for both genders) and the median age of adults at the
diagnosis is 5660.[9] The ratio between male and female adult cases tends to widen with
age. In the USA, the adult chronic population is thought to be approximately 60,000with
women outnumbering men approximately 2 to 1, which has resulted in ITP being designated
an orphan disease.[33]
The mortality rate due to chronic ITP varies but tends to be higher relative to the general
population for any age range. In a study conducted in Great Britain, it was noted that ITP
causes an approximately 60 percent higher rate of mortality compared to gender- and agematched subjects without ITP. This increased risk of death with ITP is largely concentrated
in the middle-aged and elderly. Ninety-six percent of reported ITP-related deaths were

individuals 45 years or older. No significant difference was noted in the rate of survival
between males and females.[34]

History
After initial reports by the Portuguese physician Amato Lusitano in 1556 and Lazarus de la
Rivire (physician to the King of France) in 1658, it was the German physician and poet Paul
Gottlieb Werlhof who in 1735 wrote the most complete initial report of the purpura of ITP.
Platelets were unknown at the time.[35] The name "Werlhof's disease" was used more widely
before the current descriptive name became more popular.[35][36] Platelets were described in
the early 19th century, and in the 1880s several investigators linked the purpura with
abnormalities in the platelet count.[35][37] The first report of a successful therapy for ITP was in
1916, when a young Polish medical student, Paul Kaznelson, described a female patient's
response to a splenectomy.[35] Splenectomy remained a first-line remedy until the introduction
of steroid therapy in the 1950s.[35]

Synonyms
This unreferenced section requires citations to ensure verifiability.
ITP is known by a number of synonyms, but idiopathic or immune thrombocytopenic purpura
are the most common names. Others include: essential thrombocytopenia, haemogenia,
haemogenic syndrome, haemorrhagic purpura, idiopathic thrombopenic purpura, morbus
haemorrhagicus maculosus, morbus maculosis haemorrhagicus, morbus maculosus werlhofii,
peliosis werlhofi, primary splenic thrombocytopenia, primary thrombocytopenia, primary
thrombocytopenic purpura, purpura haemorrhagica, purpura thrombocytopenica, purpura
werlhofii, splenic thrombocytopenic purpura and thrombocytolytic purpura.

Background
Idiopathic thrombocytopenic purpura (ITP), also known as primary immune
thrombocytopenic purpura and autoimmune thrombocytopenic purpura, is defined as isolated
thrombocytopenia with normal bone marrow and the absence of other 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.

Pathophysiology
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.

Epidemiology
Frequency
United States

The incidence of ITP in adults is approximately 66 cases per 1,000,000 per year.
An average estimate of the incidence in children is 50 cases per 1,000,000 per year.
New cases of chronic refractory ITP comprise approximately 10 cases per 1,000,000 per year.
International

According to studies in Denmark and England, childhood ITP occurs in approximately 10-40
cases per 1,000,000 per year. A study in Kuwait reported a higher incidence of 125 cases per
1,000,000 per year.

Mortality/Morbidity

Hemorrhage represents the most serious complication; intracranial

hemorrhage is the most significant. The mortality rate from hemorrhage is
approximately 1% in children and 5% in adults. In patients with severe
thrombocytopenia, predicted 5-year mortality rates from bleeding are
significantly raised in patients older than 60 years versus patients younger
than 40 years, 47.8% versus 2.2%, respectively.
Older age and previous history of hemorrhage increase the risk of severe
bleeding in adult ITP.
Spontaneous remission occurs in more than 80% of cases in children but is
uncommon in adults.

Sex

In chronic ITP (adults), the female-to-male ratio is 2.6:1. More than 72% of
patients older than 10 years are female.
In acute ITP (children), distribution is equal between males (52%) and
females (48%).

Age

Peak prevalence occurs in adults aged 20-50 years.

Peak prevalence occurs in children aged 2-4 years.

Approximately 40% of all patients are younger than 10 years.

History

Focus on the symptoms of bleeding (eg, type, severity, duration) and on symptoms
that may exclude other causes of thrombocytopenia.
Elicit risk factors for HIV and systemic symptoms linked to other illnesses or to
medications (eg, heparin, alcohol, quinidine/quinine, sulfonamides) that may cause
thrombocytopenia. Medications can be a common etiology for inducing
thrombocytopenia, and patients should have their medications carefully reviewed.
One study used 3 distinct methods to document drugs that may be associated with
drug-induced immune thrombocytopenia (DITP).[1, 2] Approximately 1500 drugs are
associated with thrombocytopenia, but, using this analysis, 24 drugs had evidence of
causing thrombocytopenia by all 3 methods.

Address risk factors for increased bleeding, such as GI disease, CNS disease, urologic
disease, or active lifestyle, as these may determine the aggressiveness of management.

Common signs, symptoms, and precipitating factors include the following:

Abrupt onset (childhood ITP)

Gradual onset (adult ITP)

Purpura

Menorrhagia

Epistaxis

Gingival bleeding

Recent live virus immunization (childhood ITP)

Recent viral illness (childhood ITP)

Bruising tendency

Limited data are available on the recurrent form of the disease. One study showed a
6% prevalence of recurrent ITP with most patients (69%) having only one recurrence.
Though one third of patients had their recurrent episode within 3 months of their
initial one, the remainder of patients had at least a 3-month interval between episodes.

Physical
Evaluate the type and the severity of bleeding and try to exclude other causes of bleeding.
Seek evidence of liver disease, thrombosis, autoimmune diseases (eg, nephritis, cutaneous
vasculitis, arthritis), and infection, particularly HIV.
Common physical findings include the following:

Nonpalpable petechiae, which mostly occur in dependent regions

Hemorrhagic bullae on mucous membranes

Purpura

Gingival bleeding

Signs of GI bleeding

Menometrorrhagia, menorrhagia

Retinal hemorrhages

Evidence of intracranial hemorrhage, with possible neurologic symptoms

Nonpalpable spleen: The prevalence of palpable spleen in patients with ITP is

approximately the same as that in the non-ITP population (ie, 3% in adults, 12% in
children).

Spontaneous bleeding when platelet count is less than 20,000/mm3.

Causes

Immunoglobulin G (IgG) autoantibodies on the platelet surface

Differentials

Disseminated Intravascular Coagulation

HIV Infection and AIDS

Thrombocytopenic Purpura