| Idiopathic thrombocytopenic purpura | |
|---|---|
| Classification and external resources | |
Purpura, or small bruise-like markings, may occur in ITP |
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| 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 immunosuppresive 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.
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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 μl.[2] A very low count (<10,000 per μl) 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 μl) 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 μl.
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 Harrington–Hollingsworth 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]
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 5–10 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.[9][2] 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]
A platelet count below 20,000 per μl is generally an indication for treatment. Patients with a count between 20,000 and 50,000 per μl 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 μl.[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 μl is potentially a medical emergency, as the individual may be vulnerable to subarachnoid or intracerebral hemorrhage as a result of moderate head trauma. Treatment is typically administered under the direction of a hematologist and treatment recommendations sometimes differ for adult and pediatric ITP.[12]
The first line 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. 60–90% percent of people will experience a relapse during dose reduction or cessation.[13][9] Long-term steroids are usually avoided, as they can cause numerous side-effects such as osteoporosis, diabetes and cataracts.
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]
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 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:
Medicare in the USA will cover most of the cost of romiplostim or eltrombopag treatment under Part-A.
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 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.
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]
A normal platelet count is considered to be in the range of 150,000–450,000 per microlitre (μl) 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 50–100 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 20–40 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 56–60.[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 60,000—with 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 age-matched 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]
After initial reports by the Portugese physician Amato Lusitano in 1556 and Lazarus de la Rivière (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]
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.
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