Idiopathic thrombocytopenic purpura (ITP)

Idiopathic thrombocytopenic purpura (ITP) is the condition of having a low platelet count (thrombocytopenia) of no known cause (idiopathic). As most causes appear to be related to antibodies against platelets, ITP is also known as immune thrombocytopenic purpura or immune-mediated thrombocytopenic purpura. Often ITP is asymptomatic, however a very low platelet count can lead to visible symptoms, such as purpura (bruises), or more seriously, bleeding diathesis.

Signs and symptoms

Symptoms of ITP include the development of bruises (purpura) and petechiae, especially on the extremities, bleeding from the nostrils and bleeding at the gums, any of which may occur if the platelet count is below 20,000 per mm3.  A very low count (<10,000 per mm3) may result in the formation of hematomas in the mouth or on other mucous membranes.

Serious and possibly fatal complications due to an extremely low count (<5,000 per mm3) may include subarachnoid or intracerebral hemorrhage, lower gastrointestinal bleeding or other internal bleeding.  An ITP patient with an extremely low count is also vulnerable to major internal bleeding caused by abdominal trauma, as might be experienced in a motor vehicle crash.  Fortunately, these complications are not likely in a patient whose platelet count is above 20,000.

Pathogenesis

In many cases, ITP's cause is not idiopathic but autoimmune, 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 IgG type.  The famous Harrington–Hollingsworth experiment established the immune pathogenesis of ITP.

The coating of platelets with IgG renders them susceptible to opsonization and phagocytosis by splenic macrophages.  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.

The stimulus for auto-antibody production in ITP is probably abnormal T cell activity.  Preliminary findings suggest that these T cells can be influenced by drugs that target B cells, such as rituximab.

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 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 and others.  In approximately one percent of cases, autoimmune hemolytic anemia and immune thrombocytopenic purpura coexist, which is a condition called Evans syndrome.

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 prolonged in ITP patients.  However, the use of bleeding time in diagnosis is discouraged by the American Society of Hematology practice guidelines.  A normal bleeding time does not exclude a platelet disorder.

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.  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.

Treatment

A platelet count below 20,000 is generally an indication for treatment.  Patients with a count between 20,000 and 50,000 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.  Hospitalization may be recommended in cases of very low counts, and is highly advisable if the patient presents with significant internal or mucocutaneous bleeding.  A count below 10,000 is potentially a medical emergency, as the patient may be vulnerable to subarachnoid or intracerebral hemorrhage as a result of moderate head trauma.

Steroids/IVIG

Treatment usually is initiated with intravenous steroids (methylprednisolone or prednisone), intravenous immunoglobulin (IVIg) or a combination of these drugs.  A platelet infusion may be administered in an emergency bleeding situation in order to attempt to quickly raise the count.  After the platelet count has increased to a safe level, an orally administered steroid, such as prednisone (1–2 mg/kg per day), is usually prescribed.  Most cases respond during the first week of treatment.  After several weeks of oral steroid therapy, the dose is gradually reduced.  However, 60 to 90 percent of patients relapse after the dose is decreased below 0.25 mg/kg per day and subsequently stopped.

Surgery

Splenectomy is sometimes undertaken, as platelets targeted for destruction will often 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 patients. Splenectomy is generally a last resort since the advent of other less risky therapies, such as Nplate.

Anti-D

A relatively new strategy is treatment with anti-D, but the patient must be Rh-positive.  This treatment (with products such as WinRho, Rhophylac or RhoGAM) 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, but has been demonstrated effective on some Rh-positive ITP patients.  Treatment with anti-D is costly, produces a short-term improvement and is not recommended for post-splenectomy patients.

Steroid-sparing agents

Immunosuppresants such as mycophenolate mofetil and azathioprine are becoming more popular for their effectiveness.  Intravenous immunoglobulin, while sometimes effective, is expensive and the improvement is temporary (generally lasting less than a month).  However, in the case of a pre-splenectomy ITP patient with dangerously low platelet counts, and a poor response to other treatments, IVIg treatment can increase the count, making splenectomy less dangerous.  IVIg is also commonly used as a long-term (though monthly) treatment.

Extreme cases (very rare, especially in children) may require the infusion of vincristine, a chemotherapy agent, to stop the immune system from destroying platelets.  However, vincristine, a vinca alkaloid, has significant side-effects and its use in treating ITP must be approached with caution.

Thrombopoietin Receptor Agonists

• Romiplostim (trade name Nplate) is a new treatment for stimulating platelet production.  Designated an orphan drug in 2003 under USA law, it is a thrombopoiesis stimulating Fc-peptide fusion protein (peptibody) that is administered by subcutaneous injection.  Clinical trials showed it to be effective in treating chronic ITP, especially in post-splenectomy patients.  Romiplostim was approved by the United States Food and Drug Administration (FDA) for long-term treatment of adult chronic ITP on August 22, 2008.
• Eltrombopag (trade name Promacta) is an orally-administered agent with an effect similar to that of romiplostim.  It has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner.  Developed by GlaxoSmithKline and also designated an orphan drug by the FDA, Promacta was approved by the FDA on November 20, 2008.

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 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 40–50 percent of patients administered the drug.
• 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. 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 are lacking.
• 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 >100,000 platelets/uL counts.

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

Researchers in Japan (including Ryugo Sato, Oita University) and Italy (including Massimo Franchini, University of Verona) have found a possible connection between H. pylori (Helicobacter pylori) infection and ITP.  Some patients given antibiotic treatment to eradicate the bacterial infection have had their platelet count increase dramatically.

Synonyms

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.