Idiopathic thrombocytopenic purpura

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, it is also known as immune thrombocytopenic purpura or immune-mediated thrombocytopenic purpura. Although most cases are asymptomatic, very low platelet counts can lead to bleeding diathesis and purpura.

Epidemiology

The incidence of ITP is estimated at 50–100 new cases per million per year, with children accounting for half of that amount. In the USA, ITP is considered an orphan disease.

More than 70 percent of childhood cases end up in remission within six months, whether treated or not.^[1][2][3] Moreover, a third of the remaining chronic cases remitted during the follow-up observation, and another third ended up with only mild thrombocytopenia (>50,000 platelets per μL).^[1] ITP is usually chronic in adults^[4] and the probability of durable remission is 20–40%.^[5] The male:female ratio in the adult group is 1:1.2–1.7 (for children it is 1:1) and the median age of adults at the diagnosis is 56–60.^[6]

Signs and symptoms

Usually, ITP patients suffer from bruising; petechiae, nosebleeds and bleeding gums may occur if the platelet count is below 20,000,^[7] compared to a normal range of 150,000–400,000 per mm³.

Subarachnoid, intracerebral hemorrhage or other internal bleeding are very serious possible complications of this disease. Fortunately, these are unlikely in patients with the platelets count above 20,000.

Pathogenesis

In many cases, the cause is not actually idiopathic but autoimmune,^[8] 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.^[9]

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.^[10][11][12] Preliminary findings suggest that these T cells can be influenced by drugs that target B cells, such as rituximab.^[13]

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.^[6][7] In approximately one percent of cases, autoimmune hemolytic anemia and immune thrombocytic purpura coexist, which is a condition called Evans syndrome.^[6]

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.^[14] A normal bleeding time does not exclude a platelet disorder.^[15]

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.^[6] On examination of the bone marrow, an increase in the production of megakaryocytes is seen and can help in determining if it's ITP. The blood analysis for the antiplatelet antibodies is a matter of clinician's preference, as there is a disagreement whether the 80 percent specificity of this test is sufficient.^[6]

Treatment

Steroids/IVIG

A platelet count below 20,000/μL is an indication for treatment. Patients with 20,000–50,000 platelets/μL are considered on a case-by-case basis, and there is generally no need to treat patients with a count above 50,000.^[6] Hospitalization is recommended in cases of significant internal or mucocutaneous bleeding.

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 order to quickly raise the count. After the platelet count has stabilized, orally administered prednisone (1–2 mg/kg per day) is usually prescribed. Most cases respond during the first week of treatment. After several weeks of oral prednisone 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.^[6][5]

Splenectomy

Splenectomy (removal of the spleen) is sometimes undertaken, as platelets targeted for destruction will often meet their fate in the spleen. Splenectomy is said to be successful in 60 to 65 percent of cases, although it is less successful in older people.^[16]

Anti-D

A relatively new strategy is treatment with anti-D, but the patient must be Rh+. This treatment (with products such as Rhophylac and RhoGAM) is normally administered to Rh- women during pregnancy and after the birth of an Rh+ baby to prevent sensitization to the Rh factor. Anti-D is not recommended for post-splenectomy patients.^[17]

Steroid-sparing agents

Immunosuppresants like mycophenolate mofetil and azathioprine are becoming more popular for their effectiveness. Rituximab has also been used successfully for some patients. ^[18][19]

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

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 platelet counts, making splenectomy less dangerous. IVIg is also commonly used as a long-term (though monthly) treatment.

Thrombopoietin Receptor Agonist

Romiplostim (formerly known as AMG 531, trade name Nplate) is a new treatment for stimulating platelet production. It is a thrombopoiesis stimulating Fc-peptide fusion protein (peptibody). Clinical trials showed it to be effective in treating chronic ITP, especially in post-splenectomy patients.^[20] Romiplostim was approved by the U.S. Food and Drug Administration for long-term treatment of adult chronic ITP on August 22, 2008.^[21]

Platelet transfusion

Platelet transfusion is not normally recommended and is usually unsuccessful in raising a patient's platelet count. This is because the underlying autoimmune mechanism that destroyed the patient's platelets to begin with will also destroy donor platelets. An exception to this rule is when a patient is bleeding profusely, when transfusion of platelets can quickly form a platelet plug to stop bleeding.

Experimental and novel agents

• 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 a safe and effective alternative to splenectomy in some patients.^[13] However, many patients experience side-effects, there is a small risk of death due to progressive multifocal leukoencephalopathy caused by a reactivated JC virus, and randomized controlled trials are lacking.^[22]

• 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 of around 40–50 percent of patients administered the drug. ^[23][24]

• The novel agent eltrombopag has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner.^[25]

• 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.^[26]

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 knows many synonyms, but idiopathic or immunological thrombocytopenic purpura are the most common names. There's also an eponym, Werlhof's disease,^[27] but this is used infrequently.

Other synonyms 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, thrombocytolytic purpura.

References

External links

• The ITP Foundation - A nonprofit organization dedicated to helping children with Immune Thrombocytopenic Purpura
• ITPeducation.com This educational curriculum is designed to provide evidence-based clinical information on the diagnosis and management of patients with ITP to hematologists, oncologists, and other health care professionals
• Platelet Disorder Support Association A non-profit corporation to provide information, support, and encourage research about ITP and other platelet disorders
• ITP Support Association. A UK registered charity which aims to promote and improve the general welfare of patients, and the families of patients, with Idiopathic Thrombocytopenic Purpura.