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. Although most cases are asymptomatic, very low platelet counts can lead to a bleeding diathesis and purpura.

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Signs and symptoms

The incidence of ITP is 50–100 new cases per million per year, with children accounting for half of that amount.

More than 70% of the cases in children end up in remission within 6 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]

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% 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.

Recent evidence suggests that the stimulus for autoantibody production in ITP is due to abnormal T helper cells reacting with platelet antigens on the surface of antigen presenting cells.^[10] This important finding suggests that therapies directed towards T cells may be effective in treating ITP.

Diagnosis

The diagnosis of ITP is a diagnosis of exclusion. First, one has to make sure that there are no other blood abnormalities except for low platelet count and no physical signs except for signs of bleeding. Then, the secondary causes (usually 5-10% 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 1% 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^[11] as useless. For example the BMJ review of the basics of hematology states: "The bleeding time may or may not be prolonged in congenital or acquired platelet dysfunction, and therefore a normal bleeding time does not exclude these conditions."^[12]

A bone marrow examination may be performed on patients over the age of 60 and people who do not respond to treatment, or when the diagnosis is in doubt.^[6] The blood analysis for the antiplatelet antibodies is a matter of clinician's preference, as there is a disagreement whether the 80% specificity of this test is sufficient.^[6]

Treatment

Steroids/IVIG

Platelet count below 20,000 is an indication for treatment; the patients with 20,000–50,000 platelets/μL are considered on a case by case basis, and there is generally no need to treat the patients with above 50,000 platelets/μL.^[6] Hospitalization is recommended in the cases of significant internal or mucocutaneous bleeding. The treatment begins with intravenous steroids (methylprednisolone or prednisone), intravenous immunoglobulin (IVIg) or their combination and sometimes platelet infusions in order to raise the count quickly. After the platelet count stabilized and in the less severe cases oral prednisone (1–2 mg/kg) is used. Most cases respond during the first week of treatment. After several weeks of prednisone therapy, the dose is gradually reduced. However, 60–90% of patients relapse after the dose decreased below 0.25 mg/kg and 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% of cases although it is less successful in older people.^{[citation needed]}

Anti-D

A relatively new strategy is treatment with anti-D, an agent also used in mothers who have been sensitized to rhesus antigen by a Rh+ baby, but the patient must be Rh+.

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. ^[13][14]

Extreme cases (very rare, especially rare in children) may require vincristine, a chemotherapy agent, to stop the immune system from destroying platelets.

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 the splenectomy operation less dangerous. It is also commonly used as a long-term (though monthly) treatment.

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/novel agents

AMG 531 is an experimental treatment for stimulating platelet production. It is a thrombopoiesis stimulating Fc-peptide fusion protein (peptibody). Initial clinical trials show it to be effective in chronic ITP.^[15]

The novel agent eltrombopag has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner.^[16]

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% of patients taking the drug. ^[17][18]

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.^{[citation needed]}

Synonyms

ITP knows many synonyms, but idiopathic or immunological thrombocytopenic purpura are the most common names. There's also an eponym, Werlhof's disease,^[19] 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