Immune thrombocytopenic purpura
Immune thrombocytopenic purpura, also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is an autoimmune primary disorder of hemostasis characterized by a low platelet count in the absence of other causes. ITP often results in an increased risk of bleeding from mucosal surfaces or the skin. Depending on which age group is affected, ITP causes two distinct clinical syndromes: an acute form observed in children and a chronic form in adults. Acute ITP often follows a viral infection and is typically self-limited, while the more chronic form does not yet have a specific identified cause. Nevertheless, the pathogenesis of ITP is similar in both syndromes involving antibodies against various platelet surface antigens such as glycoproteins.
Diagnosis of ITP involves identifying a low platelet count through a complete blood count, a common blood test. However, since the diagnosis relies on excluding other potential causes of a low platelet count, additional investigations, such as a bone marrow biopsy, may be necessary in certain cases.
For mild cases, careful observation may be sufficient. However, in instances of very low platelet counts or significant bleeding, treatment options may include corticosteroids, intravenous immunoglobulin, anti-D immunoglobulin, or immunosuppressive medications. Refractory ITP, which does not respond to conventional treatment or shows constant relapse after splenectomy, requires treatment to reduce the risk of significant bleeding. Platelet transfusions may be used in severe cases with extremely low platelet counts in individuals experiencing bleeding. In some cases, the body may compensate by producing abnormally large platelets.
Signs and symptoms
Signs of ITP include the spontaneous formation of bruises and petechiae, especially on the extremities. Additionally, bleeding from the nostrils and/or gums, as well as menorrhagia, may occur if the platelet count falls below 20,000 per μL. A platelet count below 10,000 per μL can lead to the spontaneous formation of hematomas in the mouth or on other mucous membranes. Furthermore, bleeding time from minor lacerations or abrasions is usually prolonged.In cases where platelet counts drop to extremely low levels, serious and potentially fatal complications may arise. These complications include subarachnoid or intracerebral hemorrhage, lower gastrointestinal bleeding, or other internal bleeding. A person with ITP with an extremely low platelet count is susceptible to internal bleeding resulting from blunt abdominal trauma, such as in a motor vehicle crash. These complications are more likely to occur when the platelet count is less than 20,000 per μL.
Pathogenesis
In approximately 60 percent of cases, antibodies against platelets can be detected. Most often these antibodies are against platelet membrane glycoproteins IIb-IIIa or Ib-IX, and are of the immunoglobulin G type. The 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, as well by Kupffer cells in the liver. The IgG autoantibodies are also thought to damage megakaryocytes, the precursor cells to platelets, although this is believed 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 medications referred to as thrombopoietin receptor agonists.
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 medications that target B cells, such as rituximab.
Diagnosis
The diagnosis of ITP is a process of exclusion. First, it has to be determined that there are no blood abnormalities other than a low platelet count, and no physical signs other than bleeding. Then, secondary causes should be excluded including medications, viral infection, malignancy, autoimmune conditions, onyalai, and others. All patients with presumed ITP should be tested for HIV and hepatitis C virus, as platelet counts may be corrected by treating the underlying disease. In approximately 2.7 to 5 percent of cases, autoimmune hemolytic anemia and ITP coexist, a condition referred to as Evans syndrome.Despite the destruction of platelets by splenic macrophages, the spleen is normally not enlarged. In fact, an enlarged spleen should lead to a search for 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 and a normal bleeding time does not exclude a platelet disorder.
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 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 to be clinically useful.
Treatment
With rare exceptions, there is usually no need to treat based on platelet counts. Many older recommendations suggested a certain platelet count threshold as an indication for hospitalization or treatment. Current guidelines recommend treatment for adults with significant bleeding or counts below 30/nL, with very low certainty of evidence.Treatment recommendations sometimes differ for adult and pediatric ITP.
Steroids
Initial treatment usually consists of the administration of corticosteroids, a group of medications that suppress the immune system. The dose and mode of administration is determined by platelet count and whether there is active bleeding: in urgent situations, infusions of dexamethasone or methylprednisolone may be used, while oral prednisone or prednisolone may suffice in less severe cases. Once the platelet count has improved, the dose of steroid is gradually reduced while the possibility of relapse is monitored. 60–90 percent will experience a relapse during dose reduction or cessation. Long-term steroids are avoided if possible because of potential side-effects that include osteoporosis, diabetes and cataracts.Anti-D
Another option, suitable for Rh-positive patients with functional spleens is intravenous administration of Rho immune globulin . The mechanism of action of anti-D is not fully understood. However, following administration, anti-D-coated red blood cell complexes saturate Fcγ receptor sites on macrophages, resulting in preferential destruction of red blood cells, therefore sparing antibody-coated platelets. There are two anti-D products indicated for use in patients with ITP: WinRho SDF and Rhophylac. The most common adverse reactions are headache, nausea/vomiting chills and fever.. Following a black-box warning of possible uncontrolled hemolytic reactions, use of intravenous anti-D declined sharply. Intramuscular anti-D has been suggested as an alternative, with one case series reporting a 73% response rate.Steroid-sparing agents
There is increasing use of immunosuppressants such as mycophenolate mofetil and azathioprine because of their effectiveness. In chronic refractory cases, where immune pathogenesis has been confirmed, the off-label use of the vinca alkaloid and chemotherapy agent vincristine may be attempted. However, vincristine has significant side effects and its use in treating ITP must be approached with caution, especially in children.Intravenous immunoglobulin
may be infused in some cases in order to decrease the rate at which macrophages consume antibody-tagged platelets. However, while sometimes effective, it is costly and produces improvement that generally lasts less than a month. Nevertheless, in the case of an ITP patient already scheduled for surgery who has a dangerously low platelet count and has experienced a poor response to other treatments, IVIg can rapidly increase platelet counts, and can also help reduce the risk of major bleeding by transiently increasing platelet counts.Thrombopoietin receptor agonists
receptor agonists are pharmaceutical agents that stimulate platelet production in the bone marrow. In this, they differ from the previously discussed agents that act by attempting to curtail platelet destruction. Two such products are currently available:- Romiplostim is a thrombopoiesis stimulating Fc-peptide fusion protein that is administered by subcutaneous injection. Designated an orphan drug in 2003 under United States law, clinical trials demonstrated romiplostim to be effective in treating chronic ITP, especially in relapsed post-splenectomy patients. Romiplostim was approved by the United States Food and Drug Administration for long-term treatment of adult chronic ITP on August 22, 2008.
- Eltrombopag 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. Developed by GlaxoSmithKline and also designated an orphan drug by the FDA, Promacta was approved by the FDA on November 20, 2008.
Side effects of thrombopoietin receptor agonists include headache, joint or muscle pain, dizziness, nausea or vomiting, and an increased risk of blood clots.