NORD gratefully acknowledges the Platelet Disorder Support Association and PDSA Medical Advisors James Bussel, MD and Douglas Cines, MD, for assistance in the preparation of this report.
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by abnormally low levels of blood cells called platelets, a situation which is referred to as thrombocytopenia. Platelets are specialized blood cells that help maintain the integrity of the walls of our blood vessels and help prevent and stop bleeding by accelerating clotting. A normal platelet count ranges from approximately 150,000 to 400,000 per microliter of blood depending on the laboratory. If someone has a platelet count lower than 100,000 per microliter of blood with no other reason for low platelets, that person might have ITP. There is currently no definitive laboratory test to diagnose ITP. Rather ITP is considered a diagnosis of exclusion (see below) meaning that other causes have been eliminated or are unlikely. What tests to do to exclude other causes is not well-established and can differ among patients and hematologists.
As the platelet count falls, the risk of developing bleeding symptoms increases. ITP can be discovered incidentally based on a blood count ordered for other reasons, such as a routine yearly checkup. However, most patients with ITP present to their doctor with abnormal bleeding into the skin resulting in bruising, also known as purpura or tiny red dots on the skin called petechiae. Bleeding from mucous membranes also may occur and may subsequently result in low levels of circulating red blood cells (anemia; this usually means bleeding in the mouth and nose but could also include blood in the urine. Internal bleeding at presentation is very uncommon. ITP is generally called newly diagnosed when it has been present for less than 3 months, persistent when present for 3-12 months and chronic when present for longer. The term “acute” is not used currently. The clinical onset may be rapid with overnight onset of skin bleeding or gradual over months.
Eighty percent (80%) of children who present with ITP have a self-limited form that resolves with or without treatment (i.e. spontaneously) within 12 months and often sooner. In contrast, the proportion of adults with ITP who have a chronic condition is much higher, exceeding 50% in most series. ITP that develops in adolescents most often follows the clinical course seen in adults.
Mechanistically, the fundamental abnormality in ITP is that the patient’s immune system recognized their own platelets as “foreign” leading their B-lymphocytes to produce self-reactive anti-platelet antibodies that attach to platelet surfaces. A type of white blood cells in the spleen and in other organs, called macrophages (scavenger cells), recognize antibody-coated particles, in this case antibody-coated platelets, leading to their ingestion into the macrophages and subsequent destruction. The bone marrow attempts to compensate but is often unable, especially in severe cases, to keep up with the destruction. Platelet production may also be impaired when anti-platelet antibodies bind to the cells in the bone marrow that produce platelets, called megakaryocytes.
While it may seem like ITP is a simple disease, there are many nuances to diagnosis, mechanism of disease, and management, in addition to the variability of outcomes between and among children and adults. This includes variation in the severity of bleeding at any given platelet count as well as how individual patients respond to various forms of treatment.
In addition to serious physical bleeding-related manifestations of the disease, ITP is associated with debilitating fatigue (reported in up to 39% of adults with ITP), as well as impaired quality of life across domains of emotional, functional, and reproductive health, and work and social life. These symptoms that accompany the disease can interfere with daily activities and lead to anxiety, fear, depression, embarrassment of unexplained bruising and nosebleeding (epistaxis), isolation, inadequacy, and frustration with a patient’s inability to control their body and their health. This list does not even encompass the side effects of treatments which, while possibly improving part of the above problems, can be devastating in different ways. Together, these multi-faceted effects of ITP often take a significant toll on patients’ quality of life.
Management depends on severity of symptoms, platelet count, age, lifestyle, response to therapy and its side effects, the presence of other medical issues that affect the risk of bleeding, quality of life as discussed above, and, of course, personal preferences of both the patient and the doctor.
As mentioned, there is variation among individuals in their tendency to bruise and bleed when they have a low platelet count, i.e. some patients tolerate quite low platelet counts for long periods of time with minimal or no bruising and bleeding, while others have substantial bleeding at the same counts. A child or adult with immune thrombocytopenia may display no symptoms (be asymptomatic) or the symptoms may appear when the platelet count is very low. Such symptoms may include:
– Skin that bruises very easily and even spontaneously
– A rash consisting of small red dots (petechiae) that represent small hemorrhages caused by broken blood vessels or leaks in a capillary wall
– Bleeding from the gums
– Frequent and long-lasting nose bleeds that are hard to stop
– Blood blisters on the inside of cheeks
– Excessive and prolonged menstrual bleeding
– Less likely, signs of internal bleeding, with blood in urine, vomit, or bowel movements
-in rare patients, bleeding in the brain called intracranial hemorrhage that is very much like a stroke
-Debilitating fatigue, depression, low mental and physical energy
In severe cases, frequent bleeding episodes may result in low levels of circulating red blood cells (anemia), which may cause fatigue and impair response to exertion. In rare cases, serious bleeding into the brain (intracranial hemorrhage) may occur. Fatigue (even in the absence of anemia), anxiety, and depression are common experiences for some people with ITP resulting in difficulties at work or school and also in social difficulties. These symptoms may be caused by the disease itself, by anxiety, or as side effects of medical treatment.
Antibodies are normally produced by the body’s immune system only in response to foreign substances, known as antigens, for example on certain viruses and bacteria or on red blood cells or tissue from unrelated people. Immune thrombocytopenia belongs to a group of disorders in which the body’s natural immune defenses inappropriately act against its own cells or tissues (autoimmune disorders). In ITP, such an abnormal immune reaction leads to destruction of the individual’s own platelets. For reasons that remain as yet unknown, lymphocytes in the bone marrow, spleen and elsewhere are stimulated to produce antibodies that attach to platelet surfaces,and the platelets are recognized as foreign by the immune system. In most individuals, the platelets are the only target of the misdirected immune response. However, in some, ITP develops in the context of another disorder that predisposes to making autoantibodies. This is called secondary ITP and is discussed below. In most individuals, however, no such connection to another disease is evident and the cause of anti-platelet antibody production remains unknown.
The autoantibodies in ITP bind to otherwise normal platelets in the blood that then circulate through the spleen, the liver and elsewhere. The antibody-platelet complexes are recognized by tissue macrophages, which ingest and destroy antibody-coated platelets as they would normally when then encounter any antibody-coated foreign particle. The bone marrow attempts to compensate by producing more platelets but the rate of platelet destruction may exceed the marrow capacity and thrombocytopenia develops. Platelet production by megakaryocytes in the bone marrow may also be impaired when the same autoantibodies that bind to the platelets attach to megakaryocytes, the platelet precursors in the bone marrow. Therefore, the mechanisms underlying ITP and the resulting very low platelet counts can be characterized as including increased platelet destruction, reduced or inadequate platelet production, or both. It is not currently possible to define the relative importance of these two possibilities in a specific patient.
In children, ITP often appears soon after an acute viral infection. This suggests that antibodies produced to fight foreign viral substances (antigens) may “cross-react” with similar appearing antigens on platelets, which in turn lead to platelet destruction. This has been shown in the case of chicken pox, for example. However, as mentioned, identification of the exact mechanism of ITP in a given patient is not possible and predicting in a child (or adult) who will get better and who will not, who will bleed and who will not, is not possible in a precise way.
It is quite rare for more than one family member or members of more than one generation to have ITP. When there is such a family history of thrombocytopenia, a genetic disorder involving platelets is much more likely.
As mentioned, some people have secondary ITP, meaning that their ITP is part of another condition. Secondary ITP can be caused by inherited immune disorders (such as autoimmune lymphoproliferative syndrome, ALPS, some of whom also have antibody-mediated red cell destruction), systemic autoimmunity such as systemic lupus (in which the immune system attacks other cells as well as platelets), persistent infections (such as HIV, hepatitis B or C, and the ulcer-causing stomach bacterium, Helicobacter pylori), and lymphoproliferative disorders such as chronic lymphocytic leukemia that impair the immune system. A few cases resembling ITP may result from the use of certain drugs, after a viral or bacterial infection or in approximately one in 40,000 children after vaccination for measles-mumps-rubella (MMR). The effect of drugs may be either to suppress the bone marrow from making platelets or to induce the formation fo antibodies that attack platelets but involve the drug as a target. A good source of information on this subject is:
The incidence (how many people are diagnosed each year) of ITP among adults in the USA is estimated to be 3.3 per 100,000 adults/year. The prevalence (how many adults have ITP at any time) is 9.5 cases per 100,000. The annual prevalence is estimated at 5.3 per 100,000 among children; because children with ITP usually recover, the number of children who have ITP at any one time is almost equal to those diagnosed annually. Worldwide, it is estimated that there are well over 200,000 people affected by ITP.
The incidence of ITP increases with age and is more common over the age of 60. Among adults (age 30-60) diagnosed with chronic ITP, there are 2.6 cases among women for every case involving a male. In older adults, about the same number of men and women are diagnosed with ITP. Among children diagnosed with acute ITP, the male to female ratio is also almost equal, with 52% male to 48% female. About 40% of all patients diagnosed with one or another form of ITP are children younger than 10 years of age. Among children, the incidence is greatest between 2 and 4 years of age. However, ITP can occur at any age from 3 months of age to over 100 years of age.
The diagnosis of ITP is made by excluding other causes of thrombocytopenia, including certain medications or disorders that affect the bone marrow and reduce platelet production, such as acute leukemia and aplastic anemia. On occasion, a low platelet count may be detected incidentally by blood tests such as a complete blood count (CBC) ordered for other purposes and the individual is without apparent symptoms (asymptomatic). Inspection of the blood smear under the microscope will verify the platelets are truly reduced in number and not simply clumped (stuck together so they are too big to be counted by automated machines as platelets), and that the platelets are not uniformly very small or exceeding large (giant platelets approximating the size of red blood cells). The red blood cells and white blood cells are normal in number and appear normal to the eye, which helps to exclude consideration of leukemia and/or aplastic anemia, among other causes of thrombocytopenia. The presence of unusual appearing cells in the blood or additional abnormalities in the blood counts, might indicate the need for a biopsy of the bone marrow to exclude other causes of impaired platelet production and/or consideration of secondary ITP.
In a patient who is otherwise in his/her usual state of good health who has not taken a new medication, has thrombocytopenia and no other abnormality found in a complete blood count or upon inspection of the blood smear, and has no family history of thrombocytopenia, the diagnosis of ITP is favored. There is no definitive test (such as measurement of platelet autoantibodies) to make the diagnosis or to exclude the diagnosis of ITP. A robust response to ITP-specific treatments such as IVIG (intravenous immunoglobulin) or glucocorticoids (described below) provides strong evidence in favor of the diagnosis.
While there is no well-established cure for ITP, fortunately almost all patients find their platelet count improves following treatment. What proves difficult for many ITP patients is finding the treatment that works for them without unwanted side effects. In some individuals, the disease can go into remission for an extended period of time, perhaps for the remainder of a person’s life. ITP can also recur at any time. There is currently no way to predict the course of the disease. Changes in diet or lifestyle may improve (or worsen) the sense of well-being.
Criteria for Treatment
In many children and some adults, therapy may not be necessary at the time they first see the doctor and the disorder may resolve spontaneously. The decision to initiate treatment depends on the severity of bleeding, the severity of the thrombocytopenia, the age of the patient (increased risk of bleeding in adults and especially in the elderly), coincidental disorders that might predispose to bleeding (tendency to fall, concurrent anti-platelet or anticoagulants), life-style (such as young and athletic) and risks and side effects of each intervention. These same factors can also contribute to deciding which treatment to use.
The goal of therapy is to prevent bleeding, to stabilize and hopefully to improve the platelet count, and help restore the patient’s ability to have a normal lifestyle. When treatment is deemed necessary, there are many options that have proven successful. Treatments differ in likelihood of benefit and risks and some are considered more toxic and are therefore, generally deferred unless it is proven they are needed. Treatments also differ in their intended effect: short term platelet increase versus long-term maintenance of a stable platelet count. It is important to understand both the success rate and potential side effects before beginning any form of treatment. Hematologists may even recommend several treatments at once to increase their success rate and minimize their side effects.
First Line/Emergency Therapy
Treatment with corticosteroid drugs (e.g., prednisone, dexamethasone, methylprednisolone) is usually the mainstay of initial therapy. These drugs function by suppressing the clearance of antibody-coated platelets and perhaps by increasing platelet production. They may also decrease the risk of bleeding by improving blood vessel lining cell function. Very high doses (especially of dexamethasone) may impair the production of anti-platelet antibodies with the hope that the platelet count will remain elevated after the patient stops taking prednisone. However, additional studies are needed to affirm the long-term benefit of such a “high-dose” approach. In general, the duration and dose of corticosteroids should be minimized because of their immediate and long-term side effects. Therefore, corticosteroids are used to control the disease until a transition can been made to other forms of treatment in patients who do not achieve a spontaneous remission.
If platelet counts do not improve after corticosteroid treatment or if when individuals present with severe bleeding, treatment may include adding intravenous immunoglobulins (IVIG), usually by infusions given as needed based on the count and bleeding every 2-4 weeks, but this rarely leads to a cure. Platelet transfusions are reserved for emergent situations because they are likely to be destroyed relatively quickly by the autoantibodies.
The orphan drug anti-D (WinRho SDF, Rhophylac), a specific form of gamma globulin, was approved by the Food and Drug Administration (FDA) to treat ITP in individuals who are red blood cell RhD antigen positive, do not already have antibodies on their red cells, and have not undergone splenectomy. The drug can be used repeatedly, including in children who have the acute or chronic form of ITP. However, concerns have been raised because of a small number of individuals who have had severe side effects from brisk red cell destruction and its consequences soon after infusion.
Second Line Therapy
The criteria for determining whether second line therapy is needed are the same as those involving initiation of treatment plus patients with suboptimal responses to first line approaches. As mentioned, corticosteroids should be used for the shortest duration possible to achieve these objectives and to provide a bridge to less toxic alternatives. Many adults and some children will require such long-term management because their platelet count will fall once the dose of corticosteroids is tapered.
One option in the second-line setting involves the use of thrombopoietin receptor agonists (TPO-RAs). TPO-RAs function by stimulating the body’s production of platelets by megakaryocytes in the bone marrow, which release proplatelets that mature into platelets. By increasing the rate at which platelets are produced in the body, TPO-RAs may overcome the heightened rate of platelet destruction caused by antiplatelet antibodies and their ability to impair megakaryocyte function. Three TPO-RAs approved by the FDA for use in ITP are eltrombopag (Promacta), romiplostim (Nplate) and avatrombopag (Doptelet), while others are in development or approved for other related indications.
In 2008, the FDA approved both romiplostim (Nplate) manufactured by Amgen Inc. and eltrombopag (Promacta) manufactured by GlaxoSmithKline (GSK) to treat both children and adults with ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Romiplostim is typically given by weekly subcutaneous injection, most often in a doctor’s office. Novartis Pharmaceuticals Corporation acquired eltrombopag from GSK. There are a few important dietary restrictions that are needed to maximize the benefit of this oral agent, which is administered once daily. In 2015, eltrombopag was approved for the treatment of children 1 year and older with ITP who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy; romiplostim was similarly approved in late 2018. Response rate, depending upon the definition of response, to both agents ranges from 40- 80% and, once obtained consistently, was durable with ongoing treatment. The drugs are generally well tolerated and long-term safety studies have mitigated initial concerns about thrombosis and bone marrow scarring. Some patients (an unknown percent) will experience sufficient improvement in their ITP over time to discontinue treatment. In 2019, the FDA approved avatrombopag (Doptelet) manufactured by Dova Pharmaceuticals to treat ITP in adults with chronic ITP who have had insufficient response to a previous treatment. This is the only oral TPO-RA medication approved to treat ITP that can be taken with food. Avatrombopag is generally considered safe and well tolerated.
Another option is anti-CD20 antibody, rituximab (Rituxan), which reduces IgG antibody production; there are now several biosimilars. About half the patients respond initially, but only 20-30% are cured in long-term outcome studies. Women of child-bearing age of duration of ITP < 1-2 years have an over 50% cure rate; all others have a very low rate of cure. Rituximab is generally well tolerated but infusion reactions can occur. Administration may be repeated when a durable response has been seen, but concern over repetitive administration of this immunosuppressant is warranted. One to 3-4-day courses of high dose dexamethasone have been used in an effort to increase responses. A third option is splenectomy, (typically laparoscopic) because the spleen plays a major role in destroying antibody-covered platelets and in making antiplatelet antibodies. Splenectomy improves platelet counts in approximately 70 percent of patients initially and can induce a long-term remission in 60 percent. The high long-term success rate must be weighed against the small but real increased risk of thrombosis and serious infection, which necessitates appropriate vaccinations and urgent evaluation for serious febrile illnesses. Most guidelines recommend deferral of splenectomy for a year from diagnosis in order to determine if a patient will go into remission. However, splenectomy remains an option in patients who fail other forms of treatment or in resource challenged areas where more expensive alternatives are not available. Lastly, in 2018, Tavalisse (fostamatinib disodium hexahydrate) was approved by the FDA for the treatment of thrombocytopenia in adults with ITP who have had insufficient response to a previous treatment. Tavalisse is manufactured by Rigel Pharmaceuticals, Inc. Approximately 20% of patients who are refractory to other forms of management responded based on pre-specified criteria but almost 40% did so using less stringent but clinically meaningful endpoints. It has a number of side effects (hypertension, diarrhea, headache, and abnormal liver tests) but one advantage is that it has the least risk of thrombosis of any licensed treatment of ITP.
Third Line Therapy
A small percentage of patients fail to respond or tolerate first or second line treatments. For those, options include dapsone, Imuran (azathioprine), Cytoxan (cyclophosphamide), Sandimmune (cyclosporine), Danocrine (danazol), Cellcept (mycophenolate mofetil), Vincristine (vinca alkaloids), or combinations. Several other novel forms of treatment are in clinical trials.
If the patient has antibodies or evidence of Helicobacter pylori infection, treatment with antibiotics and proton pump inhibitors may ameliorate the condition. Antibiotic associated remission of ITP is much more common in Asia and in some parts of Europe than in patients who have lived their entire life in North America.
Some patients report success with complementary therapies such as vitamins, supplements, diet changes, herbs, and energy work, such as Reiki. However, there are no controlled trials in ITP patients demonstrating utility or safety of any of these agents.
ITP treatments vary with the disease severity, age of the patient, experience of the hematologist, patient preference and other factors.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
The PDSA website also lists the most current ITP clinical trials at https://pdsa.org/clinical-trials.html
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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