The American Society of Hematology defines immune thrombocytopenia purpura (ITP) as isolated thrombocytopenia (platelet count <100,000/microL) with normal white blood cells and normal hemoglobin in the setting of a generalized purpuric rash. ITP was previously known as idiopathic thrombocytopenic purpura or immune thrombocytopenic purpura. ITP without a secondary cause or underlying disorder is known as primary ITP and the focus of this article. Secondary ITP is defined as ITP with an underlying cause or disorder, which includes drug-induced or systemic illness-induced (eg. SLE, HIV, CVID, etc).
Primary ITP is further categorized into three phases based on the timing and continuation of symptoms. Newly diagnosed ITP is defined as from the time of diagnosis to 3 months from diagnosis. Persistent ITP is the continuation of ITP from 3 to 12 months from initial diagnosis and chronic ITP is the continuation of ITP after 12 months from initial diagnosis until resolution.
The etiology of ITP is autoantibody-mediated, usually, immunoglobulin G mediated. Patients with ITP develop autoantibodies against platelet membrane proteins, specifically glycoprotein (GP) IIb/IIIa complex, GP Ib/IIa, and GP VI. The antibody-coated platelets are then cleared by tissue macrophages, specifically in the spleen, at an accelerated rate, leading to a shortened half-life of the platelet. These same antibodies also inhibit platelet destruction, leading to thrombocytopenia. However, an alternative mechanism has also been proposed involving T-cell mediated cytotoxicity. In this mechanism, cytotoxic T cells attack megakaryocytes in the bone marrow. However, the mechanism is not well understood.
In either mechanism, there is always an inciting event that sets off the cascade to platelet destruction. The two most common inciting events include infection or immune alteration. Cases of ITP associated with infection usually have a preceding viral infection, which is the most common, or bacterial infection. Antibodies develop against the viral or bacterial antigen, which cross-react with normal platelet antigens, a form of molecular mimicry. The most common viral infections include HIV, Hepatitis C, Cytomegalovirus, and Varicella Zoster.
Cases of ITP associated with immune alteration occur due to autoimmune conditions causing loss of peripheral tolerance and promote the development of auto-antibodies. The most common autoimmune conditions include antiphospholipid syndrome, systemic lupus erythematosus, Evans syndrome, hematopoietic cell transplantation, chronic lymphocytic leukemia, common variable immunodeficiency, and autoimmune lymphoproliferative syndrome.
In children, the annual incidence is estimated to be between 1 and 6.4 cases per 100,000 people. Researchers believe pediatric annual incidence is probably higher due to reported cases are based on symptomatic ITP needing hospitalization and not total ITP cases. However, children can present at any age but there is a peak incidence between the ages of 2 years and 5 years as well as another peak in adolescence. In infancy to childhood, there is a slight predominance in males than females. However, in adolescents to young adulthood (ie.18 to 45 years old), there is a predominance in females than males, consistent with higher levels of estrogen which can promote autoimmunity in these patients. In children, seasonal fluctuations have also been noted, with increased incidence in the spring and early summer consistent with viral infections.
In adults, the annual incidence is estimated to be between 1 to 6 cases per 100,000 people. However, in adults, ITP is more of chronic disease, so the prevalence is approximately 12 per 100,000 cases. Peak incidence in adults occurs around 60 years old, however, incidence increases with increasing age. Over the age of 60 years, there is a similar incidence in males and females.
Since ITP is mainly a diagnosis of exclusion, it is mainly seen in well-appearing patients with a history of mucocutaneous bleeding, the sudden appearance of a petechial rash, and/or bruising. The history should focus on any secondary causes of thrombocytopenia, bleeding, or bruising. About sixty percent of children diagnosed with ITP have a preceding viral illness within the past month. Studies have also shown a small increased risk of ITP within six weeks after measles, mumps and rubella (MMR) vaccination, as well as varicella, hepatitis A and tetanus-diphtheria-acellular pertussis vaccinations in older children. Other secondary causes of thrombocytopenia should be explored in the history, including any systemic symptoms (ie. fever, weight loss, anorexia, night sweats, or bone pain), exposure to any medications that can induce thrombocytopenia, any personal bleeding history, family history of bleeding or platelet disorders, recent infections, and any underlying conditions including rheumatologic diseases or liver disease. Questions about bleeding symptoms, bruising and petechiae should also be explored.
Most children are well-appearing other than presenting with the classic petechial rash, which does not blanch when pressure is applied. In adults, about two-thirds may present with bleeding, ranging from a petechial rash, mucosal bleeding, or rarely hemorrhage. The priority of the physical exam is on signs of bleeding, specifically of the skin and oral mucosa, as well as the presence of lymphadenopathy or hepatosplenomegaly, which suggests an underlying condition causing secondary ITP. Mucocutaneous bleeding presents in the form of petechiae, purpura, or ecchymosis on the skin. It can also involve the nasal passages (epistaxis), buccal and gingival surfaces (gum bleeding), GI tract, genitourinary system, or vaginal bleeding. However, conjunctival or retinal hemorrhages are rarely seen in ITP.
Initial laboratory evaluation for both children and adults should include a complete blood count with differential, reticulocyte count, peripheral blood smear, blood type, and direct antiglobulin test (DAT), and if suspecting an underlying immunodeficiency, immunoglobulin levels.
In ITP, the white blood count, hemoglobin concentration, red cell indices, and differential are usually normal and the only abnormality seen is a platelet count less than 100,000/microL. If considerable blood loss has occurred, microcytic anemia can be seen on the CBC. If a patient had a recent infection, the white cell count can be high or low depending on the cause of the infection (ie. bacterial cause showing high WBC vs viral cause showing low WBC). The reticulocyte count is usually normal unless the patient presents with considerable acute blood loss anemia. On the peripheral blood smear, typically white and red blood cells have a normal appearance with a decreased number of platelets and the platelets will be normal to increased size. If there are other findings seen on peripheral smear, this may suggest another underlying cause of thrombocytopenia. For example, if WBC precursor cells (ie. Blasts) are seen on peripheral smear, one must consider leukemia or lymphoma as the cause of thrombocytopenia.
If polychromasia, reticulocytes, or spherocytes are seen on peripheral smear, hemolytic anemia may be the cause of thrombocytopenia and if schistocytes are seen, microangiopathic hemolytic anemia may be the cause of the underlying thrombocytopenia. Blood type and direct antiglobulin test (DAT) are usually performed in the event the patient may need a blood transfusion and DAT testing is usually negative.
For many adults and children, an initial bone marrow biopsy is no longer performed for a typical presentation of ITP. Bone marrow aspiration and biopsy are indicated if there are clinical or laboratory signs suggesting malignancy or bone marrow failure (ie. lymph node enlargement, splenomegaly, bone pain, fevers, unintentional weight loss, neutropenia, leukocytosis, atypical lymphocytes, or anemia) or the patient is unresponsive to treatment with glucocorticoids, IVIG, and/ or anti-D immune globulin.
Children with ITP should be restricted from activities associated with a bleeding risk from trauma when their platelet count is less than 30,000/microL. These activities include but are not limited to contact and collision sports (i.e. football, boxing, lacrosse, and hockey) or any other activities associated with a risk for head injury (i.e. baseball, soccer, skiing or gymnastics). Both children and adults should avoid antiplatelet medications, which include aspirin, ibuprofen, and other nonsteroidal anti-inflammatories (NSAIDs). Anticoagulants (i.e. heparin, enoxaparin, warfarin) should also be avoided in patients with platelet counts less than 20,000/microL.
The American Society of Hematology 2019 guidelines recommend children with no bleeding, or mild bleeding (i.e. bruising or petechiae) can be observed with monitoring of bleeding regardless of platelet count. This includes repeat laboratory studies under the care of a pediatric hematologist to monitor platelet levels. Fifty to seventy percent of children will recover without intervention within three to six months from the initial presentation. For those children with non-life-threatening mucosal bleeding and/or decreased health-related quality of life, guidelines recommend prednisone 2 to 4 mg/kg/day (maximum 120 mg daily) for 5 to 7 days. For children where corticosteroids are contraindicated or not preferred, intravenous immunoglobulin (IVIG) or anti-D immunoglobulin can be used.
The American Society of Hematology 2019 guidelines recommend adults with a platelet count over 30 x 10/L who are asymptomatic and have minor mucosal bleeding should be observed without treatment. This includes repeat laboratory studies under the care of a hematologist to monitor platelet levels. Whereas, adults with a platelet count of less than 30 x 10/L who are asymptomatic and have minor mucosal bleeding should be treated with corticosteroids for less than six weeks. Also, adults with a platelet count of less than 20 x 10/L who are asymptomatic and have minor mucosal bleeding should be admitted to the hospital for initial treatment with corticosteroids for less than six weeks. Guidelines suggest using either prednisone (0.5-2 mg/kg/day) or dexamethasone (40 mg/kg/day for four days) as corticosteroids of choice.
The American Society of Hematology 2019 guidelines recommend children with non-life-threatening mucosal bleeding and/or decreased health-related quality of life who also do not respond to first-line therapies or who have chronic ITP should be trialed on a thrombopoietin receptor agonist (i.e. eltrombopag or romiplostim) first. If the child fails to respond to a thrombopoietin receptor agonist after a period of time, then Rituximab should be used as the next therapy of choice. Splenectomy is usually reserved for those children with severe thrombocytopenia and severe hemorrhagic symptoms, which require multiple pharmacological interventions and should be delayed as long as possible due to the high potential for spontaneous remission and risk for asplenic sepsis. The current recommendation for splenectomy in children is waiting at least 12 months from initial diagnosis and waiting until the child is older than five years of age.
The American Society of Hematology 2019 guidelines recommend adults with ITP who are dependent on corticosteroids or unresponsive to corticosteroids for three months or more or are considered chronic ITP, second-line therapies are recommended. These include thrombopoietin receptor agonists (i.e. eltrombopag or romiplostim), rituximab, and Splenectomy. The choice of a second-line agent is more individualized based on the duration of ITP, the number of hospitalizations, comorbidities, and desires of the patient. If a patient desires a long-term response and avoid surgery, then thrombopoietin receptor agonists are the therapy of choice. If a patient does not desire to take a medication for a long period of time and also avoid surgery, then Rituximab is the therapy of choice. Splenectomy should be considered for those patients desiring a long-term response but should be delayed until after the first year of diagnosis due to the potential for remission within the first year.
The differential diagnosis for thrombocytopenia includes but is not limited to:
In children, the majority recover from ITP within three to six months from initial presentation, regardless of treatment. Studies show approximately ten to twenty percent of children with ITP progress to chronic ITP, defined as thrombocytopenia for more than twelve months from initial diagnosis. Risk factors associated with an increased risk of developing chronic ITP include older age at diagnosis, less severe thrombocytopenia at initial diagnosis, gradual onset of symptoms, absence of preceding infection or vaccination prior to ITP diagnosis, and absence of mucosal bleeding at presentation. Spontaneous remission occurs in about 50% of cases after years from diagnosis in children with chronic ITP, many occurring within the first two years but can occur as long as five years from initial diagnosis.
Children less than 10 years of age with chronic ITP are more likely to undergo remission than older children. Mortality from ITP in children is rare and mainly due to complications from catastrophic bleeding, specifically intracranial hemorrhage. The majority of mortality and morbidity in pediatric chronic ITP comes from complications of long-term immunosuppressive treatment, mainly infections.
Most adults will reach a stable platelet count with one or more therapies. In about 10% of adults, spontaneous remission occurs most often within the first 6 months. Those who do not undergo spontaneous remission, about one-third to two-thirds, will reach a stable platelet count with first-line treatments. The remaining adults affected with ITP will have refractory disease, requiring additional second-line therapies or eventual splenectomy. Cases have been reported where the initial ITP was induced through an autoimmune pathway and subsequently, those adults went on to develop systemic lupus erythematosus or chronic lymphocytic leukemia, however, the overall risk is unknown.
Mortality from ITP in adults is only slightly higher than the age-matched population and mainly due to complications from bleeding, similar to children. The majority of patients with ITP are more likely to die of conditions unrelated to ITP than to complications of ITP or treatment.
The majority of complications associated with ITP in both children and adults is correlated to the bleeding risk associated with low platelet counts, specifically when the platelet count is less than 20,000/microL. Most people affected with ITP will have bruising and petechiae. Some patients with ITP may experience mucosal bleeding, such as epistaxis or gum bleeding. In some severe cases, patients may have gastrointestinal tract bleeding causing heme-positive stools, hematuria, or menorrhagia.
The most feared complication of ITP is intracranial hemorrhage (ICH). In newly diagnosed children, the risk of ICH is about 0.5% and is slightly increased in those children with chronic ITP, but still less than 1%. Most cases of ICH occur at platelet levels less than 10,000/microL. Symptoms concerning for ICH in both children and adults include headache, persistent vomiting, altered mental status, seizures, focal neurological findings, and/or recent head trauma.
Urgent evaluation, including neuroimaging and treatment, is imperative should a patient have an ICH. Risk factors for ICH include very low platelet counts (< 10,000/microL), head trauma, use of antiplatelet medications, and severe bleeding. Severe bleeding is defined as epistaxis lasting 5 to 15 minutes, GI bleeding, and/or any other severe mucosal bleeding requiring hospitalization or blood transfusion.
Patient and family education on the diagnosis of ITP, bleeding risks associated with this disease, and proper treatment, especially compliance with medical therapy is essential for patients. Additional education to caregivers and patients on avoidance of certain sports and activities associated with an increased bleeding risk as well as avoidance of certain medications, including aspirin and NSAIDS, to avoid decreasing platelet counts further. Patients and caregivers will need to be counseled on proper treatment and when to seek medical care.
Clinically significant ITP presents in both childhood and adulthood, making it a familiar diagnosis for all clinicians providing pediatric and adult care. While the pediatrician or primary care provider may be the first to discover the initial rash with an associated hematologic abnormality, coordination with an interprofessional team comprising hematologists, pathologists, and nurses familiar with ITP is necessary for optimal diagnosis and management. Care plans may include education on the diagnosis of ITP, bleeding risks associated with the disease, and proper treatment. Many patients and caregivers must undergo education to avoid certain sports and activities associated with an increased bleeding risk as well as avoidance of certain medications, including aspirin and NSAIDS, to avoid decreasing platelet counts further.
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