CONTENTS:
When Should You Worry It’s More Than ITP?
By Kristin S. Shimano, MD
Dr. Shimano is a pediatric hematologist and bone marrow transplant physician at the UCSF Benioff Children’s Hospital in San Francisco, CA. Dr. Shimano has a particular interest in immune cytopenias, including ITP. She is the Operations Committee Chair of the ITP Consortium of North America (ICON).
Immune thrombocytopenia is a clinical diagnosis made by exclusion of other causes of thrombocytopenia. This means that there is no specific “ITP test” that can be sent to the lab to determine that a person has ITP. Instead, when a patient has a low platelet count, the hematologist uses a combination of elements, including the medical history, the physical exam, and lab results, to make a diagnosis of ITP. Especially important in this evaluation are the other blood counts and the peripheral smear – the appearance of the blood cells under the microscope.
When one first considers the diagnosis of ITP, it is important to think about other medical problems that could cause low platelets and possibly masquerade as ITP. Common causes of low platelets include side effects from medications or a temporary decrease in production due to a virus. Other rarer causes of low platelets include problems with the bone marrow, such as bone marrow failure syndromes, metabolic storage diseases, and malignancies. Doing a bone marrow biopsy is not necessary to make an initial diagnosis of ITP, unless the hematologist is concerned based on a patient’s history or exam or other lab findings that one of these marrow failure diagnoses is possible. Finally, inherited platelet disorders – genetic causes for abnormal platelet counts – should be considered if there are multiple family members with low platelets, or if the appearance of the platelets under the microscope is suggestive of a particular disorder or if they have another feature (not related to the blood count) that suggests one of these syndromes. If one is confident that a patient doesn’t have any of these other causes of low platelets, and the history, physical exam, and labs all fit with immune thrombocytopenia, then the patient is diagnosed with ITP.
But even once a patient is diagnosed with ITP, that may not be the end of the story. ITP is classified as either “primary” (ITP with no underlying cause) or “secondary” (ITP with an underlying cause). ITP can be secondary to infection, primary immunodeficiency disorders, autoimmune disorders, lymphoproliferative diseases, or malignancies. ITP may also be due to an underlying hereditary cause in rare situations. Sometimes other features of the disorder may be present before or at the time of the ITP diagnosis, but at other times ITP may be the first manifestation of an underlying problem. For this reason, it is important to revisit the question of secondary ITP over the course of a patient’s illness and treatment. Clues in a patient’s medical history may suggest the presence of an underlying diagnosis. Recurrent infections (multiple sinus and ear infections and pneumonias, frequent viral infections, molluscum or warts) or infections that are severe (requiring hospitalization or prolonged treatment) or unusual (organisms that wouldn’t typically cause infection in a healthy person) are a red flag that there may be an underlying immunodeficiency. A history of other autoimmune problems, such as inflammatory bowel disease or severe eczema, also raises concern for an underlying disorder. Although patients with ITP often have fatigue, other symptoms (such as joint pain and swelling, or certain rashes, like the classic “malar rash” in lupus) may prompt consideration of an underlying autoimmune disease. Physical exam findings can be helpful as well: congenital anomalies such as heart defects or skeletal problems can be seen in some immunodeficiencies, and a large spleen or lymph nodes may be concerning for a lymphoproliferative disorder. Every time one sees patients with ITP in clinic, it is important to ask about any new symptoms that have arisen and examine the patient to make sure the hematologist doesn’t need to look harder for an underlying cause of the ITP.
There are features about a patient’s ITP course that make one think harder about underlying causes. Evans syndrome, or more than one immune cytopenia, refers to more than one blood cell type being destroyed by autoantibodies (for instance, ITP + autoimmune hemolytic anemia). These can occur either at the same time or more commonly are separated in time and are often seen with secondary ITP. Any patient who has multi-lineage immune cytopenias needs to be evaluated for common variable immunodeficiency and autoimmune lymphoproliferative syndrome. Also, patients who have chronic or relapsing ITP warrant consideration of underlying disorders. While primary ITP can absolutely be chronic, especially in children being chronic should make one at least consider secondary ITP.
If a hematologist does suspect an underlying disorder, additional evaluations will be needed, which are tailored to the specific problem being considered. For immunodeficiencies, we assess different components of the immune system and their function. Genetic panels to test for an array of underlying primary immunodeficiencies and inherited thrombocytopenias can also be helpful. For autoimmune disorders, measurement of other autoantibodies may aid in the diagnosis. Phenotyping of the lymphocytes may be useful in evaluating some immune deficiencies, infections, lymphoproliferative disorders or malignancies especially lymphoma and leukemia.
There are several reasons that making a diagnosis of an underlying disorder may be helpful in treating a patient with ITP. Patients with underlying disorders may be at risk for other associated conditions, and screening for or treating these can have a profound effect on health. For example, identifying an underlying immune deficiency may allow prevention of infections. It can also affect how we approach treatment of the ITP. Certain immunodeficiencies, such as CVID, are treated with monthly IVIg replacement (which may or may not be sufficient to treat the ITP). In some disorders, like ALPS, avoiding splenectomy is recommended, because the likelihood of long-term remission of the ITP is low and the risk of infectious complications is high and also avoiding rituximab is recommended because of the possibility that the immunoglobulin (antibody) levels will not only become low but remain low indefinitely. Finally, secondary ITP may respond best to particular treatments, depending on the underlying disorder. CTLA-4 immunoglobulin fusion proteins, for instance, are a promising defect-targeted therapy for patients with CTLA-4 insufficiency; sirolimus works well in patients with ALPS. Rituximab is highly effective in ITP related to CVID but usually mandates lifetime replacement IVIG. Thus, when ITP is more than “just ITP,” making a diagnosis of an underlying disorder can provide information about prognosis, related health problems, and treatment options that are crucial for managing the disease and optimizing a patient’s health.
PDSA Medical Advisor James Bussel, MD Offers the Adult Perspective:
In evaluating the diagnosis of ITP, one can consider causes of low platelets (thrombocytopenia) that are not ITP and causes that are ITP (autoimmune). ITP can then be primary or secondary as discussed. It is important to realize that for these other thrombocytopenias, which often can be diagnosed with specific tests, there are far too many tests to do to consider performing them on anywhere near all patients. In some cases of secondary ITP there may be no hint of the underlying cause and the test would need to be done “blindly” to find out if that is the case. Which tests to do when in which patients, if there are no specific clinical findings suggestive of a specific disease or syndrome, are a source of debate currently with no set agreed upon pattern.
How do we divide the causes as to which are more likely in children versus adults? Children are more likely to have unusual immunodeficiencies (like CTLA4 and ALPS) but CVID (low antibody levels) is commonly diagnosed between the ages of 30 and 40 in young adults. Lymphomas can cause secondary ITP in adolescents but are more common in elderly adults. Leukemia usually causes thrombocytopenia by replacing the normal bone marrow cells with leukemia cells (not ITP) but chronic lymphocytic leukemia can be linked to ITP, and this occurs primarily in older adults. An important cause of ITP that again occurs primarily but not solely in adults is myelodysplastic syndrome. This can be especially confusing because it can shift over time from primarily driving the thrombocytopenia to marrow replacement with abnormal cells driving the thrombocytopenia. Because MDS leads to a “hypercellular” (lots of cells) marrow, it may look a lot like ITP and be impossible to distinguish early on. Sometimes only repeat bone marrows and/or genetic studies will reveal that a case of ITP that seems to be getting harder and harder to manage is a case in which ITP evolves into MDS. In a study of misdiagnosis of ITP in Canada, MDS was the most common cause. Drug-induced thrombocytopenia is more common in adults only because they are more likely to take more medications. Infections can occur at any age, but CMV infection (and possibly EBV) occurs more frequently in children. However, H. Pylori (which is of uncertain significance as far as ITP in the United States) is more common in older people. Other autoimmune diseases such as systemic lupus (SLE) can occur at any age but are more common in women and in adolescents and adults.
In conclusion, we are not certain how often ITP is secondary instead of primary: current estimates are 75-80% of cases of ITP are primary, but these are very rough estimates. As described above, it is important to consider secondary ITP at any age and in any patient with ITP. Certain types of secondary ITP are more likely in children and others in adults. It can be exceedingly difficult to know when a case of ITP is secondary which is why it needs to be thought of at each visit in case anything changes that points to such a possibility. Finally, secondary ITP occurs when ITP is caused by other underlying problems. Knowing when to do which tests for it or other causes of thrombocytopenia can be difficult; there is no set pattern of testing.
The Jim Tarantino BCDI Hero Award
Each year, the Bleeding and Clotting Disorders Institute (BCDI) recognizes and honors individuals who go above and beyond in impacting the bleeding and clotting disorders community with the BCDI Hero Award. This honor was bestowed on our very own Caroline Kruse, PDSA President and CEO, on Friday, April 19th at the 13th Annual BCDI Trivia Night for her significant impact, support and leadership in the bleeding and clotting disorders community.
“Through Caroline’s direction of PDSA, she has helped thousands of people with ITP with advocacy, support groups, annual meetings and conferences, and the PDSA website,” Dr. Michael Tarantino said. “I really consider her one of my heroes. She is the model for advocacy for people that need a voice.”
The Hero Award was renamed “The Jim Tarantino BCDI Hero Award” this year. Jim Tarantino, brother of Dr. Michael Tarantino who is currently the Chair of PDSA’s Medical Advisory Board and CEO/CMO of BCDI, passed away unexpectedly this past January. Whether through generous donations or lending his expertise to drive the construction of BCDI’s state of the art campus, Jim’s support of the bleeding and clotting disorders community and BCDI was abundant.
The 24-karat themed event featured attendees in gold attire, a trivia contest, fun games and a photo booth. To top off the evening, an attendee and ITP patient graciously thanked Caroline for the impact of PDSA and the resources provided on the website as they have been a savior and guiding light in her own ITP journey.
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