Medical Grand Rounds

Immune thrombocytopenia: No longer ‘idiopathic’

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ABSTRACTImmune thrombocytopenia (ITP) is a common hematologic disorder. Its pathogenesis involves both accelerated platelet destruction and impaired platelet production. First-line agents are usually effective initially but do not provide long-term responses. Splenectomy remains an effective long-term therapy, as does rituximab (Rituxan) in a subset of patients. Thrombopoietic agents offer a new alternative, although their place in the overall management of ITP remains uncertain.

KEY POINTS

  • ITP is defined as an isolated platelet count of less than 100 × 109/L (100,000/μL) and usually presents without symptoms.
  • Patients without symptoms who have a platelet count above 30 × 109/L should generally not be treated unless they have an increased risk of bleeding.
  • Recent studies suggest that viruses and other pathogens play an important role in secondary ITP.
  • Initially, corticosteroids are usually given as prednisone (1–2 mg/kg/day, then tapered), though recent studies suggest that dexamethasone pulses (40 mg/day for 4 days) may provide more durable responses when used in this setting.
  • Thrombopoietic agents are important new treatments, although their place in the overall therapy of ITP has not been established.


 

References

Once regarded as idiopathic, immune thrombocytopenia (ITP) is now understood to have a complex pathogenesis, involving the evolution of antibodies against multiple platelet antigens leading to reduced platelet survival as well as impaired platelet production. For this reason, multiple therapies with different mechanisms of action are available to treat ITP, though not all of them are effective for individual patients.

In this article, I discuss the pathogenesis, demographics, manifestations, diagnosis, and management of ITP.

THE NAME AND THE CUTOFF HAVE CHANGED

The term ITP formerly was used to refer to “idiopathic” or “immune” thrombocytopenic purpura. However, although not all aspects of the pathogenesis of ITP are understood, the disease can no longer be considered idiopathic. In addition, many patients do not have purpura at the time of diagnosis. Though the abbreviation “ITP” remains the same, it now refers to immune thrombocytopenia, which can be either primary or secondary.1

ITP is defined as a platelet count of less than 100 × 109/L (100,000/μL) with no evidence of leukopenia or anemia. This cutoff point is new: in the past, ITP was defined as a platelet count of less than 150 × 109/L, which is the threshold for a normal platelet count in most laboratories.

The platelet threshold of 100 × 109/L was based on a study by Stasi et al,2 who followed 217 otherwise healthy people who had an incidental finding of mild thrombocytopenia (platelet count 100–150 × 109/L). Within 6 months, the platelet count rose to more than 150 × 109/L in 23, while three had either worsening thrombocytopenia or were diagnosed with other conditions. During long-term follow-up (median 64 months), 109 of the remaining 191 individuals remained stable, 13 developed counts greater than 150 × 109/L, 12 developed ITP, 13 developed an autoimmune disorder, 18 developed other disorders, and 26 were lost to follow-up. The 10-year probability of developing ITP, defined as a platelet count persistently below 100 × 109/L, was only 6.9%, indicating that the chances are small that a person with an isolated finding of mild, stable thrombocytopenia will develop ITP.

Categories of ITP

An international working group designated to standardize terminology has divided ITP into two major diagnostic categories.1 The proportion of patients within each is not well established and varies by region and demographic characteristics.

Primary ITP accounts for the majority of cases in most studies; other conditions associated with thrombocytopenia are absent.

Secondary ITP can be due to infection with a number of agents, including hepatitis C virus (HCV), human immunodeficiency virus (HIV), and Helicobacter pylori. Other causes include underlying autoimmune and lymphoproliferative disorders such as systemic lupus erythematosus, Wiskott-Aldrich syndrome, chronic lymphocytic leukemia, antiphospholipid syndrome, and common variable immunodeficiency, as well as drugs such as quinine and trimethoprim-sulfamethoxazole.

Categories of ITP have also been established to facilitate management decisions, as follows:

Newly diagnosed ITP refers to ITP diagnosed within the preceding 3 months.

Persistent ITP refers to ITP diagnosed 3 to 12 months previously, and includes ITP in patients not reaching spontaneous remission and in those not maintaining a complete response off therapy. (When ITP spontaneously remits in adults, it usually does so within the first 12 months after the condition is diagnosed.)

Chronic ITP: Lasting for more than 12 months.

Severe ITP is defined by bleeding at presentation sufficient to mandate treatment, or new bleeding symptoms requiring additional therapeutic intervention with a different platelet-enhancing agent or an increased dosage of a current agent.

ITP IS COMMON IN OLDER ADULTS

We previously believed that ITP was a disorder that primarily affected women in their third and fourth decades. However, this was not borne out in recent epidemiologic studies, which have demonstrated that the highest age-specific incidence of ITP occurs in the elderly. This may potentially reflect the development of immune dysregulation as a consequence of aging. There is a female preponderance in the incidence of ITP throughout adulthood until around age 60, after which the overall incidence increases in both sexes, and the ratio of affected women to men is about equal.3,4 Thus, even though thrombocytopenia in the elderly may reflect myelodysplasia in some individuals, ITP is much more common than previously appreciated.

Previous guidelines from the American Society of Hematology suggested that a bone marrow examination be strongly considered in patients over age 60 with suspected ITP. With the realization that ITP occurs more commonly in the elderly, it is apparent that bone marrow examination is not necessary in this group if there are no other cytopenias present and the physical examination and blood smear are consistent with ITP.

In children, ITP has a peak incidence between ages 5 and 6, and behaves differently from the adult syndrome. ITP in children usually follows an apparent viral infection and tends to be self-limited, with approximately 80% of cases resolving spontaneously within 6 months. In contrast, adult ITP usually develops into a chronic disease.

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