Immune thrombocytopenia: No longer ‘idiopathic’
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.
ANOTHER MECHANISM OF ITP: REDUCED PLATELET PRODUCTION
In addition to accelerated platelet destruction, ITP is also associated with decreased platelet production by megakaryocytes in the bone marrow.21–25
Increased platelet destruction and reduced platelet production are likely two ends of a spectrum of ITP, and most patients likely have some degree of both processes. This concept helps explain why different drug strategies are more effective in some patients than in others.
ARE THE RISKS OF THERAPY JUSTIFIED?
It is important to understand the natural history of ITP to determine whether the risks of therapy are justified.
A 2001 study from the Netherlands26 followed 134 patients with primary ITP for 10 years: 90% had taken prednisone or had had a splenectomy. Within 2 years, 85% of these patients had platelet counts above 30 × 109/L off therapy. Although this group likely experienced more bleeding and bruising than the general population, the mortality rate was not increased. Another 6% also achieved a platelet count above 30 × 109/L, but required chronic maintenance therapy (usually steroids) to do so. This group led a nearly normal life but had more hospitalizations. The remaining 9% of patients had refractory ITP, with platelet counts remaining below 30 × 109/L despite therapy. This group had a death rate 4.2 times that of age-matched controls. About half died of bleeding and the others died of opportunistic infections to which they were susceptible because of long-term steroid therapy.
This study was influential in the general opinion that 30 × 109/L is a reasonable cutoff for treating ITP. An international consensus report states that treatment is rarely indicated in patients with platelet counts above 50 × 109/L in the absence of bleeding due to platelet dysfunction or other hemostatic defect, trauma, or surgery.27 Although this number is not supported by evidence-based data, it is a reasonable threshold endorsed by an international working group.27 Individual factors must be weighed heavily: for example, an athlete involved in contact sports requires a higher platelet count in order to play safely.
FIRST-LINE THERAPIES
First-line therapies for ITP include corticosteroids, IVIG, and anti-Rho(D) immune globulin (WinRho).27
Corticosteroids are standard therapy
Corticosteroids can be given in one of two ways:
Standard prednisone therapy, ie, 1 to 2 mg/kg per day, is given until a response is seen, and then tapered. Some maintain therapy for an additional week before tapering. There are no guidelines on how to taper: some decrease the dosage by 50% per week, although many recommend going more slowly, particularly at the lower range of dosing.
Up to 85% of patients achieve a clinical response, usually within 7 to 10 days, with platelet counts peaking in 2 to 4 weeks. Unfortunately, only about 15% of patients maintain the response over the subsequent 6 to 12 months. Restarting prednisone often initiates a vicious circle and makes patients vulnerable to steroid toxicities.
“Pulse” dexamethasone therapy consists of 40 mg per day for 4 days for one to three cycles. (Dexamethasone 1 mg is equivalent to about 10 mg of prednisone.)
Pulse dexamethasone therapy as an initial approach to ITP has been developed during the past decade and has been used primarily in research studies. This regimen evolved from studies of patients with multiple myelomas and has the potential to induce more durable remissions in some patients with newly diagnosed ITP.29 However, high-dose corticosteroids may be associated with increased toxicity, at least in the short term, and should be used cautiously. A study to address the role of high-dose vs standard-dose steroid therapy has recently been opened under the guidance of the Transfusion Medicine–Hemostasis Clinical Trials Network of the National Heart, Lung, and Blood Institute.
Immunoglobulin is useful for very low platelet counts and bleeding
Another primary therapy for ITP is IVIG 0.5 to 2.0 g/kg over 2 to 5 days. Its efficacy is similar to that of prednisone: about 65% of patients achieve a platelet count above 100 × 109/L, and 85% achieve 50 × 109/L. However, most responses are transient, and a significant minority of cases become refractory to IVIG after repeated infusions.
IVIG is associated with numerous adverse effects, including thrombosis, renal insufficiency, headache, and anaphylaxis in IgA-deficient patients. It also converts the direct antiglobulin test to positive. IVIG is expensive, is inconvenient to administer, and may require lengthy infusions depending on the formulation.
Although IVIG is not a good long-term therapy, it can help raise the platelet count relatively quickly in patients who present with severe thrombocytopenia accompanied by bleeding. Such patients should be treated with high-dose steroids, IVIG, and platelet transfusions. IVIG may also be useful to increase platelet counts prior to interventional procedures.
Intravenous anti-Rho(D)
Anti-Rho(D) is an alternative to IVIG in patients who are Rho(D)-positive and have an intact spleen. Anti-Rho(D) binds to Rh-positive red blood cells, causing them to be cleared in the reticuloendothelial system and blocking the clearance of antibody-coated platelets. In effect, red cells are sacrificed to save platelets, but because there are many more red cells than platelets, the benefits usually outweigh the risks.
The initial dose is 50 μg/kg given intravenously over 2 to 5 minutes. Anti-Rho(D) should not be given to patients whose hemoglobin level is less than 10 g/dL or who have compromised bone marrow function. It is ineffective in Rh-negative patients or those who have undergone splenectomy.
Accelerated hemolysis is a rare but severe possible adverse event associated with this therapy, occurring in slightly more than 1 in 1,000 infusions. About 1 out of every 20,000 patients develops disseminated intravascular coagulation.30 Its cause is poorly understood, and it is probably an accelerated extravascular rather than an intravascular event. The US Food and Drug Administration has recently issued a black-box warning cautioning that patients who receive anti-Rho(D) should remain in a health care setting for 8 hours after treatment, although most cases of accelerated hemolysis occur within 4 hours. Moreover, it is possible that many of these cases can be avoided by appropriate patient selection.
