Initial Treatment of Chronic ITP
**Please note! The drug doses that are described in some of the sections represent those commonly prescribed. Drug doses in individual patients may differ from those listed here and depend on the patient's clinical situation and the doctor's preferences. Decisions on the treatment of individual patients with ITP are the sole responsibility of the treating physician.
Some ITP patients have stable disease with platelet counts that are consistently greater than 25-30,000. No treatment is needed in these patients (there are occasional exceptions which should be discussed with your doctor). For patients with chronic ITP who have platelet counts consistently less than 25-30,000 and who have received no previous therapy, treatment is aimed at obtaining a stable, safe platelet count (>30,000) on no treatment.
Concepts Guiding Treatment
Corticosteroids, intermittent doses of intravenous gammaglobulin or anti-D have been used successfully in childhood ITP to keep the platelet count at safe levels until the ITP enters a remission, which in children occurs in about 80-90%. Even though many adult ITP patients (prior to splenectomy) will respond temporarily to these treatments, most investigators felt that they were not indicated for long-term use in adult ITP patients since they rarely entered a spontaneous remission and eventually required splenectomy. However, some investigators challenged that hypothesis and felt that if the platelet count could be maintained over a long interval with some form of therapy, some adult ITP patients might improve or recover completely without the need for splenectomy. There is now evidence to support this approach.
Study 1. In this study (Blood 99:1922, 2002), anti-D was used to support the platelet count. The following results were noted at the time of publication. Twenty-eight Rh+ ITP patients were give anti-D therapy (Winrho SDF) whenever their platelet count fell below 30,000 (68% responded consistently to anti-D). Patients were treated for 18 months or until they required splenectomy. Of the 28 patients, 12 (43%) were off all treatment for an average of 16 (6-33) months with either platelet counts of >100,000 (6 patients) or safe platelet counts >30,000 (6 patients). Eight patients required splenectomy (6 obtained normal counts) and 7 patients were on periodic therapy (anti-D or other therapy). One patient was lost to followup.
Study 2. A second study (Am J Hematol 74:161, 2003), was designed to provide a most important answer: if spontaneous recovery does occur, is it more common when using anti-D treatment to support the platelet count or can the same result be obtained with corticosteroids (prednisone). In this study, ITP patients were assigned randomly (by chance) to receive either anti-D or routine care (prednisone) as a means of supporting their platelet count in the hope that spontaneous recovery would occur. The results showed that anti-D-treatment initially deferred splenectomy when compared to prednisone, but the eventual requirement for splenectomy was the same in both groups.
Personal Observations. We obtained long-term followup on several ITP patients whom we studied over the years. Of this group, 21 patients were of particular interest. They were seen in consultation and advised to have a splenectomy, after having failed to attain a complete remission following an initial response to prednisone. These patients, or their physicians, decided to postpone splenectomy and continue treatment (in most cases with either prednisone or danazol) at doses which resulted in safe platelet counts. Over the next several weeks, the platelet count stabilized and all treatment was eventually stopped. Ten of the patients had normal platelet counts and 11 patients had counts of more than 50,000 which have been stable, off all treatment, with an average followup of more than 8 years.
Conclusion: A significant number of adult chronic ITP patients will remit spontaneously (and not require splenectomy) if the platelet count is supported with some form of therapy. Patients should be given this opportunity.
To be determined.
- What percentage of adult ITP patients will remit spontaneously?
- How long will these remissions last?
- How long should treatment continue before advising splenectomy?
- What is the best agent to maintain the platelet count?
- corticosteroids (prednisone): inexpensive and convenient/severe side effects at high doses over a long time.
- Anti-D: expensive/few side effects (rare occurence of severe anemia/renal failure/death)
- IvIgG: expensive, inconvenient/few side effects (rare thrombosis in elderly patients)
Recommended Initial Treatment of Adult ITP
Summary of Initial Treatment.
- Corticosteroids: prednisone. Begin prednisone as the first treatment, in view of its convenience (pills) and low cost. Start with high doses (50-100 mg/d) and taper the dose as the platelet count increases, with the aim of maintaining safe platelet counts on doses which do not cause significant side effects (~10-15 mg/day).
- Corticosteroids: high-dose dexamethasone. An alternate treatment method for giving corticosteroids has been reported with encouraging results in a substantial number of patients (Blood 109:1401, 2007). This treatment uses very high doses of dexamethasone given in one of two ways: (1) dexamethasone, 40 mg per day for 4 consecutive days, given every 28 days for 6 courses or (2) dexamethasone, 40 mg per day for 4 consecutive days, given every 14 days for 4 courses. Persistent complete responses were noted in about two thirds of the adult patients with an average followup of about 2 years. For further details, discuss this protocol with your doctor.
- Anti-D. In Rh positive patients, who either do not respond to prednisone or dexamethasone or whose prednisone dose can not be tapered within a few weeks to doses which are not associated with side effects, anti-D should be substituted. Anti-D is administered whenever the platelet count falls below 25-30,000. Note: anti-D is not useful in Rh negative patients.
This approach should be continued for at least 6-12 months if possible. The exact duration of this therapy must be decided by the patient and treating physician since there are no studies available to determine how long this approach should be pursued before advising removal of the spleen (splenectomy).
- Splenectomy. Splenectomy is recommended if: (a) the platelet count can not be maintained at safe levels using these measures; (b) the physician feels that a spontaneous remission is unlikely to occur or (c) if the approach becomes too burdensome for the patient (frequent blood tests, office visits, lost work time, etc).
Treatment Details.
Prednisone (corticosteroids). About three-fourths of patients will increase their platelet count on treatment and about one-half will attain normal platelet counts. In some patients, the platelet count can be maintained at safe levels, after tapering to prednisone doses which are not associated with side effects. However, many patients will note an initial improvement in their platelet count with high doses of steroids but, when the dose is lowered, will relapse.
Dose. The starting oral dose of prednisone is 50-100 mg/day depending on the patient's weight. This dose is usually continued for no more than 4-6 weeks. If a normal platelet count is attained, the dose is gradually tapered over several weeks to the lowest dose which will maintain safe platelet counts.
Side effects. These occur only at high doses over a period of time. They include gradual swelling of the face, neck and shoulders; fluid retention; gastric hyperacidity (heartburn); anxiety, difficulty sleeping and potassium loss. Osteoporosis (thinning of the bones) and an increased risk of infection may be problems if treatment is given over several months. Since hyperacidity is common, antacids or acid inhibitors are often needed. The serum potassium should be monitored and potassium supplements given as required.
High-dose dexamethasone (corticosterods). This form of corticosteroid therapy may be recommended instead of prednisone. Side effects are similar but, due to the high doses, may be more pronounced. Details concerning dosage and side effects should be discussed with your doctor.
Anti-D (Winrho SDF). About two-thirds of Rh positive ITP patients will respond consistently to this drug. Rh negative patients should not receive this treatment since it will be ineffective.
Dose. The standard dose is 50 ug/kg/d by intravenous injection over 3-5 minutes. Although recent data show a better and more prolonged response to 75 ug/kg/d, this higher dose is associated with more side effects. Injections are advised anytime the platelet count falls below 30,000.
Side effects. Most side effects occur during or shortly after anti-D injection and include: fever, chills and headache. Rarely, severe anemia may occur (requiring red cell transfusion) and, in a small number of cases, this has been associated with kidney failure and death.
Splenectomy (removal of the spleen). Splenectomy gives the highest cure rate of all treatments. In a recent review of the results of several large studies (47 studies) with long followup, splenectomy resulted in a permanent complete response (normal platelet count on no treatment) in 1761 of 2623 patients (66%). If only patients with followup of more than 5 years were evaluated, the same results were noted: 456 of 707 (65%) were in complete remission with an average followup of 7.3 years. Therefore, two thirds of ITP patients require no additional treatment for their ITP after splenectomy.
Who will respond? At present, there is no way to predict, prior to surgery, who will respond to splenectomy. One article suggested that patients whose platelet count increases after treatment with intravenous gammaglobulin are more likely to respond to splenectomy (Law C, Marcaccio M, Tam P et al. New England Journal of Medicine 336:1494, 1997). However, other groups could not confirm this result.
Surgical Method. There are two ways to remove the spleen: (1) abdominal surgery through a standard incision (the old-fashioned way) or (2) laparoscopy, where several small incisions are made in the abdomen and a telescope-like instrument (laparascope) is inserted. After the blood vessels are tied, the spleen is encased in a bag and ground up so that it can be removed through the small opening. Laparascopic surgery is associated with less post-operative side effects, a shorter recovery period and results are as good as those obtained with 'standard' surgery. If this method is chosen, be sure that the surgeon has experience with this approach (has performed ~20 such procedures) since there is a 'learning curve'.
Post-operative Course. The platelet count increases rapidly after surgery with normal counts appearing within 2 weeks in most responding patients. About one third of patients either fail to respond to splenectomy or develop recurrent thrombocytopenia after an intial response, usually within a few weeks after surgery. Youth, a short disease duration and an increase in the platelet count to greater than 400-600,000 after surgery are good prognostic signs.
Side effects. Surgical mortality is extremely low and is primarily due to the risk of anesthesia. Although the risk of overwhelming infection after splenectomy is substantial in young children (less than 6 years old), this is rare in adults and should not influence the decision to have surgery. Prior to surgery, each patient should be vaccinated against the common bacteria (germs) that can cause serious infection in patients who have no spleen: pneumococcus, Hemophilus influenza and meningococcus. Wound infection, post-operative bleeding, pneumonia, etc. may occur but these problems are uncommon.
Accessory spleens. Some ITP patients who relapse at a later time after surgery have an accessory spleen (small amounts of splenic tissue that are not connected to the main organ which may not have been removed at the time of surgery). All patients who relapse after surgery should be evaluated for an accessory spleen. If present, strong consideration should be given for their removal unless there is some medical reason that prevents surgery.
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