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Abbreviations: D, decreased; N, normal.

Abbreviations: D, decreased; N, normal.

b. Improves capillary resistance and thereby improves platelet economy.

c. Inhibits platelet antibody production.

2. Dose and duration:

a. A course of prednisone, 2 mg/kg/day (maximum 60 mg/day), is given in divided doses. Prednisone is reduced in a stepwise fashion at 5- to 7-day intervals, irrespective of the platelet count, and is stopped at the end of 21-28 days, regardless of the response. A shorter course of prednisone at 4 mg/kg/day for 4 days has also been used with success.

b. In severe cases, methylprednisolone (Solu-Medrol) 30 mg/kg/day (500 mg/m2/day; maximum 1 g/day) for 3 days produces a more rapid response than steroids in conventional doses.

c. Prolonged use of steroids in ITP is undesirable. Large doses or prolonged steroid usage may perpetuate the thrombocytopenia and depress platelet production. It also leads to side effects including weight gain, cushingoid facies, fluid retention, acne, hyperglycemia, hypertension, mood swings, pseudotumor cerebri, cataracts, growth retardation, and avascular necrosis.

High-Dose Intravenous Gammaglobulin

1. Mechanisms of action for high-dose intravenous gammaglobulin (IVGG) include:

a. Reticuloendothelial Fc-receptor blockade b. Activation of inhibitory pathways c. Decrease in autoantibody synthesis.

2. Indications in acute ITP:

a. Neonatal symptomatic immune thrombocytopenia and infants less than 2 years of age who are generally more refractory to steroid treatment b. Alternative therapy to corticosteroid therapy but is much more expensive, has significant side effects, is not significantly clinically better than steroid therapy to justify expense and side effects of its use.

3. Dosage:

a. Acute ITP: a total dose of 2 g/kg body weight given as follows:

Lower doses of 800 mg/kg/day as a single dose or 250 mg/kg/day for 2 days have been used with success.

b. Chronic ITP:

(1) Initial IVGG dose of 1 g/kg body weight daily for 2 days, followed by periodic single infusions (0.4-1 g/kg depending on response) to maintain platelet count at a safe level (>20,000/mm3)

(2) Alternate-day corticosteroids is useful adjunctive therapy when IVGG is used.

4. Response:

a. Acute ITP: 80% respond initially

More rapid increase in platelet counts compared to steroid treatment.

5. IVGG toxicity:

a. Anaphylaxis in IgA-deficient patients because of preexisting IgA antibodies that react with small amounts of IgA present in commercially available gam-maglobulin.

b. Postinfusion headache in 20% of patients; transient and possibly severe (in severe cases, administer postinfusion dexamethasone 0.15-0.3 mg/kg IV). Severe headache in ITP may suggest the presence of intracranial hemorrhage and if clinically indicated may require a CT scan.

c. Fever and chills in 1-3% of patients; prophylactic acetaminophen (10-15 mg/kg, 4 hourly, as required) and diphenhydramine (1 mg/kg, 6-8 hourly, as required) to reduce the incidence and severity.

d. Coombs-positive hemolytic anemia because of the presence of blood group antibodies (anti-A, anti-B, and anti-D) present in IVGG.

e. Hepatitis C virus (HCV) infection reported in patients receiving IVGG; however, no reports of HIV infection with any licensed preparation in the United States has been described.

Anti-D Therapy

Anti-D is a plasma-derived gamma immune globulin containing a high titer of antibodies to Rh antigens of the red blood cells (RBC) for IV injection. WinRho SDF (Nabi, Boca Raton, FL, USA) has been licensed in the United States, Canada, and Ireland.

Infusion of IV anti-D immunoglobulin to Rh-positive individuals causes a transient hemolytic anemia in the recipient. The mechanism for the beneficial effect of anti-D in ITP is blockade of the Fc receptors of reticuloendothelial cells with antibody-coated autologous red blood cells (Table 10-6). Because the Fc receptors are blocked with antibody-coated RBCs, the receptors are not available to antibody-coated platelets in ITP. The increase in platelet count occurs after 48 hours; therefore, this therapy is not appropriate for emergency treatment. Patients who have not undergone splenectomy are more likely to respond to IV anti-D than are splenec-tomized patients.

Prerequisite for use

The patient must be Rh positive for this mode of therapy to be beneficial.

Dose

Anti-D 50-75 |g/kg IV infusion over a 3- to 5-minute period. The hemoglobin level should be checked approximately 1 week later, but no sooner than 3-4 days. If the hemoglobin level decrease is 1 g/dL or less, the dose can be increased up to 70-80 |g/kg dose. Repeat anti-Rh D treatment at 3- to 8-week intervals, maintaining a platelet count of more than 20,000/mm3.

Viral safety

No cases of viral transmission have been reported in patients receiving WinRho, anti-D.

Adverse drug reactions

Fever

Chills

Headache

Drop in hemoglobin and hematocrit attributed to anti-D-related hemolysis.

These symptoms are directly attributable to anti-D-related hemolysis and a positive Coombs reaction.

Hypersensitivity reactions

Acute anaphylactic reaction is a remote possibility. IgE-mediated and immune complex reactions have been reported with the use of anti-D. No reactions to anti-D have been reported in IgA-deficient patients.

Hemolysis

In four clinical studies with a mean dose of 50 |g/kg WinRho, the mean decrease of hemoglobin was 1.7 g/dL (range, 0.4-6.1 g/dL). Hemolysis is usually extravascular. A few cases of intravascular hemolysis resulting in renal impairment have been reported.

Results

This is a safe, convenient, inexpensive, and effective therapy for chronic ITP. It is more effective in children than in adults.

Rituximab

Rituximab is a humanized mouse monoclonal antibody against the B-cell surface antigen CD-20. It is used for the treatment of non-Hodgkin lymphoma and causes B-cell lysis. The rationale for its use in ITP is to eliminate autoreactive B cells.

Dose

375 mg/m2 IV weekly for 4 weeks.

Adverse drug reactions

• Headache, dizziness

• Nausea, vomiting

• Hypotension, sinus tachycardia

• Mucocutaneous reactions including Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis

• Immunosuppression.

The following drugs, while effective, are rarely necessary or employed in ITP.

Vinca alkaloids Vincristine Vinblastine Danazol

Cyclophosphamide

Azathioprine

Cyclosporine a-Interferon 2b

Dapsone

Colchicine

Epsilon-aminocaproic acid Recombinant factor Vila.

Plasmapheresis

In patients who manifest thrombocytopenia and life-threatening bleeding despite medical intervention and splenectomy, protein A column treatment of plasma and reinfusion can be used for rapid removal of platelet antibodies. By accelerating the clearance of circulating antiplatelet factors, this may be useful in patients with severe ITP.

Platelet Transfusions

Platelet transfusions are indicated when there are neurologic signs suggestive of intracranial bleeding, signs of internal bleeding, or if an emergency surgery is indicated. Although platelet survival is short, a platelet transfusion may have a temporary beneficial hemostatic effect. Fear of prolonging the duration of ITP by enhancing sensitization is theoretical.

Splenectomy

Indications

Splenectomy is indicated for severe acute ITP with acute life-threatening bleeding, which is nonresponsive to medical treatment. Splenectomy is also indicated for chronic purpura with bleeding symptoms or platelet count persistently below 30,000/mm3, which is nonresponsive to medical treatment for several years. In very active patients subject to frequent trauma, earlier splenectomy may be indicated. Because of the hazards of overwhelming postsplenectomy infection (OPSI), the procedure should be undertaken only when clearly indicated. Indications for splenec-tomy are rare because of judicious use of steroids and IVGG. It is rarely necessary to perform a splenectomy before 2 years after diagnosis because the thrombocytopenia is generally well tolerated and easily controlled. Spontaneous recovery may occur after 4 or 5 years and, therefore, a very conservative approach to splenectomy in ITP should be adopted. Laparoscopic splenectomy appears to be preferable to open splenectomy in experienced hands.

Preparation for splenectomy

Corticosteroids, IVIG, or anti-D can be used to raise the platelet count periopera-tively. If active bleeding is occurring just prior to surgery, platelet transfusion may be required before surgery as well as methylprednisolone 500 mg/m2/day IV. If the patient undergoing splenectomy has adrenal suppression following previous corticosteroid administration, corticosteroids at full dosage should be administered the day before, the day of, and for a few days after surgery. Patients should be immunized with pneumococcal and meningococcal vaccines preferably 2 weeks prior to splenectomy. They should also receive Haemophilus influenzae b vaccine if they have not received it before. Because the protection provided by the vaccines is incomplete, daily prophylaxis with penicillin 250 mg twice daily is recommended. All febrile episodes should be carefully assessed, and patients should be empirically treated with parenteral antibiotics pending blood culture results.

Prognosis

Up to 70% of patients have a complete and long-lasting recovery after splenectomy. Response to steroids and IVGG is a good indication of the likelihood of response to splenectomy (about 80-90%). Forty percent of patients with persistent thrombocy-topenia after splenectomy have an accessory spleen.

Treatment of Children with Life-Threatening Hemorrhage

1. Platelet transfusion

2. methylprednisolone 500 mg/m2 IV per day for 3 days

4. Emergency splenectomy.

These measures can be used singly or in combination, depending on the severity and response to treatment. Patients refractory to these measures may benefit from vincristine sulfate 2 mg/m2 IV and protein A column treatment of plasma and reinfusion of the plasma.

Prognosis

1. Excellent; 50% recover usually within 1 month and 70-80% recover within 6 months.

2. Spontaneous remission after 1 year is uncommon, although may occur even after several years.

3. When a demonstrable underlying cause of ITP exists, the prognosis is related to cause.

4. Age older than 10 years, insidious onset, and female gender are associated with the development of chronic ITP.

5. Of all chronic patients, 50-60% eventually stabilize without any therapy and without recourse to splenectomy.

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