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First line therapy

Standard first line therapy

In general, patients with platelet counts exceeding 30 ×10⁹/ l require no treatment unless they are undergoing any procedure likely to induce blood loss including surgery, dental extraction or delivery (Yang & Zhong, 2000) (Grade C recommendation).

Recommendation for "safe" platelet counts in adults
Dentistry≥10×10⁹/ l
Extractions≥30×10⁹/ l
Regional dental block≥30×10⁹/ l
Minor surgery≥50×10⁹/ l
Major surgery≥80×10⁹/ l
Obstetrics see Thrombocytopenia in pregnancy
Evidence Level IV

First line therapy comprises oral corticosteroids and intravenous immunoglobulin (IVIg). Splenectomy is often cited as first line therapy but this mode of treatment is seldom used as first line, and rather should be considered as second line therapy.
Prednisolone. Prednisolone (or prednisone) is the initial therapy for most patients with ITP who require treatment (McMillan, 1981; Bussel, 1990; Warkentin & Kelton, 1990). Some two-thirds of patients will respond to prednisolone at 1 mg / kg body weight per day for 2–4 weeks, tapering off over several weeks (Ben-Yehuda et al, 1994; George et al, 1994; Stasi et al, 1995). Reported response rates vary widely (from 3% to 50%) (George et al, 1996). A single randomized trial showed no difference in response to low dose 0.25 mg /kg /d vs 1 mg / kg /d in 160 children and 223 adults (Bellucci et al, 1988). Relapse of thrombocytopenia is common when the dose is reduced. Around one-third of patients can expect a long-term response (Berchtold & McMillan, 1989; George et al, 1996; Manoharan, 1991; Blanchette et al, 1998). Corticosteroids should be rapidly tapered and stopped in patients who fail to respond to oral prednisolone after 4 weeks (Pizzuto & Ambriz, 1984; BenYehuda et al, 1994). Long-term remission is seen in only 10–20% of patients following cessation of prednisolone therapy (Ben-Yehuda et al, 1994; Stasi et al, 1995). Patients who fail to respond to treatment with corticosteroids or require unacceptably high doses of corticosteroid in order to maintain a safe platelet count should be considered for splenectomy (Ben-Yehuda et al, 1994; George et al, 1994).

IVIg. Pooled normal human immunoglobulin is effective in elevating the platelet count in 75% of patients, of which 50% will achieve normal platelet counts. However, responses are transient and 3–4 weeks following IVIg treatment platelet counts drift back to pre-treatment levels (Dwyer, 1992; George et al, 1996), and there is little evidence of a lasting effect. A prospective randomized trial involving 30 adult patients with chronic ITP (comparing IVIg, prednisolone or combination of the two) with a minimum follow-up of 2 years showed quite clearly that the response rates, duration of response and requirement for splenectomy were the same in all arms (Jacobs et al, 1994) (Evidence level Ib, Grade B). A single randomized study showed no difference in ef?cacy between the two dosing schedules 0.4 g /kg /d for 5 d and 1 g /kg/d as a single infusion (Godeau et al, 1993). The mechanism of action of IVIg in ITP remains largely unknown but is believed to involve the blockade of Fc receptors on macrophages and other effectors of antibody-dependent cytotoxicity (Geha & Rosen, 1996), the presence of anti-idiotype antibodies in IVIg which block autoantibody binding to circulating platelets and immune suppression (Godeau et al, 1993; Chong, 1995). While IVIg is a pooled blood product, it has an excellent safety record although renal impairment or failure has been reported with some preparations (Schiavotto et al, 1993; Cayco et al, 1997).

Recommendations for first line therapy in adults:
There are no randomized studies comparing no treatment vs. therapy with corticosteroids or IVIg. There is no indication for therapy in adults in whom there are no symptoms or signs, or in whom the platelet count is greater than 30×10⁹/ l (Grade C recommendation). IVIg is useful in 75% of patients in whom the platelet count has to be raised either due to symptoms or signs, or where there is predictable bleeding (e.g. surgery, pregnancy ? labour or operative dentistry).

Second line therapy

Splenectomy

Splenectomy has been used for many years, before steroid therapy was introduced in 1950 (Chong, 1995; George et al, 1996), as a means of prolonging the survival of antibody-coated platelets. The procedure is not strictly 'curative' since opsonization still takes place but the effector of platelet destruction is removed. Two-thirds of patients with ITP who undergo splenectomy will achieve a normal platelet count, which is often sustained with no additional therapy. Patients who do not have a complete response can still expect some improvement in counts (e.g. partial response) or transient increases in platelet count (George et al, 1996).

Intraoperative platelet support. There is a suggestion, with little evidence, that if random donor platelets are deemed necessary to cover the surgery, these should be given once the splenic artery has been clamped. Physiologically this would appear logical but has never been subjected to rigorous study (Level IV evidence).

Post-operative complications of splenectomy. Early studies reported complication rates of around 22% and two series from New Zealand and France showed no mortality and morbidity of only 7% in 48 and 72 patients respectively (Shaw, 1966; Naouri et al, 1993). In the study by Portielje et al (2001), two deaths occurred (out of 78 patients undergoing splenectomy) and 26% had early post-operative complications (pulmonary embolism, intraabdominal bleeding, abdominal abscess, abdominal wall haematoma, gram negative sepsis, and others). Some 5% of patients suffered late complications. Overall, the complication rate was higher in patients greater than 65 years of age.

Platelet count pre-splenectomy. Stasi et al (1995) recommended a platelet count of 30 ? 109? l; this may require treatment with oral corticosteroids or IVIg pre-operatively if the platelets are below 30×10⁹/ l. Others have used oral dexamethasone (40 mg / d for 4 d) to prepare 13 patients for splenectomy, 11 of whom had sufficient rise in the platelet count for surgery (Gillis & Eldor, 1998).

Predicting response to splenectomy. Various indicators of the likely response to splenectomy have been reviewed including response to oral steroids, which has a low predictive value, response to high dose IVIg which, in two small series, correlated well with response to splenectomy (Chirletti et al, 1992; Law et al, 1997), and indium-labelled autologous platelet scanning which appears to be the most sensitive predictor of response to splenectomy, to date (Najean et al, 1997). Recent work using indium-labelled autologous platelets in 528 patients, has shown that when platelet destruction was splenic, then 96% of patients between the age of 5–30 years and 91% of those above the age of 30 years could expect to obtain a remission. However, where the platelet destruction was hepatic or diffuse (mixed splenic and hepatic) 92% of patients failed to normalize their platelet counts or had incomplete responses to splenectomy (Najean et al, 1997; Evidence level III). The indium-labelled autologous platelet scan appears to offer objective evidence of likely response to splenectomy and is recommended, where available, prior to splenectomy. (Evidence level III.)

Accessory splenic tissue. The presence of an accessory spleen (or spleens) should be considered in patients who fail to respond to splenectomy or relapse following an initial response (George et al, 1994). Imaging techniques have shown the presence of accessory splenic tissue in up to 12% of such patients (Facon et al, 1992).

Prevention of infection post-splenectomy. Patients should be given prophylactic polyvalent pneumococcal vaccine (Pneumovax II), Haemophilus in?uenzae b (Hib) and meningococcal C conjugate vaccinations at least 2 weeks prior to splenectomy (Centers for Disease Control (CDC), 1993; British Committee for Standards in Haematology (BCSH), 1996). Revaccination with pneumococcal vaccine should be offered every 5 years but is not currently recommended for Hib. The recommendation for booster doses of meningococcal C conjugate virus may be introduced in the future. Annual in?uenza vaccine is recommended in asplenic patients. The patients’ vaccination status should be recorded in the case notes. Following splenectomy patients should be offered phenoxymethylpenicillin 250–500 mg twice daily, or equivalent, or erythromycin (500 mg bd) possibly for life, in order to reduce the incidence of postsplenectomy pneumococcal infection (McMullin & Johnston, 1993; Reid, 1994) (Grade C recommendation). The efficacy of such a regimen remains unproven (Makris et al, 1994). Some authorities would suggest antibiotic prophylaxis for 3 years post-splenectomy. Patients should have a supply of broad-spectrum antibiotics at home for use if fever develops. In addition there are cards available that should be carried by patients, to alert physicians that the patient is asplenic. Some patients may wish to purchase alert bracelets or pendants.