In 1981, Imbach et al. [1] reported that treatment with high-dose intravenous immunoglobulin (IVIG) (0.4 g (kg day)) for 5 days improved platelet counts in 13 children with idiopathic thrombocytopenic purpura (ITP). All 13 children had initial platelet counts less than 3 × 10⁹/L. This clinical study demonstrated an increase in platelet counts in 12 of the 13 children within 5 days, but a transient increase over the following 10 days. Subsequently, more than 100 clinical studies have confirmed the safety and efficacy of IVIG for the treatment of ITP in children and adults [2–7].

Spontaneous and permanent remission was observed in more than 70% of children with ITP within 1 year of onset [8, 9]. First-line treatment for children newly diagnosed with ITP is IVIG at a total dose of 0.8–1.0 g/kg given on 1 day or over 2 consecutive days (grade IB) [10]. The use of IVIG in children with ITP will be discussed in detail in another chapter.

Spontaneous remission is much less common in adults with ITP. The 2011 ASH guidelines recommend longer courses of corticosteroids over either shorter courses of corticosteroids or IVIG in adults newly diagnosed with ITP. In addition, the guidelines recognize that the majority of clinicians use a platelet count of less than 30 × 10⁹/L as a threshold for treatment [12]. The decision to use IVIG should be based on the patient’s severity of bleeding, bleeding risk, activity level, likely side effects of treatment, and patient preference [11]. Take it for example, the indication should be based on the patients with life-threatning bleeding or before surgery or delivery. Cohen et al. [12] described bleeding risk according to age, in which patients older than 60 years of age with a platelet count less than 3 × 10⁹/L had an estimated 5 year fatal bleeding risk of 48% compared with a risk of 2.2% for those younger than 40 years.

When IVIG is chosen, the response is transient and platelet counts usually return to pretreatment levels within 3–4 weeks [13]. The EU recommendations indicate the current IVIG core SPC (core summaries of product characteristics) indication and dosing as follows [14, 15]: for primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count, there are two alternative treatment schedules, (1) 0.8–1 g/kg given on day 1 (this dose may be repeated once within 3 days), or (2) 0.4 g/kg given daily for 2–5 days. The treatment can be repeated if relapse occurs.

Though the 2011 ASH guidelines recommend an initial dose of 1 g/kg, this recommendation is based on the results of a small, randomized trial [16]. This dosage may be repeated if necessary (grade 2B). IVIG has been proven to have a rapid onset of action (grade 2B) and should be considered along with corticosteroids (grade 2B) with the aim of rapidly increasing the platelet count.

Since the report of Imbach et al. [1], investigators have recognized the effectiveness of IVIG for patients with ITP. In a review of 28 published reports of IVIG in 282 adults, 64% of patients had a peak platelet count >100,000/μL, and 83% had a peak platelet count >50,000/μL after the initial infusion [17]. IVIG is more likely to cause a platelet increase within 24 h at a dose of 1 g/kg (1–2 infusions over 2 days) compared with the previous regimen (0.4 g/(kg day) over 5 days) [18]. A randomized trial to compare the efficacy of 1 g/(kg day) IVIG for 2 days with the conventional dose (0.4 g/(kg day)) for 5 days was performed. This study indicated that the 2-day regimen required shorter hospitalization and corrected thrombocytopenia slightly faster than the 5-day course [18]. Godeau et al. [16] reported the results of a randomized IVIG trial comparing 0.5 and 1 g/kg. In their study, on day 4, the proportion of responses, defined by a platelet count >80 × 10⁹/L and at least twice the initial platelet count, was significantly higher in the group receiving 1 g/kg (P = 0.05). They concluded that initial treatment with 1 g/kg of IVIG was more effective than 0.5 g/kg in adults with autoimmune thrombocytopenic purpura. The 2011 ASH guidelines recommend that the dose should initially be 1 g/kg as a one-time dose and that this dosage may be repeated if necessary (grade 2B) [11].

Peng et al. [19] reported that the presence of anti-GPIb-IX autoantibodies was a predictor for poor response to IVIG treatment in adults with ITP. Patients with ITP that had anti-GPIb-IX autoantibody present had only a 36.4% response rate compared with an 80.0% response rate for those who were negative for anti-GPIb-IX autoantibodies (relative risk 2.2; 95% confidence interval 1.6–3.1).

Papagianni et al. [20] reported IVIG responsiveness and outcome might be correlated with FcγRIIa and FcγRIIIa polymorphic variants. The high-affinity FcγRIIIa variant 158 V for the Fc portion of the immunoglobulin was implicated in the pathogenesis of ITP, whereas FcγRIIa (131R) and FcγRIIIa (158V) variants, which have low affinity for the Fc portion of immunoglobulin, did not seem to impact the therapeutic efficacy of IVIG.

Adverse events with IVIG are common, but generally acceptable, and include headache, backache, nausea, increase in blood pressure, and fever [21, 22]. In 2007, Bussel et al. [23] evaluated the safety and tolerability of IVIG for patients with ITP when IVIG was infused at rates ranging from 0.08 mL/(kg min) (the standard maximum licensed rate) to 0.14 mL/(kg min). The incidence of infusion-related adverse events was similar for all infusion rates. Headache was the most commonly reported infusion-related adverse event (17%). Urticaria (5.5%), hypertension (5.5%), and other symptoms less than 5% were observed. The majority were mild in severity. No other drug-related, treatment-emergent events were serious.

The potential immunomodulatory mechanisms of IgG have been described [24, 25]. High doses of immunoglobulin are thought to be involved in the Fc receptor blockade of macrophages in the reticuloendothelial system [26–28], neutralization of autoantibodies (anti-idiotypes), binding to variable regions of T and B cells (V-connected network) [29], downregulation of T-cell and B-cell function, and upregulation of Treg-cell function [30, 31].