Intravenous (IV) Rho(D) immune globulin (anti-D), instead of high-dose immunoglobulin, is used in children and adult patients with idiopathic thrombocytopenic purpura (ITP) [1–3]. Increase in platelet count begins at 2–3 days after the IV anti-D administration, and response rates of 27–63% are usually achieved. The increase in platelets lasts for several weeks and patients respond well to re-treatment. Generally, children respond better than adults do. In addition, nonsplenectomized patients respond better than splenectomized patients do [1–5]. The most common side effect associated with the treatment is slight to moderate anemia, which results from mild hemolysis with decreased haptoglobin, increased lactate dehydrogenase, and increase in indirect bilirubin levels [6]. The mechanism by which the platelet count increases is not clearly understood. However, it is believed that anti-D-coated red blood cells block Fc receptors on macrophages. Other mechanisms that have been reported include reduction in antigen-specific B-cell priming and modulations of Fcγ receptors and inflammatory cytokine levels [7, 8].

The anti-D products of Cangene (WinRho SDF) and CSL Behring (Rhophylac) were approved by the FDA in 1995. However, WinRho SDF was voluntarily withdrawn from the European market in August, 2009, because of safety concerns [9].

In the United States of America, corticosteroids, IV immunoglobulin, and anti-D are all considered appropriate frontline treatments for ITP in both adults and children. In 2010, a specific warning was issued by the US Food and Drug Administration, which highlighted the risks of intravascular hemolysis and acute renal failure and disseminated intravascular coagulation after anti-D administration to patients with ITP [10]. However, Despotovic and Neunert [11] revealed that the estimated incidence of an acute hemolytic reaction in such patients was 0.03%. The authors also concluded that there was sufficient evidence to support the use of anti-D as a frontline treatment for ITP in adults and children (grade 2B recommendation). Until the full nature of these adverse effects is assessed, this agent should be used with caution.

Since 1960 [12], a variety of nonsteroidal immunosuppressant agents have been used to treat ITP that is refractory to splenectomy and glucocorticoid treatment. Finch et al. [13] described that the expected success rate of nonsteroidal immunosuppressant therapy in chronic refractory ITP is 15–35% in adults and probably higher in children. Laros and Penner [14] were the first to use cyclophosphamide for the treatment of refractory ITP. In that study, 7 out of the 11 treated patients showed excellent responses to the cyclophosphamide therapy and remained in complete hematologic remission for 10–40 months after therapy discontinuation. Verlin et al. [15] also reported that 15 out of 22 splenectomized patients with refractory ITP responded well to cyclophosphamide treatment, whereas 7 out of 8 unsplenectomized patients with refractory ITP responded well to the treatment.

Reiner et al. [16] reported that out of 20 patients treated with pulse cyclophosphamide therapy, 13 (65%) achieved complete response, 4 (20%) achieved partial response, and 3 (15%) failed to respond. In the aforementioned clinical studies, cyclophosphamide was administered either at a dosage of 50–200 mg/day or intermittently over a 4-h period every 2–3 weeks [15–17]. Furthermore, platelet count usually increased 2–4 weeks after the treatment and reached a maximum increase in 4–6 weeks. This indicates that continuous treatment would be necessary to maintain an effective response to the treatment. The major adverse events recorded were leukopenia, infection, alopecia, hemorrhagic cystitis, and secondary malignancy. Although no randomized large-scale clinical trial has been performed, the use of cyclophosphamide for the treatment of refractory ITP patients is worth considering.

Vincristine and vinblastine [18–21] are vinca alkaloids that were introduced for the treatment of ITP. They may be as effective as cyclophosphamide is; however, they act more rapidly than cyclophosphamide does. Vincristine is usually administered at a dose of 0.025 mg/kg to a maximum dose of 2 mg in adults [21]. On the other hand, vinblastine is usually administered at a dose of 0.125 mg/kg [21]. Platelet count usually increases in 1 week after treatment initiation with the vinca alkaloids. Ahn et al. [22] and Manoharan [23] introduced the administration of the vinca alkaloids by slow infusion. The authors reported that 11 out of 34 treated patients achieved complete remission at 7–10-day intervals with vincristine or vinblastine. However, Simon et al. [24] reported of prolonged complete remission in only 2 out of 12 patients with refractory ITP who were treated with vincristine or vinblastine. The major adverse event from treatment with vinca alkaloids is peripheral neuropathy; however, it is reversible after treatment is discontinued. The mechanism of action of vincristine and vinblastine has been postulated to be via the inhibition of microtubule-dependent events that are required for monocyte-macrophage function [25].

The administration method of vinca alkaloids was modified from a slow infusion of the drugs to a vinca alkaloid-loaded platelet infusion in some studies [26–28]. In one of the studies, after 11 patients with refractory ITP were administered the treatment, six achieved complete remissions, three had partial remissions, and two experienced treatment failure [26]. The platelets were initially incubated with vinca alkaloids in vitro, after which they were infused into the patients. The “vinca alkaloid-loaded platelets” were opsonized with an antiplatelet antibody and phagocytosed by macrophages in the spleen, which resulted in the destruction of the macrophages.

Danazol is an attenuated androgen that has been reported to be useful for treating ITP that is refractory to corticosteroid therapy and/or splenectomy. For instance, Ahn et al. [29] reported that out of 22 patients who were treated with danazol, 15 benefited from the treatment, and 11 achieved sustained normalization of their platelet counts. Furthermore, Buelli et al. [30] have reported on 14 patients with ITP that was refractory to steroid treatment and/or splenectomy. The patients were treated with danazol for 2 months. After treatment, the authors observed excellent responses (platelet count >100 × 10⁹/l) in five patients, good responses (platelet count >50 × 10⁹/l) in two patients, and poor responses (no increase in platelet count) in seven patients. The authors concluded that danazol was well tolerated in most of the patients and is therefore better suited for long-term treatment than steroids are. Maloisel et al. [31] have reported on the efficacy and safety of danazol in the treatment of patients with refractory ITP. The study showed that 38 patients experienced partial or complete response to therapy (67%), among whom 27 (46%) remained in remission for a median (± SD) of 119 (± 45) months. In addition, severe adverse events were reported in nine patients (16%). The general adverse events observed were acne, hirsutism, dyslipidemia, amenorrhea, and liver function abnormalities. The postulated mechanism of action of danazol is induction of a reduction in Fc receptor expression on monocytes or macrophages [32].

Syk (spleen tyrosine kinase) is a non-receptor tyrosine kinase that plays an important role in biological functions. For instance, it plays a critical role in intracellular signal transduction of B-cell receptors on B lymphocytes and Fc receptors on macrophages. Taniguchi et al. [33] were the first to identify and succeed in cloning Syk, which is highly expressed in the cells of the hematopoietic system.

It is generally accepted that the ligand-binding receptor chain contains one or more immunoreceptor tyrosine-based activation motifs (ITAMs). Receptor ligation leads to phosphorylation of ITAMs, which primarily occurs in the membrane Src tyrosine kinase [34]. In ITP, platelets that are bound by antiplatelet antibody bind to Fc receptors on macrophages. This is followed by phosphorylation of the tyrosine units of ITAMs by Src tyrosine kinase. The phosphorylated ITAMs then phosphorylate Syk, which results in the autophosphorylation of Syk. The phosphorylated Syk activates PI3 kinase and phospholipase C, which then induce actin polymerization and result in phagocytosis by macrophages. Syk is therefore a critical molecule in phagocytosis.

Fostamatinib disodium (R788) is the oral prodrug of R406, a relatively selective small molecule inhibitor of Syk. It was reported that treatment with R788 effectively prevented antiplatelet antibody-induced thrombocytopenia in mice [35]. Furthermore, a phase II study revealed that treatment with R788 (75–175 mg, twice daily) induced a sustained improvement in platelet count in 50% of 16 patients with refractory ITP [35]. Neutropenia was the common adverse event reported in the phase II study [36]. The most common adverse event that has been observed from R788 treatment in clinical studies is gastrointestinal toxicity, including diarrhea (in up to 45% of the patients) and nausea.

In the past, many patients with refractory ITP required treatment with third-line agents; however, the use of such drugs was limited by modest response rates. Therefore, evidence to support their use in refractory ITP is generally limited to uncontrolled case series [37–39]. Some of the third-line agents are azathioprine [40–42], cyclosporine [43–45], mycophenolate mofetil [46], interferon [47–49], and ascorbic acid [50–52].

In the near future, the following drugs might be used clinically [53] for treating refractory ITP: tocilizumab (IDEC-151) [54]; ruplizumab, an anti-CD40 ligand (hu5c8) [55]; GMA161, a humanized anti-human FcγRIII antibody [56]; rozrolimupab, a human anti-RhD monoclonal antibody [57]; SM101, a soluble FcγRIIB [58]; avatrombopag (E5501), a small molecule thrombopoietin receptor agonist [59]; 23A11, a murine anti-VPAC1 monoclonal immunoglobulin G1 antibody [60]; amifostine, a cytoprotective agent that improves thrombopoiesis [61]; and oseltamivir phosphate, a sialidase inhibitor [62].