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Keywords:

  • romiplostim;
  • intravenous immunoglobulin;
  • splenectomy;
  • immune thrombocytopenic purpura;
  • thrombopoietin-receptor agonist

We describe a patient with refractory immune thrombocytopenic purpura (ITP) in whom both intravenous immunoglobulin (IVIg) and thrombopoietin-receptor (TPO-R) agonists failed to increase the platelet count sufficiently to perform a splenectomy. However, IVIg in combination with romiplostim rapidly increased the platelet count, thus facilitating splenectomy.

A 72-year-old man was referred for thrombocytopenia in March 2009. Physical examination indicated petechiae and purpura over his entire body. A complete blood count showed severe thrombocytopenia (platelet count 12 × 109/l), normal numbers of red and white blood cells, and no fragmented erythrocytes. No coagulation abnormalities were observed. Blood chemistry analysis showed no renal or liver dysfunction. Tests for antinuclear antibodies (ANA) and anti-β2-glycoprotein I antibody were negative. Anti-platelet antibody screening was positive and an elevated platelet-associated IgG level of 346 ng/107 cells was observed. No hepatitis virus or human immunodeficiency virus was detected. Helicobacter pylori infection was negative based on a urea breath test. Bone marrow examination indicated no abnormalities except for the presence of megakaryocytic hyperplasia. These findings led to the diagnosis of ITP.

Treatment consisted of two courses of high-dose dexamethasone (40 mg/d for 4 d) and prednisolone (1 mg/kg per day initially, then tapered), but this treatment proved ineffective. Therefore, we decided to perform splenectomy. The patient received IVIg (400 mg/kg per day) for 5 d; however, his platelet count was insufficient to safely perform splenectomy. In September 2009, rituximab (375 mg/m2 per day) was initiated as a second-line therapy but was discontinued due to the development of sepsis (Fig 1A). Thereafter, danazol, methenolone, and diaphenylsulfone were administered in addition to low-dose prednisolone. However, his platelet count fluctuated between 3 and 9 × 109/l, and the severe bleeding tendency continued (data not shown).

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Figure 1. Changes in the platelet count according to treatment. (A) Corticosteroids and intravenous immunoglobulin (IVIg) failed to increase the platelet count. Rituximab was discontinued due to the development of sepsis. (B) Thrombopoietin-receptor (TPO-R) agonist monotherapy had only a modest effect on the platelet count. However, subsequent combination therapy of romiplostim with IVIg rapidly increased the platelet count and facilitated splenectomy.

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In January 2011, the novel TPO-R agonists, eltrombopag and romiplostim, were approved for use in Japan. In March 2011, we attempted to increase the platelet count prior to performing splenectomy by administering eltrombopag with low-dose prednisolone. Eltrombopag was well tolerated and was continued for 16 weeks at a dose of 25 mg/d, but the platelet count did not increase above 17 × 109/l. Subsequently, romiplostim treatment was initiated in August 2011. Romiplostim was administered subcutaneously at an initial dose of 1 μg/kg per week, which was gradually increased, raising the platelet count to 20–50 × 109/l. When the dose of romiplostim was increased to 4 μg/kg, the patient developed arthralgia, which improved when the dose was reduced to 2 μg/kg. In spite of the long-term treatment with romiplostim over 12 weeks, the platelet count remained too low to perform splenectomy. Therefore, IVIg (400 mg/kg per day for 5 d), although previously proved to be ineffective for this patient as a single agent, was re-administered in combination with romiplostim (2 μg/kg). As shown in Fig 1B, a rapid increase in the platelet count to 150 × 109/l was observed. Subsequently, successful laparoscopic splenectomy was performed at 10 d after IVIg and romiplostim administration. Nine days post-splenectomy, the pateints' platelet count further increased, to 589 × 109/l and then gradually decreased to normal values within 1 month (Fig 1B). At 4 months post-splenectomy, his platelet count remained stable (platelet count 162 × 109/l).

Primary ITP is an autoimmune disorder characterized by autoantibody-induced platelet destruction, leading to a low peripheral blood platelet count (Cooper & Bussel, 2006). In addition, antiplatelet antibodies have been shown to suppress megakaryocyte production in vitro (McMillan et al, 2004). Recent observations suggested that endogenous thrombopoietin (TPO) levels in ITP are lower than anticipated, and the resulting reduced platelet production may be involved in the pathogenesis of ITP (Aledort et al, 2004).

The evidence-based practice guideline for ITP (Neunert et al, 2011), recommends that corticosteroids should be the standard initial first-line treatment (IVIg is used with corticosteroids when a more rapid increase in platelet count is required) and splenectomy is the main second-line therapy for ITP patients who fail to respond sufficiently to first-line therapy. TPO-R agonists are recommended for patients at risk of bleeding who relapse following splenectomy or who have a contraindication to splenectomy (Neunert et al, 2011).

IVIg inhibits autoantibody-mediated platelet destruction by blocking the Fc receptors on phagocytic reticuloendothelial cells of the spleen (Bierling & Godeau, 2005). IVIg is generally used for increasing platelet count prior to performing splenectomy, and up to 80% of patients respond to this treatment. The second generation TPO-R agonists, eltrombopag and romiplostim, have been reported to yield high response rates (>80%) in patients with refractory ITP (Kuter et al, 2008; Cheng et al, 2011). TPO-R agonists are administered as an alternative agent to increase platelet count prior to splenectomy.

In this present case, splenectomy was not indicated because IVIg or TPO-R agonists had no or only a modest effect on the platelet count. However, subsequent combination therapy of romiplostim with IVIg rapidly increased platelet count and facilitated splenectomy.

The development of thrombocytopenia in ITP might be associated with increased platelet destruction and insufficient platelet production. Corticosteroid and IVIg therapy reduces platelet destruction, whereas TPO-R agonists increase platelet production. The reason for the modest or no effect induced by monotherapy with either IVIg or TPO-R agonist in this patient is unclear, but a likely explanation is that both an increase in platelet destruction and a reduction in platelet production evidently resulted in severe thrombocytopenia in this patient. Therefore, the combination therapy may have indicated increased efficacy by reducing platelet destruction and stimulating platelet production.

Splenectomy remains the only treatment that provides sustained remission in a high proportion of ITP patients. The present case report suggests that combination therapy with romiplostim and IVIg is a promising pre-splenectomy strategy for refractory ITP patients who fail to respond to single use of IVIg or romiplostim. The full validation of this strategy will require further investigation in a larger number of cases.

References

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