Intravenous immunoglobulin as salvage therapy for refractory thrombotic thrombocytopenic purpura
Authors: Jennifer Ding, Maria R. Baer, John R. Hess, Ann B. Zimrin
Journal: American Journal of Hematology (2017)

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by deficiency of a plasma metalloprotease, ADAMTS13, leading to dysfunctional regulation of von Willebrand factor activity and widespread microvascular thrombi. Following introduction of plasma exchange (PE) as therapy for TTP, the survival rate at 6 months increased to more than 80%.1 Nevertheless, the clinical course of TTP remains unpredictable. Some patients develop refractory disease and require salvage therapy such as rituximab, cyclosporine, vincristine, intravenous immunoglobulin (IVIG), and splenectomy. We report here the results of a retrospective registry study examining the efficacy of IVIG in patients with refractory TTP at our institution, a 757-bed tertiary-care hospital. From 2000 to 2013, a total of 156 adult (>18 years of age) patients were diagnosed with TTP, based on the findings of microangiopathic anemia and thrombocytopenia (<100 × 109/L) in the appropriate clinical setting. The diagnosis was confirmed by low ADAMTS13 levels in 107 of 156 patients. All 156 patients were treated with PE within 24 hours of admission, generally in conjunction with corticosteroids. Twenty-nine patients had disease that did not respond to PE, with or without steroids, and they were treated with additional salvage therapy at the discretion of the treating physician. Eleven patients received IVIG because of clinical deterioration despite PE. This was manifested by worsening platelet counts after initial improvement in five patients, new seizure activity in five patients, and new focal neurologic signs in one patient. One patient was treated with IVIG because of lack of response to plasmapheresis and reluctance to use other agents due to the patient's pregnancy. These 11 patients were included in a more comprehensive analysis (Table 1). Of these 11 patients, 8 were female (mean age was 38 years) and 3 were male (mean age was 47). Eight patients had ADAMTS13 levels sent; 6 were unmeasurably low (2 of these were sent during subsequent relapses). IVIG was combined with PE in all patients and with corticosteroids in 10 (90.9%), rituximab in 7 (63.6%), cyclosporine in 3 (27.2%), and vincristine in 1 (9.09%). All patients received a median of 0.4 g/kg/day IVIG divided into equal doses and administered as a series of 2–6 infusions (median, 5). The total dose ranged from 1 to 4.6 g/kg, with a median of 1.9 g/kg. Eight achieved remission (defined as a platelet count of >150 × 109/L for longer than 7 days after discontinuation of PE) and three died of disease progression. Of the eight who achieved remission, six (54.5%) showed a positive response to IVIG, defined as a steady rise in platelet counts within 7 days of initiating the first dose of IVIG before new therapies were added. Detailed clinical courses of each of the patients who responded to IVIG can be found in the Supporting Information materials. Among the six patients initiated on IVIG therapy because of new neurological complications, four had clinical improvement. The temporal relationship between resolution of neurologic symptoms and IVIG varied. For instance, both patient #2 and #11 had seizures despite daily PE, and both had resolution of their neurological symptoms after receiving three doses of IVIG. Patient #4 developed expressive aphasia and focal weakness during a prolonged hospital stay. His expressive aphasia improved within minutes of receiving the first dose of IVIG. Patient #1 developed new intracranial hemorrhages and recurrent seizures. After IVIG was administered, he had gradual clinical improvement with no continued seizure activity. These four patients achieved remission and did not experience residual neurologic sequelae. Three out of these 11 patients (27%) died despite therapy, which is a high mortality rate. IVIG was typically used as an adjunctive salvage therapy in patients who either had very severe disease or contraindications to other adjunctive therapies. Thus, our analysis naturally selected for patients who had severe disease. There was no temporal relationship between administration of IVIG and death, suggesting there is no direct correlation between IVIG and the high mortality rate. IVIG is known to cause transient renal insufficiency, which was seen in patient #1. His renal function eventually recovered, and he did not suffer any long-lasting toxicities from IVIG. The use of IVIG for TTP has been described in multiple case reports and small group series, with variable results. In a retrospective analysis of 17 patients, 4 had clinical improvement with early administration of IVIG, 6 achieved remission without temporal correlation with IVIG use, and 7 did not respond.2 On the other hand, two reports of patients with refractory TTP and neurologic symptoms did not respond to therapy until the addition of IVIG, which resulted in resolution of hematological and neurological abnormalities.3, 4 Vural et al. also reported using IVIG in 4 of 15 patients with neurological abnormalities, and 3 of these 4 patients achieved remission.5 IVIG has been found to have therapeutic activity in multiple autoimmune and inflammatory diseases. We describe here patients who received IVIG for TTP, but a plausible mechanism of IVIG activity in this disease remains unknown. It has been theorized that the therapeutic activity of immunoglobulin is linked to its ability to suppress autoantibodies.6 Since the mechanism of immunoglobulin activity is unclear, the optimal dosing and schedule of IVIG are unknown. We used a total of 2 g/kg, given in equally divided infusions, usually over a period of 5 days, but cannot say whether an alternative dose and/or schedule would be more effective. We propose that IVIG can be an effective salvage therapy for patients who have refractory TTP, especially those with new neurological manifestations, despite conventional treatment. The exact mechanism of IVIG effect in TTP remains unknown, but patients who respond to IVIG usually have clinical improvement within a matter of days of initiation, without any signs of lasting toxicity. Given the potential benefits of IVIG and a low incidence of toxicity, we suggest that IVIG should be considered as a complementary therapy for refractory TTP. Note: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.3 The authors declare that they have no conflict of interest. Additional Supporting Information may be found online in the supporting information tab for this article. Supporting Information 1 Supporting Information 2 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.