Association between Platelet Autoantibody Specificity and Response to Intravenous Immunoglobulin G in the Treatment of Patients with Immune Thrombocytopenia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3987-3987
Author(s):  
Kaye L. Johnston ◽  
Ronald S. Go
Keyword(s):  
Platelet Count ◽  
Intravenous Immunoglobulin ◽  
Hodgkin Lymphoma ◽  
Murine Model ◽  
Immunoglobulin G ◽  
Immune Thrombocytopenia ◽  
Lymphocytic Leukemia ◽  
Ivig Treatment ◽  
Number Of Patients ◽  
Intravenous Immunoglobulin G

Abstract Background: Recent studies in murine model of immune thrombocytopenia (ITP) suggest that autoantibodies against GPIba may cause thrombocytopenia through Fc-independent pathway and ITP mediated by anti-GPIb may be less responsive to intravenous immunoglobulin G (IVIG) treatment (Nieswandt B, et al. Blood 2000; Webster ML, et al. Blood 2006). The objective of this study was to investigate the potential association between platelet autoantibody specificity and response to intravenous immunoglobulin G (IVIG) treatment in patients with ITP. Methods: We retrospectively reviewed the clinical history of ITP patients who had platelet autoantibody test and received IVIG for treatment of thrombocytopenia. ITP was diagnosed by usual clinical criteria. All platelet autoantibody tests were performed by the Blood Center of Wisconsin (Milwaukee, WI) using ELISA, which detects antibodies reactive with platelet GPIIb/IIIa, GPIb/IX, and GPIa/IIa. A response was defined as a platelet count of > 50 x 109/L with a minimum increment of 30 x 109/L. Results: We found 17 patients who received IVIG and had platelet autoantibody test performed. The median age was 58 years (range, 20–83) and 10 (59%) were males. ITP was considered idiopathic in 12 patients. In the remaining 5 patients, the following hematologic conditions were present: chronic lymphocytic leukemia (2), Hodgkin lymphoma (1), myelodysplastic syndrome (1), and non-Hodgkin lymphoma (1). Antibodies reactive with GPIIb/IIIa, GPIb/IX, and GPIa/IIa were detected in 13, 10, and 8 patients, respectively. In 3 patients, none of these antibodies were detected. Among the 14 patients with antibodies, 9 (64%) had antibodies against more than 1 glycoprotein. The median pre-treatment platelet count was 9 x 109/L (range, 1–68). Overall, 10 (59%) patients responded to IVIG. A response occurred in 7 of 7 patients without anti-GPIb/IX but in only 3 of 10 patients with anti-GPIb/IX. The difference in the response rates between the 2 groups was statistically significant (P= .0098). Conclusions: Our clinical results support the murine model findings that ITP mediated by anti-GPIb may be less responsive to IVIG treatment. However, because of the small number of patients investigated and the retrospective nature of the study, our findings must be confirmed by other groups in a larger patient population.

Relative efficacy of intravenous immunoglobulin G in ameliorating thrombocytopenia induced by antiplatelet GPIIbIIIa versus GPIbα antibodies

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 943-946 ◽  
Author(s):  
Michelle Lee Webster ◽  
Ebrahim Sayeh ◽  
Min Crow ◽  
Pingguo Chen ◽  
Bernhard Nieswandt ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Intravenous Immunoglobulin ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Immunoglobulin G ◽  
Ivig Treatment ◽  
Relative Efficacy ◽  
Thrombocytopenic Purpura ◽  
Antiplatelet Antibodies ◽  
Intravenous Immunoglobulin G

Abstract Intravenous immunoglobulin G (IVIG) is used to treat idiopathic thrombocytopenic purpura (ITP). Although many patients benefit from IVIG, some are refractory to this therapy. ITP is characterized by platelet clearance mediated primarily by antiplatelet antibodies against GPIIbIIIa and/or the GPIbα complex. These 2 groups of antibodies may induce ITP through different mechanisms. We tested the hypothesis that IVIG may not be equally effective in preventing ITP caused by anti-GPIIbIIIa versus anti-GPIbα antibodies in mice. Thrombocytopenia was induced in BALB/c mice using monoclonal antibodies against either mouse GPIIbIIIa (JON1, JON2, and JON3) or GPIbα (p0p3, p0p4, p0p5, p0p9, and p0p11). Pretreatment with IVIG significantly ameliorated ITP in all anti-GPIIbIIIa–injected animals. Conversely, IVIG failed to prevent ITP in all anti-GPIbα–treated mice, except for p0p4. These results were repeated in C57BL/6 mice, and with different IVIG preparations. These data in mice suggest that patients with ITP mediated by anti-GPIbα antibodies may be less responsive to IVIG treatment.

A double-blind, cross-over trial of intravenous immunoglobulin G in multiple sclerosis: Preliminary results

1997 ◽  
Vol 3 (2) ◽  
pp. 145-148 ◽  
Author(s):  
P. Soelberg Sørensen ◽  
B. Wanscher ◽  
K. Schreiber ◽  
M. Blinkenberg ◽  
C.V. Jensen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Intravenous Immunoglobulin ◽  
Immunoglobulin G ◽  
Progressive Multiple Sclerosis ◽  
Ivig Treatment ◽  
Double Blind Study ◽  
Intravenous Methylprednisolone ◽  
Double Blind ◽  
Relapsing Remitting ◽  
Intravenous Immunoglobulin G

We enrolled 25 patients with relapsing-remitting or relapsing progressive multiple sclerosis (MS) in a randomized placebo-controlled double-blind study of intravenous immunoglobulin G (IVIG). IVIG Iglkg daily for 2 days was administered every 4 weeks for 24 weeks. Seventeen patients completed the whole trial, whereas eight patients discontinued the trial; four during IVIG treatment and four on placebo. Of the 17 patients who completed the trial, II had no exacerbations during IVIG treatment compared with only six on placebo (P=0.05). The total number of exacerbations in the IVIG period was I / and in the placebo period 15 (NS), and the number of severe exacerbations requiring treatment with intravenous methylprednisolone was four during treatment with IVIG and six on placebo (NS). The results suggest that IVIG treatment may be of beneft for prevention of exacerbations in patients with relapsing MS.

Thymic-Derived Tolerizing Dendritic Cells Are up-Regulated upon Treatment with Intravenous Immunoglobulin or Splenectomy in a Murine Model of Immune Thrombocytopenia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2251-2251 ◽  
Author(s):  
Rick Kapur ◽  
Rukhsana Aslam ◽  
Edwin R. Speck ◽  
Michael Kim ◽  
Anne Zufferey ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Intravenous Immunoglobulin ◽  
Murine Model ◽  
Immune Thrombocytopenia ◽  
Conflicts Of Interest ◽  
Scid Mice ◽  
Ivig Treatment ◽  
High Dose ◽  
Platelet Counts ◽  
Inflammatory State

Abstract Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by low platelet counts. ITP has a complex pathogenesis, in which both anti-platelet antibodies as well as T cells have been shown to be important. Initial management of newly diagnosed ITP may be either watchful waiting or pharmacologic intervention, such as glucocorticoids or Intravenous Immunoglobulin (IVIg), a blood product consisting of polyclonal immunoglobulin G (IgG) derived from thousands of donors. Second-line therapy may include dexamethasone, high-dose methylprednisolone, rituximab, thrombopoietin (TPO)-receptor agonists, or splenectomy. The working mechanism of IVIg is actively under investigation and is still a matter of debate, as various different working mechanisms have been suggested. One of them is that IVIg may shift the balance from a pro- to anti-inflammatory state through immunomodulating the activity of dendritic cells (DCs). To gain more insights into the role of DCs in ITP, upon IVIg treatment or splenectomy, we analyzed DC subsets in a murine model of ITP, which features both the antibody and T cell mediated thrombocytopenia. Severe combined immunodeficient (SCID) mice were administrated 4x104 splenocytes from CD61 (GPIIIa) knockout mice immunized against CD61 (or naïve control splenocytes) and the mice were treated with or without 1 g/kg IVIg twice a week. Also the same type of splenocytes were transferred into splenectomized SCID mice. Weekly platelet counts were assessed and after 4 weeks the mice were sacrificed and spleen and thymuses were harvested. Splenocytes and thymocytes were isolated and examined by flow cytometry for cross-presenting (XCR1+) and non-presenting tolerizing (SIRP alpha+) DCs. Without IVIg or splenectomy, both splenic DC subset numbers correlated positively with platelet counts and both the thymic DC subset numbers correlated negatively with platelet counts, indicating thymic retention of DC in a setting of thrombocytopenia. Interestingly, splenectomized SCID mice, apart from increased platelet counts, demonstrated a complete reversal of the DC pattern in the thymus, as thymic DC subsets correlated positively with platelet counts in splenectomized mice. Upon IVIg treatment, apart from a general increase in platelet counts, the splenic tolerizing DCs significantly increased in numbers. Moreover, the thymic retention of tolerizing DCs and thus the negative correlation with platelet counts (R2: 0.46, p<0.05) was fully abrogated upon IVIg treatment (R2: 0.02, NS). Overall, our results indicate that both splenectomy as well as IVIg treatment can immunomodulate thymic tolerizing DCs significantly, in a murine model of ITP. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombocytopenia

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2087-2093 ◽  
Author(s):  
Ryan J. Hansen ◽  
Joseph P. Balthasar
Keyword(s):  
Platelet Count ◽  
Intravenous Immunoglobulin ◽  
Rat Model ◽  
Immune Thrombocytopenia ◽  
Time Course ◽  
Ivig Therapy ◽  
Ivig Treatment ◽  
Antiplatelet Antibody ◽  
Dose Dependent

Experiments were conducted to investigate the effects of intravenous immunoglobulin (IVIG) in a rat model of immune thrombocytopenia (ITP). Rats were pretreated with 0 to 2 g/kg IVIG and then challenged with an antiplatelet antibody (7E3, 8 mg/kg). IVIG effects on 7E3-induced thrombocytopenia and on 7E3 pharmacokinetics were determined. IVIG pretreatment led to significant changes in the degree and time-course of 7E3-induced thrombocytopenia (P = .031). Nadir percent platelet counts were 121% to 279% greater in animals treated with IVIG (0.4-2 g/kg) than in animals receiving 7E3 alone. IVIG treatment also led to dose-dependent increases in 7E3 clearance (P < .001), with more than 2-fold increases in 7E3 clearance seen following the highest dose of IVIG. In vitro experiments showed that IVIG effects on platelet count are not likely due to anti-idiotypic inhibition of 7E3-platelet binding and that IVIG did not directly bind to 7E3. Consequently, IVIG-7E3 binding cannot explain the increase of 7E3 clearance following IVIG treatment. We propose that the observed increase in 7E3 clearance with IVIG therapy is due to saturation of the FcRn salvage receptor for IgG. The importance of the effect of IVIG on 7E3 clearance to the prevention of thrombocytopenia in these animals is unclear at present; nonetheless, these data provide experimental support for a new mechanism of IVIG action in ITP (ie, IVIG-mediated increases in antiplatelet antibody elimination). This model of ITP will be useful for further investigations of IVIG mechanism of action and for development of new therapies for ITP.

scholarly journals Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2260-2262 ◽  
Author(s):  
Upendra P. Hegde ◽  
Wyndham H. Wilson ◽  
Therese White ◽  
Bruce D. Cheson
Keyword(s):  
Platelet Count ◽  
Chronic Lymphocytic Leukemia ◽  
Intravenous Immunoglobulin ◽  
Immune Thrombocytopenia ◽  
Lymphocytic Leukemia ◽  
Platelet Response ◽  
Idiopathic Thrombocytopenia ◽  
Platelet Counts

Fludarabine can exacerbate idiopathic thrombocytopenia (ITP) in chronic lymphocytic leukemia (CLL). We report 3 CLL patients with refractory fludarabine-associated ITP who responded to rituximab. The patients had Rai stages III, III, and IV disease. Before fludarabine treatment, the platelet counts were 141 000/μL, 118 000/μL, and 70 000/μL. ITP developed within week 1 of cycle 3 in 2 patients and within week 2 of cycle 1 in 1 patient. Platelet count nadirs were 4000/μL, 1000/μL, and 2000/μL, respectively, and did not respond to treatment with steroids or intravenous immunoglobulin. Rituximab therapy (375 mg/m2 per week for 4 weeks) was begun on days 18, 23, and 20 of ITP. Patient 1 achieved a platelet count of more than 50 000/μL at day 21 and more than 133 000/μL at day 28, patient 2 achieved a platelet count of more than 50 000/μL at day 4 and more than 150 000/μL at day 10, and patient 3 achieved a platelet count of more than 50 000/μL at day 5 and 72 000/μL at day 28 of rituximab therapy, with platelet response durations of 17+, 6+, and 6 months. These results suggest rituximab can rapidly reverse refractory fludarabine-associated ITP.

scholarly journals Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2260-2262 ◽  
Author(s):  
Upendra P. Hegde ◽  
Wyndham H. Wilson ◽  
Therese White ◽  
Bruce D. Cheson
Keyword(s):  
Platelet Count ◽  
Chronic Lymphocytic Leukemia ◽  
Intravenous Immunoglobulin ◽  
Immune Thrombocytopenia ◽  
Lymphocytic Leukemia ◽  
Platelet Response ◽  
Idiopathic Thrombocytopenia ◽  
Platelet Counts

Abstract Fludarabine can exacerbate idiopathic thrombocytopenia (ITP) in chronic lymphocytic leukemia (CLL). We report 3 CLL patients with refractory fludarabine-associated ITP who responded to rituximab. The patients had Rai stages III, III, and IV disease. Before fludarabine treatment, the platelet counts were 141 000/μL, 118 000/μL, and 70 000/μL. ITP developed within week 1 of cycle 3 in 2 patients and within week 2 of cycle 1 in 1 patient. Platelet count nadirs were 4000/μL, 1000/μL, and 2000/μL, respectively, and did not respond to treatment with steroids or intravenous immunoglobulin. Rituximab therapy (375 mg/m2 per week for 4 weeks) was begun on days 18, 23, and 20 of ITP. Patient 1 achieved a platelet count of more than 50 000/μL at day 21 and more than 133 000/μL at day 28, patient 2 achieved a platelet count of more than 50 000/μL at day 4 and more than 150 000/μL at day 10, and patient 3 achieved a platelet count of more than 50 000/μL at day 5 and 72 000/μL at day 28 of rituximab therapy, with platelet response durations of 17+, 6+, and 6 months. These results suggest rituximab can rapidly reverse refractory fludarabine-associated ITP.

scholarly journals Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombocytopenia

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2087-2093 ◽  
Author(s):  
Ryan J. Hansen ◽  
Joseph P. Balthasar
Keyword(s):  
Platelet Count ◽  
Intravenous Immunoglobulin ◽  
Rat Model ◽  
Immune Thrombocytopenia ◽  
Time Course ◽  
Ivig Therapy ◽  
Ivig Treatment ◽  
Antiplatelet Antibody ◽  
Dose Dependent

Abstract Experiments were conducted to investigate the effects of intravenous immunoglobulin (IVIG) in a rat model of immune thrombocytopenia (ITP). Rats were pretreated with 0 to 2 g/kg IVIG and then challenged with an antiplatelet antibody (7E3, 8 mg/kg). IVIG effects on 7E3-induced thrombocytopenia and on 7E3 pharmacokinetics were determined. IVIG pretreatment led to significant changes in the degree and time-course of 7E3-induced thrombocytopenia (P = .031). Nadir percent platelet counts were 121% to 279% greater in animals treated with IVIG (0.4-2 g/kg) than in animals receiving 7E3 alone. IVIG treatment also led to dose-dependent increases in 7E3 clearance (P < .001), with more than 2-fold increases in 7E3 clearance seen following the highest dose of IVIG. In vitro experiments showed that IVIG effects on platelet count are not likely due to anti-idiotypic inhibition of 7E3-platelet binding and that IVIG did not directly bind to 7E3. Consequently, IVIG-7E3 binding cannot explain the increase of 7E3 clearance following IVIG treatment. We propose that the observed increase in 7E3 clearance with IVIG therapy is due to saturation of the FcRn salvage receptor for IgG. The importance of the effect of IVIG on 7E3 clearance to the prevention of thrombocytopenia in these animals is unclear at present; nonetheless, these data provide experimental support for a new mechanism of IVIG action in ITP (ie, IVIG-mediated increases in antiplatelet antibody elimination). This model of ITP will be useful for further investigations of IVIG mechanism of action and for development of new therapies for ITP.

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