Recognition of highly restricted regions in the β-propeller domain of αIIb by platelet-associated anti-αIIbβ3 autoantibodies in primary immune thrombocytopenia

Kiyomizu, Kazunobu; Kashiwagi, Hirokazu; Nakazawa, Tsutomu; Tadokoro, Seiji; Honda, Susumu; Kanakura, Yuzuru; Tomiyama, Yoshiaki

doi:10.1182/blood-2012-02-409995

Cited by 28 publications

(24 citation statements)

References 36 publications

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“…However, in this and other studies a direct correlation between the platelet count and severity of bleeding was not uniformly demonstrated, reflecting the observation that occasional individuals with very low platelet counts exhibit little bleeding, while others with platelet counts > 30 × 10 9 /L bleed frequently. This conundrum might be explained by binding of some antiplatelet antibodies to highly restricted regions in GP IIb β-propeller domain 66 near the ligand (fibrinogen) binding site, potentially interfering with platelet aggregation.…”

Section: Clinical Features Of Itpmentioning

confidence: 99%

Immune Thrombocytopenia

Kistangari

McCrae

2013

Hematology/Oncology Clinics of North America

175

157

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Immune thrombocytopenia (ITP) is a common hematologic disorder characterized by isolated thrombocytopenia. ITP presents as a primary form characterized by isolated thrombocytopenia (platelet count < 100 × 109/L) in the absence of other causes or disorders that may be associated with thrombocytopenia, or a secondary form in which immune thrombocytopenia develops in association with another disorder that is usually immune or infectious. ITP may affect individuals of all ages, with peaks during childhood and in the elderly, in whom the age specific incidence of ITP is greatest. Bleeding is the most common clinical manifestation of ITP, with the risk of bleeding and related morbidity increased in elderly patients. The pathogenesis of ITP is complex, involving alterations in humoral and cellular immunity. Thrombocytopenia is caused by antibodies that react with glycoproteins expressed on platelets and megakaryocytes (glycoprotein IIb/IIIa, Ib/IX and others), causing shortened survival of circulating platelets and impairing platelet production. Diminished numbers and function of regulatory T cells, as well as the effects of cytotoxic T cells also contribute to the pathogenesis of ITP. Corticosteroids remain the most common first line therapy for ITP, occasionally in conjunction with intravenous immunoglobulin (IVIg) and anti-Rh(D). However, these agents do not lead to durable remissions in the majority of adults with ITP, and considerable heterogeneity exists in the use of second line approaches, which may include splenectomy, Rituximab, or thrombopoietin receptor agonists (TRAs). This review summarizes the classification and diagnosis of primary and secondary ITP, as well as the pathogenesis and options for treatment. Remarkable advances in the understanding and management of ITP have been achieved over the last decade, though many questions remain.

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Section: Clinical Features Of Itpmentioning

confidence: 99%

Immune Thrombocytopenia

Kistangari

McCrae

2013

Hematology/Oncology Clinics of North America

175

157

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“…More detailed epitope mapping using serial human/mouse chimera αIIb showed that the Abs mainly recognized the W3:4‐1 loop in the β‐propeller domain of αIIb. Thus, the epitopes of the Abs in this patient were not so unique but were located on one of the major recognition sites of anti‐αIIbβ3 Abs detected in chronic ITP (Figure S6) .…”

Section: Resultsmentioning

confidence: 86%

“…However, we detected neither inhibition nor activation of αIIbβ3 by anti‐αIIbβ3 autoAbs of the patient. We hypothesized that the patient's Abs recognize a unique epitope of αIIbβ3 and performed epitope mapping as previously described . However, the patient's Abs recognized common recognition sites of PA anti‐αIIbβ3 autoAbs detected in chronic ITP patients, suggesting that the difference in epitope does not account for the unique phenotype of the patient's platelets.…”

Section: Discussionmentioning

confidence: 98%

A unique phenotype of acquired Glanzmann thrombasthenia due to non‐function‐blocking anti‐αIIbβ3 autoantibodies

Akuta

Kashiwagi

Yujiri

et al. 2019

Journal of Thrombosis and Haemostasis

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Acquired Glanzmann thrombasthenia (aGT) is generally caused by function‐blocking antibodies (Abs). We demonstrated a unique aGT case due to marked reduction of αIIbβ3 with anti‐αIIbβ3 Abs. The anti‐αIIbβ3 Abs of the patient did not inhibit platelet function but reduced surface αIIbβ3. Internalization of αIIbβ3 induced by the Abs binding may be responsible for the phenotype. Summary BackgroundAcquired Glanzmann thrombasthenia (aGT) is a bleeding disorder generally caused by function‐blocking anti‐αIIbβ3 autoantibodies. AimWe characterize an unusual case of aGT caused by marked reduction of surface αIIbβ3 with non‐function‐blocking anti‐αIIbβ3 antibodies (Abs). MethodsA 72‐year‐old male suffering from immune thrombocytopenia since his 50s showed exacerbation of bleeding symptom despite mild thrombocytopenia. Platelet aggregation was absent with all agonists but ristocetin. Analysis of αIIbβ3 expression and genetic analysis were performed. We also analyzed effects of anti‐αIIbβ3 Abs of the patient on platelet function and αIIbβ3 expression. ResultsSurface αIIbβ3 expression was markedly reduced to around 5% of normal, whereas his platelets contained αIIbβ3 to the amount of 40–50% of normal. A substantial amount of fibrinogen was also detected in his platelets. There were no abnormalities in ITGA2B and ITGB3 cDNA. These results indicated that reduced surface αIIbβ3 expression caused a GT phenotype, and active internalization of αIIbβ3 was suggested. Anti‐αIIbβ3 IgG Abs were detected in platelet eluate and plasma. These Abs did not inhibit PAC‐1 binding, indicating that the Abs were non‐function‐blocking. Surface αIIbβ3 expression of a megakaryocytic cell line and cultured megakaryocytes tended to be impaired by incubation with the patient's Abs. After 2 years of aGT diagnosis, his bleeding symptom improved and surface αIIbβ3 expression was recovered to 20% of normal with reduction of anti‐αIIbβ3 Abs. ConclusionWe demonstrated a unique aGT phenotype due to marked reduction of surface αIIbβ3. Internalization induced by anti‐αIIbβ3 Abs may be responsible in part for the phenotype.

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“…Primary ITP is an autoimmune disorder characterized by isolated thrombocytopenia due to accelerated PLT destruction and impaired PLT production . Thrombocytopenia is frequently encountered in patients with cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Primary ITP is an autoimmune disorder characterized by isolated thrombocytopenia due to accelerated PLT destruction and impaired PLT production. 1,2 Thrombocytopenia is frequently encountered in patients with cancer. This is commonly caused by bone marrow infiltration of malignant cells, cancerinduced disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and intratumor hemorrhage.…”

Section: Discussionmentioning

confidence: 99%

Secondary immune thrombocytopenic purpura with renal cell carcinoma

et al. 2019

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Introduction Several types of cancers are reported to induce secondary immune thrombocytopenia resembling immune thrombocytopenic purpura‐like syndrome. However, renal cell carcinoma‐induced immune thrombocytopenic purpura is an extremely rare phenomenon. Case presentation A 73‐year‐old male with right renal tumor and multiple enlarged lymph nodes presented severe thrombocytopenia, without bone or hepatic metastasis. Although platelet transfusion and high‐dose immunoglobulin treatment were refractory, surgical resection of the tumor and lymph nodes promptly improved thrombocytopenia. After recurrence, he presented thrombocytopenia again. Tyrosine kinase inhibitor treatment was ceased due to uncontrollable hemorrhagic gastric ulcer. The patient eventually died of cancer 4 months after surgery. Flow cytometry analysis revealed the presence of integrin glycoprotein IIb/IIIa, which is a fibronectin/fibrinogen receptor on platelets and as an antigen in immune thrombocytopenic purpura. Conclusion To the best of our knowledge, this is the first reported case of renal cell carcinoma‐induced immune thrombocytopenic purpura that demonstrates the presence of platelet‐autoantibody glycoprotein IIb/IIIa.

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Recognition of highly restricted regions in the β-propeller domain of αIIb by platelet-associated anti-αIIbβ3 autoantibodies in primary immune thrombocytopenia

Cited by 28 publications

References 36 publications

Immune Thrombocytopenia

Immune Thrombocytopenia

A unique phenotype of acquired Glanzmann thrombasthenia due to non‐function‐blocking anti‐αIIbβ3 autoantibodies

Secondary immune thrombocytopenic purpura with renal cell carcinoma

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