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Maternal anti-platelet ?3 integrins impair angiogenesis and cause intracranial hemorrhage.

ABSTRACT: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disease in which intracranial hemorrhage (ICH) is the major risk. Although thrombocytopenia, which is caused by maternal antibodies against ?3 integrin and occasionally by maternal antibodies against other platelet antigens, such as glycoprotein GPIb?, has long been assumed to be the cause of bleeding, the mechanism of ICH has not been adequately explored. Utilizing murine models of FNAIT and a high-frequency ultrasound imaging system, we found that ICH only occurred in fetuses and neonates with anti-?3 integrin-mediated, but not anti-GPIb?-mediated, FNAIT, despite similar thrombocytopenia in both groups. Only anti-?3 integrin-mediated FNAIT reduced brain and retina vessel density, impaired angiogenic signaling, and increased endothelial cell apoptosis, all of which were abrogated by maternal administration of intravenous immunoglobulin (IVIG). ICH and impairment of retinal angiogenesis were further reproduced in neonates by injection of anti-?3 integrin, but not anti-GPIb? antisera. Utilizing cultured human endothelial cells, we found that cell proliferation, network formation, and AKT phosphorylation were inhibited only by murine anti-?3 integrin antisera and human anti-HPA-1a IgG purified from mothers with FNAIT children. Our data suggest that fetal hemostasis is distinct and that impairment of angiogenesis rather than thrombocytopenia likely causes FNAIT-associated ICH. Additionally, our results indicate that maternal IVIG therapy can effectively prevent this devastating disorder.

SUBMITTER: Yougbare I

PROVIDER: S-EPMC4396473 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Maternal anti-platelet β3 integrins impair angiogenesis and cause intracranial hemorrhage.

Yougbaré Issaka I Lang Sean S Yang Hong H Chen Pingguo P Zhao Xu X Tai Wei-She WS Zdravic Darko D Vadasz Brian B Li Conglei C Piran Siavash S Marshall Alexandra A Zhu Guangheng G Tiller Heidi H Killie Mette Kjaer MK Boyd Shelley S Leong-Poi Howard H Wen Xiao-Yan XY Skogen Bjorn B Adamson S Lee SL Freedman John J Ni Heyu H

The Journal of clinical investigation 20150316 4

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disease in which intracranial hemorrhage (ICH) is the major risk. Although thrombocytopenia, which is caused by maternal antibodies against β3 integrin and occasionally by maternal antibodies against other platelet antigens, such as glycoprotein GPIbα, has long been assumed to be the cause of bleeding, the mechanism of ICH has not been adequately explored. Utilizing murine models of FNAIT and a high-frequency ultrasound ...[more]

PMID: 25774504

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Project description:Background and purposeAndexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH).MethodsANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding ≤18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as ≤35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days.ResultsA total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population).ConclusionsAndexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT02329327.

Dataset Information

Maternal anti-platelet ?3 integrins impair angiogenesis and cause intracranial hemorrhage.

Publications

Maternal anti-platelet β3 integrins impair angiogenesis and cause intracranial hemorrhage.

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