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Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.

ABSTRACT: beta3 integrins have been implicated in a wide variety of functions, including platelet aggregation and thrombosis (alphaIIbbeta3) and implantation, placentation, angiogenesis, bone remodeling, and tumor progression (alphavbeta3). The human bleeding disorder Glanzmann thrombasthenia (GT) can result from defects in the genes for either the alphaIIb or the beta3 subunit. In order to develop a mouse model of this disease and to further studies of hemostasis, thrombosis, and other suggested roles of beta3 integrins, we have generated a strain of beta3-null mice. The mice are viable and fertile, and show all the cardinal features of GT (defects in platelet aggregation and clot retraction, prolonged bleeding times, and cutaneous and gastrointestinal bleeding). Implantation appears to be unaffected, but placental defects do occur and lead to fetal mortality. Postnatal hemorrhage leads to anemia and reduced survival. These mice will allow analyses of the other suggested functions of beta3 integrins and we report that postnatal neovascularization of the retina appears to be beta3-integrin-independent, contrary to expectations from inhibition experiments.

SUBMITTER: Hodivala-Dilke KM

PROVIDER: S-EPMC407888 | biostudies-literature | 1999 Jan

REPOSITORIES: biostudies-literature

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Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.

Hodivala-Dilke K M KM McHugh K P KP Tsakiris D A DA Rayburn H H Crowley D D Ullman-Culleré M M Ross F P FP Coller B S BS Teitelbaum S S Hynes R O RO

The Journal of clinical investigation 19990101 2

beta3 integrins have been implicated in a wide variety of functions, including platelet aggregation and thrombosis (alphaIIbbeta3) and implantation, placentation, angiogenesis, bone remodeling, and tumor progression (alphavbeta3). The human bleeding disorder Glanzmann thrombasthenia (GT) can result from defects in the genes for either the alphaIIb or the beta3 subunit. In order to develop a mouse model of this disease and to further studies of hemostasis, thrombosis, and other suggested roles of ...[more]

PMID: 9916135

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Project description:Standard treatment for Glanzmann thrombasthenia is platelet transfusion. Recombinant activated factor VII has been shown to be successful in patients with Glanzmann thrombasthenia with platelet antibodies or who are refractory to platelet transfusions. The Glanzmann Thrombasthenia Registry prospectively collected worldwide information on the effectiveness and safety of platelet transfusion, recombinant activated factor VII and/or antifibrinolytics for the treatment of bleeds in patients with Glanzmann thrombasthenia. Data relating to 829 non-surgical bleeding episodes were entered into the Glanzmann Thrombasthenia Registry (severe/moderate: 216/613; spontaneous/post-traumatic: 630/199). Recombinant activated factor VII alone was used in 124/829 bleeds, recombinant activated factor VII+antifibrinolytics in 107/829, platelets±antifibrinolytics in 312/829, antifibrinolytics alone in 219/829, and recombinant activated factor VII+platelets±antifibrinolytics in 67/829. The proportion of successful treatments to stop bleeding was 91.0% in cases treated with recombinant activated factor VII only, 82.7% for recombinant activated factor VII+antifibrinolytics, 72.7% for treatment with recombinant activated factor VII+platelets±antifibrinolytics, 78.8% for platelets±antifibrinolytics and 84.7% for antifibrinolytics alone. Treatment failure was documented in 18 bleeding events (2% of the total treatments), the majority of which were in patients receiving treatment with antifibrinolytics; bleeding re-started in 6% of bleeds after initial effective treatment. Thirty-five adverse events were reported, none of which was a thromboembolic event. Among treatments that included recombinant activated factor VII, only one patient reported three possibly drug-related non-serious adverse events (nausea, dyspnea and headache). To conclude, non-surgical bleeds were common and often severe in Glanzmann thrombasthenia; both platelets and recombinant activated factor VII appeared to be effective, and with good safety profiles, for the treatment of non-surgical bleeds. This trial was registered at clinicaltrials.gov identifier: NCT01476423.

Dataset Information

Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.

Publications

Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.

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