Dataset Information

Itgb3-integrin-deficient mice may not be a sufficient model for patients with Glanzmann thrombasthenia.

ABSTRACT: Itgb3‑integrin‑deficient (Itgb3‑/‑) mice have been reported as a Glanzmann thrombasthenia (GT) model and have been used for platelet research. However, it remains unclear whether this mouse model can fully simulate patients with GT or whether it has different characteristics from these patients. The present study aimed to answer this question. Itgb3‑/‑ mice were tested for platelet function, tail bleeding, whole‑blood count, bone marrow hematopoiesis and organ enlargement. Itgb3‑/‑ platelets showed impaired functions, including fibrinogen binding, aggregation, adhesion or spreading. Itgb3‑/‑ mice demonstrated decreased platelet count and microcytic hypochromic anemia. Reduced iron staining of bone marrow and decreased plasma ferritin level confirmed the diagnosis of iron deficiency anemia. Evident splenomegaly was observed in Itgb3‑/‑ mice. Immunohistochemical analysis of spleen biopsy revealed normal expression of CD3 and CD19, but elevated expression of CD71, which suggested that the splenomegaly in Itgb3‑/‑ mice may be associated with extramedullary hematopoiesis. In conclusion, Itgb3‑/‑ mice exhibited some unique characteristics that differed from those of human patients with GT and thus cannot completely simulate patients with GT.

SUBMITTER: Li D

PROVIDER: S-EPMC8060805 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Itgb3-integrin-deficient mice may not be a sufficient model for patients with Glanzmann thrombasthenia.

Li Dongya D Peng Jie J Li Tiantian T Liu Yichen Y Chen Min M Shi Xiaofeng X

Molecular medicine reports 20210421 6

Itgb3‑integrin‑deficient (Itgb3<sup>‑/‑</sup>) mice have been reported as a Glanzmann thrombasthenia (GT) model and have been used for platelet research. However, it remains unclear whether this mouse model can fully simulate patients with GT or whether it has different characteristics from these patients. The present study aimed to answer this question. Itgb3<sup>‑/‑</sup> mice were tested for platelet function, tail bleeding, whole‑blood count, bone marrow hematopoiesis and organ enlargement. ...[more]

PMID: 33880575

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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.

Project description:This report identifies a novel variant form of the inherited bleeding disorder Glanzmann thrombasthenia, exhibiting only mild bleeding in a physically active individual. The platelets cannot aggregate ex vivo with physiologic agonists of activation, although microfluidic analysis with whole blood displays moderate ex vivo platelet adhesion and aggregation consistent with mild bleeding. Immunocytometry shows reduced expression of αIIbβ3 on quiescent platelets that spontaneously bind/store fibrinogen, and activation-dependent antibodies (ligand-induced binding site-319.4 and PAC-1) report β3 extension suggesting an intrinsic activation phenotype. Genetic analysis reveals a single F153Sβ3 substitution within the βI-domain from a heterozygous T556C nucleotide substitution of ITGB3 exon 4 in conjunction with a previously reported IVS5(+1)G>A splice site mutation with undetectable platelet messenger RNA accounting for hemizygous expression of S153β3. F153 is completely conserved among β3 of several species and all human β-integrin subunits suggesting that it may play a vital role in integrin structure/function. Mutagenesis of αIIb-F153Sβ3 also displays reduced levels of a constitutively activated αIIb-S153β3 on HEK293T cells. The overall structural analysis suggests that a bulky aromatic, nonpolar amino acid (F,W)153β3 is critical for maintaining the resting conformation of α2- and α1-helices of the βI-domain because small amino acid substitutions (S,A) facilitate an unhindered inward movement of the α2- and α1-helices of the βI-domain toward the constitutively active αIIbβ3 conformation, while a bulky aromatic, polar amino acid (Y) hinders such movements and restrains αIIbβ3 activation. The data collectively demonstrate that disruption of F153β3 can significantly alter normal integrin/platelet function, although reduced expression of αIIb-S153β3 may be compensated by a hyperactive conformation that promotes viable hemostasis.

Dataset Information

Itgb3-integrin-deficient mice may not be a sufficient model for patients with Glanzmann thrombasthenia.

Publications

Itgb3-integrin-deficient mice may not be a sufficient model for patients with Glanzmann thrombasthenia.

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