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C560R?3 caused platelet integrin ?II b ?3 to bind fibrinogen continuously, but resulted in a severe bleeding syndrome and increased murine mortality.

ABSTRACT: ?(3)-Deficient megakaryocytes were modified by human ?(3)-lentivirus transduction and transplantation to express sufficient levels of a C560R?(3) amino acid substitution, for investigation of how an activated ?II b ?(3) conformation affects platelets in vivo in mice.As in our previous report of an R560?(3) mutation in a patient with Glanzmann thrombasthenia, R560?(3) murine platelets spontaneously bound antibody that only recognizes activated ?II b ?3 bound to its ligand, fibrinogen.With this murine model, we showed that ?II b -R560?3 mutation-mediated continuous binding of fibrinogen occurred in the absence of P-selectin surface expression, indicating that the integrin was in an active conformation, although the platelets circulated in a quiescent manner. Remarkably, only 35% of R560?(3) 'mutant' mice survived for 6 months after transplantation, whereas 87% of C560?(3) 'wild-type' mice remained alive. Pathologic examination revealed that R560?(3) mice had enlarged spleens with extramedullary hematopoiesis and increased hemosiderin, indicating hemorrhage. R560?(3) megakaryocytes and platelets showed abnormal morphology and irregular granule distribution. Interestingly, R560?(3) washed platelets could aggregate upon simultaneous addition of fibrinogen and physiologic agonists, but aggregation failed when platelets were exposed to fibrinogen before activation in vitro and in vivo.The results demonstrate that continuous occupancy of ?IIb ?3 with fibrinogen disrupts platelet structure and function, leading to hemorrhagic death consistent with Glanzmann thrombasthenia rather than a thrombotic state.

SUBMITTER: Fang J

PROVIDER: S-EPMC3702628 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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C560Rβ3 caused platelet integrin αII b β3 to bind fibrinogen continuously, but resulted in a severe bleeding syndrome and increased murine mortality.

Fang J J Nurden P P North P P Nurden A T AT Du L M LM Valentin N N Wilcox D A DA

Journal of thrombosis and haemostasis : JTH 20130601 6

<h4>Background and objectives</h4>β(3)-Deficient megakaryocytes were modified by human β(3)-lentivirus transduction and transplantation to express sufficient levels of a C560Rβ(3) amino acid substitution, for investigation of how an activated αII b β(3) conformation affects platelets in vivo in mice.<h4>Patient/methods</h4>As in our previous report of an R560β(3) mutation in a patient with Glanzmann thrombasthenia, R560β(3) murine platelets spontaneously bound antibody that only recognizes activ ...[more]

PMID: 23551977

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Project description:BACKGROUND:Hypofibrinogenaemia is associated with increased morbidity and mortality, but the optimal treatment level, the use of preemptive treatment and the preferred source of fibrinogen remain disputed. Fibrinogen concentrate is increasingly used and recommended for bleeding with acquired haemostatic deficiencies in several countries, but evidence is lacking regarding indications, dosing, efficacy and safety. OBJECTIVES:We assessed the benefits and harms of fibrinogen concentrate compared with placebo or usual treatment for bleeding patients. SEARCH METHODS:We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 8); MEDLINE (1950 to 9 August 2013); EMBASE (1980 to 9 August 2013); International Web of Science (1964 to 9 August 2013); CINAHL (1980 to 9 August 2013); LILACS (1982 to 9 August 2013); and the Chinese Biomedical Literature Database (up to 10 November 2011), together with databases of ongoing trials. We contacted trial authors, authors of previous reviews and manufacturers in the field. SELECTION CRITERIA:We included all randomized controlled trials (RCTs), irrespective of blinding or language, that compared fibrinogen concentrate with placebo/other treatment or no treatment in bleeding patients, excluding neonates and patients with hereditary bleeding disorders. DATA COLLECTION AND ANALYSIS:Three review authors independently abstracted data; we resolved any disagreements by discussion. Our primary outcome measure was all-cause mortality. We performed subgroup and sensitivity analyses to assess the effects of fibrinogen concentrate in adults and children in terms of various clinical and physiological outcomes. We presented pooled estimates of the effects of intervention on dichotomous outcomes as risk ratios (RRs) and on continuous outcomes as mean differences, with 95% confidence intervals (CIs). We assessed the risk of bias through assessment of trial methodological components and the risk of random error through trial sequential analysis. MAIN RESULTS:We included six RCTs with a total of 248 participants; none of the trials were determined to have overall low risk of bias. We found 12 ongoing trials, from which we were unable to retrieve any data. Only two trials provided data on mortality, and one was a zero event study; thus the meta-analysis showed no statistically significant effect on overall mortality (2.6% vs 9.5%, RR 0.28, 95% CI 0.03 to 2.33). Our analyses on blood transfusion data suggest a beneficial effect of fibrinogen concentrate in reducing the incidence of allogenic transfusions (RR 0.47, 95% CI 0.31 to 0.72) but show no effect on other predefined outcomes, including adverse events such as thrombotic episodes. AUTHORS' CONCLUSIONS:In the six available RCTs of elective surgery, fibrinogen concentrate appears to reduce transfusion requirements, but the included trials are of low quality with high risk of bias and are underpowered to detect mortality, benefit or harm. Furthermore, data on mortality are lacking, heterogeneity is high and acute or severe bleeding in a non-elective surgical setting remains unexplored. Currently, weak evidence supports the use of fibrinogen concentrate in bleeding patients, as tested here in primarily elective cardiac surgery. More research is urgently needed.

Dataset Information

C560R?3 caused platelet integrin ?II b ?3 to bind fibrinogen continuously, but resulted in a severe bleeding syndrome and increased murine mortality.

Publications

C560Rβ3 caused platelet integrin αII b β3 to bind fibrinogen continuously, but resulted in a severe bleeding syndrome and increased murine mortality.

Similar Datasets

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