Expression and function of IL-1R8 (TIR8/SIGIRR): a regulatory member of the IL-1 receptor family in platelets.

AIMS: Platelets express functional interleukin-1 receptor-1 (IL-1R1) as well as a repertoire of toll-like receptors (TLRs) involved in platelet activation, platelet-leucocyte reciprocal activation, and immunopathology. IL-1R8, also known as single Ig IL-1-related receptor (SIGIRR) or TIR8, is a member of the IL-1R family that negatively regulates responses to IL-1R family members and TLRs. In the present study, we addressed the expression of IL-1R8 in platelets and megakaryocytes and its role in the control of platelet activation during inflammatory conditions and thromboembolism. METHODS AND RESULTS: Here, we show by flow cytometry analysis, western blot, confocal microscopy, and quantitative real-time polymerase chain reaction that IL-1R8 is expressed on human and mouse platelets at high levels and on megakaryocytes. IL-1R8-deficient mice show normal levels of circulating platelets. Homotypic and heterotypic (platelet-neutrophil) aggregation triggered by Adenosine DiPhosphate (ADP) and IL-1 or lipopolysaccharide (LPS) was increased in IL-1R8-deficient platelets. IL-1R8-deficient mice showed increased soluble P-selectin levels and increased platelet-neutrophil aggregates after systemic LPS administration. Commensal flora depletion and IL-1R1 deficiency abated platelet hyperactivity and the increased platelet/neutrophil aggregation observed in Il1r8(-/-) mice in vitro and in vivo, suggesting a key role of IL-1R8 in regulating platelet TLR and IL-1R1 function. In a mouse model of platelet-dependent pulmonary thromboembolism induced by ADP administration, IL-1R8-deficient mice showed an increased frequency of blood vessel complete obstruction. CONCLUSION: These results show that platelets, which have a large repertoire of TLRs and IL-1 receptors, express high levels of IL-1R8, which plays a non-redundant function as a regulator of thrombocyte activity in vitro and in vivo.

Prevalence of inherited thrombophilia in patients with documented stent thrombosis.

BACKGROUND: Stent thrombosis (ST) is a multi-factorial process involving different mechanisms. The impact of inherited coagulation disorders in the genesis of ST has never been assessed. The aim of the present study was to evaluate the prevalence of G1691A Factor V Leiden mutation, G20210A Factor II (prothrombin) mutation and C677T homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism in patients with ST. METHODS AND RESULTS: The prevalence of the aforementioned gene variations was assessed in 127 patients: 50 admitted for ST and 77 previously treated with percutaneous coronary intervention not developing ST. A control cohort of 529 healthy volunteers was sampled from the same geographical area. Patients with ST were carriers of at least 1 gene variation in 28% of cases. The prevalence of G1691A Factor V Leiden mutation (odds ratio [OR]=0.64; 95% confidence interval [CI]: 0.04-10.5), G20210A Factor II mutation (OR=0.63; 95% CI: 0.12-3.28) and C677T MTHFR homozygous polymorphism (OR=1.13; 95% CI: 0.47-2.72) did not differ significantly among patients with or without ST. The logistic regression model did not show a significant association between gene variations and ST (OR=0.61; 95% CI: 0.24-1.60; P=0.32). CONCLUSIONS: A specific association between studied gene variations and ST has not been detected. The relatively high prevalence of at least 1 gene anomaly in such a rare subset of patients, and its consequences in term of secondary prevention therapy, suggests that screening for thrombophilia might be justifiable in cases of ST.

New perspectives on von Willebrand factor functions in hemostasis and thrombosis.

The adhesive protein, von Willebrand factor (VWF), mediates the initiation and progression of thrombus formation at sites of vascular injury by means of specific interactions with extracellular matrix components and platelet receptors. The essential biologic properties of VWF have been elucidated, with progress particularly in the areas of genetic regulation, biosynthesis, and specific bimolecular interactions. The three-dimensional structure of selected domains has been solved, but our understanding of detailed structure-function relationships is still fragmented, partly because of the complexity and size of the VWF molecule. The biomechanical properties of the interaction between the VWF A1 domain and the platelet receptor glycoprotein (GP) Ibalpha also are better known, but we can still only hypothesize how this adhesive bond can oppose the fluid dynamic effects of rapidly flowing blood to initiate thrombus formation and contribute to platelet activation. Elucidating the details of VWF and GPIbalpha function will lead to a more satisfactory definition of the role of platelets in atherothrombosis, since hemodynamic forces greatly influence responses to vascular injury in stenosed and partially occluded arteries. Progress in this direction is also aided by rapidly expanding novel information on the mechanisms that regulate VWF multimer size in the circulation, a topic of relevance to explain microvascular thrombosis and, perhaps, arterial thrombosis in general. Developments in these areas of research will refine our understanding of the role played by VWF in vascular biology and pathology.