Background:

Subclinical Inflammation is a cardiovascular risk factor that predisposes individuals to atherothrombosis. Pharmacological inhibition of the Inflammasome-IL1b axis has demonstrated an effective therapeutic approach to reduce atherothrombotic events. Platelets play a key role in atherothrombosis and are able to synthesise and release IL1b from mRNA. However, their role in the setting of subclinical inflammation remains ill defined.  

Aim: 

To investigate platelet activity, platelet pro-inflammatory mRNA transcripts and platelet inflammasome activity in patients with stable, subclinical inflammation. 

Methods and results:  

Sixty-five patients with stable coronary artery disease were stratified into risk groups according to their hsCRP plasma levels (i.e. low risk: 0.0 – 0.9 mg/L; intermediate risk: 1.0 – 2.9 mg/L and high risk: 3.0 – 9.9 mg/L). Patients were only included in the study when hsCRP was stable (i.e. hsCRP remained within the margin of a defined risk group in two independent measurements; at least >24hours between measurements). The average hsCRP levels in the three groups were 0.53mg/L ±0.19 (N = 22, low risk ), 1.6mg/L ± 0.54 (N = 14, intermediate risk) and 4.3mg/L ± 1.0 (N = 29, high risk). Patients in the high-risk group were characterised by significant higher leucocyte (7.2 x10³/µl ± 1.8; p < 0.05) and platelet counts (240 x10³/µl ± 75; p<0.05). Despite higher platelet counts, there was no significant difference in platelet activity among the groups as indicated by platelet markers for degranulation (i.e. P-selectin expression) and aggregation (i.e. aIIbb3 expression) when stimulated with Thrombin-receptor agonist peptide (TRAP). However, platelets from patients in the high risk-group contained less IL1b and secreted 60% less Il1b upon stimulation with the inflammasome inducer Melittin (Intracellular IL1b: Low risk: 14 MFI ± 7; Intermediate risk: 15MFI ± 11; High risk 7MFI ± 6; p = 0.004). The reduced presence of Il1b in platelets was paralleled by a selective reduction in mRNA transcripts for IL1b (p < 0.001) while other Inflammasome-associated transcripts including Caspase-1, NLRP3,  TLR2, TLR4 and MyD88 remained unaltered (all p > 0.05). To exclude altered thrombopoiesis as underlying cause of reduced presence of Il1b we compared granularity and platelet size between the groups and found no statistically significant difference (all p > 0.05). In summary, this suggests chronic platelet IL1b transcription and secretion in the context of an inflammatory environment.  

Conclusions: 

In subclinical inflammation platelets express a signature that suggests selective transcription and secretion of IL1b. This data could point to an active contribution of platelets to the subclinical the inflammatory environment. Further studies are needed to understand the role and consequence of IL1b secretion in platelets.