Salivary tissue factor induces thrombin generation in a diurnal rhythm

Abstract

BackgroundUpon tooth extraction, extravascular tissue factor (TF) initiates coagulation to arrest bleeding. Additionally, saliva is in constant contact with the wound and contains extracellular vesicle‐derived procoagulant TF. Since the duration of postextraction bleeding is highly variable between patients, we hypothesized this may be caused by variation in saliva‐derived TF‐induced clotting activity.ObjectivesWe aimed to assess the variability of saliva‐induced thrombin generation (TG) in healthy individuals.Methods TG was performed according to the calibrated automated thrombinography (CAT) method. Diluted saliva was added (instead of recombinant TF and phospholipids [PL]) to normal pooled plasma (NPP) in the absence/presence of anti‐TF antibodies. Saliva was collected from healthy individuals in the morning, afternoon and evening.ResultsAddition of saliva to NPP induced TG curves similar to those induced by r‐TF and PL. Moreover, addition of anti‐TF antibodies abolished saliva‐induced TG, indicating TF‐dependence. A large inter‐individual variability (peak CV 31%, range 73‐220 nmol/L thrombin) in saliva‐induced TG was observed. Interestingly, within subjects, saliva‐induced TG was significantly (P = 0.009) increased in the morning (167 ± 40 nmol/L thrombin) compared to the afternoon (124 ± 39 nmol/L thrombin) and evening (123 ± 38 nmol/L thrombin). This diurnal variation was not attributable to gingival stimulation or damage induced by tooth brushing.ConclusionsWe identified a diurnal rhythm in salivary TF activity that may have implications for tooth extraction and dental surgery, as performing invasive procedures in the morning may be beneficial for rapid coagulation. Future studies should correlate salivary TF to clinical outcome (ie, postextraction bleeding) and assess a possible relation with bacterial status in the oral cavity.

Human milk triggers coagulation via tissue factor–exposing extracellular vesicles

“…A limitation of this study is that human milk was collected at a single time point. The coagulant activity of human milk may have a diurnal rhythm, as has been observed for saliva, 45 study do not allow such speculation, but a longitudinal study to investigate the coagulant activity in human milk according to time of day and during the course of lactation is currently scheduled. It should also be mentioned that although we show that TF is clearly associated with EVs in human milk, we were unable to demonstrate the presence of TF in individual EVs by cryo-EM or flow cytometry (data not shown), which is likely explained by low TF protein density.…”

Extracellular Vesicles in Liquid Biopsies: Potential for Disease Diagnosis

“…The quality of EVs isolated from saliva can depend on numerous factors that affect the quality of the saliva sample, including the timing and location of sampling [ 70 , 83 , 84 ], as well as the technique of sample collection [ 85 ], which can be through passive drooling [ 86 ] or stimulation by chewing or administration of a chemical [ 87 ]. Concentrations of salivary tissue factors [ 88 ] and cortisol [ 89 ] follow a circadian rhythm, which can affect the isolation and analysis of EVs. It may be better to collect saliva only from the parotid gland [ 90 ].…”