Role of matrix metalloproteinases 2 and 9, toll-like receptor 4 and platelet-leukocyte aggregate formation in sepsis-associated thrombocytopenia

Abstract

BackgroundThe development of thrombocytopenia in sepsis is a poor prognostic indicator associated with a significantly increased mortality risk. Mechanisms underlying this phenomenon remain to be clearly elucidated. Matrix metalloproteinases (MMPs) are enzymes that regulate the turnover of the extra-cellular matrix. MMP-2 is recognised as a platelet agonist with MMP-9 proposed as an inhibitor of platelet activation. The existence of MMP-9 in platelets is a subject of debate. There is limited evidence thus far to suggest that toll-like receptor 4 (TLR-4) and platelet-leukocyte aggregate (PLA) formation may be implicated in the development of sepsis-associated thrombocytopenia.ObjectivesTo investigate whether MMP -2/-9, toll-like receptor 4 (TLR-4) or platelet-leukocyte aggregate (PLA) formation are implicated in a decline in platelet numbers during septic shock.MethodsThis was an observational study which recruited healthy controls, non-thrombocytopenic septic donors and thrombocytopenic septic donors. MMP-2, MMP-9 and TLR-4 platelet surface expression as well as PLA formation was examined using flow cytometry. In addition MMP-2 and MMP-9 were examined by gelatin zymography and enzyme-linked immunosorbent assay (ELISA) using a 3 compartment model (plasma, intraplatelet and platelet membrane).ResultsThere was no difference found in MMP-2, MMP-9 or TLR-4 levels between non-thrombocytopenic and thrombocytopenic septic donors. PLA formation was increased in thrombocytopenic patients. MMP-9 was detected in platelets using flow cytometry, gelatin zymography and ELISA techniques.ConclusionsPlatelet consumption into PLAs may account for the development of thrombocytopenia in septic shock. MMP-9 is found in platelets and it is upregulated during septic shock.

Cardiac arrest survival post-resuscitation in-hospital (CASPRI)—a tool to predict neurological outcome after ROSC

“…Leite et al [19] has found that low serum albumin was associated with higher mortality-every 1 g/dL increase in serum albumin at admission reduced the risk of death by 73% (OR: 0.27, 95%CI: 0.14-0.51: P<0.001). Similarly, many other studies have confirmed that albumin is closely related to the prognosis of neurological function [20,21]. Our study is consistent with the results mentioned above.…”

“…Akca et al [37] studied 1,440 patients admitted to the ICU and showed that 30% of patients had a reduced platelet count at admission (PLT<150×10 9 /L), and the survivors had higher platelet counts. During the inflammatory period before CPR, reduced production or increased depletion of platelets leads to thrombocytopenia, which can cause microvascular thrombosis and multiple organ dysfunction [21]. The dysregulated platelets interact with vascular endothelium, lead to leakage of inflammatory factors and further damage brain tissue [38].…”

Platelet TLR4 at the crossroads of thrombosis and the innate immune response

“…However, a more recent study showed that although there was a tendency toward higher levels of TLR4 expression in the platelets of septic and thrombocytopenic patients, this did not reach statistical significance compared with nonthrombocytopenic septic patients. Remarkably, whereas platelets from normal donors increased their TLR4 expression upon stimulation a similar effect was not observed in septic patients, probably due to the already higher levels of TLR4 . In addition, in a very small sample of patients ( n = 7), Claushuis et al.…”

“…Remarkably, whereas platelets from normal donors increased their TLR4 expression upon stimulation a similar effect was not observed in septic patients, probably due to the already higher levels of TLR4. 53 In addition, in a very small sample of patients (n = 7), Claushuis et al found that platelets from septic patients showed platelet activation but unaltered TLR4 expression. 23 Because pre-clinical studies have shown that platelet TLR4 and platelet activation are required for NET formation, 42 we studied the relationship between NETosis and platelet activation in septic and burned patients, that is, two acute inflammatory diseases, one infectious and the other sterile.…”

Comparison of the central human and mouse platelet signaling cascade by systems biological analysis

“…Matrix metalloproteinases (MMPs) are reorganizing the extracellular matrix [48,49]. MMP9 is only present in humans, its low expression affects platelet activation [50] (Table S2 and [51]). Platelet expression differences in tissue inhibitors of metalloproteinase (TIMPs), such as TIMP1, TIMP2 and TIMP3 affect activities of MMPs and by this platelet aggregation [52,53].…”