Elevated fibrinogen fragment levels in uremic plasma inhibit platelet function and expression of glycoprotein IIb‐IIIa

Abstract

Hemostatic dysfunction is frequently noted in uremia, but the mechanisms responsible for it are poorly understood and are assumed to be multifactorial. Preliminary findings from our laboratory suggest that elevated levels of circulating fibrinogen fragments (FF) might contribute to the hemostatic defect in uremic patients. Defibrinated plasma obtained from chronic hemodialysis (HD) patients as well as normal subjects were examined by SDS-PAGE and immunoblotting and quantified by an immunoassay. In addition, endogenous FF isolated from normal and uremic plasma using affinity chromatography were examined by flow cytometry for their effect on glycoprotein (GP) IIb-IIIa receptor expression and tested for their ability to inhibit platelet aggregation. The mean FF concentration in uremic plasma (1.14 ± 0.85 mg/ml) was noted to be eight times greater than in normal plasma (0.15 ± 0.01 mg/ml) (P < 0.05). Moreover, the mean FF level decreased by 48.25% following HD (from 1.14 ± 0.85 mg/ml to 0.59 ± 0.33 mg/ml; P < 0.05). SDS-PAGE and immunoblotting experiments showed that the decrease was observed in both medium-sized (20-60 kDa) as well as large (>100 kDa) FF. Further, FF isolated from uremic plasma inhibited platelet aggregation by (46.8 ± 18.1)% (P < 0.05) and the GP IIb-IIIa receptor expression by (28.0 ± 7.6)% (P < 0.05 vs. control). The results show that (1) FF levels are elevated in uremic plasma, (2) HD results in significant decrease in FF and (3) endogenous FF inhibit platelet function, presumably via competitive binding to the fibrinogen receptor GP IIb-IIIa. The decrease in plasma levels of FF > 100 kDa following HD suggests that adsorption to the dialysis membrane contributes to their removal. Am. J. Hematol. 81:915-926, 2006. V V C 2006 Wiley-Liss, Inc.

Efficacy and Safety of Abciximab in Diabetic Patients Who Underwent Percutaneous Coronary Intervention with Thienopyridines Loading: A Meta-Analysis

“…Nonetheless, considering the limited sample size involved in the analysis of bleeding complications, further trials are needed to clarify this issue, especially in the ACS patients with primary-PCI. In addition, abciximab has been reported to reduce estimated glomerular filtration rate(eGFR)in CAD patients [60], [61]. Thus, diabetic patients, who are prone to renal lesion themselves due to the underlying disease, might be at increased risk of renal insufficiency, which would aggravate the outcomes [62], [63].…”

Aspects of platelet disturbances in haemodialysis patients

“…Functionally, PLTs in the case of uraemia are less responsive to ADP-induced stimulation, as demonstrated with PLT aggregation tests in PRP plasma [22, 23]. Moreover, fibrinogen, which inhibits PLT function by competitive binding to the fibrinogen receptor GP IIb–IIIa on PLTs, is increased in uraemic plasma [24]. PLT aggregates block pores of the dialyser membrane, reducing exchange of harmful substances like urea.…”

Impact of pre-transplant antiaggregant and anticoagulant therapies on early hemorrhagic and cardiovascular events after kidney transplantation

“…deceased donor KTx-is an evolving issue: international consensus and guidelines suggest to evaluate bleeding and thrombotic risk for decision making, but no specific recommendation is made for kidney transplant surgery [12]. Actually, kidney transplant recipients (KTR) represent a very peculiar population in which baseline thrombotic and hemorrhagic risk are both elevated if compared with the general population [10], as end-stage renal disease (ESRD) is associated with complex and severe vascular alterations [13,14] and sub-clinical inflammation [15] and, on the other side, platelet aggregation defects [16,17]. Therefore, results inferred from different populations might not directly apply to KTx surgery or recipients.…”