What is the clinical evidence from this study?

Study design: Case-Control. Population: Diabetes mellitus and thrombosis. Intervention: Aspirin (acetylsalicylic acid) vs. Healthy subjects or non-diabetic patients. Primary outcome: Urinary levels of 11-dehydro-TXB2 (TX-M) in pg/mg creatinine.

October 17, 2011Open Access

Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane

WTWai Ho TangHong Kong Observatory JSJeremiah StithamWashington University in St. Louis SGScott GleimNovartis (United States)

Key Result

Diabetic patients on low-dose aspirin exhibited significantly increased urinary levels of the thromboxane metabolite 11-dehydro-TXB2 (median 208.8 pg/mg creatinine) compared to healthy subjects (median 77.5 pg/mg creatinine).

Study Design

Type

Case-Control

Multicenter

Yes

Structured PICO

Does aldose reductase mediate hyperglycemia-induced platelet hyperactivity and thromboxane generation in patients with diabetes and thrombosis?

Population

Human platelets from healthy subjects for in vitro assays. Three clinical observational cohorts: 1) 102 patients with diabetes mellitus (DM) and 10 healthy subjects, all on low-dose aspirin (100 mg/day); 2) 34 patients with deep vein thrombosis (DVT) and 23 controls; 3) severe coronary artery disease patients with or without saphenous vein coronary artery bypass graft (CABG) thrombosis, all on aspirin (325 mg/day).

Intervention

In vitro: High glucose (25 mmol/l) and collagen (1 μg/ml) exposure, with or without aldose reductase inhibitor (epalrestat 1-10 μmol/l). Clinical: Observational evaluation of diabetes and thrombosis status.

Comparator

In vitro: Normal glucose (5.5 mmol/l) and vehicle. Clinical: Healthy subjects, non-diabetic patients, or patients without thrombosis.

Outcome

Thromboxane generation (urinary 11-dehydro-TXB2 [TX-M] in clinical cohorts, TXB2 release in vitro) and platelet aggregation.surrogate

Hyperglycemia and collagen synergistically activate platelets via an aldose reductase-dependent pathway, leading to increased thromboxane generation that persists despite aspirin therapy in diabetic patients.

Main Result

Absolute Event Rate: 208.8% vs 77.5%

Limitations

The sizes of the clinical studies are relatively small.
The study focuses on acute increases in glucose without addressing the effects of chronic increases.
The reductionist approach focuses on platelet-dependent mechanisms, excluding other factors from blood cells, endothelium, and vascular smooth muscle cells.

Abstract

Diabetes mellitus is associated with platelet hyperactivity, which leads to increased morbidity and mortality from cardiovascular disease. This is coupled with enhanced levels of thromboxane (TX), an eicosanoid that facilitates platelet aggregation. Although intensely studied, the mechanism underlying the relationship among hyperglycemia, TX generation, and platelet hyperactivity remains unclear. We sought to identify key signaling components that connect high levels of glucose to TX generation and to examine their clinical relevance. In human platelets, aldose reductase synergistically modulated platelet response to both hyperglycemia and collagen exposure through a pathway involving ROS/PLCγ2/PKC/p38α MAPK. In clinical patients with platelet activation (deep vein thrombosis; saphenous vein graft occlusion after coronary bypass surgery), and particularly those with diabetes, urinary levels of a major enzymatic metabolite of TX (11-dehydro-TXB2 TX-M) were substantially increased. Elevated TX-M persisted in diabetic patients taking low-dose aspirin (acetylsalicylic acid, ASA), suggesting that such patients may have underlying endothelial damage, collagen exposure, and thrombovascular disease. Thus, our study has identified multiple potential signaling targets for designing combination chemotherapies that could inhibit the synergistic activation of platelets by hyperglycemia and collagen exposure.

Ask AI

Helpful

Bookmark

View Full Paper