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P.P. Kulkarni et al.
0.74 /lpf; versus control 8.1 ± 0.95/lpf) with erythrocyte extravasation in some fields. These observations establish that prohibition of platelet aerobic glycolysis or the PPP prevents thrombosis, and may impair hemostasis.
We next evaluated the effect of metabolic modulators on primary hemostasis in mice by a tail-bleeding assay. Administration of DCA (200 mg/kg, intraperitoneal), DHEA (50 mg/kg, intraperitoneal) or DASA (40 mg/kg, intravenous) to the mice was associated with prolonged bleeding times (Figure 5C) as well as an increase in the
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amount of bleeding compared to that of vehicle-treated animals (Online Supplementary Figure S9). These observa- tions establish that aerobic glycolysis and consequent flux through the PPP are also essential for hemostasis.
Discussion
The essence of platelet function is response to stimuli. Platelets respond to hemostatic cues with a series of activ-
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Figure 5. Small-molecule inhibitors of aerobic glycolysis and the pentose phosphate pathway impair pulmonary embolism and hemostasis. (A) Representative light microscopy images (100X magnification) of hematoxylin & eosin-stained lung sections from mice administered collagen (1 mg/kg) plus epinephrine (10 mg/kg) after pre-treatment with vehicle (control), DCA, DHEA, or DASA as indicated. Black arrows indicate thrombi within the lumen of pulmonary vessels. Yellow arrows indicate extravasated erythrocytes. (B and C) Scatter dot plots showing number of thrombosed pulmonary vessels per low power field and tail-bleeding times, respectively, of mice administered with vehicle, DCA, DHEA or DASA. Data are presented as the mean ± standard error of mean. Each dot represents an independent observation. DASA: diarylsulfonamide; DCA: dichloroacetate; DHEA: dehydroepiandrosterone sulphate.
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haematologica | 2019; 104(4)