Increased biosynthesis of thromboxane A₂ by diabetic platelets

Abstract

Abstract. Because ADP has been reported to produce a secondary wave of platelet aggregation in diabetic subjects, and since ADP is known to enhance normal platelet biosynthesis of pro‐aggregating thromboxane A2, we tested whether or not the reported increased sensitivity of diabetic platelets to ADP may also result in increased platelet biosynthesis of thromboxane A2. To test this hypothesis, 14C‐arachidonic acid (14C‐AA) was incubated in vitro with washed human platelets' in the presence or absence of ADP. These studies included platelets isolated from thirty normal volunteers, twenty‐six diabetic subjects with and without known vascular complications, eighteen non‐diabetic pregnant females and fourteen pregnancy‐induced diabetic females. Data from these studies demonstrated: (i) a significant increase in the capability of diabetic platelets in response to ADP to biosynthesize thromboxane A2 from arachidonic acid when compared to platelets from normal controls (P < 0.001); (ii) a significant increase in thromboxane A2 biosynthesis by platelets from pregnancy‐induced diabetic subjects over nondiabetic pregnant females (P < 0.001); (iii) a two‐fold increase in thromboxane A2 biosynthesis by platelets from diabetic subjects with vascular complications when compared to those without vascular complications. Although our data also showed approximately a twofold increase in thromboxane A2 biosynthesis by platelets from diabetic subjects with greater than 10 years of the disease when compared to diabetic subjects with less than 10 years, these latter results were, however, not statistically significant. Results from these studies suggest that a relationship may exist between the markedly increased ADP‐induced platelet aggregation in diabetes mellitus and the vascular complications associated with this disease. Whether or not increased capacity of the diabetic platelet to biosynthesize pro‐aggregating thromboxane A2 in response to ADP or other pro‐aggregating agents is per se a triggering factor in occlusive vascular diseases reported in diabetic subjects must await further studies.

Increased arachidonic acid incorporation into platelet phospholipids in Type 2 (non-insulin-dependent) diabetes

“…The arachidonic acid content in the phosphatidylcholine and phosphatidylinositol fraction is known to be an important modulating factor for TXA2 synthesis [3,11]. Therefore, increased arachidonic acid content in diabetic platelet phospholipids [3,4] was considered as one possible cause of increased TXA2 synthesis in diabetic platelets [12][13][14]. However, Jones et al [15] recently reported a significant decrease in arachidonic acid levels in diabetic platelet phospholipids, a result quite different from ours.…”

“…3). Production of TXA2 by platelets after ADP, arachidonic acid or thrombin stimulation was higher in the diabetic patients with microangiopathy than in those without complications [12][13][14]20]. On the other hand, prostacyclin synthesis was decreased in the diabetic patients with microangiopathy [21].…”

Vasoreactivity and prostacyclin release in streptozotocin‐diabetic rats: effects of insulin or aldose reductase inhibition

“…There is evidence to suggest that, with the possible exception of the kidney where early increases in prostaglandin production may mediate early increases in renal blood flow (Craven & De Rubertis, 1989), the production of the vasodilator and anti-platelet agent, prostacyclin, is reduced in experimental and clinical diabetes (Silberbauer et al, 1979;Rosenblum & Hirsh, 1984;Carreras et al, 1980). Conversely, the production of the vasoconstrictor and platelet aggregating agent, thromboxane A2, is increased (Lagarole et al, 1980;Ziboh et al, 1979;Rosenblum & Hirsh, 1984). The production of the potent vasoconstrictor endothelin may also be increased in diabetic animals (Takeda et al, 1991) and patients (Takahashi et al, 1990) while endotheliumdependent relaxation is reduced in diabetic animals (Durante et al, 1988;Hattori et al, 1991) possibly as a consequence of a reduced production of nitric oxide.…”

Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals.

“…Nerve biosynthesis of 6-keto-prostaglandin Fia, the stable metabolite of prostacyclin, is significantly reduced in chronic, but not in acute, experimental diabetic neuropathy (2). Platelet thromboxane B2 is increased (3)(4)(5)(6), resulting in a reduced prostacyclin/ thromboxane ratio and resultant vasoconstriction. Improvement in blood flow by chemical sympathectomy (7) or an increase in the oxygen supply by supplementation (8) or hyperbaric oxygenation (9) has been shown to improve nerve electrophysiology.…”