Increased Prevalence of Microthromboses in Retinal Capillaries of Diabetic Individuals

Abstract

In diabetic retinopathy, capillary nonperfusion and eventual obliteration can lead to retinal ischemia and sight-threatening neovascularization. The occurrence of retinal microthrombosis in human diabetes has long been suspected and occasionally observed but never systematically demonstrated. We used trypsin digestion to isolate the intact vascular network from retinas obtained postmortem from nine diabetic donors (age 64 ؎ 11 years, duration of diabetes 6 ؎ 4 years; mean ؎ SD) and eight age-matched nondiabetic donors. Topographically matched sectors (each one-sixth of retina) of diabetic and nondiabetic retinas were tested sequentially with antibodies to fibrin cross-linking factor XIII and platelet glycoprotein (GP)-IIIa to identify fibrinplatelet thrombi. In some trypsin digests, we also examined vascular cell apoptosis. The retina from a nondiabetic donor, 24 years of age, who had died of trauma, was used to exclude confounding influences caused by the postmortem period. When compared with those of nondiabetic donors, the retinas of diabetic donors showed double the number of capillary segments with colocalized immunostaining for factor XIII and GPIIIa (P ‫؍‬ 0.02). The total area of the positive segments was fourfold greater in the diabetic than in the nondiabetic donors (P ‫؍‬ 0.02) and correlated with the duration of diabetes (r ‫؍‬ 0.71, P < 0.05). Large thrombi were six times more frequent in the diabetic donors (P ‫؍‬ 0.03), and there was a significant topographical association of microthrombosis with apoptotic cells in both diabetic and nondiabetic vessels (P ‫؍‬ 0.0001). Hence, diabetes of short duration was found to be associated with a greater than normal number and size of platelet-fibrin thrombi in the retinal capillaries. These thrombi can contribute to capillary obliteration and retinal ischemia and may be a practical target for early drug intervention.

The pathogenesis of diabetic retinopathy: old concepts and new questions

“…It has been reported that chronic hyperglycemia causes an increase in diacylglycerol (DAG) levels in the retina, which may activate PKC. 110 Through increased intracellular Ca 2ϩ , PKC stimulates endothelial cells, leuckocytes and platelets to produce platelet-activating factor (PAF). [111][112][113] PAF, confined to membranes, stimulates PAF receptors 114 on platelets, inducing activation of these platelets.…”

“…122 Excess activation of endothelial PKC promotes PAF synthesis in diabetes. 110,123,124 PAF stimulates PAF receptors on peripheral leukocytes rolling on the lumenal endothelial membrane leading to their activation. 125 Activated leukocytes also synthesise PAF 126 and leukotriene B4 (LTB4), 127,128 which further enhance activation of leukocytes via autocrine action.…”

Different mechanisms of saturated versus polyunsaturated FFA-induced apoptosis in human endothelial cells

“…In vitro, high FFA concentrations contribute to accelerated apoptosis of the endothelium (3-7), which ranks among the most endangered target tissues in diabetes. In diabetic retinopathy, endothelial apoptosis occurs before other histopathology is detectable (8), and procoagulatory apoptotic endothelial cells, topographically associated with microthromboses (9), could contribute to vascular occlusion. In atherosclerosis, in addition to its contribution to initial lesion formation owing to detachment of endothelial cells from the underlying intimal layer, endothelial apoptosis leads to increased vascular permeability, plaque erosion, and plaque rupture (10,11).…”

Diabetic LDL Triggers Apoptosis in Vascular Endothelial Cells

“…Endothelial dysfunction plays a key role in the development of diabetic angiopathy (13,14), which is characterized by the increased turnover and exaggerated proliferation (neoangiogenesis) of the vascular endothelium and by procoagulant as well as proadhesive activity of apoptotic endothelial cells (15)(16)(17)(18).…”