AIMS To investigate whether lupus anticoagulant (LA) positivity, a marker of endothelial dysfunction, might be relevant to the pathogenesis of diabetic retinopathy (DR).
METHODS 32 IDDM patients were examined for LA, fibrinogen, prothrombin (PT), PTT, prothrombin degradation products (F1+2), and activated protein C (APC).
RESULTS APC decreased and F1+2 increased significantly in LA positive but not in LA negative patients; 60% of LA positive and 18% of LA negative subjects had DR. PT, PTT, and fibrinogen levels were insignificant.
CONCLUSION These preliminary findings suggest that LA positivity could represent an additional risk factor for DR, acting as a link between the immunological and haemostatic systems.
- lupus anticoagulant positivity
- insulin dependent diabetes
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The natural history and aetiopathogenesis of diabetic retinopathy (DR) are still not completely understood. Vascular damage and disturbed endothelial function occur early in the course of diabetic microangiopathy converting the endothelium from a thromboresistant to a thrombogenic surface.1 2 Moreover, it has been suggested that immunological mechanisms have a role in the pathogenesis of diabetic microangiopathy via immune complex deposition.3 Autoantibodies directed against endothelial antigens could be responsible for initiating vascular injury,4 but could also be a marker of endothelial dysfunction.
Lupus anticoagulant (LA), an antiphospholipid antibody, is thought to be involved in this endothelial alteration and is frequently associated with thromboembolic events, miscarriage, systemic lupus erythematosus, diabetic vascular complications (overt nephropathy or macroangiopathy), and retinal occlusive vasculopathies.5-9
Because of the evidence of immune and haemostatic abnormalities in diabetes and the strong correlation observed between LA and similar alterations in other diseases, our study was designed to determine whether LA positivity was associated with thrombotic tendency and increased prevalence of DR.
Materials and methods
A total of 32 IDDM patients (14 males, 18 females; age range 25–68 years), classified according to the National Diabetes Data Group criteria,10 with a duration of the disease longer than 5 years, were enrolled. Poor glycaemic control (HbA1c >7%), borderline hypertension (>140/90), hypertriglyceridaemia (>1.9 mmol/l), or hypercholesterolaemia (>5.6 mmol/l) were exclusion criteria. Fifty healthy, non-diabetic subjects aged between 20 and 50 years, served as a control group.
All diabetics were treated with subcutaneous human insulin (regular and long acting) only. Both diabetics and controls were non-smokers and had not taken drugs which could affect haemostasis for at least 4 weeks before the study.
Plasma samples were examined for LA, fibrinogen, prothrombin (PT), PTT, prothrombin degradation products (F1+2), and activated protein C (APC). DR was classified according to the ETDRS-Airlie House Classification.11
Informed consent was obtained from all subjects after full explanation of the nature of the study. This investigation was approved by the bioethics committee of the University of Rome “La Sapienza”.
Data were expressed as mean (SD) and statistical analyses were performed using the Mann–Whitney U test. Bonferroni's correction was applied to control for the increase of type 1 error probability due to multiple comparison. A p value of less than 0.05 was considered significant.
Table 1 summarises both the clinical features and the laboratory findings of diabetic patients and controls. While the 50 control subjects were all negative for LA, the presence of LA (>1.31), in contrast, was detected in 10 (four males, six females) of the 32 enrolled diabetics (31.2%). The mean titre in the positive patients was 1.59 (0.03) (v 0.98 (0.001) in the LA negative subjects, p <0.001) (Table 2). LA positive and LA negative patients were similar for clinical, biochemical, and haemodynamic variables (Table 1) but anticardiolipin antibodies were found in 80% of LA positive and in only 9% of LA negative patients (χ2 = 12.959, p <0.01).
Clinically manifest microangiopathy (retinopathy and/or nephropathy) was found in six of 10 LA positive (60%) and in four of 22 LA negative (18%) diabetics with similar duration of the disease and metabolic control (Table 1). Background and proliferative retinopathy were observed only. In particular, a higher prevalence of proliferative DR was observed in LA positive patients (66.6%v 50%), although this difference did not achieve statistical significance, probably because of the small number of subjects. Other diabetic complications (for example, neuropathy, macroangiopathy) were not observed.
There were no statistically significant differences for PT, PTT, and fibrinogen levels between both groups of patients (p >0.05). In contrast, APC levels were reduced (p <0.05) and F1+2 concentrations were increased (p <0.05) in LA positive compared with LA negative cases (Table 2).
The clinical association between LA positivity and thrombotic events in other diseases is thought to be due to an LA induced endothelial cell dysfunction.5 6 In IDDM, a similar dysfunction of the coagulant and anticoagulant pathways, as a result of endothelial cell damage, has been described.12-19 In fact, altered coagulation is manifested by enhanced prothrombin conversion to thrombin—as demonstrated by increased prothrombin degradation fragments (F1+2) plasma concentrations20—and downregulation of the anticoagulant pathway, caused by reduced antithrombin III activity20 and thrombomodulin's endothelial receptors.21
In our study, decreased APC concentrations and increased F1+2 plasma levels were observed in LA positive compared with LA negative patients (Table 2), as an evident expression of prothrombotic condition and endothelial dysfunction. APC and F1+2 values in LA negative cases and in healthy controls were similar. The lack of macroangiopathy in LA positive subjects may be due to the chronic nature of the endothelial dysfunction: in fact, comparable PT, PTT, and fibrinogen values were observed in both groups.
In conclusion, this investigation pointed out a significant correlation between LA positivity and: increased prothrombin conversion to thrombin, downregulation of the endothelial anticoagulant pathway, and higher prevalence of DR (χ2 = 7.35, p <0.05). No correlations were found between LA titre and other specific factors (for example, age, duration of diabetes, HbA1c level, type of DR) (χ2 = 15.2, p = 0.83).
Although not conclusive, these preliminary results suggest that LA positivity might be considered an additional risk factor in the pathogenesis of microangiopathy (retinopathy and/or nephropathy) in IDDM patients, representing an intersection point between immune and haemostatic alterations. Nevertheless, further investigations on larger diabetic populations are required in order to clarify and support this issue.
To F Chiarotti, for performing all statistical analyses, and Janet Hill, for her generous help in reviewing the manuscript.
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