Blood rheology in patients with diabetes mellitus.

Blood rheology is now receiving increasing attention as an important potential contributory factor to diabetic angiopathy. This study was designed to provide evidence for and against early hemorheological abnormalities in diabetes mellitus (DM). For this purpose, blood viscosity, RBC aggregation, hematocrit, and plasma protein's levels of both fibrinogen and albumin were measured in 86 uncomplicated patients with DM (45 type 1 and 41 type 2). Patients with HbA1c < 7.5% were considered as having good glycemic control (GGC), while those with HbA1c > 8.5% as having poor glycemic control (PGC). Patients with type 1 DM showed normal blood viscosity at both shear rates high and low, while native hematocrit, fibrinogen, and RBC aggregation were significantly elevated and albumin significantly reduced when compared with healthy volunteers. Patients with type 2 DM showed more marked impairments associated with an increased low shear rate blood viscosity, when compared with patients with type 1 DM. Comparison between two subgroups of patients, both of which with type 1 DM and of similar disease duration of <5 yrs, with GGC or PGC showed that impaired blood rheology does depend on the quality of glycemic control. Differences were attenuated after a disease duration of >15 yrs. These findings suggest that early hemorheological impairments in patients with type 1 DM are dependent upon the glycemic control. In contrast, hemorheological impairments appear to be inevitable after a mean disease duration of 15 yrs even if there is a GGC. Aggravation of hemorheological abnormalities in patients with type 2 DM might depend upon the hemorheological effects of other metabolic abnormalities related to insulin resistance rather than the quality of glycemic control.

Measurements of transcutaneous oxygen pressure and changes in blood rheology as markers of prognosis of critically ischemic limb in diabetes mellitus patients.

The aims of this study were to compare variations of the transcutaneous oxygen pressure (TcPO(2)) and blood rheology in diabetic patients. Diabetic patients with critical limb ischemia were compared with those who were either asymptomatic or had mild peripheral vascular disease (PVD). The results showed a significant decrease in TcPO(2) in patients with critical limb ischemia. Low shear rate blood viscosity, red blood cell (RBC) aggregation, plasma viscosity, and fibrinogen level were significantly higher in the group with critical severe limb ischemia. The group with critical limb ischemia was subdivided on the basis of clinical outcomes after 1 year and the prognostic values of these measurements examined. A TcPO(2) value of 10 mm Hg was associated with a positive predictive value of 94%. RBC aggregation index and fibrinogen levels offered positive predictive values of 89% and 88%, respectively, when cut off values were derived from means + 1 SD of same parameters in patients with asymptomatic or mild PVD. TcPO(2) is useful to follow the deterioration of diabetics with critical limb ischemia.

Impaired hemorheological properties in diabetic patients with lower limb arterial ischaemia.

The rheological properties of blood play an important role in the regulation of blood flow resistance in vessels. Numerous data show evidence for an impaired hemorheological characteristic in diabetes mellitus. The aim of this study was to investigate whether chronic severe leg ischaemia in diabetes may be associated with further hemorheologic impairment. To do this, whole blood viscosity, erythrocyte aggregation/disaggregation, plasma viscosity and proteins were measured in 32 healthy control subjects, in 32 diabetic patients without micro- and macroangiopathy, in 21 diabetic patients with chronic tissue hypoxia of lower limbs and in 23 diabetic patients with severe leg ischaemia. The diabetic patients with leg hypoxia and leg ischaemia were selected according to their value of transcutaneous oxygen pressure (TcPO2) measured on dorsal side of the foot in supine position. The TcPO2 value was within 10-30 mmHg or less than 10 mmHg in patients with chronic hypoxia and severe ischaemia, respectively. Results in diabetic patients without micro- and macroangiopathy showed an increased erythrocyte aggregation associated with an increased fibrinogen level while albumin levels were decreased. Both diabetic patients with chronic hypoxia and those with severe ischaemia exhibited similarly more aggravated hemorheological disturbances including an increased whole blood viscosity at low shear rate, an increased erythrocyte hyperaggregation, increased plasma viscosity, increased fibrinogen level, decreased albumin level and decreased hematocrit. In conclusion, the hemorheological disturbances are present even in diabetic patients without clinically detectable micro- and/or macroangiopathy. The fact that the extent of disturbances was similar in the two later diabetic groups, emphasizes that the hemorheological disturbances are not the consequences of chronic hypoxia and/or severe ischaemia but are likely among factors promoting the maldistribution of blood flow in nutritive capillaries as evidenced by decreased TcPO2 in patients with chronic leg hypoxia or severe leg ischaemia.

[Diabetes mellitus and fibrinogen. Hemorrheological and microcirculatory consequences]. / Diabète sucré et fibrinogène. Conséquences hémorhéologiques et microcirculatoires.

Fibrinogen level, erythrocyte aggregation and transcutaneous oxygen pressure (TcPO2) were measured in the two populations of 32 healthy volunteer subjects and 119 diabetic patients without any clinical sign of micro and/or macroangiopathy. Measured parameters were studied according to both the long term glycemic control (HbA1C) and the type of diabetes. Results showed a significant elevation of plasma fibrinogen in all diabetic patients even when they had good glycemic control. Hyperfibrinogenemia appeared to be related to both long term glycemic control and type of diabetes. Hyperfibrinogenemia in studied diabetic patients was associated with a tendency to erythrocyte hyperaggregation. Indeed, this hyperaggregation like fibrinogen level, seem to be related to both HbA1C level and the type of diabetes. In contrast, the TcPO2 was found to be significantly decreased in all patients irrespective to either HbA1C or the type of diabetes. Besides, TcPO2 was not correlated with fibrinogen nor erythrocyte aggregation. In conclusion, the decrease in TcPO2 as observed here, does not directly depend upon the type of diabetes, or the HbA1C level, i.e the quality of mid and/or long term glycemic control.

Tissular oxygenation and venoarteriolar reflex disturbances in diabetes mellitus: vasoregulator effect of Buflomedil.

The present study was designed to investigate whether the Veno-Arteriolar Reflex (VAR) mediated via a local nervous reflex mechanism may be used as a microvascular approach to predict the effect of vasoactive drugs in diabetic patients. The vasoactive drug we studied here was Buflomedil. The effect of a single infusion of 400 mg of Buflomedil was examined on VAR and on transcutaneous oxygen pressure (TcPO2). Investigations were performed in 42 diabetic patients. The VAR was assessed on dorsal foot and dorsal big toe by measuring changes in skin blood flux induced by lowering the leg. TcPO2 was measured on dorsal foot. Before Buflomedil infusion, patients were characterized by a loss of the VAR in comparison to healthy volunteers. The loss of the VAR was associated to significant decreases in TcPO2 values. Buflomedil infusion led to significant increases in VAR at the two sites of measurement and also in TcPO2 values. These findings indicate that the VAR can be used as a sensitive microvascular test, as it allows to detect the effect of Buflomedil. Furthermore, our findings demonstrate that the Buflomedil-induced improvement in VAR is identical in the two diabetic groups with or without complications. This result emphasizes the benefit of Buflomedil not only in diabetics with microangiopathy or those suffering from a peripheral vascular disease for reducing pain or healing trophic lesions, but also in those patients without any clinically detectable macro- or microangiopathy in order to prevent or to reduce as long as possible the risk of developing diabetes related complications by the normalization of functional microangiopathy.

Haemorheological consequences of hyperglycaemic spike in healthy volunteers and insulin-dependent diabetics.

The present study has been designed to examine the role of a hyperglycaemic spike of short duration as a factor possibly involved in haemorheological microcirculatory and (or) haemostatic dysfunctions in ten insulin-dependent diabetes mellitus patients (IDDM) and five healthy volunteers. The hyperglycaemic spike was induced by glucose infusion via GCIIS Biostator. Blood viscosity, erythrocyte aggregation, erythrocyte deformability, plasma viscosity and proteins' levels, cell counts, and transcutaneous oxygen pressure were investigated during normoglycaemic period and at the end of a 1 h hyperglycaemic spike. Hyperglycaemia induced in IDDM patients significant decreases in erythrocyte aggregation, in blood and plasma viscosities and in both fibrinogen and albumin levels. The number of platelets was significantly decreased as a result of the hyperglycaemic spike. There was no significant change induced by the hyperglycaemic spike in healthy volunteers. These findings show that a hyperglycaemic spike of 280 mg/dl (15.6 mmol/l) of short duration in IDDM patients causes numerous significant changes in both blood components and rheological behaviour. These changes were accompanied by a significant decrease in transcutaneous oxygen tension indicating an impaired tissue oxygenation during the hyperglycaemia.

Evaluation of haemorheological and microcirculatory disturbances in chronic venous insufficiency: activity of Daflon 500 mg.

The use of Daflon 500 mg has been shown to improve venous tone, microvascular permeability, lymphatic activity, and microcirculatory nutritive flow. This study aimed to assess the effects of Daflon 500 mg at a daily dose of 2 tab/day on microcirculatory, haemorheologic parameters, white blood cell counts and neutrophil activation in patients suffering from chronic venous insufficiency (CVI). This was a single-centre double-blind placebo-controlled study comparing two parallel groups of CVI patients who were treated for 2 months with Daflon 500 mg (n = 39) or placebo (n = 38). Evaluations were performed before treatment (D0) and at the end of treatment (D60). Blood samples were drawn from a foot vein before and at the end of a 15-min period of venous hypertension provoked by a cuff inflated to 100 mm Hg. Red blood cell (RBC) deformability was determined by the initial flow rate filtration technique using a Hanss haemorheometer. RBC aggregation was evaluated by a Myrenne aggregometer based on analysis of transmitted light through a blood sample during flow. RBC disaggregation was evaluated by Sefam erythro-aggregometer based on analysis of the backscattered light through a blood sample in a Couette flow. Microcirculatory parameters were assessed by means of laser Doppler fluxmetry and transcutaneous oxymetry measurements and consisted of continuous records of blood flux (BF) and TcPO2 before and during 15 min of venous hypertension. Results are expressed as absolute values at baseline (before stasis) and at the end of stasis, before and after 2 months of treatment. Univariate analysis showed a significant reduction of the stasis-induced RBC aggregation index (Daflon 500 mg: -0.07+/-0.20; placebo: 0.04+/-0.18; mean +/- SD; p = 0.03). Multivariate analysis identified a subset of 5 variables (RBC aggregation, RBC count, microcirculatory BF, amplitude and frequency of vasomotion) that produced a good discrimination model between the two treatments. Linear combination of these 5 variables in 48 patients with complete data showed a significant difference (p < 0.001) between the groups. These changes suggest a protective effect of Daflon 500 mg on the deleterious influence of stasis on microcirculatory (BF) and hemorheologic (RBC aggregation) parameters in CVI patients in comparison to patients receiving placebo.

The autoregulation of the skin microcirculation in healthy subjects and diabetic patients with and without vascular complications.

The skin microvascular autoregulatory capacity was investigated in healthy volunteers and diabetic patients without or with vascular complications. To assess this capacity, skin blood flux (SBF) of different areas was examined during different procedures of venous stasis, standing position, and passive lowering of the leg. SBF was evaluated by laser doppler fluxmetry. There was, in healthy control subjects, the same degree of vasoconstriction, i.e., the same reduction in SBF irrespective of the site of measurement and the procedure used. In diabetic patients, the vasoconstriction elicited in the finger pulp by venous stasis was normal. By contrast, the vasoconstrictor responses to standing or lowering of the leg were impaired. In fact there was, in some patients, an increased SBF instead of a decreased one during standing or lowering of the leg. Impaired vasoconstrictor responses to standing or lowering of the leg was observed even in patients without complications; the impairment, however, was more marked in patients with complications. Thus, the inability of the diabetic skin microvasculature to respond normally to postural changes may be an important factor initiating the development of foot complications. The contribution of local and central reflexes to microvascular autoregulation in diabetic patients and control subjects was also discussed.

Role and limits of glycemic regulation in the pathogenesis of diabetic microangiopathy.

The relationship between either an acute or a chronic hyperglycemia and functional microcirculatory disturbances was studied in insulin-dependent diabetic (IDD) patients in comparison to healthy volunteers. Acute hyperglycemia, provoked in 10 IDD patients, was accompanied by an increase in laser doppler skin blood flux while transcutaneous oxygen pressure (TcPO2) decreased. These changes, accompanied by that in the concentration of moving blood cells indicate that acute hyperglycemia results in a vasodilation in favour of non-nutritive microvascular shunts. The effect of chronic hyperglycemia was studied in 36 IDD patients who had a duration of diabetes of less than 5 years and had no clinical signs of micro- and macroangiopathy. In these patients, erythrocyte aggregation, plasma viscosity and fibrinogen concentration were increased and transcutaneous oxygen pressure reduced, compared with the levels seen in healthy subjects. More marked impairments were observed in patients with poor glycemic control. This suggests that chronic hyperglycemia involves functional disturbances which will contribute to the development of the vascular complications of diabetes. In 34 patients with poorly controlled diabetes who received intensive insulin therapy for 36 months, these changes were reversed in patients in whom good glycemic control was achieved within 2 months, but not in those in whom glycemic control remained poor. It is concluded that disturbances in blood flow and TcPO2 occur early in diabetes, and are consequences of poor glycemic control. These disturbances can be reversed or normalized if glycemic control is improved by intensive treatment.

Relationship between hemorheological and microcirculatory abnormalities in diabetes mellitus.

From numerous studies, it is now well known that diabetes mellitus is usually accompanied by miscellaneous hemorheological disturbances. These may alter the microcirculatory flow and lead ultimately to tissue chronic hypoxia. In this report, red blood cell aggregation characteristics and transcutaneous oxygen pressure (TcPO2) have been evaluated in diabetic patients without any sign of angiopathy. Results showed a tendency towards erythrocyte hyperaggregation in diabetic patients, even when under good glycaemic control. TcPO2 measurements, were found to be significantly lower in diabetic patients than in control subjects. Furthermore, the TcPO2 values were related with the aggregation parameters, confirming thereby the existence of an inter-relationship and thus the possible role played by hemorheological parameters in oxygen transport to tissues and hence in the pathogenesis of microangiopathy at the functional level.

Effects of buflomedil on microvascular disorders in diabetic patients.

The aim of this work was to evaluate the effect of buflomedil on hemorheologic, hemodynamic and microcirculatory properties in diabetic patients. Patients were 20 noninsulin-dependent diabetics with distal arteriopathy characterized by chronic hypoxia (transcutaneous oxygen pressure = 25.2 +/- 4.8 mm Hg). They were randomly assigned to two groups for a double-blind study versus placebo. The treatment consisted of a 4-hour intravenous perfusion of 400 mg of buflomedil or placebo as a daily dose during 7 days. Results showed significant improvements in hemodynamic parameters such as post-occlusive peak flow and time to peak flow at the end of buflomedil treatment. In the same manner, the transcutaneous oxygen pressure was found to be significantly increased after buflomedil treatment, whereas there was no modification by placebo. Indeed, red cell aggregation was significantly less important as a result of buflomedil treatment whilst red cell deformability was found to be significantly increased. These hemorheological improvements make the blood flow redistribution through the microcirculatory network easier and lead ultimately to better tissue oxygenation.

Red blood cell aggregation in diabetes mellitus.

The aim of this work is to study the red blood cell aggregation in diabetic patients. Investigations have been performed via rheometric technics on four various types of diabetics (diabetics with good metabolic control, diabetics with poor metabolic control, diabetics with a distal angiopathy, without clinical signs, diabetics with a distal angiopathy characterized by cutaneous trophic disorders). Results, compared with those of healthy subjects, show that the reversible phenomenon of erythrocyte aggregation is significantly modified in diabetic. Indeed, the red cell aggregation tendency is found to be increased in diabetics. This hyperaggregation becomes more important when the diabetes is characterized by a poor metabolic control or a distal angiopathy with or without cutaneous trophic disorders. Disturbances of red cell aggregation observed in this report are discussed as a result of plasma protein changes and may confirm the role of hemorheological properties in the pathogenesis of diabetic angiopathy.

[Hemorheology of venous insufficiency]. / Aspects hémorhéologiques de l'insuffisance veineuse.

UNLABELLED: The aim of this paper is to study the rheological properties of blood in patients with venous insufficiency. MATERIAL AND METHODS: Measurements have been performed for 20 healthy control subjects and 20 patients presenting a venous insufficiency with varicose veins of lower limbs. Blood has been withdrawn from the veins of the lower limbs at rest and after 10 minutes of venous stasis (standing position and 100 mmHg tourniquet). The following measurements have been performed: hematocrit by microcentrifugation; fibrinogen by nephelometry; plasma viscosity by means of capillary viscosimeter (Myrenne KSPV4); deformability by Hanss hemorheometer using nucleopore membranes and red blood cell aggregation and disaggregation by means of a SEFAM erythro-aggregometer. RESULTS: 1. Hematocrit was not significantly different between both groups of subjects at rest. However, it increased significantly after venous stasis in patients with varicose veins but it was not found to be increased in healthy subjects. 2. Before and after stasis, the fibrinogen level was higher in patients than in controls. After stasis, a significant increased was found only in the patient group. 3. Plasma viscosity was found to be modified as the same manner as the fibrinogen level. Besides, the fibrinogen level and plasma viscosity were found to be correlated to each other. 4. Before and after stasis, red cells of patients were significantly less deformable than those of controls. After stasis, they were found to be more altered, in patients. But there were no difference in controls before and after stasis. 5. Aggregation and disaggregation parameters have been found to be disturbed in patient group. Disturbances were more pronounced after stasis. CONCLUSION: Venous insufficiency can be characterized by alteration of rheological parameters and the blood stasis in varicose veins may enhance these alterations. These results indicate the importance of hemorheological disturbances in the pathogenesis of this disease.

[Venous insufficiency and hemorheology. Influence of venous stasis on erythrocyte aggregation and disaggregation]. / Insuffisance veineuse et hémorhéologie. Influence de la stase veineuse sur l'agrégation et la désagrégation érythrocytaires.

UNLABELLED: The aim of this study was to assess the rheological properties of blood in patients with superficial venous insufficiency, in the very exact place of the hemodynamic disturbance i.e. in the veins of the lower limbs. MATERIAL AND METHODS: Several hemorheological parameters were studied in 20 patients (12 females and 8 males, 20 to 44 years old) with varicose veins of the lower limbs (insufficiency of the superficial venous system and no history of thrombosis). The results were compared to those obtained in 20 healthy controls matched for sex, age, weight and schedule for blood withdrawal. Two blood samples were obtained from the veins of the lower limbs of each subject: the first one at rest and the second after 10 minutes of "venous stasis" (standing position and 100 mm Hg tourniquet), in a temperature controlled room (22 degrees C). Every blood test was performed within one hour after blood withdrawal: --hematocrit (microcentrifugation) and fibrinogen (nephelometry); --plasma viscosity in a 37 degrees C temperature controlled capillary viscometer (Myrenne KSPV4); --erythrocyte filterability using the Hemorheometer (8% hematocrit and polycarbonate nuclepore membrane with a pore diameter of 5 microns); --erythrocyte aggregation and disaggregation (Myrenne AMM1 aggregometer and Erythroaggregometer SEFAM). RESULTS: 1. Hematocrit was not significantly different between both groups of subjects at rest. However, it increased significantly after venous stasis in patients with varicose veins (44.2% vs 41.8%, p. less than 0.05) and that was not found in controls. 2. At rest, the fibrinogen level was higher in patients than in controls (3.54 milligrams vs 2.41 milligrams, p less than 0.01). After statis, a significant increased was found only in the patients group (3.93 milligrams, p less than 0.05). 3. In a similar way, plasma viscosity at rest was significantly higher in patients (1.23 mPa.s) than in controls (1.11 mPa.s, p less than 0.01), and after stasis a further increase was found in the patients group (1.32 mPa.s, p less than 0.01). 4. Also the erythrocyte filterability index was altered at rest in patients (20.9) when compared to controls (15.1, p less than 0.01). A significant increase of this index was only found in the patients group (23, p less than 0.01). 5. Every aggregation parameters were significantly different at rest when comparing subjects groups, the most significant difference concerning the threshold of disaggregation (171.2 s-1 vs 106.8 S-1, p less than 0.001. Erythrocyte aggregation index was increased after stasis in patients but not in controls, with both 600 S-1 and 3 S-1 shear rates. 6. Positive correlations were found between low shear rate aggregation index on one hand and fibrinogen (r = 0.61), plasma viscosity (r = 0.51) and erythrocyte filterability index (r = 0.47) on the other hand...

Pharmacoclinical study of the action of vinburnin versus placebo: study of the hemodynamic, microcirculatory and rheological effects in angiopathy of the lower limbs in diabetes mellitus.

The diabetic macroangiopathy of lower limbs in characterized by chronic hypoxia with several abnormalities of hemodynamic, microcirculatory, rheological and metabolic red cell parameters. This study, in a double blind test with placebo was carried out on 40 subjects: 20 normal subjects and 20 diabetic patients suffering from microangiopathy of lower limbs. Ten are treated by 45 mg iv per day of Vinburnin, the 10 others received a placebo. Before and after treatment, the following parameters were measured: arterial flow rate at rest and after hyperhemia, transcutaneous oxygen level (TCpO2), red cell deformability, plasma viscosity, fibrinogen, red cell 2,3-diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP). In this study, we have proved several effects of Vinburnin on the microcirculatory and rheological parameters the most essential for the transport of oxygen. The significant improvement of TCpO2, of ATP and 2,3-DPG red cell levels, of plasma viscosity and red cell deformability, even though we have no haemodynamic changes, confirm the rheological effects of Vinburnin. These pharmacological properties prove the interest and the special position of Vinburnin in the treatment of vascular diseases with acute or chronic tissular hypoxia.