Relationships between Haemostatic Factors and Capillary Morphology in Human Diabetic Neuropathy

Summary

We have examined haemostatic factors in 15 diabetic patients with peripheral neuropathy and 10 diabetic patients without clinical complications. Plasma and blood viscosity, fibrinogen, factor VIIIc, von Willebrand factor activity, spontaneous platelet aggregation and fibrinolytic activity were not significantly different between diabetic patients without clinical complications and diabetic patients with peripheral neuropathy. Platelet aggregation was enhanced in diabetic patients with neuropathy compared with those without complications. In the 15 patients with neuropathy and 3 without complications, who underwent biopsy of sural nerve, skin and muscle, associations were found between haemostatic variables and measures of nerve capillary pathology, notably: plasma fibrinogen and nerve capillary basement membrane thickness (r = 0.70, p <0.001); thromboxane B2 production and nerve capillary basement membrane thickness (r = –0.61, p <0.01); plasma fibrinolytic activity and endoneurial capillary lumen size (r = 0.60, p <0.01) and endothelial cell outer perimeter (r = 0.65, p <0.01). The main associations of skin and muscle capillary abnormalities were with measures of in vitro platelet aggregation, and the correlations found with nerve capillary measurements were not echoed in the overlying muscle and skin. The results are supportive of the involvement of haemostatic abnormalities in the pathogenesis of diabetic neuropathy.

• REFERENCES

• 1 Thomas PK. The pathogenesis of diabetic neuropathy: current problems and prospects. In: Diabetic Neuropathy. Ward JD, Goto Y. (eds) Wiley, Chichester: 1990. pp 03-16
• 2 Greene DA, Lattimer S, Ulbrecht J, Carroll P. Glucose-induced alterations in nerve metabolism: current perspective on the pathogenesis of diabetic neuropathy and future directions for research and therapy. Diabetes Care 1985; 8: 290-299
• 3 Dyck PJ, Sherman WR, Hallcher LM, Service JF, O’Brien P, Grisa LS, Palumbo PJ, Swanson CJ. Human diabetic endoneurial sorbitol, fructose and myoinositol related to sural nerve morphometry. Ann Neurol 1980; 8: 590-596
• 4 Hale PJ, Nattrass M, Silverman SH, Sennit C, Perkins CM, Aden A, Sundkvist G. Peripheral nerve concentrations of glucose, fructose, sorbitol and myoinositol in diabetic and non-diabetic patients. Diabetologia 1987; 30: 464-467
• 5 Dyck PJ, Zimmerman BR, Vilen TH, Minnerath SR, Karnes JL, Yao JK, Poduslo JF. Nerve glucose, fructose, sorbitol, myoinositol, and fibre degeneration and regeneration in diabetic neuropathy. N Engl J Med 1988; 319: 542-548
• 6 Fagerberg SE. Diabetic neuropathy, a clinical and histological study on the significance of vascular affections. Acta Med Scand 1959; 164 (suppl 345): 01-97
• 7 Woltman HW, Wilder RM. Diabetes mellitus: pathological changes in the spinal cord and peripheral nerves. Arch Intern Med 1929; 44: 576-603
• 8 Greaves M, Preston FE. Haemostatic abnormalities in diabetics. In: Diabetes and Heart Disease. Jarrett RJ. (ed) Elsevier Science Publishers, Amsterdam,: 1984. pp 47-80
• 9 Timperley WR, Ward JD, Preston FE, Duckworth T. Clinical and histological studies in diabetic neuropathy: a reassessment of vascular factors in relation to intravascular coagulation. Diabetologia 1976; 12: 237-243
• 10 Dyck PJ, Hansen S, Karnes J, O’Brien P, Yasuda H, Windebank A, Zimmerman B. Capillary number and percentage closed in human diabetic sural nerve. Proc Natl Acad Sci USA 1985; 82: 2513-2517
• 11 Powell HC, Rosoff J, Myers RR. Microangiopathy in human diabetic neuropathy. Acta Neuropathol (Berl) 1985; 68: 295-305
• 12 Yasuda H, Dyck PJ. Abnormalities of endoneurial micro vessels and sural nerve pathology in diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy. Neurology 1987; 37: 20-28
• 13 Malik RA, Newrick PG, Sharma AK, Jennings A, Ah-See AK, Mayhew TM, Jakubowski J, Boulton AJM, Ward JD. Microangiopathy in human diabetic neuropathy. Diabetologia 1989; 32: 092-102
• 14 Newrick PG, Wilson AJ, Jakubowski J, Boulton AJM, Ward JD. Sural nerve oxygen tension in diabetes. Br Med J 1986; 293: 1053-1054
• 15 Dyck PJ. Hypoxic neuropathy: does hypoxia play a role in diabetic neuropathy?. Neurology 1989; 39: 111-118
• 16 Stoebner P, Mezin P, Vila A, Grosse R, Nopp N, Paramelle B. Microangiopathy of endoneurial vessels in hypoxaemic chronic obstructive pulmonary disease (COPD). A quantitative ultrastructural study. Acta Neuropathol 1989; 78: 388-395
• 17 Malik RA, Masson EA, Sharma AK, Lye RH, Ah-See AK, Compton AM, Tomlinson DR, Hanley SP, Boulton AJM. Hypoxic neuropathy: relevance to human diabetic neuropathy. Diabetologia 1990; 33: 311-318
• 18 Greaves M, Preston FE. The laboratory investigation of acquired and congenital platelet disorders. In: Blood Coagulation and Haemostasis. A Practical Guide. Thomson JM. (ed) Churchill Livingstone, Edinburgh: 1985. pp 056-134
• 19 Biggs R, Eveling J, Richards G. The assay of antihaemophilic-globulin activity. Br J Haematol 1955; 1: 20
• 20 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-240
• 21 Short PE, Williams CE, Picken AM, Mill FGH. Factor VIII related antigen: an improved enzyme immunoassay. Med Lab Sci 1982; 39: 351-355
• 22 Laurell CB. Antigen-antibody crossed electrophoresis. Ann Biochem 1965; 10: 358-361
• 23 Evans RJ, Austen DEG. Assay of ristocetin cofactor using fixed platelets and a platelet counting technique. Br J Haematol 1977; 37: 289-294
• 24 Preston FE, Davidson JF, Samama MM, Desmoyers PC. Automated euglobulin clot lysis time. In: Progress in Chemical Fibrinolysis and Thrombosis, Vol. 2. Davidson JF, Samama MM, Desmoyers PC. (eds) Raven Press; New York: 1976. pp 25-35
• 25 Verheijen JH, Chang G, Kluft C. Evidence for the occurrence of a fast-acting inhibitor for tissue-type plasminogen activator in human plasma. Thromb Haemostas 1984; 51: 392-395
• 26 Fluckiger R, Winterhalter KM. In vitro synthesis of haemoglobin A1. FEBS Lett 1976; 71: 356-360
• 27 Simpson LO. Altered blood rheology in the pathogenesis of diabetic and other neuropathies. Muscle Nerve 1988; 2: 725-744
• 28 Colwell JA, Halushka PV, Sarji KE, Sagel J. Platelet function and diabetes mellitus. Med Clin North Am 1978; 62: 753-766
• 29 Fuller JH, Keen H, Jarrett RJ, Omer T, Meade TW, Chakrabarti R, North WRS, Stirling Y. Haemostatic variables associated with diabetes and its complications. Br Med J 1979; ii: 964-966
• 30 Jones RL, Peterson CM. Haematologic alterations in diabetes mellitus. Am J Med 1981; 70: 3339-3352
• 31 O’Malley BC, Timperley WR, Ward JD, Porter NR, Preston FE. Platelet abnormalities in diabetic peripheral neuropathy. Lancet 1975; ii: 1274-1280
• 32 Fritschi J, Christe M, Lämmle B, Marbet GA, Berger W, Duckert F. Platelet aggregation, β-thromboglobulin and platelet factor 4 in diabetes mellitus and in patients with vascułopathy. Thromb Haemostas 1984; 52: 236-239
• 33 MacRury SM, Lockhart JC, Small M, Weir AI, MacCuish AC, Lowe GDO. Do rheological variables play a role in diabetic peripheral neuropathy?. Diabet Med 1991; 8: 232-236
• 34 Trip MD, Manger Cats V, Van Capelle FJL, Vreeken J. Platelet hypersensitivity and prognosis in survivors of myocardial infarction. N Engl J Med 1990; 322: 1549-1554
• 35 Breddin HK, Krzywanek HJ, Althoff P, Kirchmaier CM, Rosak C, Schepping M, Weichert M, Schoffling K, Uberla K. Spontaneous platelet aggregation and coagulation parameters as risk factors for arterial occlusions in diabetics. Results of the PARD study. Inter Angiol 1986; 5: 181-195
• 36 Plu G, Lecrubier C, Scarabin PY, Baudoin C, Samama M. (Damad Study Group) Does increased platelet aggregation have a prognostic value in the deterioration of background diabetic retinopathy?. Thromb Haemostas 1990; 64: 202-205
• 37 Harati Y. Diabetic peripheral neuropathies. Ann Intern Med 1987; 107: 546-559
• 38 Murphy ME, Johnson PC. Possible contribution of basement membrane to the structural rigidity of blood capillaries. Microvasc Res 1975; 9: 242-245
• 39 Meade TW, Mellows S, Brozovic M, Miller SG, Chakrabarti RR, North WRS, Haines AP, Stirling Y, Imeson JD, Thomson SG. Haemostatic factors and ischaemic heart disease: Principal results of the Northwick Park Heart Study. Lancet 1986; ii: 533-537