SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
In Vivo Platelet Activation in Diabetes Mellitus
Patients with diabetes mellitus are prone to develop vascular complications because of macro- and microangiopathy, which leads to increased morbidity and mortality from coronary heart disease compared with nondiabetics. This excess of risk of macrovascular disease in diabetics is independent of other major risk factors, such as smoking, hypertension, and hyperlipidemia.1 It has been suggested that hemostatic abnormalities (particularly platelet function changes) present in some diabetic patients may have a role in the pathogenesis of both small and large vessel disease.2 It is also possible that many of these abnormalities are a consequence, rather than a cause of vascular disease. Despite the numerous methods of studying platelet function in vitro and platelet prostaglandin metabolism, the question as to whether abnormal platelet function precedes or is a consequence of vascular disease remains to be answered. Moreover, the relationship between platelet function, diabetic treatment, and the degree of glycemic control is not fully understood. The different ex vivo techniques currently available have their limitations, and problems arise when comparing the results obtained by different platelet variables assessed; their relationship to each other, and to the in vivo situation, is unclear. Problems arise when assessing the results of studies that have used heterogeneous groups of subjects; differing types of diabetes, ages, sex and varying degrees of microvascular or macrovascular disease. Moreover, the methods of excluding subclinical vascular disease are limited, and therefore "disease free" is a term to be interpreted with caution. Several approaches used to assess platelet function ex vivo include
From the Department of Medicine, II University of Rome, Rome, Division of Hematology, University of Chieti, Chieti, and Department of Pharmacology, Catholic University School of Medicine, Rome, Italy. Reprint requests: Dr Strano, Via Vigna Stelluti 40, 00191 Rome, Italy. 422
studies of agonist (such as adenosine diphosphate (ADP), collagen, sodium arachidonate)-induced platelet aggregation and thromboxane formation. Platelet aggregation represents an index of capacity, assessing the ability of platelets to respond to varying concentrations of different agonists in a closed, nonflowing system. The relevance of such ex vivo measurements to the actual occurrence of platelet activation in vivo is far from being established.
STUDIES OF PLATELET ACTIVATION IN VIVO Plasma Measurements Platelet alpha-granules contain at least three platelet-specific proteins—platelet factor 4 (PF4), β-thromboglobulin (BTG), and platelet-derived growth factor (PDGF)—together with a number of proteins also found in plasma, including fibrinogen, fibronectin, albumin, and Factor VIII/von Willebrand factor. Since in vivo alpha-granule release occurs readily at times without dense granule release or reduced platelet viability, the appearance of these proteins in plasma appears to con stitute sensitive and objective evidence of platelet acti vation in vivo. If, as seems likely, PDGF is released in concert with other alpha-granule proteins, this mitogen may be involved in the genesis of intimal lesion forma tion, possibly even in the absence of platelet destruction or dense granule release. However, artifactual increases in plasma levels occur readily due to release during sample collection and processing. Studies performed to obtain, in normals, plasma BTG levels that approached levels in untransfused patients with severe thrombocy topenia secondary to aplastic anaemia3 demonstrated that the inhibitor system, temperature, centrifugation speed, and time taken to process the sample are all important factors. Despite the rigorous attention paid to these proce-
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
Downloaded by: University of British Columbia. Copyrighted material.
ANTONIO STRANO, M.D., GIOVANNI DAVÌ , M.D., and CARLO PATRONO, M.D.
423
DAVÌ, PATRONO
dures, a persistent difference in plasma levels between normal and aplastic subjects can be observed and this implies that it is very difficult to prevent all in vitro release of alpha-granule contents. Therefore, it is likely that measurements of platelet-derived products in peripheral venous blood reflect a sum of the true circulating levels of these compounds and of variable amounts being released by platelets during and after sampling. Similarly, the measurements of thromboxane B 2 (TXB2) in peripheral venous plasma cannot reliably reflect changes in thromboxane A2 (TXA2) synthesis and release in vivo, because TXB2 disappears rapidly from the human circulation and, moreover, it can be added to plasma by a minimal degree of platelet activation occurring in relation to blood sampling, as for the platelet alpha-granule release.
Urinary Measurements Biologically significant in vivo release of alphagranules should be manifested by the simultaneous appearance of alpha-granule proteins in the urine as well as plasma, and partial loss of alpha-granule content from platelets. BTG is catabolized by the kidneys and about 0.1 to 0.5% of the circulating BTG appears in the urine of a normal individual. Therefore urine BTG may be a reflection of the plasma BTG level. An important advantage of the BTG urine assay is that the daily total BTG release may be estimated. In fact, due the short half-life of BTG in plasma, transient in vivo release is difficult to detect by a single plasma assay. Moreover, all artifacts due to sample collection and blood handling are minimized. Therefore any conclusive statement addressing urinary clearance of alpha-granule proteins must be made using direct urinary measurements coupled with plasma determinations. In the case of TXA2 we have to consider the episodic nature of its release and the local nature of its action. These features are ensured by a very high chemical instability (due to nonenzymatic hydrolysis to TXB2) coupled with an extensive enzymatic degradation occurring in the lungs, liver, and kidneys. TXB2 undergoes two major pathways of metabolism in man, one involving beta oxidation resulting in the formation of 2,3-dinor-TxB2 and the other involving dehydrogenation (ll-dehydro-TxB2). 11-dehydro-TXB2 has a substantially longer plasma half-life and is excreted at a higher rate than 2,3-dinor-TXB2.4 Therefore, 2,3-dinor-TXB2 and 1 l-dehydro-TxB2 represent enzymatic derivatives of TXB2 with an extended plasma half-life (15 and 50 minutes, respectively) that cannot be synthesized by platelets ex vivo, providing a reliable assessment of platelet activation in vivo, as reviewed previously.5
PLATELET ACTIVATION IN DIABETES MELLITUS Many investigators have reported increased plasma BTG levels in diabetics,6,7 but Alessandrini et al8 did not observe a significant difference in plasma levels of BTG in patients with type I diabetes. These findings could reflect problems in recognizing spuriously elevated BTG levels as a consequence of in vitro platelet activation and failure in the attempts to minimize the contribution of ex vivo platelet activation through standardization of blood sampling. Due to the differing half-lives of BTG (100 minutes) and PF4 (very short as a consequence of its binding to vascular endothelium), a ratio of their plasma concentrations in the same blood sample has been suggested as being of value in determining the presence of in vitro activation as a consequence of poor venesection techniques or blood sample handling. For this reason PF4 is now routinely measured with BTG, although many reports do not state whether results with a low BTG/PF4 ratio were discarded.6 Many of the early studies involving BTG measurements in diabetic subjects used differing assay methods and did not include simultaneous measurement of PF4 levels. Furthermore, many of these studies involving diabetics with microvascular complications made no mention of renal function; this is of relevance, since renal impairment per se is associated with elevation of plasma BTG levels.6 Recently, PDGF content was found markedly decreased in type I diabetics and plasma BTG was increased compared with control subjects. A significant negative correlation was found between plasma BTG level and BTG total platelet content, associated with a significant positive correlation between platelet BTG content and PDGF. These results suggest that PDGF release might be increased in diabetic subjects and this may partially account for the cell proliferation observed in diabetic angiopathy.9 Increased urinary BTG levels were found in patients with type I diabetes10 and the difference between diabetic and normal subjects was still observed when patients with decreased creatinine clearance were excluded. We have previously demonstrated that platelets obtained from type II diabetics synthesize significantly higher amounts of TXB2 than type I diabetics and matched control subjects.11 Di Minno et al12 have suggested that the increased fibrinogen binding and aggregation of platelets from type I diabetic subjects in response to ADP or collagen is mediated by increased formation of prostaglandin H2, TXA2, or both. However, these ex vivo measurements have been questioned recently by the in vivo findings of Alessandrini et al8 who
Downloaded by: University of British Columbia. Copyrighted material.
PLATELET ACTIVATION IN DIABETES—STRANO,
SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
measured the urinary excretion of 2,3-dinor-TXB2 in type I diabetics and found no statistically significant differences between diabetics with or without retinopathy and nondiabetic control subjects. Recently, we sought to determine, in type II diabetes, whether the formation of these platelet agonists is altered in vivo.13 A cross-sectional comparison of 11dehydro-TXB2 excretion and platelet function was performed in 50 patients with type II diabetes mellitus with clinical evidence of macrovascular disease and normal renal function, and 32 healthy control subjects. Metabolite excretion was significantly higher in patients (91.1 + 56.4 ng/hr; mean + SD) than controls (23.6 + 13.1). Thirty-seven of 50 patients (74%) had urinary metabolite excretion in excess of 2 standard deviations from the normal mean. Moreover, diabetic patients had elevated TXA2 biosynthesis irrespective of the type of macrovascular complications. Patients who had serum fructosamine levels higher than 3.0 mmol/liter were characterized by significantly higher 11-dehydro-TXB2 excretion than patients with levels lower than 3.0 mmol/ liter: 76.8 + 49.1 versus 37.3 + 16.4 ng/hr. Three weeks of intensive insulin treatment was associated with a statistically significant reduction in serum fructosamine in 10 diabetic patients, and with no significant change in 5 patients. The patients who achieved tight metabolic control showed a statistically significant reduction in urinary ll-dehydro-TXB2 from 82.3 + 60.6 to 34.4 + 24.4. Eight of the 10 patients actually showed a reduction in metabolite excretion greater than 50%. 11-DehydroTxB2 did not change significantly in the other five patients, in whom intensive insulin treatment failed to achieve better metabolic control. Our results seem to show that type II diabetes is associated with a relatively reproducible and persistent abnormality of platelet function that can be detected in vivo. This is likely to reflect a systemic rather than localized stimulus to platelet activation and a continuous rather than episodic alteration. Although our study has demonstrated that biochemical indexes of platelet activation are related to the state of metabolic control and tight metabolic control can influence the actual rate of TXA2 biosynthesis in vivo, the mechanisms responsible for this relationship are largely speculative. Changes in plasma glucose or insulin levels, reduced nonenzymatic glycosylation of collagen, reduced plasma apoprotein B levels, as well as changes in the properties of red cell and platelet membranes have all been proposed as contributing to altered platelet reactivity in diabetes mellitus. Despite these uncertainties, it is tempting to speculate that TXA2-dependent platelet activation might transduce the enhanced risk of thrombotic complications associated with diabetic macrovascular disease.
This hypothesis can only be tested by controlled clinical trials of drugs suppressing TXA2 biosynthesis or action. The use of aspirin (325 mg every other day) in apparently healthy physicians followed for approximately 5 years was associated with a 60% reduction in the risk of fatal and nonfatal myocardial infarction in diabetics compared with a 40% risk reduction in nondiabetics.13 However, no formal randomized trial has examined the potential impact of antiplatelet therapy on the development and progression of macrovascular complications in diabetes. Given the evidence for platelet activation in type II diabetes mellitus and the efficacy of low-dose aspirin in suppressing enhanced TXA2 biosynthesis in these patients,12 a solid rationale now exists for a randomized clinical trial of low-dose aspirin assessing the influence of long-term antiplatelet therapy on the incidence of myocardial infarction, stroke, and vascular death in type II diabetics.
REFERENCES 1. Fuller JH, MJ Shipley, G Rose, RJ Jarret, H Keen: Mortality from coronary heart disease and stroke in relation to the degree of glycaemia; the Whitehall study. Br Med J 287:867-870, 1983. 2. Mustard JF, MA Packham: Platelets and diabetes mellitus. N Engl J Med, 311:665-667, 1984. 3. Files JC, TW Malpass, EK Yee, JL Ritchie, LA Harker: Studies of human platelet alpha-granule release in vivo. Blood 58:607618, 1983. 4. Patrono C, Ciabattoni G, Pugliese F, Pierucci A, Blair IA, Fitzgerald GA: Biochemical indices of arachidonate metabolism by platelets and vascular endothelium in vivo. In: Patrono C, Fitzgerald GA (Eds): Platelets and vascular occlusion, Raven Press, New York, 1989, pp 5. Ciabattoni G, F Pugliese, G Daví, A Pierucci, BM Simonetti, C Patrono: Fractional conversion of thromboxane B 2 to urinary 11-dehydro-thromboxane B2 in man. Biochim Biophys Acta 992:66-70, 1989. 6. Hendra T, DJ Betteridge: Platelet function, platelet prostanoids and vascular prostacyclin in diabetes mellitus. Prostagl Leukotr Essential Fatty Acids 35:197-212, 1989. 7. Zahavi J, M Zahavi: Platelet function in type I diabetes mellitus. N Engl J Med, 319:1665-1666, 1988. 8. Alessandrini P, J McRae, S Feman, GA Fitzgerald: Thromboxane biosynthesis and platelet function in type I diabetes mellitus. N Engl J Med 319:208-212, 1988. 9. Guillaussaeau PJ, E Dupuy, MC Bryckaert, J Timsit, P Chanson, G Tobelem, JP Caen, J Lubetzki: Platelet-derived growth factor (PDGF) in type 1 diabetes mellitus. Eur J Clin Invest 19:172-175, 1989. 10. Van Oost BA, B Veldhuyzen, APM Timmermans, JJ Sixma: Increased urinary beta-thromboglobulin excretion in diabetes assayed with a modified RIA technique. Thromb Haemost 49:18-20, 1983. 11. Daví G, GB Rini, M Averna, A Notarbartolo, A Strano: Thromboxane A2 formation and platelet sensitivity to prostacyclin in
Downloaded by: University of British Columbia. Copyrighted material.
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PLATELET ACTIVATION IN DIABETES—STRANO, DAVÌ, PATRONO
13. Davì G, I Catalano, M Averna, A Notarbartolo, A Strano, G Ciabattoni, C Patrono: Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med 322:17691774, 1990.
Downloaded by: University of British Columbia. Copyrighted material.
insulin-dependent and insulin-independent diabetics. Thromb Res 26:359-370, 1982. 12. Di Minno G, MJ Silver, AM Cerbone: Increased binding of fibrinogen to platelets in diabetes: The role of prostaglandins and thromboxane. Blood 65:156-162, 1985.
425
In Vivo Platelet Activation in Diabetes Mellitus
Patients with diabetes mellitus are prone to develop vascular complications because of macro- and microangiopathy, which leads to increased morbidity and mortality from coronary heart disease compared with nondiabetics. This excess of risk of macrovascular disease in diabetics is independent of other major risk factors, such as smoking, hypertension, and hyperlipidemia.1 It has been suggested that hemostatic abnormalities (particularly platelet function changes) present in some diabetic patients may have a role in the pathogenesis of both small and large vessel disease.2 It is also possible that many of these abnormalities are a consequence, rather than a cause of vascular disease. Despite the numerous methods of studying platelet function in vitro and platelet prostaglandin metabolism, the question as to whether abnormal platelet function precedes or is a consequence of vascular disease remains to be answered. Moreover, the relationship between platelet function, diabetic treatment, and the degree of glycemic control is not fully understood. The different ex vivo techniques currently available have their limitations, and problems arise when comparing the results obtained by different platelet variables assessed; their relationship to each other, and to the in vivo situation, is unclear. Problems arise when assessing the results of studies that have used heterogeneous groups of subjects; differing types of diabetes, ages, sex and varying degrees of microvascular or macrovascular disease. Moreover, the methods of excluding subclinical vascular disease are limited, and therefore "disease free" is a term to be interpreted with caution. Several approaches used to assess platelet function ex vivo include
From the Department of Medicine, II University of Rome, Rome, Division of Hematology, University of Chieti, Chieti, and Department of Pharmacology, Catholic University School of Medicine, Rome, Italy. Reprint requests: Dr Strano, Via Vigna Stelluti 40, 00191 Rome, Italy. 422
studies of agonist (such as adenosine diphosphate (ADP), collagen, sodium arachidonate)-induced platelet aggregation and thromboxane formation. Platelet aggregation represents an index of capacity, assessing the ability of platelets to respond to varying concentrations of different agonists in a closed, nonflowing system. The relevance of such ex vivo measurements to the actual occurrence of platelet activation in vivo is far from being established.
STUDIES OF PLATELET ACTIVATION IN VIVO Plasma Measurements Platelet alpha-granules contain at least three platelet-specific proteins—platelet factor 4 (PF4), β-thromboglobulin (BTG), and platelet-derived growth factor (PDGF)—together with a number of proteins also found in plasma, including fibrinogen, fibronectin, albumin, and Factor VIII/von Willebrand factor. Since in vivo alpha-granule release occurs readily at times without dense granule release or reduced platelet viability, the appearance of these proteins in plasma appears to con stitute sensitive and objective evidence of platelet acti vation in vivo. If, as seems likely, PDGF is released in concert with other alpha-granule proteins, this mitogen may be involved in the genesis of intimal lesion forma tion, possibly even in the absence of platelet destruction or dense granule release. However, artifactual increases in plasma levels occur readily due to release during sample collection and processing. Studies performed to obtain, in normals, plasma BTG levels that approached levels in untransfused patients with severe thrombocy topenia secondary to aplastic anaemia3 demonstrated that the inhibitor system, temperature, centrifugation speed, and time taken to process the sample are all important factors. Despite the rigorous attention paid to these proce-
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
Downloaded by: University of British Columbia. Copyrighted material.
ANTONIO STRANO, M.D., GIOVANNI DAVÌ , M.D., and CARLO PATRONO, M.D.
423
DAVÌ, PATRONO
dures, a persistent difference in plasma levels between normal and aplastic subjects can be observed and this implies that it is very difficult to prevent all in vitro release of alpha-granule contents. Therefore, it is likely that measurements of platelet-derived products in peripheral venous blood reflect a sum of the true circulating levels of these compounds and of variable amounts being released by platelets during and after sampling. Similarly, the measurements of thromboxane B 2 (TXB2) in peripheral venous plasma cannot reliably reflect changes in thromboxane A2 (TXA2) synthesis and release in vivo, because TXB2 disappears rapidly from the human circulation and, moreover, it can be added to plasma by a minimal degree of platelet activation occurring in relation to blood sampling, as for the platelet alpha-granule release.
Urinary Measurements Biologically significant in vivo release of alphagranules should be manifested by the simultaneous appearance of alpha-granule proteins in the urine as well as plasma, and partial loss of alpha-granule content from platelets. BTG is catabolized by the kidneys and about 0.1 to 0.5% of the circulating BTG appears in the urine of a normal individual. Therefore urine BTG may be a reflection of the plasma BTG level. An important advantage of the BTG urine assay is that the daily total BTG release may be estimated. In fact, due the short half-life of BTG in plasma, transient in vivo release is difficult to detect by a single plasma assay. Moreover, all artifacts due to sample collection and blood handling are minimized. Therefore any conclusive statement addressing urinary clearance of alpha-granule proteins must be made using direct urinary measurements coupled with plasma determinations. In the case of TXA2 we have to consider the episodic nature of its release and the local nature of its action. These features are ensured by a very high chemical instability (due to nonenzymatic hydrolysis to TXB2) coupled with an extensive enzymatic degradation occurring in the lungs, liver, and kidneys. TXB2 undergoes two major pathways of metabolism in man, one involving beta oxidation resulting in the formation of 2,3-dinor-TxB2 and the other involving dehydrogenation (ll-dehydro-TxB2). 11-dehydro-TXB2 has a substantially longer plasma half-life and is excreted at a higher rate than 2,3-dinor-TXB2.4 Therefore, 2,3-dinor-TXB2 and 1 l-dehydro-TxB2 represent enzymatic derivatives of TXB2 with an extended plasma half-life (15 and 50 minutes, respectively) that cannot be synthesized by platelets ex vivo, providing a reliable assessment of platelet activation in vivo, as reviewed previously.5
PLATELET ACTIVATION IN DIABETES MELLITUS Many investigators have reported increased plasma BTG levels in diabetics,6,7 but Alessandrini et al8 did not observe a significant difference in plasma levels of BTG in patients with type I diabetes. These findings could reflect problems in recognizing spuriously elevated BTG levels as a consequence of in vitro platelet activation and failure in the attempts to minimize the contribution of ex vivo platelet activation through standardization of blood sampling. Due to the differing half-lives of BTG (100 minutes) and PF4 (very short as a consequence of its binding to vascular endothelium), a ratio of their plasma concentrations in the same blood sample has been suggested as being of value in determining the presence of in vitro activation as a consequence of poor venesection techniques or blood sample handling. For this reason PF4 is now routinely measured with BTG, although many reports do not state whether results with a low BTG/PF4 ratio were discarded.6 Many of the early studies involving BTG measurements in diabetic subjects used differing assay methods and did not include simultaneous measurement of PF4 levels. Furthermore, many of these studies involving diabetics with microvascular complications made no mention of renal function; this is of relevance, since renal impairment per se is associated with elevation of plasma BTG levels.6 Recently, PDGF content was found markedly decreased in type I diabetics and plasma BTG was increased compared with control subjects. A significant negative correlation was found between plasma BTG level and BTG total platelet content, associated with a significant positive correlation between platelet BTG content and PDGF. These results suggest that PDGF release might be increased in diabetic subjects and this may partially account for the cell proliferation observed in diabetic angiopathy.9 Increased urinary BTG levels were found in patients with type I diabetes10 and the difference between diabetic and normal subjects was still observed when patients with decreased creatinine clearance were excluded. We have previously demonstrated that platelets obtained from type II diabetics synthesize significantly higher amounts of TXB2 than type I diabetics and matched control subjects.11 Di Minno et al12 have suggested that the increased fibrinogen binding and aggregation of platelets from type I diabetic subjects in response to ADP or collagen is mediated by increased formation of prostaglandin H2, TXA2, or both. However, these ex vivo measurements have been questioned recently by the in vivo findings of Alessandrini et al8 who
Downloaded by: University of British Columbia. Copyrighted material.
PLATELET ACTIVATION IN DIABETES—STRANO,
SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
measured the urinary excretion of 2,3-dinor-TXB2 in type I diabetics and found no statistically significant differences between diabetics with or without retinopathy and nondiabetic control subjects. Recently, we sought to determine, in type II diabetes, whether the formation of these platelet agonists is altered in vivo.13 A cross-sectional comparison of 11dehydro-TXB2 excretion and platelet function was performed in 50 patients with type II diabetes mellitus with clinical evidence of macrovascular disease and normal renal function, and 32 healthy control subjects. Metabolite excretion was significantly higher in patients (91.1 + 56.4 ng/hr; mean + SD) than controls (23.6 + 13.1). Thirty-seven of 50 patients (74%) had urinary metabolite excretion in excess of 2 standard deviations from the normal mean. Moreover, diabetic patients had elevated TXA2 biosynthesis irrespective of the type of macrovascular complications. Patients who had serum fructosamine levels higher than 3.0 mmol/liter were characterized by significantly higher 11-dehydro-TXB2 excretion than patients with levels lower than 3.0 mmol/ liter: 76.8 + 49.1 versus 37.3 + 16.4 ng/hr. Three weeks of intensive insulin treatment was associated with a statistically significant reduction in serum fructosamine in 10 diabetic patients, and with no significant change in 5 patients. The patients who achieved tight metabolic control showed a statistically significant reduction in urinary ll-dehydro-TXB2 from 82.3 + 60.6 to 34.4 + 24.4. Eight of the 10 patients actually showed a reduction in metabolite excretion greater than 50%. 11-DehydroTxB2 did not change significantly in the other five patients, in whom intensive insulin treatment failed to achieve better metabolic control. Our results seem to show that type II diabetes is associated with a relatively reproducible and persistent abnormality of platelet function that can be detected in vivo. This is likely to reflect a systemic rather than localized stimulus to platelet activation and a continuous rather than episodic alteration. Although our study has demonstrated that biochemical indexes of platelet activation are related to the state of metabolic control and tight metabolic control can influence the actual rate of TXA2 biosynthesis in vivo, the mechanisms responsible for this relationship are largely speculative. Changes in plasma glucose or insulin levels, reduced nonenzymatic glycosylation of collagen, reduced plasma apoprotein B levels, as well as changes in the properties of red cell and platelet membranes have all been proposed as contributing to altered platelet reactivity in diabetes mellitus. Despite these uncertainties, it is tempting to speculate that TXA2-dependent platelet activation might transduce the enhanced risk of thrombotic complications associated with diabetic macrovascular disease.
This hypothesis can only be tested by controlled clinical trials of drugs suppressing TXA2 biosynthesis or action. The use of aspirin (325 mg every other day) in apparently healthy physicians followed for approximately 5 years was associated with a 60% reduction in the risk of fatal and nonfatal myocardial infarction in diabetics compared with a 40% risk reduction in nondiabetics.13 However, no formal randomized trial has examined the potential impact of antiplatelet therapy on the development and progression of macrovascular complications in diabetes. Given the evidence for platelet activation in type II diabetes mellitus and the efficacy of low-dose aspirin in suppressing enhanced TXA2 biosynthesis in these patients,12 a solid rationale now exists for a randomized clinical trial of low-dose aspirin assessing the influence of long-term antiplatelet therapy on the incidence of myocardial infarction, stroke, and vascular death in type II diabetics.
REFERENCES 1. Fuller JH, MJ Shipley, G Rose, RJ Jarret, H Keen: Mortality from coronary heart disease and stroke in relation to the degree of glycaemia; the Whitehall study. Br Med J 287:867-870, 1983. 2. Mustard JF, MA Packham: Platelets and diabetes mellitus. N Engl J Med, 311:665-667, 1984. 3. Files JC, TW Malpass, EK Yee, JL Ritchie, LA Harker: Studies of human platelet alpha-granule release in vivo. Blood 58:607618, 1983. 4. Patrono C, Ciabattoni G, Pugliese F, Pierucci A, Blair IA, Fitzgerald GA: Biochemical indices of arachidonate metabolism by platelets and vascular endothelium in vivo. In: Patrono C, Fitzgerald GA (Eds): Platelets and vascular occlusion, Raven Press, New York, 1989, pp 5. Ciabattoni G, F Pugliese, G Daví, A Pierucci, BM Simonetti, C Patrono: Fractional conversion of thromboxane B 2 to urinary 11-dehydro-thromboxane B2 in man. Biochim Biophys Acta 992:66-70, 1989. 6. Hendra T, DJ Betteridge: Platelet function, platelet prostanoids and vascular prostacyclin in diabetes mellitus. Prostagl Leukotr Essential Fatty Acids 35:197-212, 1989. 7. Zahavi J, M Zahavi: Platelet function in type I diabetes mellitus. N Engl J Med, 319:1665-1666, 1988. 8. Alessandrini P, J McRae, S Feman, GA Fitzgerald: Thromboxane biosynthesis and platelet function in type I diabetes mellitus. N Engl J Med 319:208-212, 1988. 9. Guillaussaeau PJ, E Dupuy, MC Bryckaert, J Timsit, P Chanson, G Tobelem, JP Caen, J Lubetzki: Platelet-derived growth factor (PDGF) in type 1 diabetes mellitus. Eur J Clin Invest 19:172-175, 1989. 10. Van Oost BA, B Veldhuyzen, APM Timmermans, JJ Sixma: Increased urinary beta-thromboglobulin excretion in diabetes assayed with a modified RIA technique. Thromb Haemost 49:18-20, 1983. 11. Daví G, GB Rini, M Averna, A Notarbartolo, A Strano: Thromboxane A2 formation and platelet sensitivity to prostacyclin in
Downloaded by: University of British Columbia. Copyrighted material.
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PLATELET ACTIVATION IN DIABETES—STRANO, DAVÌ, PATRONO
13. Davì G, I Catalano, M Averna, A Notarbartolo, A Strano, G Ciabattoni, C Patrono: Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med 322:17691774, 1990.
Downloaded by: University of British Columbia. Copyrighted material.
insulin-dependent and insulin-independent diabetics. Thromb Res 26:359-370, 1982. 12. Di Minno G, MJ Silver, AM Cerbone: Increased binding of fibrinogen to platelets in diabetes: The role of prostaglandins and thromboxane. Blood 65:156-162, 1985.
425
