SEARCH

SEARCH BY CITATION

The role of platelets and anti-platelet therapy

  1. Top of page
  2. The role of platelets and anti-platelet therapy
  3. References

Obesity is associated with accelerated atherothrombosis and an increased incidence of cardiovascular morbidity and mortality [1,2]. Numerous observations suggest that it is the interplay of the metabolic disorders frequently accompanying excess body weight that promotes the progression of atherosclerotic lesions in obese individuals [3,4]. Platelet hyperactivity, besides hypertension, dyslipidemia, decreased fibrinolysis, and increased procoagulation factors is a consequence of the metabolic syndrome and one of the most central problems obese patients have to face [5–7].

The mechanism by which obesity leads to the development of these vascular and metabolic disorders is the development of insulin resistance which is defined as reduced insulin action in peripheral tissues, such as skeletal muscle, adipose tissue, and liver.

Obesity with a body mass index (BMI) ≥ 35 kg m−2 has been shown to increase the risk of developing Type 2 diabetes by more than 60-fold in women and by 42-fold in men [8]. Steinberg and coworkers showed that severely obese insulin-resistant individuals (mean BMI 34 kg m−2) with normal glucose tolerance have the same degree of impairment in blood flow and vascular reactivity as those with established Type 2 diabetes [9]. Thus, most of the diabetes-specific characteristics of platelets and antiplatelet therapy are attributable to obese patients.

Endothelial dysfunction

Endothelial dysfunction is considered to be a key element in the development of atherosclerosis and has also been closely associated with obesity/insulin resistance [9,10]. Endothelial dysfunction is defined as the partial or complete loss of balance between vasoconstrictors (endothelin, angiotensin II) and vasodilators [nitric oxide (NO), prostacyclin], growth promoting and inhibiting factors, proatherogenic and anti-atherogenic factors, and procoagulant and anticoagulant factors [11]. The reduced production of NO from L-arginine by NO synthase is remarkable in the stetting of insulin resistance and is a clear marker in diabetes. Cyclic nucleotides are the main effectors of platelet antiaggregation, the platelet hyperactivity can be attributed to the resistance to these vasodilating agents.

Impaired fibrinolysis and enhanced coagulation contribute to the hemotactic disorders in obesity. Plasminogen activator inhibitor-1 (PAI-1) is typically increased in the obesity/insulin-resistance state and plays an important role in the genesis of vascular abnormalities. PAI levels are strongly correlated with BMI and fasting plasma insulin levels in Type 2 diabetes and also with triglyceride levels in non-diabetic obese patients. PAI-I levels decrease and fibrinolytic activity improves when insulin resistance and hyperinsulinemia are reduced by weight loss [12–16].

Platelets and antiplatelet therapy

The physiological function of platelets is to plug local damage within the blood vessel. In pathological conditions, such as atherosclerosis, arterial thrombus formation may limit local blood supply, causing local ischemia and the progression of atherosclerosis.

Antiplatelet drugs are divided into four classes:

  • 1
    Inhibition of thromboxane production by acetylsalicylic acid (aspirin). By decreasing the synthesis of thromboxane A2 aspirin administered at a useful dosage of 70–100 mg represents the antiplatelet drug of choice for prevention of vascular complications [17–19]. Obese insulin-resistant non-diabetic patients, however, have a blunted response to the platelet inhibitory effect of acetylsalicylic acid [20].
  • 2
    Blockage of the ADP receptor by ticlopidine and clopidogrel. Thienopyridine antiplatelet agents prevent the activation of the GPIIb/IIIa receptor and the subsequent binding of fibrinogen. In the corresponding study analysing the effects of ticlopidine the progression of overall retinopathy was significantly less severe in the ticlopidine group due to its antithrombotic action [21]. The CAPRIE study revealed that clopidogrel (75 mg daily) was more effective than aspirin (325 mg daily) in reducing the elevated risk for recurrent ischemic events in diabetic patients with a history of diabetes [22].
  • 3
    Antagonists of the GP IIb/IIIa fibrinogen receptor. RGD-analogs and monoclonal antibodies to GP IIb/IIIa such as abciximab inhibit platelet aggregation by preventing the binding of von Willebrand factor, fibrinogen and adhesive molecules to the GP IIb/IIIa receptor. Treatment with abciximab reduced the number of deaths and myocardial infarctions as well as the number of emergency revascularization procedures in both diabetic and non-diabetic patients [23–24].
  • 4
    Inhibition of platelet cyclic AMP breakdown by phosphodiesterase inhibitors. Dipyridamole inhibits phosphodiesterase and thus raises platelet cyclic AMP levels. It potentiates the platelet inhibitory action of prostacyclin and stimulates prostacyclin synthesis [25].

Clinical circumstances with a known association with higher levels of prolactin and leptin such as pregnancy or obesity show an elevated risk of thromboembolic events [26]. Prolactin as well as leptin have been identified as co-activators of ADP-dependent platelet aggregation or P-selectin expression [27]. Therefore, they are suspected of being additional risk factors for both arterial and venous thrombosis. Wallaschofski and coworkers were able to show that prolactin has a stronger effect on platelet activation than leptin in vitro and in vivo. They speculate that the stronger effect of prolactin on ADP-stimulated platelet aggregation, compared with leptin, depends on higher stimulation of CD62p expression by prolactin and that hormonal factors in platelet aggregation and venous or arterial thrombosis should be considered for risk stratification of patients with venous and arterial thrombosis [28,29].

Conclusions

Platelet aggregation plays an essential role in thrombus formation, therefore treatment strategies using antiplatelet agents to prevent subsequent ischemic events are developed. Hormonal aspects should be considered in future. Low-dose enteric-coated aspirin therapy is recommend by the American Diabetes Association as a primary prevention strategy for diabetic people with high risk for cardiovascular events. Also, obese patients benefit from antiplatelet therapy, besides weight loss.

References

  1. Top of page
  2. The role of platelets and anti-platelet therapy
  3. References
  • 1
    Williamson DF, Thompson TJ, Thun M, Flanders D, Pamuk E, Byers T. Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care 2000; 23: 1499504.
  • 2
    Willett WC, Manson JE, Stampfer MJ, Colditz GA, Rosner B, Speizer FE, Hennekens CH. Weight, weight change, and coronary heart disease in women. Risk within the ‘normal’ weight range. JAMA 1995; 273: 4615.DOI: 10.1001/jama.273.6.461
  • 3
    Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes 1999; 48: 93742.
  • 4
    Howard G, O'Leary DH, Zaccaro D, Haffner S, Rewers M, Hamman R, Selby JV, Saad MF, Savage P, Bergman R. Insulin sensitivity and atherosclerosis. The insulin resistance atherosclerosis study (IRAS) investigators. Circulation 1996; 93: 180917.
  • 5
    Serrano Rios M. Relationship between obesity and the increased risk of major complications in non-insulin-dependent diabetes mellitus. Eur J Clin Invest 1998; 28 (Suppl. 2): 148.DOI: 10.1046/j.1365-2362.1998.0280s2014.x
  • 6
    Colwell JA. Multifactorial aspects of the treatment of the type II diabetic patient. Metabolism 1997; 46 (Suppl. 1): 14.
  • 7
    Brand FN, Kannel WB, Evans J, Larson MG, Wolf PA. Glucose intolerance, physical signs of peripheral artery disease, and risk of cardiovascular events: the Framingham Study. Am Heart J 1998; 136: 91927.
  • 8
    Jung RT. Obesity as a disease. Br Med Bull 1997; 53: 30721.
  • 9
    Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron A. Obesity/insulin resistance is associated with endothelial dysfunction. J Clin Invest 1996; 97: 260110.
  • 10
    Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340: 11526.DOI: 10.1056/NEJM199901143400207
  • 11
    Quyyumi AA. Endothelial function in health and disease: new insights into the genesis of cardiovascular disease. Am J Med 1998; 105: 32S39S.DOI: 10.1016/S0002-9343(98)00209-5
  • 12
    Folsom AR, Qamhieh HT, Wing RR, Jeffery RW, Stinson VL, Kuller LH, Wu KK. Impact of weight loss on plasminogen activator inhibitor (PAI-1), factor VII, and other hemostatic factors in moderately overweight adults. Arterioscler Thromb 1993; 13: 1629.
  • 13
    Palareti G, Legnani C, Poggi M, Parenti M, Babini AC, Biagi R, Baraldi L, Luchi A, Capelli M, Coccheri S. Prolonged very low calorie diet in obese subjects reduces factor VII and PAI but not fibrinogen levels. Fibrinolysis 1994; 8: 1621.DOI: 10.1016/0268-9499(94)90027-2
  • 14
    Mehrabian M, Peter JB, Bernard RJ, Lusis AJ. Dietary regulation of fibrinolytic factors. Atherosclerosis 1990; 84: 2532.
  • 15
    Svendsen OL, Hassager C, Christiansen C, Nielsen JD, Winther K. Plasminogen activator inhibitor-1, tissue-type plasminogen activator, and fibrinogen: effect of dieting with or without exercise in overweight postmenopausal women. Arterioscler Thromb Vasc Biol 1996; 16: 3815.
  • 16
    Sundell IB, Dahlgren S, Rånby M, Lundin E, Stenling R, Nilsson TK. Reduction of elevated plasminogen activator inhibitor levels during modest weight loss. Fibrinolysis 1989; 3: 513.DOI: 10.1016/0268-9499(89)90028-3
  • 17
    Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994; 30: 128794.DOI: 10.1056/NEJM199405053301808
  • 18
    Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomized trial in general practice. Lancet 2001; 357: 8995.DOI: 10.1016/S0140-6736(00)03539-X
  • 19
    ETDRS Investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. JAMA 1992; 268: 1292300.DOI: 10.1001/jama.268.10.1292
  • 20
    Tamminen M, Lassila R, Westerbacka J, Vehkavaara S, Yki-Jarvinen H. Obesity is associated with impaired platelet-inhibitory effect of acetylsalicylic acid in nondiabetic subjects. Int J Obes Relat Metab Disord 2003; 27: 90711.DOI: 10.1038/sj.ijo.0802312
  • 21
    TIMAD Study Group. Ticlopidine treatment reduces the progression of nonproliferative diabetic retinopathy. Arch Ophthalmol 1990; 108: 157783.
  • 22
    CAPRIE Steering Committee. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 132939.DOI: 10.1016/S0140-6736(96)09457-3
  • 23
    Topol EJ, Ferguson JJ, Weisman HF, Tcheng JE, Ellis SG, Kleiman NS, Ivanhoe RJ, Wang AL, Miller DP, Anderson KM, Califf RM. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin beta3 blockade with percutaneous coronary intervention. EPIC Investigator Group. Evaluation of Platelet IIb/IIIa Inhibition for Prevention of Ischemic Complication. JAMA 1997; 278: 47984.DOI: 10.1001/jama.278.6.479
  • 24
    Lincoff AM, Tcheng JE, Califf RM, Kereiakes DJ, Kelly TA, Timmis GC, Kleiman NS, Booth JE, Balog C, Cabot CF, Anderson KM, Weisman HF, Topol EJ. Sustained suppression of ischemic complications of coronary intervention by platelet GP IIb/IIIa blockade with abciximab: one-year outcome in the EPILOG trial. Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade. Circulation 1999; 99: 19518.
  • 25
    Fitzgerald GA. Dipyridamole. N Engl J Med 1987; 316: 124757.
  • 26
    Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 2925.
  • 27
    Nakata M, Yada T, Soejima N, Maruyama I. Leptin promotes aggregation of human platelets via the long form of its receptor. Diabetes 1999; 48: 4269.
  • 28
    Wallaschofski H, Kobsar A, Sokolova O, Eigenthaler M, Lohmann T. Co-activation of platelets by prolactin or leptin—pathophysiological findings and clinical implications. Horm Metab Res 2004; 36: 16.DOI: 10.1055/s-2004-814200
  • 29
    Wallaschofski H, Kobsar A, Sokolova O, Siegemund A, Stepan H, Faber R, Eigenthaler M, Lohmann T. Differences in platelet activation by prolactin and leptin. Horm Metab Res 2004; 36: 4537.DOI: 10.1055/s-2004-825727