Suneet Kumar Verma  ( Department of Internal Medicine, Alchemist Hospital, Panchkula, India; Sparsh Clinic, Panchkula. )
Sanjay Kalra  ( Department of Endocrinology, Bharti Hospital, Karnal, India; University Center for Research & Development, Chandigarh University, Mohali, India. )

This communication describes the platelet morphology and physiology noted in persons with diabetes and its complications. It reviews the effects of glucose lowering drugs on platelet function, and summarizes the role of anti-platelet drugs in diabetes management.

 

Keywords: Anaemia, aspirin, aspirin resistance, blood, dengue, haematology, hyperglycaemia, platelet.

 

DOI: 10.47391/JPMA.23-34

 

Introduction

 

The platelets are an important constituent of the blood. Though platelets are non-nucleated cells, they play an active role in various physiological and pathological process of the body.¹ Diabetes influences the structure and function of platelets in multiple ways. This communication describes the unique characteristics of “diabetic platelets”.

 

Platelet Number

 

Persons with long standing diabetes, especially with nephropathy, have been shown to have increased platelet counts. Mean platelet volume, platelet distribution width, and platelets-large cell ratio have also been shown to be increased in diabetes.² However, the number of platelets has been observed to be reduced in persons with dengue and diabetes. There is a greater risk of severe haemorrhagic dengue fever in persons with diabetes.^3,4

 

Platelet Function

 

Persons with type 2 diabetes experience continuous platelet activation, as well as an increase in platelet reactivity. This is mediated by hyperglycaemia, directly and through glycation of platelet proteins and also by hypertriglyceridaemia.¹ Platelet reactivity is increased in both insulin deficiency and insulin resistance. Oxidative stress reduces levels of nitric oxide, which normally serves to attenuate platelet reactivity. An improvement in glucose control not only decreases platelet reactivity, but also enhances the response to anti-platelet drugs.¹ Aspirin resistance, in fact, is often associated with uncontrolled hyperglycaemia.

Insulin antagonizes the effects of platelet agonists such as ADP, collagen, epinephrine, and PAF (Platelet-activating factor).⁵ Ensuring optimal endogenous or exogenous insulin concentration, and sensitivity, is one way of preventing unwarranted activation of platelets

 

Platelets And Partners

 

Platelets do not work in isolation. Red blood cells may mediate endothelial dysfunction in diabetes, through dysregulated purinergic signalling. Platelet aggregation occurs due to ADP-mediated activation of P2Y1 and P2Y12 receptors.⁶

Thrombosis, and platelet activation are linked with inflammation. The diabetic platelets play an important role in macrovascular complications of diabetes. Along with the enhanced thrombotic state due to endothelial dysfunction, and activation of the coagulation cascade, platelet activation leads to acute cardiovascular events.⁷

 

Clinical Implication: Glucose Control

 

An understanding of diabetic platelet pathophysiology helps clarify the rationale for prevention and management of macrovascular disease in diabetes. The right choice of glucose-lowering, and if required, anti-platelet, drugs, helps ensure optimal platelet junction and comprehensive cardiovascular health.

Glucose control is of utmost importance, as hyperglycaemia is known to be associated with dysfunctional diabetic platelets. Cardiovascular outcome trials have helped explore the safety and benefit of newer drugs, and the use of GLP1RA and SGLT2i is known to improve cardiovascular health.⁸ However, robust data is also available for most conventional anti-diabetic medications.

Metformin is known to reduce ADP-induced platelet aggregation in type 1 diabetes, and also reduced platelet activation in type 2 diabetes. There is a potential, also, for metformin to have a positive synergistic effect with aspirin. On the other hand, there is conflicting evidence about the interaction of metformin with aspirin +clopidogrel combination.⁸

Gliclazide has been reported to be more effective than other sulfonylureas in attenuating platelet aggregation. However, sulfonylureas compete with clopidogrel for CYP2c9, and may reduce its platelet inhibitory effect. Conversely, aspirin may potentiate the hypoglycaemic effect of sulfonylureas, by increasing insulin secretion directly, and by displacing the drugs from their protein-binding site.⁸ .

Pioglitazone has been reported to improve platelet function markers, and have a potentiating effect on aspirin. Pioglitazone is a useful drug for the management of aspirin resistance as well. Clopidogrel may increase the effect of pioglitazone, by inhibiting CYP2C8-mediated metabolism.⁸ Acarbose and sitagliptin have also been shown to reduce platelet aggregation in clinical studies, as has liraglutide.

The concept of aspirin resistance is a well-established biochemical construct, but is difficult to measure in clinical practice. Diabetic platelets, especially in persons at a greater risk of aspirin resistance.⁹ However, this does not mean that higher doses of aspirin should be prescribed to all persons with diabetes. Aspirin is indicated for secondary prevention of cardiovascular disease in diabetes. Other antiplatelet drugs should be used for tertiary prevention only. The risk of bleeding and potential risk of drug-drug interactions must be kept in mind. While choosing an aspirin dose. It must be noted that recent trials suggest an increase in risk of heart failure with aspirin use.

 

Prudent Prescription: Anti Platelet Drugs

 

Prudent practice would be to follow advice laid down in the American Diabetes Association Standards of Medical Care, 2022.¹⁰ Aspirin should be used for secondary prevention in persons with diabetes and a history of atherosclerotic cardiovascular disease, in a dose of 75-162 mg/day. Clopidogrel (75 mg/day) is an alternative for those with aspirin allergy. Dual antiplatelet therapy is indicated for 12 months after an acute coronary syndrome, and for longer term treatment in patients with prior coronary intervention, high ischaemic risk, and low risk of bleeding. Combination of aspirin and low-dose rivaroxaban can be considered for patients with stable coronary and/or peripheral artery disease and low bleeding risk to prevent major adverse limb and cardiovascular events. Aspirin (75–162 mg/day) may be considered as a primary prevention strategy in very high-risk patients, after detailed discussion and risk benefit analysis.

This should ensure optimization of platelet function in persons with diabetes, and facilitate achievement of long-term vascular health.

 

References

 

1.      van der Meijden PE, Heemskerk JW. Platelet biology and functions: new concepts and clinical perspectives. Nat. Rev. Cardiol. 2019;16:166-79.

2.      Kaur R, Kaur M, Singh J. Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: molecular insights and therapeutic strategies. Cardiovasc. Diabetol. 2018;17:1-7.

3.      Walinjkar RS, Khadse S, Kumar S, Bawankule S, Acharya S. Platelet indices as a predictor of microvascular complications in type 2 diabetes. Indian J Endocrinol Metabol. 2019;23:206-210.

4.      Tsheten T, Clements AC, Gray DJ, Adhikary RK, Furuya-Kanamori L, Wangdi K. Clinical predictors of severe dengue: a systematic review and meta-analysis. Infect. Dis. Poverty. 2021;10:1-0.

5.      Dandona P, Ghanim H. Diabetes, obesity, COVID-19, insulin, and other antidiabetes drugs. Diabetes care. 2021;44:1929-33.

6.      Koupenova M, Ravid K. Biology of platelet purinergic receptors and implications for platelet heterogeneity. Front. Pharmacol. 2018; 9:37-40.

7.      Gachet C, Hechler B. Platelet purinergic receptors in thrombosis and inflammation. Hämostaseologie. 2020;40:145-52.

8.      Nusca A, Tuccinardi D, Pieralice S, Giannone S, Carpenito M, Monte L, et al. Platelet effects of anti-diabetic therapies: new perspectives in the management of patients with diabetes and cardiovascular disease. Front. Pharmacol. 2021; 12:670155.

9.      Paven E, Dillinger JG, dit Sollier CB, Vidal-Trecan T, Berge N, Dautry R, et al. Determinants of aspirin resistance in patients with type 2 diabetes. Diabetes Metab J. 2020;46:370-6.

10.    American Diabetes Association Professional Practice Committee, American Diabetes Association Professional Practice Committee: 10. cardiovascular disease and risk management: standards of medical care in diabetes—2022. Diabetes Care. 2022;45(Supplement_1): S144-74.