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Effects of Hyperglycemia and Diabetes Mellitus on Coagulation and Hemostasis

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Effects of Hyperglycemia and Diabetes Mellitus on Coagulation and Hemostasis Journal of Clinical Medicine Review Effects of Hyperglycemia and Diabetes Mellitus on Coagulation and Hemostasis Xiaoling Li 1, Nina C. Weber 1 , Danny M. Cohn 2 , Markus W. Hollmann 1, J. Hans DeVries 3, Jeroen Hermanides 1 and Benedikt Preckel 1,* 1 Department of Anesthesiology, Amsterdam UMC Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; [email protected] (X.L.); [email protected] (N.C.W.); [email protected] (M.W.H.); [email protected] (J.H.) 2 Department of Vascular Medicine, Amsterdam UMC Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; [email protected] 3 Department of International Medicine, Amsterdam UMC location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; [email protected] * Correspondence: [email protected]; Tel.: +31-20-5669111 Abstract: In patients with diabetes, metabolic disorders disturb the physiological balance of coagu- lation and fibrinolysis, leading to a prothrombotic state characterized by platelet hypersensitivity, coagulation disorders and hypofibrinolysis. Hyperglycemia and insulin resistance cause changes in platelet number and activation, as well as qualitative and/or quantitative modifications of coagula- tory and fibrinolytic factors, resulting in the formation of fibrinolysis-resistant clots in patients with diabetes. Other coexisting factors like hypoglycemia, obesity and dyslipidemia also contribute to coagulation disorders in patients with diabetes. Management of the prothrombotic state includes antiplatelet and anticoagulation therapies for diabetes patients with either a history of cardiovascular Citation: Li, X.; Weber, N.C.; Cohn, disease or prone to a higher risk of thrombus generation, but current guidelines lack recommen- D.M.; Hollmann, M.W.; DeVries, J.H.; dations on the optimal antithrombotic treatment for these patients. Metabolic optimizations like Hermanides, J.; Preckel, B. Effects of glucose control, lipid-lowering, and weight loss also improve coagulation disorders of diabetes Hyperglycemia and Diabetes Mellitus patients. Intriguing, glucose-lowering drugs, especially cardiovascular beneficial agents, such as on Coagulation and Hemostasis. J. glucagon-like peptide-1 receptor agonists and sodium glucose co-transporter inhibitors, have been Clin. Med. 2021, 10, 2419. https:// shown to exert direct anticoagulation effects in patients with diabetes. This review focuses on the doi.org/10.3390/jcm10112419 most recent progress in the development and management of diabetes related prothrombotic state. Academic Editor: Tomoaki Morioka Keywords: metabolic disorder; platelets; coagulation factors; hypercoagulation; hypofibrinolysis Received: 5 May 2021 Accepted: 26 May 2021 Published: 29 May 2021 1. Introduction Publisher’s Note: MDPI stays neutral In 2017, the International Diabetes Federation estimated that 451 million adults are with regard to jurisdictional claims in diagnosed with diabetes mellitus (DM) worldwide, and the number would increase to published maps and institutional affil- 693 million by 2045 [1]. Anesthesiologists are increasingly facing high-risk patients with sig- iations. nificant comorbidities undergoing major surgery, including a significant risk for excessive bleeding, and hyperglycemia is associated with higher risk of perioperative complica- tions and poorer outcomes after surgery [2,3]. The hemostatic function of platelets and coagulation factors sometimes makes it difficult to control the pro-thrombotic state since global inhibition of coagulation will impair hemostasis [4]. It is essential to understand Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. the signalling partners and factors involved in platelet hyperresponsiveness or aberrant This article is an open access article activation of the coagulation system. This will eventually allow for selective targeting distributed under the terms and of pro-thrombotic cascades while preserving hemostasis. Metabolic disorders influence conditions of the Creative Commons coagulation and hemostasis, but the underlying mechanisms have yet to be clarified [5–7]. Attribution (CC BY) license (https:// Besides, the choice and optimal dosage of antithrombotic agents for patients with DM are creativecommons.org/licenses/by/ still unclear [8]. This review focuses on coagulation dysfunction and prothrombotic states 4.0/). in patients with DM. J. Clin. Med. 2021, 10, 2419. https://doi.org/10.3390/jcm10112419 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 2419 2 of 14 J. Clin. Med. 2021, 10, 2419 still unclear [8]. This review focuses on coagulation dysfunction and prothrombotic states2 of 14 in patients with DM. 2. Prothrombotic State Associated with Diabetes Mellitus 2. Prothrombotic State Associated with Diabetes Mellitus Coagulation and hemostasis involve interactions between tissue and coagulation fac- tors asCoagulation well as blood and and hemostasis endothelial involve cells, interactions finally resulting between in formation tissue and ofcoagulation fibrin clots stoppingfactors as bleeding well as blood [4]. During and endothelial this process, cells, the finally fibrinolytic resulting system in formation decomposes of fibringenerated clots clotsstopping to prohibit bleeding widespread [4]. During thrombus this process, formation the fibrinolytic and vascular system occlusion decomposes [5]. generated clotsIn to patients prohibit having widespread DM, metabolic thrombus disorder formations disturb and vascular these physiological occlusion [5]. mechanisms, leadingIn patientsto a prothrombotic having DM, state metabolic characterized disorders by disturb platelet these hypersensitivity, physiological mechanisms,coagulation factorleading disorders to a prothrombotic and hypofibrinolysis state characterized [9] (Figure by 1). platelet hypersensitivity, coagulation factor disorders and hypofibrinolysis [9] (Figure1). Figure 1. ModificationsModifications of coagulation and fibrin fibrinolysisolysis system in DM. Diabetes disturbsdisturbs the physiological balance between coagulation and fibrinolysis, fibrinolysis, leading to a prothrombotic state hallmarked with plateletplatelet hypersensitivity, coagulation factor disorders and hypofibrinolysis.hypofibrinolysis. Hyperglyce Hyperglycemiamia and insulin resistance enhance number and aggregation of platelets through increasing von Willebrand factor (vWF) level and inhibiting anti-aggregatory efficiency of nitric oxide and prostaglandin I2. increasing von Willebrand factor (vWF) level and inhibiting anti-aggregatory efficiency of nitric oxide and prostaglandin I . Hyperglycemia and insulin resistance upregulate level of pro-coagulation mediators like tissue factor (TF), coagulation fac-2 Hyperglycemia and insulin resistance upregulate level of pro-coagulation mediators like tissue factor (TF), coagulation tors (FVII, FXII, FXI and FIX) and thrombin. Diabetes also harasses fibrinolysis by decreasing tissue plasminogen activator (tPA)factors as (FVII, well FXII,as increasing FXI and FIX)plasminogen and thrombin. activator Diabetes inhibitor-1 also harasses (PAI-1) fibrinolysis and thrombin by decreasing activator fibrinolysis tissue plasminogen inhibitor activator (TAFI). (tPA)Next to as hyperglycemia well as increasing and plasminogeninsulin resistance, activator co-existing inhibitor-1 metabolic (PAI-1) disorders and thrombin like hypoglycemia, activator fibrinolysis obesity, dyslipidemia, inhibitor (TAFI). and non-alcoholicNext to hyperglycemia fatty liver and disease insulin (NAF resistance,LD) also co-existingcontribute to metabolic the pro-thrombotic disorders like state hypoglycemia, of patients with obesity, DM. dyslipidemia, and non-alcoholic fatty liver disease (NAFLD) also contribute to the pro-thrombotic state of patients with DM. 2.1. Platelet Hypersensitivity 2.1. PlateletIn physiological Hypersensitivity conditions, platelets circulate in the blood for five to seven days and constantlyIn physiological undergo a lifecycle conditions, from platelets megakary circulateocyte separation in the blood to ph foragocytosis five to seven by macro- days phages,and constantly to maintain undergo a normal a lifecycle platelet from count megakaryocyte of 150.000–450.000 separation per microliter. to phagocytosis After vas- by cularmacrophages, injury, platelets to maintain are activated a normal to platelet aggreg countate, forming of 150.000–450.000 an occlusive per thrombus microliter. and After stop bleedingvascular [10]. injury, Both platelets increased are activatedplatelet number to aggregate, and enhanced forming aggregation an occlusive capacity, thrombus the andlat- terstop referred bleeding to [10as ].platelet Both increased hypersensitivity, platelet number will contribute and enhanced to a pro-thrombotic aggregation capacity, state [11]. the Inlatter patients referred with to DM, as platelet over-activation hypersensitivity, of platelets will (mainly contribute attributed to a pro-thrombotic to hyperglycemia state [and11]. insulinIn patients resistance) with DM, plays over-activation a crucial role of for platelets pro-thrombotic (mainly attributedevents [12]. to hyperglycemia and insulin resistance) plays a crucial role for pro-thrombotic events [12]. 2.1.1. Hyperglycemia Among patients with type 2 diabetes mellitus (T2DM), mean platelet counts are up to 10% higher in patients with chronic hyperglycemia (glycated hemoglobin, HbA1c > 8%) as J. Clin. Med. 2021, 10, 2419 3 of 14 compared to euglycemia. Besides, increased
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