Complications of macrovascular disease are responsible for 50% of the deaths in patients with type 2 diabetes mellitus (DM), 27% of the deaths in patients with type 1 diabetes for 35 years or less, and 67% of the deaths in patients with type 1 diabetes for 40 years or more (1,2). The rapid progression of macroangiopathy in patients with type 2 diabetes may reflect diverse phenomena; some intrinsic to the vessel wall; angiopathic factors such as elevated homocysteine and hyperlipidemia; deleterious effects of dysinsulinemia; and excessive or persistent microthrombi with consequent acceleration of vasculopathy secondary to clot-associated mitogens (3,4). As a result of these phenomena, cardiovascular mortality is as high as 15% in the 10 years after the diagnosis of DM becomes established (5). Because more than 90% of patients with diabetes have type 2 diabetes and because macrovascular disease is the cause of death in most patients with type 2 as opposed to type 1 (insulinopenic) diabetes, type 2 diabetes will be the focus of
From: Contemporary Cardiology: Diabetes and Cardiovascular Disease, Second Edition Edited by: M. T. Johnstone and A. Veves © Humana Press Inc., Totowa, NJ
this chapter. In addition to coronary artery disease (CAD), patients with type 2 diabetes have a high prevalence and rapid progression of peripheral arterial disease (PAD), cerebral vascular disease, and complications of percutaneous coronary intervention including restenosis (6).
DM is associated with diverse derangements in platelet function, the coagulation, and the fibrinolytic system, all of which can contribute to prothrombotic state (Tables 1 and 2). Some are clearly related to metabolic derangements, particularly hyperglycemia. Others appear to be related to insulin resistance and hormonal derangements, particularly hyper(pro)insulinemia. In the material that follows, we will consider mechanisms exacerbating thrombosis as pivotal factors in the progression of atherosclerosis and their therapeutic implications.
thrombosis and atherosclerosis
Thrombosis appears to be a major determinant of the progression of atherosclerosis. In early atherosclerosis, microthrombi present on the luminal surface of vessels (7,8) can potentiate progression of atherosclerosis by exposing the vessel wall to clot-associated mitogens. In later stages of atherosclerosis, mural thrombosis is associated with growth of atherosclerotic plaques and progressive luminal occlusion.
The previously conventional view that high-grade occlusive, stenotic coronary lesions represent the final step in a continuum that begins with fatty streaks and culminates in high-grade stenosis has given way to a different paradigm because of evidence that thrombotic occlusion is frequently the result of repetitive rupture of minimally stenotic plaques. Thus, as many as two-thirds of lesions responsible for acute coronary syndromes (ACS) are minimally obstructive (less than 50% stenotic) at a time immediately before plaque rupture (9,10). Multiple episodes of disruption of lipid-rich plaques and subsequent thrombosis appear to be responsible for intermittent plaque growth that underlies occlusive coronary syndromes (11,12).
The extent of thrombosis in response to plaque rupture depends on factors potentiating thrombosis (prothrombotic factors), factors limiting thrombosis (anti-thrombotic factors), and the local capacity of the fibrinolytic system reflecting a balance between activity of plasminogen activators and their primary physiological inhibitor, plasmino-gen activator inhibitor type-1 (PAI-1). Activity of plasminogen activators leads to the generation of plasmin, an active serine proteinase, from plasminogen, an enzymatically inert circulating zymogen present in high concentration (~2 ^M) in blood. The activity of plasmin is limited by inhibitors such as a2 antiplasmin.
When only limited thrombosis occurs because of active plasmin-dependent fibrinolysis at the time of rupture of a plaque, plaque growth may be clinically silent. When thrombosis is exuberant because of factors such as limited fibrinolysis, an occlusive thrombus can give rise to an ACS (acute myocardial infarction [MI], unstable angina, or sudden cardiac death).
The principle components of thrombi are fibrin and platelets. Other plasma proteins and white blood cells are incorporated to a variable extent. The rupture of an atherosclerotic plaque initiates coagulation and adhesion of platelets because of exposure to blood of surfaces denuded of endothelium and to constituents of the vessel wall such as collagen. Coagulation is initiated by tissue factor, a cell membrane-bound glycoprotein (1315). Membrane-bound tissue factor binds circulating coagulation factor VII/VIIa to form the coagulation factor "tenase" complex that activates both circulating coagulation fac-
Potential Impact of Insulin Resistance and Diabetes on Thrombosis
Factors predisposing to thrombosis Increased platelet mass Increased platelet activation
• platelet aggregation
• platelet degranulation Decreased platelet cAMP and cGMP
• thromboxane synthesis
Increased procoagulant capacity of platelets Elevated concentrations and activity of procoagulants
• von Willebrand factor and procoagulant activity
• thrombin activity
• factor VII coagulant activity
Decreased concentration and activity of anti-thrombotic factors
• anti-thrombin III activity
• sulfation of endogenous heparin
• protein C concentration cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate. (Modified from ref. 4.)
Potential Impact of Insulin Resistance and Diabetes on Fibrinolysis
Factors attenuating fibrinolysis Decreased t-PA activity Increased PAI-1 synthesis and activity
• directly increased by insulin
• increased by hyperglycemia
• increased by hypertriglyceridemia and increased FFA
• synergistically increased by hyperinsulinemia combined with elevated triglycerides and FFA
Increased concentrations of a2-antiplasmin t-PA, tissue-type plasminogen activator; PAI-1, plasminogen activator inhibitor type-1; FFA, free fatty acid. (Modified from ref. 4.)
tors IX and X expressed on activated macrophages, monocytes, fibroblasts, and endothelium in response to cytokines in the region of the ruptured plaque. Subsequent assembly of the "prothrombinase" complex on platelet and other phospholipid membranes leads to generation of thrombin. Availability of platelet factor Va is a key constituent of the initial prothrombinase complex. Subsequently, thrombin activates coagulation factor V in blood to form Va. Thrombin in turn cleaves fibrinogen to form fibrin. The generation of thrombin is sustained and amplified initially by its activation of circulating coagulation factors VIII and V. Thrombin generation is sustained by activation of other components in the intrinsic pathway including factor XI. Platelets are activated by thrombin, and activated platelets markedly amplify generation of thrombin.
A complex feedback system limits generation of thrombin. The tissue factor pathway becomes inhibited by tissue factor pathway inhibitor (TFPI) previously called lipopro-tein-associated coagulation inhibitor (LACI). Furthermore, thrombin attenuates coagulation by binding to thrombomodulin on the surface of endothelial cells. The complex activates protein C (to yield protein Ca) that, in combination with protein S, cleaves (inactivates) coagulation factors Va and VIIIa.
Exposure of platelets to the subendothelium after plaque rupture leads to their adherence mediated by exposure to both collagen and multimers within the vessel wall of von Willebrand factor (16,17). The exposure of platelets to agonists including collagen, von Willebrand factor, adenosine diphosphate (ADP) (released by damaged red blood cells and activated platelets), and thrombin leads to further platelet activation. Activation is a complex process that entails shape change (pseudopod extension that increases the surface area of the platelet); activation of the surface glycoprotein (GP) IIb/IIIa; release of products from dense granules such as calcium, ADP, and serotonin and from a granules such as fibrinogen, factor V, growth factors and platelet factor 4 that inhibits heparin; and a change in the conformation of the platelet membrane that promotes binding to phospho-lipids and assembly of coagulation factors.
Activation of surface GP IIb/IIIa results in a conformational change that exposes a binding site for fibrinogen on the activated conformer (18). Each molecule of fibrinogen can bind two platelets, thereby leading to aggregation.
After activation, the plasma membranes of platelets express negatively charged phos-pholipids on the outer surface that facilitate the assembly of protein constituents and subsequently activity of the tenase and prothrombinase complexes (19). Thus, platelets participate in thrombosis by (a) forming a hemostatic plug (shape change, adherence to the vascular wall and aggregation); (b) supplying coagulation factors and calcium (release of a- and dense-granule contents); (c) providing a surface for the assembly of coagulation factor complexes; and (d) simulating vasoconstriction by releasing throm-boxane and other vasoactive substances.
As noted previously, thrombosis complicating plaque rupture can occlude the lumen entirely or, when limited, contribute in a stepwise fashion over time to progressive stenosis. Mechanisms by which thrombi can contribute to plaque growth include incorporation of an organized thrombus into the vessel wall (20). Exposure of vessel wall constituents to clot-associated mitogens and cytokines can accelerate neointimalizaiton and migration and proliferation of vascular smooth muscle cells (VSMCs) in the media. Fibrin and fibrin-degradation products promote the migration of VSMCs and are chemotactic for monocytes (21). Thrombin itself and growth factors released from platelet a-granules such as platelet-derived growth factor and transforming growth factor- P activate smooth muscle cells (SMCs) potentiating their migration and proliferation (22-25). The powerful role of platelets has been demonstrated by a reduction in the proliferation of SMCs after mechanical arterial injury in thrombocytopenic rabbits with atherosclerosis (26).
Both local and systemic factors can influence the extent of thrombosis likely to occur in association with plaque rupture. The morphology and biochemical composition of the plaque influence thrombogenic potential. Atheromatous plaques with substantial lipid content are particularly prone to initiate thrombosis in contrast to the antithrombotic characteristics of the luminal surface of the normal vessel wall (27).
Both the severity of vascular injury and the extent of plaque rupture influence the extent to which blood is exposed to subendothelium and consequently to thrombogenicity.
The balances between the activity of prothrombotic factors and anti-thrombotic factors in blood and between thrombogenicity and fibrinolytic system capacity are important determinants of the nature and extent of a thrombotic response to plaque rupture. in subjects with type 2 diabetes, the balances between determinants are shifted toward potentiation and persistence of thrombosis and hence toward acceleration of atherosclerosis.
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