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2294 Part XII: Hemostasis and Thrombosis Chapter 134: Atherothrombosis: Disease Initiation, Progression, and Treatment 2295

phospholipid surface for the assembly of enzymatic complexes of the Platelet membrane glycoproteins are highly polymorphic and
coagulation cascade; in particular, oxidized LDL, LDL, and VLDL have can be recognized as alloantigens or autoantigens. Polymorphisms
procoagulant effects. 195,196 In contrast, HDL has multiple antithrombotic in platelet membrane glycoprotein receptors have been considered
actions, including suppression of the coagulation cascade, stimulation to increase platelet reactivity, thereby potentially contributing to sus-
of fibrinolysis, and stimulation of endothelial cell release of prostacyclin ceptibility to arterial thrombosis. 212,213 The first such genetic variation
and NO, which are inhibitors of platelet activation. 197 reported involves the HPA-1a/HPA-1b polymorphism, which results
Arterial thrombosis is triggered by the acute exposure of cir- in a Leu33Pro substitution in the β subunit of the platelet integrin
3
culating blood to TF and anionic phospholipids, leading to explosive α β complex. The 33Pro (HPA-1b) allele was found to be associated
IIb 3
thrombin formation. Thrombin, a potent platelet agonist, further fuels with risk of MI in young individuals. Most, but not all, subsequent
214
the platelet activation process described in the previous section. These studies have agreed that the HPA-1b allele represents an inherited risk
213
reactions create a self-amplifying process that is tightly localized to the factor for ACS. Other platelet receptor polymorphisms that have
site of vascular injury. The arterial thrombus is further contained to this been inconclusively linked to risk of CVD include three different poly-
site by the restoration of normal, antithrombotic endothelium in adja- morphisms of the integrin α (HPA-3), GPIb gene, and a polymor-
IIb
cent areas of the vessel wall. phism of the collagen receptor integrin α β . However, as is the case
2 1
for the soluble hemostatic factors, lack of a clear relationship among
Systemic Factors genotype, phenotype, and clinical manifestations has failed to estab-
As described above in “Overview of Arterial Thrombotic Process,” lish convincing cause-and-effect relationships for any of these genetic
the pathophysiology of arterial thrombosis is primarily determined variations.
by local, “solid-state” factors that operate in concert in the immediate Although none of these individual hemostatic proteins or plate-
microenvironment of acute vascular injury, typically disruption of an let polymorphisms plays a clear, dominant role in the pathophysiology
atherosclerotic plaque. However, interindividual differences in systemic, of arterial thrombosis, future application of platelet proteomics and
215
circulating factors can modify susceptibility to the focal formation of an genomics are likely to reveal new disorders of platelet activation associ-
arterial thrombus. Systemic determinants of blood thrombogenicity ated with arterial thrombosis.
198
(i.e., hypercoagulability) can enhance the local risk of arterial throm- High blood levels of catecholamines likely contribute systemi-
bosis. There is increasing evidence for an association between venous cally to localized arterial thrombus formation. Catecholamines may
and arterial thrombosis, with several studies now showing that patients be increased by physical or emotional stress or by cigarette smoking,
with venous thromboembolism (deep vein thrombosis and/or pulmo- thereby triggering acute cardiovascular events in these settings. In addi-
nary embolism) are at increased risk of having coexisting asymptomatic tion to their vasoactive actions, catecholamines are direct platelet ago-
atherosclerosis or subsequent symptomatic atherothrombotic events. nists and enhance shear stress-induced platelet activation. 191,216
Conversely, patients with clinically overt atherosclerotic CVD are at Changes in lipid metabolism may exert systemic prothrombotic
increased risk of venous thromboembolism. 199–201 In addition to certain actions. The thrombogenicity of lipoprotein(a) has been attributed to
thrombophilic abnormalities, such as antiphospholipid antibody syn- its structural similarity to plasminogen, leading to reduced plasmin
drome, hyperhomocysteinemia, and the myeloproliferative neoplasms, formation and impaired thrombolysis. Elevated LDL cholesterol can
163
which are known to predispose individuals to both venous and arterial contribute to blood hypercoagulability. The prothrombotic state of
217
thromboembolism, some traditional cardiovascular risk factors (e.g., diabetes involves multiple mechanisms, including platelet hyperreactiv-
advanced age, obesity, metabolic syndrome, abnormal lipid profiles, ity and increased leukocyte procoagulant activity. 177
immobility, estrogens) also appear to be independent risk factors for
venous thromboembolism. 39,202–204
Genetic determinants of the coagulation system may exert modi- ISCHEMIC VASCULAR DISEASE
fying effects on susceptibility to arterial thrombosis. The known hyper-
coagulable states that predispose to venous thrombosis (e.g., factor V MYOCARDIAL INFARCTION
Leiden, prothrombin gene mutation, antithrombin deficiency, protein C MI is a term that reflects necrosis of cardiac myocytes caused by pro-
205
and protein S deficiencies) generally are weakly or not at all asso- longed ischemia. In the past, MI was defined by the combination of
ciated with increased risk of arterial thrombosis. However, decreased two of three characteristics: typical symptoms (i.e., chest discomfort),
mortality from ischemic heart disease has been noted in patients with a rise in serum enzymatic markers derived from myocardial cells, and
206
hemophilia A or B and even in carriers of hemophilia. This finding a typical electrocardiographic pattern involving the development of
most likely results from reduced arterial thrombotic tendency in these Q waves. The advent of sensitive and specific serologic biomarkers
individuals because early atherogenesis itself does not appear to be sig- and precise imaging techniques has led to the development of revised
207
nificantly affected by the coexistence of hemophilia. Conversely, some criteria for MI. For example, patients can be diagnosed with a
218
epidemiologic studies have correlated elevated levels of fibrinogen and “ST-segment elevation MI” or “non–Q-wave or non–ST-segment
219
some other coagulation factors with both subclinical atherosclerosis elevation” MI (NSTEMI) if certain criteria are met. The criteria agreed
220
and clinical cardiovascular events, 208,209 although cause-and-effect rela- upon by the American College of Cardiology for acute, evolving, or
tionships between elevated levels of hemostatic factors and cardiovascu- recent MI are as follows:
218
lar risk have not been established.
Several lines of evidence suggest that genetic determinants of 1. Typical rise and gradual fall (troponin) or more rapid rise and fall
increased platelet reactivity likewise enhance focal determinants of arte- (creatinine kinase-MB isoform) or biochemical markers of myo-
rial thrombosis. Animal models of atherosclerosis in pigs and mice with cardial necrosis with at least one of the following: (A) ischemic
von Willebrand disease suggest that an extremely low or absent VWF symptoms; (B) development of pathologic Q waves on the electro-
level exerts a protective effect on the development and distribution of cardiogram (ECG); (C) electrocardiographic changes indicative of
atherosclerotic lesions, 210,211 although these observations are inconclu- ischemia (ST segment elevation or depression); or (D) coronary
sive. Whether or not von Willebrand disease protects against develop- artery intervention (e.g., coronary angioplasty).
ment of human atherosclerosis remains in dispute. 2. Pathologic findings of an acute MI.

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