Page 2420 - Hematology_ Basic Principles and Practice ( PDFDrive )

2160 Part XII Hemostasis and Thrombosis

the Framingham Heart Study, have shown that a 10-mg/dL increase Although PAD is mostly caused by atherosclerosis, other causes
in total cholesterol increases the risk of PAD by 5% to 10%. In the include thromboembolism, atheroembolism, vasculitides (e.g., throm-
Strong Heart study, individuals with PAD had significantly higher boangiitis obliterans, giant cell arteritis, Takayasu arteritis), trauma,
levels of total cholesterol, triglycerides, and LDL cholesterol than popliteal artery entrapment, cystic adventitial disease, fibromuscular
those without. The Whitehall study also demonstrated that an elevated dysplasia, and endofibrosis of the iliac artery (Table 148.1). Nonvas-
total cholesterol level was associated with symptoms of intermittent cular causes of leg pain should also be considered in the differential
claudication. diagnosis, including lumbosacral spine disease (causing pseudoclau-
Chronic renal insufficiency has been recognized to be significantly dication), acute and chronic venous diseases, hip or knee osteoarthritis,
associated with PAD in several studies. In the NHANES, renal insuf- myositis, and others (Table 148.2).
ficiency (defined as a glomerular filtration rate <60 mL/min) was
associated with a 2.5-fold higher odds of PAD even after adjustment
for other cardiovascular risk factors. In the Heart and Estrogen/ CLINICAL MANIFESTATIONS
Progesterone Replacement (HERS) study, renal insufficiency was also
associated with an increased risk of incident peripheral vascular The majority of patients with PAD are asymptomatic at presentation.
events, including revascularization and amputation. Moreover, renal Typical claudication symptoms are present in only 10% to 35% of
1
insufficiency increases the mortality risk in patients with PAD irre- patients and CLI in 1% to 2%. The classic symptoms of PAD
spective of other risk factors, including diabetes. include intermittent claudication and rest pain, the latter occurring
Several other nontraditional factors have been associated with in patients with CLI. Intermittent claudication is defined as exertional
PAD. Markers of systemic inflammation, such as C-reactive protein discomfort in the muscles of the lower extremities that is variably
(CRP), are elevated in patients with PAD. In the Physicians’ Health described as pain, aching, burning, fatigue, or heaviness. Symptoms
Study, the risk of developing symptomatic PAD was approximately arise with leg exercise, typically walking, and are relieved after a
twofold higher in those in the highest CRP quartile compared with predictable duration of rest (usually <10 minutes). Intermittent
those in the lowest quartile. Other markers of inflammation, such as claudication occurs with effort and not at rest, and symptoms do not
soluble intercellular adhesion molecule 1 (sICAM-1), a leukocyte abate until activity ceases; a change in position is unnecessary.
adhesion molecule, are also associated with PAD in this population Although many patients with PAD report atypical symptoms, most
and in the Women’s Health Study. Insulin resistance is associated with have impaired walking ability exemplified by reduced walking speed
both prevalent PAD as shown in data from the NHANES study and or distance. CLI arises when there is inadequate perfusion to meet
with incident PAD as demonstrated in the Cardiovascular Health the resting metabolic demands of the tissues. Patients with CLI have
Study. The protective effect of bilirubin, an endogenous antioxidant, pain at rest, typically affecting the toes, feet, or both; they may have
was explored in NHANES; there was evidence of an inverse associa- accompanying tissue loss with nonhealing ulcers, tissue necrosis, or
tion between total serum bilirubin levels and PAD. The impact of gangrene (Fig. 148.1).
genetics on the development of PAD has not been well explored, but
a family history of PAD has been associated with development of
PAD. DIAGNOSIS
The diagnosis of PAD is often evident from the history and physical
PATHOBIOLOGY examination. An important diagnostic feature is diminished or absent
pulses in the legs. The examiner should palpate the femoral, popliteal,
Atherosclerosis is a progressive vascular disease characterized by lipid dorsalis pedis, and posterior tibial pulses. Absence of selected pulses
accumulation and formation of plaque in the arterial walls (see provides insight into the location of critical stenoses. The groin
Chapter 144). The pathophysiology of atherosclerosis includes should be auscultated for femoral artery bruits, which may be indica-
endothelial dysfunction, vascular inflammation, and cellular prolif- tive of turbulent flow from atherosclerotic plaque. Other findings
eration. Early in the atherogenic process, recruitment of inflammatory
cells and accumulation of lipids promote development of a lipid-rich
atheroma. Inflammation promotes the elaboration of proteases that TABLE Nonatherosclerotic Causes of Peripheral Artery
weaken the vessel wall and allow positive remodeling with outward 148.1 Disease
expansion of the arterial wall to accommodate the intimal expansion
that occurs as a result of plaque formation. Although positive remod- • Thromboembolism
eling initially preserves the arterial lumen, continued plaque growth • Atheroembolism
results in progressive narrowing of the lumen, which then limits • Vasculitides
blood flow and oxygen supply to target organs. This process may be • Large vessel vasculitides, such as giant cell arteritis and
enhanced by biomechanical factors, such as turbulent blood flow, Takayasu arteritis
particularly in areas of altered shear stress. This phenomenon is of • Small vessel vasculitides, such as thromboangiitis obliterans
particular significance at branch points along the arterial tree, which (Buerger’s disease)
are predisposed to atherosclerotic plaque formation. • Trauma
Increasingly, it has been recognized that atherosclerotic plaque • Popliteal artery entrapment
formation is a dynamic biologic process that exhibits marked hetero- • Cystic adventitial disease
geneity; some plaques remain “stable”, but others have a more • Fibromuscular dysplasia
“unstable” pathophysiology. Stable atherosclerotic plaques may be • Iliac artery endofibrosis
asymptomatic or symptoms can occur with exertion if demand
exceeds supply. On the other hand, “vulnerable” or unstable plaques
are prone to acute rupture, and superimposed thrombi may cause TABLE Nonarterial Causes of Leg Pain (Differential Diagnosis
sudden arterial insufficiency. Studies have shown that acute athero- 148.2 for Intermittent Claudication Symptoms)
thrombosis is not restricted to plaques that produce stenosis; many
lesions without flow-limiting disease are prone to rupture. Evidence • Lumbar radiculopathy
suggests that disruption of the fibrous cap overlying the atheroma is • Spinal stenosis
promoted by proinflammatory cytokines. Plaque disruption exposes • Hip or knee osteoarthritis
the highly prothrombotic lipid-rich core of the atheroma to • Myositis
the blood, a process that triggers platelet aggregation and fibrin • Venous claudication
formation.