Vous êtes sur la page 1sur 4

Pathophysiology of Atherosclerosis

Atherosclerosis is a type of arteriosclerosis or hardening of the arteries. The term

atherosclerosis, which comes from the Greek words atheros (gruel or paste) and sclerosis
(hardness), denotes the formation of fibrofatty lesions in the intimal lining of the large and
medium-sized arteries such as the aorta and its branches, the coronary arteries, and the cerebral
arteries that supply the brain. The disorder remains a leading cause of coronary artery disease,
stroke, and peripheral artery disease.
Mechanism of Development
Types of Atherosclerosis
The lesions associated with atherosclerosis are of three types:
the fatty streak
the fibrous atheromatous plaque
the complicated lesion.
The latter two are responsible for the clinically significant manifestations of the disease.
Fatty streaks are thin, flat, yellow intimal discolorations that progressively enlarge by becoming
thicker and slightly elevated as they grow in length. Fatty streaks are present in children, often in
the first year of life This occurs regardless of geographic setting, gender, or race. They increase
in number until about 20 years of age, and then remain static or regress.
The fibrous atheromatous plaque is characterized by the accumulation of intracellular and
extracellular lipids, proliferation of vascular smooth muscle cells, formation of scar tissue, and
calcification. The lesions begin as a gray to pearly white, elevated thickening of the vessel intima
with a core of extracellular lipid covered by a fibrous cap of connective tissue and smooth
muscle. As the lesions increase in size, they encroach on the lumen of the artery and eventually
may occlude the vessel or predispose to thrombus formation, causing a reduction of blood flow.
The more complicated atherosclerotic lesions contain hemorrhage, ulceration, and scar tissue
deposits. Thrombosis is the most important complication of atherosclerosis. It is caused by
slowing and turbulence of blood flow in the region of the plaque and ulceration of the plaque.
Pathogenesis of Atherosclerosis
Injury to the endothelial vessel layer is the initiating factor in the development of
atherosclerosis. A number of factors are regarded as possible injurious agents,
including products associated with smoking, immune mechanisms, and mechanical
stress such as that associated with hypertension. The fact that atherosclerotic lesions
tend to form where vessels branch or where there is turbulent flow suggests that
hemodynamic factors may also play a role.
One of the earliest responses to elevated cholesterol levels is the attachment of
monocytes to the endothelium. The monocytes have been observed to move through
the cell-to-cell attachments of the endothelial layer into the subendothelial spaces,
where they are transformed into macrophages.
Activated macrophages release free radicals that oxidize LDL, which, in turn, is toxic


to the endothelium, causing endothelial cell loss and exposure of the subendothelial
tissue to blood components. This leads to platelet adhesion and aggregation and fibrin
Activated macrophages also ingest the oxidized LDL (by uptake through the
scavenger receptor) to become foam cells, which are present in all stages of
atherosclerotic plaque formation.
Platelets and activated macrophages release various factors that are thought to
promote growth factors that modulate the proliferation of smooth muscle cells and the
deposition of extracellular matrix in the lesions.
Lipids released from necrotic foam cells accumulate to form the lipid core of unstable

Unstable plaques typically are characterized histologically by a large central lipid core, an
inflammatory infiltrate, and a thin fibrous cap. These vulnerable plaques are at risk of rupture,
often at the shoulder of the plaque where the fibrous cap is thinnest and the mechanical stresses

Pathophysiology of Thrombosis
Thrombosis is inappropriate activation of blood clotting in uninjured vasculature or thrombotic
occlusion of a vessel after relatively minor injury. There are three primary influences on
thrombus formation, called Virchows triad:
1. Endothelial injury is dominant and can independently cause thrombosis (e.g.,
endocarditis or ulcerated atherosclerotic plaque). Injury can be due to hemodynamic
stresses (e.g., hypertension or turbulent), endotoxin, radiation, or noxious agents (e.g.,
homocystinuria, hypercholesterolemia, or cigarette smoke). Thrombosis results from
exposed subendothelial ECM, increased platelet adhesion or procoagulant production
(i.e., tissue factor, PAI), or reduced anticoagulant activity (i.e., PGI2, thrombomodulin, tPA).

Alterations in normal blood flow can promote thrombosis. Normal blood flow is laminar
(i.e., cellular elements flow centrally in the vessel lumen, separated from endothelium by
a plasma clear zone). Stasis and turbulence disrupt laminar flow and bring platelets into
contact with the endothelium. Stasis causes thrombosis in the venous circulation, cardiac
chambers, and arterial aneurysms; turbulence causes thrombosis in the arterial circulation
as well as endothelial injury. Hyperviscosity syndromes (e.g., polycythemia) or deformed
erythrocytes (e.g., sickle cell anemia) result in small vessel stasis and also predispose to


Hypercoagulability (p. 122) is loosely defined as any alteration of the coagulation

pathways that predisposes to thrombosis. It contributes less frequently to thrombosis but
is critical in certain conditions.
a. Heritable hypercoagulable states:
i. Factor V gene mutations are the most common; 2% to 15%of caucasians
(and 60% of patients with recurrent deep vein thrombosis) carry the so-

called Leiden mutation, thereby rendering factor V resistant to protein C

ii. ii. Deficiencies of antithrombin III, protein C, or protein S also typically
present with venous thrombosis and recurrent thromboembolism.
b. Acquired hypercoagulable states due to oral contraceptives or the hyperestrogenic
state of pregnancy may cause hypercoagulability by increasing hepatic synthesis
of coagulation factors and reduced synthesis of antithrombin III.
c. Heparin-induced thrombocytopenia syndrome occurs when heparin products
(unfractionated more commonly than low molecular weight heparin) induces
circulating antibodies that activate platelets and injure ECs.
d. Antiphospholipid antibody syndrome occurs in patients with antibodies against
anionic phospholipids that activate platelets or interfere with protein C activity.

Pathophysiology of Embolism
Embolism refers to any intravascular solid, liquid, or gaseous mass carried by blood flow to a
site distant from its origin. Most (i.e., 99%) arise from thrombi, hence the term
thromboembolism. Emboli lodge in vessels too small to permit further passage, resulting in
partial or complete vascular occlusion and ischemic necrosis (infarction).
1. Pulmonary Embolism
Pulmonary emboli (PE) occur in 0.2% to 0.4% of hospitalized patients and cause about 200,000
deaths annually in the United States. Greater than 95% of PE originate from DVT, although DVT
occur roughly 3-fold more commonly than PE. PE can occlude the main pulmonary artery,
impact across the bifurcation (saddle embolus), or pass into smaller arterioles.
Rarely, emboli pass through atrial or ventricular defects into the systemic circulation
(paradoxical embolism). Most PE (60% to 80%) are small and clinically silent. They eventually
organize and get incorporated into the vessel wall or leave a delicate, bridging fibrous web.
Sudden death, right-sided heart failure (cor pulmonale), or cardiovascular collapse occurs when
60% or more of the pulmonary circulation is obstructed with emboli.
2. Systemic Thromboembolism
Systemic thromboembolism refers to emboli in the arterial circulation. Approximately 80% arise
from intracardiac mural thrombi; two thirds are secondary to myocardial infarcts, and 25% arise
in the setting of dilated left atria and fibrillation. Systemic emboli can also originate from aortic
aneurysms, thrombi on ulcerated atherosclerotic plaques, or valvular vegetations; they rarely
originate from paradoxical emboli (venous emboli that pass through an atrial or ventricular septal
defect, including patent foramen ovale); 10% to 15% are ofunknown origin. Major sites for
arteriolar embolization are the lower extremities (75%) and brain (10%); intestines, kidneys,
spleen, and upper extremities are less frequent. The consequences of arterial emboli depend on
collateral vascular supply, tissue vulnerability to ischemia, and vessel caliber; most arterial
emboli cause tissue infarction.
3. Fat and Marrow Embolism
Pulmonary embolization of microscopic fat globules (with or with- out hematopoietic marrow
elements) occurs after fractures of long bones or, rarely, after burns or soft tissue trauma. Fat

embolism occurs in 90% of severe skeletal injuries; less than 10% have any clinical findings.
4. Air Embolism
Air embolism refers to gas bubbles within the circulation that obstruct vascular flow and cause
ischemia. Small amounts in the coronary or cerebral circulation (introduced following surgery)
can be catastrophic. Generally, in the pulmonary circulation, more than 100 cc is required to have
a clinical effect; such volumes can be introduced during obstetrical procedures or after chest wall
injury. Decompression sickness is a special form of air embolism caused by sudden changes in
atmospheric pressure; deep-sea divers and individuals in unpressurized aircraft during rapid
ascent are at risk. Air breathed at high pressure causes increasing amounts of gas (particularly
nitrogen) to be dissolved in blood and tissues. Subsequent rapid ascent (depressurization) allows
the dissolved gases to expand and bubble out of solution to form gas emboli. Formation of gas
bubbles in skeletal muscles and joints causes painful bends. In lungs, edema, hemorrhage, and
focal emphysema lead to respiratory distress, or chokes. Gas emboli may also cause focal
ischemia in a number of tissues, including brain and heart.
5. Amniotic Fluid Embolism
Embolization of amniotic fluid into the maternal pulmonary circulation is a serious (mortality
rate 80%) but uncommon (1 in 40,000 deliveries) complication of labor and postpartum period.
The syndrome is characterized by sudden severe dyspnea, cyanosis, and hypotensive shock,
followed by seizures and coma.