Thrombi are composed of fibrin and blood cells and may form in
any part of the cardiovascular system, including veins, arteries, the heart, and the microcirculation. Because
the relative proportion of cells and fibrin depends on hemodynamic factors, the proportions differ in
arterial and venous thrombi.1 2 Arterial thrombi form under conditions of high flow and are
composed mainly of platelet aggregates bound together by thin fibrin strands.3 4 5 In contrast, venous thrombi form in areas of stasis and are
predominantly composed of red cells, with a large amount of interspersed fibrin and relatively few platelets. Thrombi
that form in regions of slow to moderate flow are composed of a mixture of red cells, platelets, and fibrin
and are known as mixed platelet-fibrin thrombi.4 5 When a platelet-rich arterial thrombus becomes occlusive, stasis
occurs, and the thrombus can propagate as a red stasis thrombus. As thrombi age, they undergo progressive
structural changes.6 Leukocytes are attracted by chemotactic factors released from
aggregated platelets2 or proteolytic fragments of plasma proteins and become incorporated
into the thrombi. The aggregated platelets swell and disintegrate and are gradually replaced by fibrin. Eventually,
the fibrin clot is digested by fibrinolytic enzymes released from endothelial cells and leukocytes.
The complications of thrombosis are caused either by the effects of local obstruction of the vessel, distant
embolism of thrombotic material, or, less commonly, consumption of hemostatic elements.
Arterial thrombi usually form in regions of disturbed flow and
at sites of rupture of an atherosclerotic plaque, which exposes the thrombogenic subendothelium to platelets
and coagulation proteins; plaque rupture may also produce further narrowing due to hemorrhage into the
plaque.7 8 9 10 11 Nonocclusive thrombi may become incorporated into the vessel
wall and can accelerate the growth of atherosclerotic plaques.9 12 13 When flow is slow, the degree of stenosis is severe,
or the thrombogenic stimulus is intense, the thrombi may become totally occlusive. Arterial thrombi
usually occur in association with preexisting vascular disease, most commonly atherosclerosis; they produce
clinical tissue ischemia either by obstructing flow or by embolism into the distal microcirculation. Activation
both of blood coagulation and of platelets is important in the pathogenesis of arterial thrombosis. These
2 fundamental mechanisms of thrombogenesis are closely linked in vivo, because thrombin, a key clotting enzyme
generated by blood coagulation, is a potent platelet activator, and activated platelets augment the
coagulation process. Therefore, both anticoagulants and drugs that suppress platelet function are potentially effective
in the prevention and treatment of arterial thrombosis, and evidence from results of clinical trials indicates
that both classes of drugs are effective.
Venous thrombi usually occur in the lower limbs; although
often silent, they can produce acute symptoms due to inflammation of the vessel wall, obstruction of
flow, or embolism into the pulmonary circulation. They can produce long-term complications due to venous
hypertension by damaging the venous valves. Activation of blood coagulation is the critical mechanism in pathogenesis
of venous thromboembolism, whereas platelet activation is less important. Anticoagulants are therefore very
effective for prevention and treatment of venous thromboembolism, and drugs that suppress platelet function
are of less benefit.
Intracardiac thrombi usually form on inflamed or damaged
valves, on endocardium adjacent to a region of myocardial infarction (MI), in a dilated or dyskinetic
cardiac chamber, or on prosthetic valves. They are usually asymptomatic when confined to the heart but
may produce complications due to embolism to the cerebral or systemic circulation. Activation of blood coagulation
is more important in the pathogenesis of intracardiac thrombi than platelet activation, although the
latter plays a contributory role. Anticoagulants are effective for prevention and treatment of intracardiac
thrombi, and in patients with prosthetic heart valves, the efficacy of anticoagulants is augmented by drugs
that suppress platelet function.
Widespread microvascular thrombosis is a complication of
disseminated intravascular coagulation or generalized platelet aggregation. Microscopic thrombi can
produce tissue ischemia, red cell fragmentation leading to a hemolytic anemia, or hemorrhage due to consumption
of platelets and clotting factors. Anticoagulants are effective in selected cases of disseminated intravascular
It has been estimated that venous thromboembolism is responsible
for more than 300 000 hospital admissions per year in the United States14 and that pulmonary embolism (PE) causes or contributes
to death in 12% of hospitalized patients and is responsible for 50
000 to 250 000 deaths annually in the United States. The burden of illness produced by venous thromboembolism includes
death from PE (either acute or, less commonly, chronic), long-term consequences of the postthrombotic syndrome,
the need for hospitalization, complications of anticoagulant therapy, and the psychological impact of
a potentially chronic, recurrent illness.
Arterial thrombosis is responsible for many of the acute
manifestations of atherosclerosis and contributes to the progression of atherosclerosis. The burden
of illness from atherosclerosis is enormous. As a generalized pathological process, atherosclerosis affects the
arteries supplying blood to the heart, brain, and abdomen or legs, causing acute and chronic myocardial ischemia,
including sudden death, MI, unstable angina, stable angina, ischemic cardiomyopathy, chronic arrhythmia,
and ischemic cerebrovascular disease (including stroke, transient ischemic attacks, and multi-infarct dementia).
In addition, atherosclerosis can cause renovascular hypertension, peripheral arterial disease with resulting
intermittent claudication and gangrene, and bowel ischemia, and it can compound the complications of
diabetes mellitus and hypertension. Thromboembolism that originates in the heart can cause embolic stroke and peripheral
embolism in patients with atrial fibrillation (AF), acute MI, valvular heart disease, and cardiomyopathy.
The second version of "A Guide to Anticoagulant Therapy"
was published in 1994. Since then, the following important advances have been made: (1) low-molecular-weight
heparin (LMWH) preparations have become established anticoagulants for treatment of venous thrombosis
and have shown promise for the treatment of patients with acute coronary syndromes; (2) direct thrombin inhibitors
have been evaluated in venous thrombosis and acute coronary syndromes; (3) important new information
has been published on the optimal dose/intensity for therapeutic anticoagulation with coumarin anticoagulants;
and (4) the dosing of heparin for adjunctive therapy in patients with acute coronary syndromes has been reduced
because conventional doses cause serious bleeding when combined with thrombolytic therapy or glycoprotein
(GP) IIb/IIIa antagonists.
Whenever possible, the recommendations in this review of
anticoagulant therapy are based on results of well-designed clinical trials. For some indications or
clinical subgroups, however, recommendations are of necessity based on less solid evidence and are therefore
subject to revision as new information emerges from future studies.