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The primary abnormalities that lead to thrombosis are
1. Endothelial injury
2. Stasis or turbulent blood flow
3. Hypercoagulability of the blood
Endothelial injury leading to platelet activation almost inevitably
underlies thrombus formation in the heart and the arterial
circulation, where the high rates of blood flow impede clot
Severe endothelial injury may trigger thrombosis by exposing vWf
and tissue factor.
Inflammation and other noxious stimuli may promote thrombosis
by shifting the pattern of gene expression in endothelium to one
that is “prothrombotic” (endothelial activation) which can be
produced by physical injury, infectious agents, abnormal blood
flow, inflammatory mediators, metabolic abnormalities and toxins.
Endothelial activation is believed to have an important role in
triggering arterial thrombotic events:
1. Procoagulant changes
2. Antifibrinolytic effects
ALTERATIONS IN NORMAL BLOOD FLOW
Turbulence contributes to arterial and cardiac thrombosis by causing
endothelial injury or dysfunction, as well as by forming countercurrents
that contribute to local pockets of stasis.
Stasis is a major contributor in the development of venous thrombi.
Stasis and turbulence therefore promote:
1. Endothelial activation, enhancing procoagulant activity and leukocyte
adhesion, in part through flow-induced changes in the expression of
adhesion molecules and pro inflammatory factors.
2. Disrupt laminar flow and bring platelets into contact with the endothelium.
3. Prevent washout and dilution of activated clotting factor by fresh flowing
blood and the inflow of clotting factors inhibitors.
Ulcerated and atherosclerotic plaques not only expose subendothelial
vWF and tissue factor but also cause turbulence.
Aortic and arterial dilations called aneurysms result in local stasis and
are therefore fertile site of thrombosis.
Acute myocardial infarctions result in areas of noncontractile
myocardium and sometimes in cardiac aneurysms.
Rheumatic mitral valve stenosis results in left atrial dilation, in
conjunction with atrial fibrillation resulting in thrombosis.
Hypercoagulability (thrombophilia) can be loosely defined as any
disorder of blood that predisposes to thrombosis.
It has a particular important role in venous thrombosis and can be
devided into primary (genetic) and secondary (acquired) disorders.
The most common thrombophilic genotypes found in various populations
impart only a moderately increased risk of thrombosis; when otherwise
healthy are free from thrombotic complications. Factor V and prothrombin
mutations are frequent enough that homozygosity and compound
heterozygosity are not rare and such genotypes are associated with greater
risk. Individuals with such mutations have a significantly increased frequency
of venous thrombosis in the setting of other acquired risk factors. Inherited
causes of hypercoagulability must be considered in patients younger than
age 50 who present with thrombosis-even when acquired risk factors are
Pathogenesis of acquired thrombophilia is frequently multifactorial. Some
cases, stasis or vascular injury may be most important. Oral contraceptive
use or the hyperestrogenic state of pregnancy may also result in
hypercoagulability. Hypercoagulabilty seen with advancing age may be due
to reduced PGI2 production. Smoking and obesity are aslso aggravating
factors. In cancers, release of various procoagulants from tumor predisposes
Among the acquired state the heparin induced thrombocytopenia and
the antiphospholipid antibody syndrome are most important clinically.
FATE OF THE THROMBUS
If a patients survives the initial thrombosis, in the ensuing days to
weeks thrombi undergo some combination of the following events
Propagation: thrombi accumulate additional platelets and fibrin.
Embolization: thrombi dislodge and travel to other sites of
Dissolution: it is the result of fibrinolysis, which can lead to the rapid
shrinkage and disappearance of recent thrombi. In contrast, the
extensive fibrin deposition and cross-linking in older thrombi renders
them more resistant to lysis.
Organization and recanalization: older thrombi become organized
by the ingrowth of the endothelial cells, smooth muscle cells and
fibroblasts. Capillary channels eventually form that reestablish the
continuity of the original lumen, albeit to a variable degree.
Continued recanalization nay convert a thrombus into a smaller
mass of connective tissue that becomes incorporated into the vessel
wall. With remodeling and contraction of the mesenchymal elements,
only a fibrous lump may remain to mark the original thrombus.
An embolus is a detached intravascular solid, liquid or gaseous mass that
is carried by the blood from its point of origin to a distant site, where it
often causes tissue dysfunction or infarction.
Pulmonary emboli originate from deep venous thrombosis and
are the most common form of thromboembolic disease
In more than 95% of cases, PE originate from leg DVTs.
Fragmented thrombi from DVTs are carried through progressively
larger veins and the right side of the heart before slamming into
the pulmonary arterial vasculature.
Depending on the size of the embolus, it can occlude the main
pulmonary artery, straddle the pulmonary artery bifurcation or
pass out into the smaller, branching arteries.
Frequently there are multiple emboli, occurring either sequentially
or simultaneously as a shower of smaller emboli from a single
A venous embolus passes through an interatrial or interventricular
defect and gains access to the systematic arterial circulation
Most systemic emboli arise from intracardiac mural thrombi, two
thirds of which are associated with left ventricular wall infarcts
and another one forth with left atrial dilation and fibrillation.
The remainder originates from aortic aneurysms, atherosclerotic
plaques, valvular vegetations or venous thrombi.
Arterial emboli can travel to a wide variety of sites; the point of
arrest depends on the source and the relative amount of blood
flow that downstream tissues receive.
The consequences of the systemic emboli depends on the
vulnerability of the affected tissues to ischemia, the caliber of the
occluded vessels and whether a collateral blood supply exists; in
general, however, the outcome is tissue infarction.
FAT AND MARROW EMBOLISM
Microscopic fat globules can be found in the pulmonary vasculature after
fractures of long bones or rarely in the setting of soft tissue trauma and
Fat and marrow emboli are very common incidental findings after
vigorous cardiopulmonary resuscitation and are probably of no clinical
Fat embolism syndrome is the term applied to the minority of patients
who become symptomatic. Its is characterized by pulmonary
insufficiency, neurologic symptoms, anemia and thrombocytopenia and
is fatal in 5% to 15% of patients.
Typically, 1 to 3 days after injury there is a sudden onset of tachypnea,
dyspnea and tachycardia; irritability and restlessness can progress to
delirium or coma.
Thrombocytopenia is attributed to platelet adhesion to fat globules and
subsequent aggregation or splenic sequestration; anemia can result
from similar red cell aggregation or hemolysis.
The pathogenesis of fat emboli syndrome probably involves both
mechanical obstruction and biochemical injury.
Fat microemboli and associated red cell and platelet aggregates can
occlude the pulmonary and cerebral micro vasculature.
Gas bubbles within the circulation can coalesce to form frothy masses
that obstruct vascular flow and cause distal ischemic injury.
A particular form of gas embolism called decompression sickness occurs
when individuals experience sudden decrease in atmospheric pressure.
The rapid formation of gas bubbles within skeletal muscles and
supporting tissues in and about joints is responsible for the painful
condition called the bends.
In the lungs gas bubbles in the vasculature cause edema, hemorrhage
and focal atelactasis or emphysema, leading to a form of respiratory
distress called the chokes.
A more chronic form of decompression sickness is called caisson
disease in which persistence of gas emboli in the skeletal system leads
to multiple foci of ischemic necrosis; the more common sites are the
femoral heads, tibia and humeri.
Individuals affected by acute decompression sickness are treated by
being placed in a chamber under sufficiently high pressure to force the
gas bubbles back into solution. Subsequent slow decompression
permits gradual resorption and exhalation of the gases, which prevents
the obstructive bubbles from reforming.
AMNIOTIC FLUID EMBOLISM
Amniotic fluid embolism is an ominous complication of labor and the
immediate postpartum period.
The onset is characterized by sudden svere dyspnea, cyanosis and
shock followed by neurologic impairment ranging from headaches to
seizures and coma.
If the patient survives the initial crisis, pulmonary edema typically
develops, frequently accompanied by disseminated intravascular
Much of the morbidity and mortality in amniotic fluid embolism may stem
from the biochemical activation of coagulation factors and components
of the innate immune system bys substances in the amniotic fluid, rather
than the mechanical obstruction of pulmonary vessels by amniotic
The underlying cause is the infusion of amniotic fluid or fetal tissue into
the maternal circulation via a tear in the placental membranes or rupture
of uterine veins.
Classical findings at autopsy include the presence of squamous cells
shed from fetal skin, lanugo hair, fat from vernix caseosa and mucin
derived from the fetal GIT or the respiratory tract in the maternal