Deep Vein Thrombosis, Anticoagulation and the Location of Fatal
Although the pathophysiology of venous thromboembolic disease has
been known for years, deep vein thrombosis remains a major source of
morbidity in hospitalized patients. Short-term morbidity occurs in
the form of pulmonary emboli, which are a common cause of death.
Pulmonary emboli account for about 5% of hospital deaths, or
approximately 60 000-200 000 deaths per year in the United States
depending on the diligence of search for this cause of death.1
Long-term morbidity occurs primarily due to the sequellae of the
postphlebitic leg and due to the development of chronic pulmonary
hypertension as a result of the embolization. Only about 30% of the
fatal cases of pulmonary emboli are diagnosed before death. This is
a consistent figure across many autopsy series. The statistics on
incidence and consequence of pulmonary emboli are highly variable
thru the literature. One important unifying feature of this vast
literature, however, is that the incidence of deep vein thrombosis
and pulmonary embolism is critically dependant on the diligence with
which these diagnoses are sought. Pulmonary emboli are often
asymptomatic, so reports of the incidence of "clinical embolism,"
meaning patients found by history and physical examination to have
pulmonary embolus, will not accurately reflect the true incidence.
Autopsies in which only proximal pulmonary arteries are examined
will underestimate the incidence. Venous diagnostic tests which do
not evaluate the entire venous system of the lower extremities will
underestimate the incidence of deep venous obstruction. Such studies
Role of Deep Venous Thrombosis (DVT) in Pulmonary Embolus
Over 90% of pulmonary emboli originate from clots in the deep
veins of the pelvis and leg. Of patients admitted for DVT, 40% have
experienced pulmonary emboli before admission according to a careful
study by Moser et al.2 While they consider the figure of
40% to be a minimal figure, they studied patients more thoroughly
than is usually done, and studied only patients in whom DVT was
suspected, making their incidence higher. Remember that DVT is often
present when in is not suspected. Clearly the extent of pretreatment
embolization determines the amount of additional clot burden which
is tolerable should further embolization occur. Of the patients with
DVT, the incidence of pulmonary emboli varies according to location.
Proximal clots, designated in the literature as ileofemoral
thrombosis, have the highest incidence and calf veins have the least
incidence. Norris,3 for example, studied the occurrence
of clinically evident pulmonary emboli in 78 patients with
ileofemoral thrombosis treated with adequate heparin
anticoagulation. Almost 10% of these patients had clinically evident
pulmonary emboli documented by lung scan in spite of adequate
anticoagulation. Had he studied all patients with lung scans, he
probably would have found more. Kistner noted that when phlebitis
extended into the iliac veins, pulmonary embolism occurred in 50% of
patients, many before the diagnosis of DVT was recognized.4
In his entire series, 15% of patients experienced embolism after the
onset of anticoagulation. Since he tended to perform thrombectomy on
patients with iliac thrombosis, the incidence would have been a bit
higher had this high risk group been included. Moser also noted a
much higher incidence of thromboembolism in patients with more
proximal deep vein thrombosis.5 Free floating thrombi
were found to be particularly dangerous and were associated with a
60% incidence of embolization in spite of treatment.3 At
the other end of the spectrum, calf vein thrombosis appears to have
a 20% incidence of embolization if untreated, and some believe that
the incidence is even less.
Mechanisms of Death from Pulmonary Emboli
Several mechanisms contribute to death from pulmonary emboli.
Increased pulmonary vascular resistance leads to decreased blood
flow thru the pulmonary vascular bed and decreased pumping ability
on the part of the heart. There is impaired gas exchange due to loss
of blood flow and loss of functioning units of lung tissue. There is
spasm of the bronchi and pulmonary vessels causing obstruction out
of proportion to the clot burden. The lungs become stiff due to
edema, hemorrhage and loss of surfactant. These mechanisms are
discussed in most major textbooks.6 Although these
secondary factors may be contributing, patients die for mechanical
reasons. Fifty per cent or more of their pulmonary vascular bed is
occluded, and the heart simply can not pump enough blood thru the
obstruction to provide oxygen to the body. It does not matter which
50% is occluded, and this 50% number is consistent across the
Goldhaber suggests that 30% of the vascular bed can be occluded
by multiple emboli without major compromise. Obviously an additional
clot thrown in on top of an asymptomatic 30% obstruction of the
pulmonary bed carries a worse prognosis that one landing in a normal
vascular bed. "Obviously, the volume and orientation of the embolus
dictate the effects on the pulmonary circulation.8"
Proximal emboli require a smaller volume of clot to occlude the
requisite 50% of the vascular bed and cause "massive pulmonary
embolism." The literature on transfemoral pulmonary embolectomy
confirms that dramatic effects are often produced by removing small
amounts of critically placed clot.9 This has been my
experience with this technique as well. When the critical volume has
been removed the patient notes a sudden improvement in breathing and
pulmonary hemodynamics are much improved. Follow-up angiography
often demonstrates multiple pruned distal branches, indicating
distal embolization. Sometimes improvement is produced by simply
breaking up the thrombus and dispersing it into the
periphery--providing that the peripheral vessels aren't already
overloaded. Death from overloading the distal pulmonary circulation
is not uncommon (see autopsy info).
Autopsy Findings in Fatal Pulmonary Embolus.
"Differences in size of thromboemboli have great consequences not
only for the clinical effects and for mortality, but also for the
evaluation of the prevalence of pulmonary thromboembolism. Large
emboli obstructing pulmonary trunk or main pulmonary arteries will
not remain undetected when these vessels are opened at autopsy.
However, lobar and segmental pulmonary arteries are not regularly
cut systematically, so that emboli in these vessels may escape
detection. This explains that the percentage of grossly recognizable
emboli in routine autopsies of adult patients varies widely, from
1.5% to almost 30%.10"
Although anticoagulation has been remarkably effective in
preventing pulmonary emboli in patients with deep vein thrombosis,
all patients are not protected. Kistner believed it to be 89%
effective for clots at the inguinal ligament and belowiv Schafer
(1999) reported that anticoagulants are up to 90% effective in
preventing repeated episodes of pulmonary embolism.11
Sandler12 reported an autopsy study from the Royal
Hallamshire Hospital in 1989. Unfortunately he did not describe the
location of the fatal pulmonary emboli, but he did note that 6% of
the 239 fatal pulmonary emboli occurred while the patient was
anticoagulated. Dismuke et al13 reported, in an autopsy
study from North Carolina Memorial Hospital, that the use of
anticoagulants increased dramatically between the start of the study
in 1966 and the end of the study in 1980. Although the proportion of
patients dying from pulmonary emboli decreased as a result, 40% of
the patients who died (17/43) during the last 5 years of the study
were receiving anticoagulants when they experienced their fatal
pulmonary embolus. They too did not report the locations of the
emboli found. Anticoagulation may not be the best treatment for DVT,
however. Marder's studies14 show that when DVT is treated
with heparin 50% of patients retain the same clot burden, 25% lyse
some of the clot, but fully 25% experience clot propagation.
Morpurgo summarized his extensive studies on the pathology of
pulmonary embolism as follows: "Often a fatal embolus is relatively
small but hardly tolerated because of the underlying cardiopulmonary
situation. For this reason also, an hemodynamic rather than anatomic
stratification of prognosis proves to be suitable. In 1948 Neuhof
already wrote the following: 'Embolism of peripheral branches of the
pulmonary arteries, leaving the main branches free, may produce
symptoms of marked severity and may even cause death.' Also in our
experience covering 49 cases of sudden and unexpected death,
pulmonary embolization often involved only peripheral and unilateral
Most autopsy studies do not give the locations of the fatal
pulmonary emboli found. Since studies of this type are carried out
using the same technology as would be used today, and since they are
studies of the natural history of the disease, older articles remain
relevant. An extensive autopsy survey of pulmonary embolism
published by Coon and Coller in 195916 studied 4391
consecutive autopsies done at the University of Michigan on
hospitalized patients. A careful search was made for all pulmonary
emboli. Pulmonary embolism was found in 606 patients (13.8%) and was
considered the cause of death in 198, or 4.5%. An additional 190
patients (4.3%) had emboli which contributed to death but were not
the cause. In patients whose cause of death was pulmonary embolism,
33% had thrombi in the main pulmonary artery, left or right
pulmonary arteries. In 48% the thrombi were in lobar arteries, and
in 19% they were in smaller arteries only. These patients died
suddenly. Twenty-two per cent died immediately, 47% were dead within
15 minutes from the onset of symptoms, and 62% were dead in one
hour. In the patients with emboli contributing to death the
percentages were 19% in the main, right or left pulmonary artery,
43% in lobar arteries, and 38% in even smaller arteries. They
concluded that "Massive occlusion with myriads of microscopic emboli
to almost all of the terminal branches of the pulmonary arterial
system appear to be responsible for almost one-fifth of the deaths
attributed to pulmonary embolism.....Very frequently, routine
microscopic section of various areas of grossly normal lung is the
only way to detect this entity."
The most pertinent autopsy series defining the location of fatal
pulmonary emboli is the series reported by the Mayo Clinic in 1995.17
These authors studied autopsy cases from the Mayo clinic between
1985 and 1989. Among 2427 autopsies, death was clinically and
pathologically judged to be caused by pulmonary embolism in 92 or
3.8% of autopsies. Of these 92 patients, 46% were on some form of
thrombophlebitis prophylaxis. 7% were fully anticoagulated. 8% had
vena cava filters in place. Sudden death occurred in 26% without any
symptoms. If you include patients unable to report symptoms (coma,
respirators, etc) then the incidence rose to 35%. In this group of
patients pulmonary embolism was considered as a diagnosis by the
physicians caring for the patient in 49% and was correctly assigned
as the cause of death on the death certificate or in the medical
records in only 32%. Half of these patients had several generations
of pulmonary emboli. The importance of complete autopsy was
emphasized by the locations of the fatal emboli. 27 patients had
saddle emboli, meaning emboli occluding both main pulmonary
arteries. 9 had occlusions of one main pulmonary artery. The
remainder, or 60% had their emboli confined to lobar or sublobar
pulmonary arteries. These data are Strikingly similar to those
reported by Coon and Coller in 1959.
Surgical papers have commented on the impossibility of saving
patients with massive peripheral pulmonary emboli by emergency
pulmonary embolectomy. The trouble, of course, is in identifying
these patients preoperatively, as the lung scan is unable to make
the differentiation.18, 21
Fragmentation of Pulmonary Emboli
As can be seen by the diagram of the pulmonary vasculature, the
volume of clot required to occlude the pulmonary vasculature depends
on where it located and how much of the pulmonary vascular bed has
previously been occluded. The main pulmonary artery divides in three
dimensions so that by the time the capillary bed is reached
distally, the cross sectional area of the vascular bed in huge
compared to the main pulmonary artery. Since deep vein thrombosis is
commonly associated with asymptomatic pulmonary emboli it is
difficult to know how much of the vascular bed is involved at the
time of diagnosis.
"...thromboemboli may break up into numerous small fragments,
either mechanically or during the process of endogenous thrombolysis."
"Thrombotic microembolism al-most certainly may give rise to
extensive pulmonary arterial obstruction and to thrombo-embolic
pulmonary hyper-tension. Cases of widespread peripheral pulmonary
arterial occlusion by post thrombotic lesions which are clearly of
embolic origin, may be masquerading as primary pulmonary
hypertension.10" Clearly if widespread enough, death may
occur before chronic pulmonary hypertension is a consideration.
Fragmentation of pulmonary emboli is a well-known phenomenon.
Coon and Coller reported "A difficult problem is the explanation for
sudden death in a patient with occlusion of only one major pulmonary
artery or several secondary branches which one would not expect to
be fatal on the basis of mechanical obstruction of the arterial tree
alone. This has usually been attributed to the generalized reflex
changes mentioned previously. [also mentioned above in this paper].
Another equally logical explanation would be that a large embolus
had fragmented at the bifurcation of the main pulmonary artery with
secondary undetected microscopic obstruction of the smaller branches
to the other lung. We believe that such fragmentation occurs
frequently in pulmonary embolism and is very often fatal, although
difficult to detect unless one examines routine sections from each
In fact a proximal clot can lead to cardiac arrest and then be
broken up into the periphery during CPR, thus disappearing from the
major pulmonary vessels. Brady mentioned this phenomenon in
describing a technique for mechanical disruption of the occluding
thrombus as a means of therapy.19 "Because the volume of
thrombus is large relative to that of the main pulmonary arteries,
but small when compared with the total volume of the smaller
vessels, dispersing the clot into the distal branches will
substantially increase pulmonary blood flow." His critics noted
failure with this technique, presumably because distal vessels were
already overloaded in their patient.20 Elliott (1995)21
Noted that "Because chest compression may fragment large central
pulmonary emboli, the need for embolectomy following a successful
cardiopulmonary resuscitation for acute pulmonary embolism remains
less certain. Indeed, a number of centers do not perform
embolectomies for patients whose condition has stabilized." As far
as I can tell, formal studies on clot fragmentation during CPR have
not been carried out. To demonstrate this phenomenon due to CPR, one
would have to know the exact location of the clot before CPR was
started and then document where it was after CPR was concluded. The
impossibility of obtaining such data in humans is obvious.
Nonetheless, Price noted that "If cardiac arrest occurs, external
cardiac massage should be undertaken as it is sometimes successful
and disseminates and fragments the clot in the pulmonary artery.22"
Thus fatal pulmonary emboli found only in the periphery may be
the natural presentation of fatal pulmonary embolism, or may be due
to fragmentation of the clot as a part of its natural history or as
the result of instrumentation or resuscitation.
Dr Brantigan wrote this paper in December 2000.
1 I have
not referenced much of this basic data, as it appears at the
beginning of most articles on the subject.
KM, Fedullo, PF, LittleJohn, JK, Crawford, R, Frequent asymptomatic
pulmonary embolism in patients with deep vein thrombosis, J Amer Med
Ass (1994) 271:223-5.
CS, Greenfield, LJ, Free-floating iliofemoral thrombus, Arch Surg
RL, Ball, JJ, Nordyke, RA, Freeman, GC, Incidence of pulmonary
embolism in the course of thrombophlebitis of the lower extremities,
Amer J Surg (1972) 124:169-176.
KM, LeMoine, JR, Is embolic risk conditioned by location of deep
venous thrombosis?, Ann Int Med (1981) 94 (part 1): 439-444.
SZ, Pulmonary embolism, in Braunwald, E, Heart Disease, WB Saunders,
Philadelphia 1997 p1585.
SZ in Braunwald op cit. table 46-7.
Greenfield, LJ, Zocco, JJ, Intraluminal management of acute massive
pulmonary thrombembolism, J Thor Cardiovasc Surg (1979)77:402-410.
Greenfield's other articles on the subject, such as Greenfield, LJ,
Reif, ME, Guenter, CE, Hemodynamic and respiratory responses to
transvenous pulmonary embolectomy, J Thor Cardiovasc Surg (1971)
Wagenvoort, CA, Pathology of pulmonary thromboembolism, Chest (1995)
107:10s-17s. Note that this article is against us in some respects
when it notes that most PE's that cause sudden death are located in
major arteries. He does go on to describe fragmentation of clots and
distal embolization as a cause of major problems, however. Note that
this is not an article with data, just opinions.
AI, Editorial: Venous thrombosis as a chronic disease, New Engl J
Med (1999) 340:955-6.
DA, Martin, JF, Autopsy proven pulmonary embolism in hospital
patients: are we detecting enough deep vein thrombosis, J Roy Soc
Med (1989) xxxxxxxx
SE, Wagner, EH, Pulmonary embolism as a cause of death; The changing
mortality in hospitalized patients, JAMA (1986) 255:2039-2042.
remember these articles-they are on a slide from my DVT lecture-but
do not remember the reference.
M, Schmid, C, The spectrum of pulmonary embolism: clinicopathologic
correlations, Chest (1995) 107:18s-20s. He refers to Morpurgo,
Clinico-pathological correlation in pulmonary embolism;a posteriori
evaluation. Progr Respir Res (1980) 13:8-15, and Neuhof, H, Venous
thrombosis and pulmonary embolism, Grune and Stratton, 1948, p
92-105, references that I don't have.
WW, Coller, FA, Clinicopathological correlation in thromboembolism,
Surg Gynec Obstet (1959) 109:259-269.
Morgenthaler, TI, Ryu, JH, Clinical characteristics of fatal
pulmonary embolism in a referral hospital, Mayo Clin Proc (1995)
P, Schlapfer, R, Feer, R, Habicht, J, Gradel, E, Decision making in
the surgical treatment of massive pulmonary embolism, Eur J Cardio-thorac
Surg (1994), 8:188-93.
AJB, Crake, T, Oakley, CM, Percutaneous catheter fragmentation and
distal dispersion of proximal pulmonary embolus, Lancet (1991)
20 Meyer, G
et al, Letter to the editor, Chest (1992) 102:1306.
CG, Embolectomy, catheter extraction, or disruption of pulmonary
emboli: editorial review, Current Opinion in Pul Med (1995)
DG, Pulmonary embolism. Prophylaxis and treatment, Anaesthesia