Historical Review
Venous Thrombosis: On the History of Virchow’s Triad
Brendan Craig Dickson, B.A., B.Sc., M.D. (OT3), M.Sc.
Abstract
Etiology
Rudolf Virchow, the renowned father of Modern
Pathology, is credited with many monumental medical
findings that continue to pervade the realms of modern
medicine. His numerous discoveries notwithstanding,
Virchow is remarkable in that he is attributed a theory on
the complex pathogenesis of venous thrombosis – in an
age limited by a rudimentary understanding of pathobiology and crude experimental resources – and this triad
remains clinically relevant to date. The importance of
Virchow’s Triad is impressed upon generations of students
of medicine; consequently, this paper traces the history of
venous thrombosis, focusing on its relationship to
Virchow’s Triad and highlighting major trends in our
understanding of the pathogenesis of this condition.
Utilizing the Index Medicus, Surgeon General’s
Catalogue, and period texts, a comprehensive review of
both the English and French literature was undertaken.
The results suggest that the ideas presented in the triad
were neither original to Virchow, nor did he appear to synthesize them in the manner in which they are currently
held. It is not until the middle of the 20th century that
the triad ascribed to Virchow appears in the literature, and
considerably later in most major pathology texts.
In reviewing both the English and French literature on the history of venous thrombosis and Virchow’s Triad, several
resources were employed. The following search terms were
used in the Index Medicus, Surgeon General’s Catalogue, and
Medline. These terms included, but were not restricted to:
Virchow, Virchow’s Triad, thrombosis (venous), embolism (pulmonary), phlebitis, hypercoagulable, inflammation (venous), stasis (blood), and clot (blood). Brackets denote the use of the
more specific term, where applicable. Some indices included
references to texts, in addition to journal articles (e.g., Surgeon
General’s Catalogue). Other texts were identified applying the
same search terms into the library catalogue at the University
of Toronto, during the spring of 2003.
Introduction
Rudolf Ludwig Karl Virchow (1821 – 1902) is recognized for
numerous medical discoveries that continue to influence generations of pathologists and clinicians alike.1 Ideally situated at the
cusp of a revolution in medical advance, many of Virchow’s
accomplishments continue posthumously to bear his name.
One such attribution is a theory delineating the pathogenesis of
venous thrombosis: Virchow’s Triad, which proposes that venous
thrombosis occurs as a result of (i) alterations in blood flow,
(ii) vascular endothelial injury, or (iii) alterations in the constitution of the blood.2 Proposed at a time when both pathology and haematology were in their infancies, the triad remains
clinically relevant over 150 years later. Considered standard
knowledge for all students of medicine, the triad is of obvious
historical importance;2 consequently, this paper traces the history and application of Virchow’s Triad from its preconception
to the present day.
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University of Toronto Medical Journal
Early History of Venous Thrombosis
Pathologic haemostasis was described as early as 2650 BC by
the Chinese physician Huang Ti; unfortunately, this account
fails to distinguish between venous and arterial thrombosis.2
Anning suggested the earliest recorded observation of venous
thrombosis occurred around 1400 AD as depicted from the
account of the Consilia of Ugo Benzi of Sienna.2 More recently, rediscovery of an illustrated manuscript presented to the
Cardinal of Bourbonnoys in the 15th century suggests the first
documented account in a young man clearly suffering from
venous thrombosis in 1271 AD.3
More steadfast reports of venous thrombosis emerged towards
the end of the 17th century. Wiseman (1686) offered an early
theory on the etiology of venous thrombosis, which bears interesting semblance to Virchow’s Triad:
The caufe of which may be referred either to the coagulation of the Serum, or grumoufnefs of the Bloud, or to the
obftruction of the Vein fomewhere in its paffage by fome
anguftation upon it by part of the tumour; from whence it
will often happen that the Vein beyond it hath its current
ftopped, and is forced to fwell. Nay, not only the contraction of the Veffels by preternatural Tumours doth this,
but alfo any other preffure.4
Wiseman thus attributed the cause of thrombosis to: (i) coagulation of the serum; (ii) thickening of the blood; and, (iii)
decreased venous blood flow by either impingement by tumour
or any other back pressure on the venous system (Table 1). He
proceeded to describe the increased occurrence of thrombosis
during pregnancy and malignancy;4 Van Swieten (1705) is credited with describing the incidence and outcome of clots during
the puerperium.5 White (1784) illustrated that phlegmasia alba
dolens is associated with thrombosis of the iliac or femoral
veins.6 That same year, Hunter published Observations of the
inflammation of the internal coats of veins where phlebitis is first
described.7
Virchow: Thrombosis and Emboli
Upon his appointment to the Charité Hospital in Berlin,
Virchow came under the direction of Robert Froriep (1804
–1861), who tasked him with investigating the assertion of the
leading French pathologist Cruveilhier (1791 – 1874) that “La
phlébite domine toute la pathologie [Phlebitis dominates all pathology].”1,6 It bears mention that phlebitis and thrombosis, until
Virchow’s urging, were described synonymously.6,8
Virchow combined clinical and experimental investigations in
pursuing Cruveilhier’s assertion. In a series of 76 autopsies he
identified 18 cases of ‘venous plugs,’ 11 involving concurrent
pulmonary emboli.9 In several instances he noted that the distal margin of the clots isolated from pulmonary arteries “. . . fit
to the end of the [venous] thrombus like a cap. . . it was easy to demonstrate the separation of those pieces from a certain location by the upper
concave, the lower convex, and inversely terraced surfaces.”9 Thus, he
correctly determined that the clot wedged in the vasculature of
the lungs represented a fragment derived from a distal source.
Virchow coined the term embolism to describe this process and
reasoned that the majority of clots originate from the deep veins
of the lower extremities;1,5,10 thereby contradicting the prevailing
belief that thrombosis occurred in the lungs de novo as a result
of inflammation of the veins.9 Virchow substantiated his
necropsy observations by a series of studies in which he injected various materials into the venous circulation of dogs, ultimately examining the characteristics of the material lodged in
the pulmonary vasculature. In addressing the pathogenesis of
the pulmonary embolism, it was presupposed that Virchow proposed his triad to describe the precipitants of the original
venous thrombus.
Virchow’s Triad
Alterations in Blood Flow
Prior to Virchow’s work, the role of stasis towards venous
thrombosis was already well established, as exemplified by
Wiseman’s work in 1686 (previously quoted herein).4 As well,
Baillie (1793),2 Davies (1823),11 Andral (1830)10 and Bouchut
(1845)10 are all credited with observing that stasis contributes to
an increased risk of venous thrombosis.
Humphry (1881), after personally incurring venous thrombosis,
proposed that clotting also stemmed from turbulence in blood
flow.12 He reasoned that eddies, generated as a result of the
venous valves, facilitated clotting; the idea of ‘valve pockets’
was re-popularized nearly 100 years later.13
By the 1930s, consensus emerged that stasis alone was insufficient for generating thrombosis.14,15 Nevertheless, it was appreciated that reduced blood flow contributes to thrombosis,
which is speculated to facilitate interactions between blood constituents and the vessel wall, or alter the balance of activated
clotting factors and inhibitors within the blood stream.16
Additional support for this hypothesis came from emerging
observations of an increased risk of thrombosis in patients
paralysed from stroke and spinal cord injuries, as well as
patients confined to bed-rest or immobility.17 The theory in this
instance being that the veins, dependent on the pumping action
of adjacent muscles to return blood to the heart, developed
increased pooling of the blood which potentiates interactions
between the erythrocytes and the endothelium.4
Recent media attention has revived interest in the contribution
of venous stasis, particularly as it pertains to passengers on long
trans-oceanic flights with the ‘economy class syndrome’.18 It
remains noteworthy, however, that consistent with studies
almost 150 years earlier, stasis alone does not appear to cause
thrombosis; rather, it requires the addition of vessel injury or
hypercoagulability.14
Endothelial Injury
The notion that injury to the intima causes thrombosis – also
known as the ‘doctrine of Cruveilhier,’ reflecting its obvious origins
– was known prior to Virchow’s research on venous thrombosis.19 Hodgson (1815), followed by others, described how trauma to a vein predisposes to thrombosis.2 Meanwhile, Davies
(1823),11 Andral (1830),10 and Lee (1842)11 were of the opinion
that inflammation of the endothelium could also contribute to
this phenomenon.
Baumgarten (1876) demonstrated that blood trapped in a doubly ligated vein for months failed to clot, but inoculation of the
isolated blood with infectious material resulted in prompt
thrombosis.20 Injury alone was subsequently demonstrated to
be insufficient for generating thrombosis. Barrett (1924) inflicted aseptic trauma to veins, noting that coagulation failed to
occur even in subsequent experiments when he injected bacteria at the site of injury. It was only when he anchored bacteria-inoculated threads in the vasculature did he generate a
venous thrombus and in some cases a pulmonary embolus.21
Advances in anaesthesia – which enabled longer and more invasive surgical procedures – along with subsequent casualties from
the Great War, heralded the contribution of the endothelium
which hitherto had been considered a minor contributor to
venous thrombosis.10 Injury to the intima was thought to be
due to direct trauma, but more importantly from damage as a
result of infection and bacterial toxins, thus “some workers go so
far as to say that there cannot be any thrombosis in the absence of
infection.”14
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167
Table 1
Historical Summary of the Proposed Contributors to Venous Thrombosis
AUTHOR
YEAR
ETIOLOGY
Wiseman4
1686
1. Coagulation of the serum
2. Thickening of the blood
3. Decreased venous blood flow by impingement or backward pressure on the venous system
Loeb41
1903
1. Constitution of the blood
2. Influence of surrounding tissue upon coagulable fluids
3. Influence of foreign elements such as bacteria and ligatures
Bland-Sutton5
1909
1.
2.
3.
4.
Mechanical disturbances in the blood
Lesions of the endothelium
Alterations in the blood
Sepsis
Wilson31
1912
1.
2.
3.
4.
Slowing or stagnation of the blood stream
Injury of the vascular walls
Disintegration of the corpuscles of blood from toxic substances
Bacteraemia
Duckworth19
1913
1.
2.
3.
4.
Feeble state of the circulation due to cardiac debility
Injury to, or alteration of, the intima of vessels
Direct blocking of their lumen by the intrusion of foreign or toxic material
Increased blood viscosity.
Aschoff42
1924
1.
2.
3.
4.
Changes
Changes
Changes
Changes
McCartney14
1927
1. Slowing of the blood stream
2. Injury to vascular endothelium
3. Changes in the composition of blood
Bancroft31
1931
1.
2.
3.
4.
Vance43
1934
1. Slowing of the blood stream
2. Injury to vascular endothelium
3. Changes in the composition of blood
Anning2
1957
1. Changes in the velocity of the blood stream
2. Lesions of the vascular intima
3. Alterations in the constitution of blood
in
in
in
in
blood-plasma (coagulability)
blood elements (agglutination)
blood flow (slowing, or eddies)
vessel (endothelial damage)
Trauma
Infection
Slowing of the blood stream
Dehydration
Table 2
Summary of Relevant Terms
Venous Thrombosis
The antemortem occurrence of coagulated blood within a vein.
Pulmonary Embolism
The process by which a lesion derived from the downstream venous circulation migrates to the pulmonary vasculature. This is most commonly attributed to a fragment of venous clot; however, it could also include other material such as air, amniotic fluid, and fat.
Phlebitis
Inflammation of the vein.
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University of Toronto Medical Journal
Appreciation for the complex intrinsic biology of the endothelium reveals how interdependence amongst many factors governs
the dynamic interplay between the occurrence of thrombosis and
thrombolysis. For example, exposure to the circulation of factors which are normally sequestered in the subendothelial space,
disorganization of the cell matrix, or alterations of the structure
and function of the endothelial cells proper may all off-set this
delicate balance.22
Alterations in the Constitution of the Blood
It is paradoxical that Virchow would endorse a role for hypercoagulability as a contributor to venous thrombosis, given the
lack of tangible evidence – only now revealed with the multitude
of experimental resources at our disposal – for such a nebulous
assertion. Re-examination of Virchow’s original intent demonstrates that by ‘alterations in the constitution of the blood’ he
implied more banal factors such as changes in the relative
amount of fibrin9 and platelets, and dehydration, rather than
foreshadowing a myriad of amorphous illnesses.
Wiseman (1686) proposed that either coagulation of the serum,
or thickening of the blood contributed to venous thrombosis.4
Andral (1830) also preceded Virchow by suggesting that venous
thrombosis may be the result of an increased tendency of blood
to coagulate.10 Nevertheless, prior to the 1930s, tangible factors
contributing to thrombosis by altering the composition of blood
were lacking.15,23 While it was known that the injection of certain snake venoms could precipitate thrombosis, few endogenous
factors were known to have a similar effect.14 Lotheisen (1901)
theorized that pregnancy, malignancy and chlorosis, amongst
other factors, may affect thrombosis in this regard.23
Subsequently, increases in globulin, fibrinogen, and calcium were
all postulated to increase agglutinability; as well, it was suggested that obesity and infection may potentiate coagulability.15,23
Hypercoagulability ranks unequivocally as the broadest category
contributing to the triad at present.22 We better appreciate the
host of genetic and environmental factors contributing to alterations in blood coagulability, far too innumerable to summarise
herein.
Virchow’s Triad Revisited
In its simplest form Virchow’s Triad is thus summarized: (i) alterations in blood flow, (ii) vascular endothelial injury, and (iii)
alterations in the constitution of the blood.2 The literature references several of Virchow’s works as the source for the triad,
including Die Cellularpathologie [Cellular Pathology], Thrombose und
Embolie [Thrombosis and Emboli], and Gesammelte Abhandlungen
zur Wissenschaftlichen Medicin [Collective Treatises on Scientific
Medicine]. The former two texts have been translated into
English and fail to explicitly mention a triad. This author’s
efforts to obtain translation of the most frequently cited portions
of the latter text also fail to identify the triad (data not shown).
Virchow does outline a tetrad for the etiology of pulmonary
artery thrombosis bearing some resemblance to the triad; nevertheless, this theory is specifically intended to explain thrombosis
in the pulmonary artery. Consequently, it remains unclear if
Virchow considered the pathogenesis of thrombosis in the pulmonary artery similar – except for the fourth criteria – to that
of venous thrombosis.
Owing to the fact that each of the three elements of the triad
may be assembled from various parts of Virchow’s extensive
writings, it would seem that he appreciated the contributors to
venous thrombosis; nevertheless, he never assembled a formal
triad to delineate the contributors to venous thrombosis24 (A
Matzdorff, personal communication). Given that each of these
three elements was previously established as contributing to
venous thrombosis, it can only be assumed that Virchow was
aware of this literature; further, there is no direct evidence to
suggest that he ever laid claim to these observations. Matzdorff
(2004) points out that Virchow constructed a triad, bearing
resemblance to that which we associate today as Virchow’s Triad,
but that he expressly intended it as an explanation for the
adverse consequences in the pulmonary vasculature following a
pulmonary embolism.25 It remains yet to be discovered if and
how this triad became misapplied to describe the pathogenesis
of venous thrombosis in the literature.
Diagnosis and Treatment
Since Virchow’s lifetime, the utility of a clinical diagnosis of
venous thrombosis remains relatively unchanged. A thorough
history may identify pertinent risk factors, or a complaint from
the patient regarding anxiety, anorexia, or insomnia.10
Examination of the limbs infrequently yields a diagnosis, but
may reveal a warm, swollen, edematous, or discoloured
appendage;4,26,27 dorsiflexion may exaggerate tenderness, denoting ‘Homan’s sign.’10 Venography allowed X-ray visualization
of the patency of veins around the early 1930s,28 which at present remains the ‘gold standard.’29 Less invasive, but operator
dependent, ultrasound offers an efficient tool for examining the
patency of veins. In the future, spiral CT venography, and MRI
are predicted to facilitate the diagnosis of venous thrombosis.30
In Virchow’s era, treatments for venous thrombosis included
leeches, bed-rest, and warm compresses alternated with various
lotions and liniments;11,27 a subtle improvement from the purging and bleeding advocated in the 1680s.4 Surgical interventions, such as the proximal ligation and excision of thrombosed
veins, were favoured in the 1860s but were employed as early
as the 1680s4 albeit with limited success.31
Identification of some of the risk factors for venous thrombosis – namely venous stasis and bacteremia – led to the suggestion that they could be minimized via prophylaxis.32 Examples
included early ambulation following surgery, breathing exercises, and in some cases intraoperative exercise.10,32 Optimizing
venous return to the heart was the goal of most early therapies.
Attempts to improve cardiac output were attempted with digitalis, intravenous fluids, thyroid extract, alcohol and carbon
dioxide.10,19 Elevating the foot of the bed was initially recommended but later abandoned as potentially dangerous, in favour
of raising the head of the bed.10
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169
Researchers predicted early that anticoagulants and thrombolytic treatment might be efficacious in preventing and treating this
condition.10 Initial anticoagulants included the application of
leeches (Hirudo medicinalis) which in 1884 were discovered to
have anticoagulant properties.33 It was some 20 years later
before the anticoagulant hirudin was extracted and purified33
but it was not until the early 1900s that it found clinical acceptance;23 unfortunately, low yields of the active ingredient ultimately limited its applicability.
Heparin was discovered in 1916 as an anticoagulant, and its
purification in the 1930s enabled its clinical introduction.34 In
Toronto, Murray (1947) noted that heparin decreased the rates
of pulmonary embolism in both postoperative patients, and
those with known leg clots.34 Heparin remains a mainstay in
the prophylaxis and management of thrombosis.22 Similarly,
coumadin was introduced in the treatment of venous clots near
the start of the 1940s and it too remains invaluable in limiting
the incidence of clots.22,35 Meanwhile, intravenous filters, and
in limited cases thrombectomy, can be offered to patients with
contraindications to anticoagulation.
The discovery in the late 1950s that streptokinase lyses thrombi heralded its successful introduction into a clinical setting.36
Streptokinase speeds up resolution of venous clots; however,
the use of this and other thrombolytics has generally fallen out
of favour for fear of complications arising from haemorrhage.37
Conclusion
Venous thrombosis and pulmonary embolism remain frequently encountered medical conditions; remarkably, despite significant advances in our understanding of haemostasis and thrombosis over the last 150 years, Virchow’s Triad has endured as an
explanation for the etiology of venous thrombosis. The diagnosis of thrombosis remains loosely rooted in the clinical tradition; however, investigations such as venography and ultrasound markedly improve our diagnostic capabilities. Treatment
options have greatly progressed since Virchow’s time, although
few significant breakthroughs have emerged since the introduction of heparin and coumadin therapy.
The origins and intent of Virchow’s Triad remain nebulous;
moreover, it is unclear to whom ownership should be duly
ascribed. Clearly, the components of the triad were neither
original to Virchow, nor did he purposefully organize them as
a means to explain venous thrombosis. Almost 50 years after
he published his work on pulmonary embolism there remains
no evidence that he coined a triad for venous thrombosis; it is
not until the 1930s that the three current components of the
triad appear generally agreed upon in the literature (Table 1).
Virchow’s Triad itself does not seem to arise in the English or
French literature until the 1950s2 and almost a decade later in
most major pathology texts. Indeed, a comprehensive review
of the German literature might be anticipated to advance the
appearance date of the theory. Stanley Robbins’ (1962)
renowned pathology text originally cites four factors as the
cause of thrombosis: (i) derangement in the composition of the
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University of Toronto Medical Journal
blood, (ii) stasis, (iii) turbulence, and (iv) alteration in the
integrity of the endothelium.38 An earlier text by the Canadian
pathologist William Boyd (1932) cites injury to the vascular surface from (i) trauma, or (ii) inflammation as the most significant causes of thrombosis.39 Both of the aforementioned texts
neglect to mention Virchow as influential in the development
of this theory; however, the 1964 re-edition of Boyd’s text
offers a modified explanation on the etiology of thrombosis:
More than a hundred years ago Rudolf Virchow. . .
stated that there were three factors (Virchow’s Triad)
involved in its causation. These were: (1) slowing of the
blood stream, (2) changes in the vessel wall, and (3)
changes in the blood itself. In the intervening years
almost nothing of real importance has been added to our
knowledge.40
Its tenuous origins notwithstanding, Virchow’s Triad remains
clinically relevant. The persistence of this term, as it applies to
the pathogenesis of venous thrombosis, may be attributable to
several factors. First, broad ambiguity in the phrasing of the
triad’s categories facilitates the assimilation of new discoveries
into the paradigm (eg., hypercoagulable states). It is also possible that without a clearly established point of reference for its
intent, the triad remains loosely open to interpretation (e.g., its
applicability to arterial thrombosis). As well, the possibility
remains that the resilience of Virchow’s Triad reflects the ongoing limits of our appreciation for the pathogenesis of venous
thrombosis.
Acknowledgements
The author wishes to thank Drs. D.H. Dickson, E. Shorter and
J.R. Wright, Jr., and D-Y Leu for their invaluable assistance and
advice in reviewing this manuscript. Part of this paper was presented at the 2003 Meeting of Royal College of Physicians and
Surgeons of Canada in Halifax, NS.
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