Virchow and his triad: a question of attribution

Authors


  • The references for all English translations of German and Latin quotations used in this document are provided alongside the references for the original language documents at the end of this paper. A similar system has been used for any English quotations unable to be taken from the original text due to the age of the primary source.

Dr Catherine N. Bagot, Department of Haematology, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. E-mail: catherine.bagot@kch.nhs.uk

Summary

Virchow’s triad describes three factors that contribute to the development of venous thrombosis: hypercoagulability, stasis and endothelial injury. Yet, extensive review of the historical literature casts doubt on the existence of a triad described by Virchow in the form it is currently quoted throughout contemporary medical literature. Certainly his work involved extensive study of venous thrombosis and pulmonary embolism, with these two terms being coined by Virchow, but a triad of factors relating to the development of venous thrombosis is elusive. Interestingly, Virchow only began to be routinely credited with this triad one hundred years after publication of his work on venous thrombosis. This acknowledgement coincided with the accumulation of experimental evidence for the role these factors play in thrombogenesis. Controversial as the origins of Virchow’s triad might be, it is apt given his substantial contribution to our knowledge of venous thromboembolism, and the fact that the triad continues to be clinically relevant today that a triad pertaining to Virchow should remain.

‘Omnis cellula e cellula [All cells from pre-existing cells]’ R Virchow (Virchow, 1855)

Introduction

Every medical student is taught that the pathophysiological basis for venous thrombosis is explained by the triad of Rudolf Virchow, an eminent scientist and physician working in Berlin in the nineteenth century (Fig 1). The above statement, made by Virchow in 1855, is an example of how his scientific mind reached beyond that of the majority of his contemporaries. In mid-nineteenth century Germany, the cell was a novel concept and its origins more contentious still, with doctors favouring a more romantic and empirical approach to medicine and science. Virchow, however, had strongly held views on the need to use a combination of physiology, microscopy and experimentation to prove scientific and medical hypotheses. Interestingly, a review of the literature reveals limited support for the claim that the triad of conditions that precipitates the development of venous thrombosis was proposed by him. The claim is re-examined in this review and asks the following questions: Did Virchow prove this triad and subsequently claim it for his own? Did his position in history appropriately place him to make such an assertion? Was he the first to put forward such a hypothesis? And if Virchow did prove and make claim to the triad, why was he not credited with such in the medical literature until at least hundred years after the work was completed?

Figure 1.

 Rudolf Virchow, 1902, the year of his death at the age of 81 (Adapted from: http://commons.wikimedia.org/wiki/Image:Grab_rudolf_Virchow.jpg).

Early descriptions of venous thrombosis

Extensive reviews of historical documents have been undertaken by numerous authors (Anning, 1957; Mannucci, 2002; Dickson, 2004a) revealing that references to venous thrombosis were rare in the literature prior to the eighteenth century. The first probable reference was in 1271. Raoul of Normandy, a 20-year-old man, developed unilateral oedema in his right ankle, which subsequently extended up to his thigh with no obvious symptoms in the contralateral leg (Dexter & Folch-Pi, 1974). He prayed to the saints and his symptoms resolved within the year.

The concept that blood could clot and congeal in a vein was first documented by Ambroise Paré in 1576 with reference to superficial veins:

‘they [the varicose veins] often swell with congealed and dryed bloud and cause pain which is increased by going and compression.’ (Johnson, 1678)

Childbirth as a cause of deep vein thrombosis began to be described towards the end of the seventeenth century. A shift from midwife to doctor as the main practitioner caring for women during childbirth, with the doctors’ more common practice of recording the cases in which they were involved, probably led to the increased documentation around this time. Examples of this are in two descriptions from the late seventeenth century. In 1668, Francois Mauriceau of Paris described an aunt who had a permanently swollen leg following childbirth, which lasted for thirty-eight years (Mauriceau, 1712), perhaps the earliest recording of prolonged post thrombotic syndrome. Richard Wiseman (Fig 2), highly revered surgeon to Charles II, wrote prolifically and in great detail on the huge number of cases he saw during his career. He described in detail the clinical manifestations of venous thrombosis following childbirth and in particular, what might cause such symptoms to develop.

Figure 2.

 Portrait of Richard Wiseman (1625–1686) by Sir Balthazar Gerbier (1601–1667) (Adapted from: British Journal of Surgery, (1929) 16, 358).

‘An Apothecary’s wife, living in my Neighbourhood in the Old Bailey, after a hard Child-bed labour was seized with a fever and great pain in her right Thigh, from the Groin and Hip downward to the Knee, swelling the Member round, without inflammation or discolouring of the Skin.’ (Wiseman, 1676)

He does not explain on recounting this story what he believes the cause of the swelling to be. However, in a later passage he describes why blood might clot. He explains this in relation to varicose veins:

‘It [the development of varices] proceedeth from the restagnation of gross [whole] Blood, which being transmitted into the Veins, either by reason of the depending of the Part, or from some other pressure upon the Vessel, or else by its own grossness, proves unapt for Circulation. Then instead of continuing its current proportionably to the other Parts, it stops in the place and coagulates...’ (Wiseman, 1676)

Wiseman is describing two of the three factors subsequently ascribed to Virchow’s triad as causes of coagulating blood; stasis (‘depending of the Part or from some other pressure upon the Vessel’) and hypercoagulability (‘by its own [the bloods] grossness’ [def: something within itself]), almost two hundred years before Virchow.

Theories on thrombogenesis prior to Virchow

Despite these early descriptions of thrombosis, humoral theories for lower limb swelling following childbirth predominated prior to 1800. During pregnancy, lochia was thought to accumulate in the lower limbs leading to swelling; postpartum, this retained fluid was thought to be milk. In fact, the term ‘milk leg’ for the development of a swollen leg postpartum secondary to venous thrombosis has remained in common usage until the very recent past. Towards the end of the eighteenth century, doctors began to dispute the humoral theory as a cause of postpartum leg swelling. More began to appreciate that the development of a swollen leg following childbirth was as a result of clots in the blood vessels of the legs. The surgeon and physiologist, William Hewson, abandoned the theory of humours for lower limb swelling in favour of ‘coagulable lymph’, which clotted blood in veins and caused lower limb oedema (Hewson, 1846).

Charles White, an eminent obstetrician in the then new industrial city of Manchester, described his theory on leg swelling in pregnant women:

‘not owing to any defect of the lochia as it happens to those who have the most regular discharge, nor to a deposit of milk as it happens under every circumstance attending that secretion. The proximate cause of this disorder is an obstruction, detention and accumulation of lymph in the limb.’ (White, 1784)

He believed this was brought about by rupture of the lymphatics from pressure of the foetus’ head. For this reason, he believed that only pregnant and postpartum women could develop such a phenomenon and was the first to use the term ‘phlegmatia alba dolens puerperarium’ (White, 1801). It was another twenty years before there was an appreciation that other patient groups could suffer with a similar complaint (Ferriar, 1810).

Doctors who questioned humoral theory at this time and put forward alternative explanations were numerous and began to direct their attention towards explanations that eventually formed part of Virchow’s triad. The Swiss physiologist, Albrecht von Haller, believed that pressure on veins and the slowing of blood flow would encourage the development of thrombosis (Haller, 1786). A similar theory of blood stasis was promoted by numerous eminent medical men including Matthew Baillie (Baillie, 1793) Laënnec (Laënnec, 1819), and John Ferriar (Ferriar, 1810). Although not coined as such, endothelial damage was suggested as a cause for thrombosis by the surgeons Joseph Hodgson and Alexander Copland Hutchinson who believed that thrombosis could result from damage to the veins (Hodgson, 1815; Hutchinson, 1829). Finally, Andral put forward the theory that venous thrombosis occurred due to something inherent in the blood, over 100 years before the first identification of an inherited thrombophilia (Hellsten, 1942).

These men were typically theorising based on their own personal experience but despite this, the triad of factors that we recognise today: hypercoagulability, stasis and endothelial damage, were clearly being considered a number of decades prior to Virchow. However, by the early nineteenth century many of these theories were being superseded by inflammation as the major cause of thrombogenesis. Postmortem procedures were increasing dramatically during this period, with thromboses frequently observed in association with abscesses and other signs of infection. This led to the proposition that one must be linked to the other.

Such a theory was referred to in many medical treatises of the early nineteenth century. The famous London surgeon, John Hunter, described ‘phlebitis’ as the cause of clotting and plugging of veins (Hunter, 1793). Charles Trye, a surgeon based in Gloucester, England, referring to postpartum women, stated that:

‘…the obstruction to the return of the lymph may commence in the primary inflammation of a trunk or trunks.’ (Trye, 1792)

An eminent British obstetrician, David Davis, concurred with the theory of inflammation causing thrombosis:

‘…violent inflammation of one or more of the principle veins within and in the immediate neighbourhood of the pelvis’ [with a] ‘gradual coagulation of their contents…’ (Davis, 1822)

One further advocate of inflammation as the underlying cause of thrombogenesis during this period was the eminent French pathologist Jean Cruveilhier. He is of particular relevance, not only because his opinions were held in high regard and added weight to the theory of inflammation, but because it was his work that Virchow was later to dispute and discredit in his own work on venous thrombosis.

Virchow, the man

It is interesting to review the early life and career of Virchow to understand how he came to form his own views regarding venous thrombosis and the position these opinions held in the wider medical community of the mid-nineteenth century.

Rudolf Ludwig Karl Virchow was born in 1821 in eastern Pomerania, now part of modern day Poland. He was the only son of a merchant farmer and well educated. In 1839, he was awarded a place to study medicine at the military academy of Prussia, the Friedrich-Wilhelms-Institut, in Berlin, which provided free medical education to talented young men in exchange for later service in the army.

At this time, medical science in Germany was held in low esteem when compared to its European contemporaries. In England, post mortems were frequently performed and seen as the vehicle for expanding anatomical knowledge. In France, following the Revolution at the end of the eighteenth century, large hospitals had been built which had become huge inspiring centres of medical education, with learning based not on books but on clinical examination and autopsy (Porter, 1997). However, Germany still based medical education on book learning and maintained a disregard for science being inclined more towards ‘romantic speculation’ and ‘naked empiricism’ (Ackerknecht, 1953).

It was into this culture of German medicine that Virchow launched himself. His mentor at the Institut was Johannes Peter Mueller (Fig 3), a man whose scientific beliefs were unlike many of his medical contemporaries. He was Professor of Physiology and Anatomy and had a strong belief in the use of microscopy and animal experimentation to push forward the boundaries of medical knowledge. This association with such a scientist, whose peers in Germany most likely thought him extreme in his medical views, probably influenced Virchow’s subsequent radical scientific opinions and progressive work.

Figure 3.

 Johannes Peter Mueller, Virchow’s mentor (1801–1858) (Adapted from: http://en.wikipedia.org/wiki/Image:Mueller.Joh.jpg).

Virchow completed his studies in 1843 and immediately went on to employment at the Charité Hospital in Berlin as a Company Surgeon. He appears to have been popular with his patients (he was referred to by them as ‘der kleine doctor’ [the little doctor]) (Virchow, 1907a) but was concurrently busy with scientific investigation, learning microscopy alongside Robert Froriep. Froriep was the editor of an abstract journal that specialised in foreign work, allowing Virchow to be exposed to the more forward-looking scientific ideas of France and England.

In 1845 Virchow was asked to give a speech at a celebration of the birthday of the founder of the Institut. This was entitled ‘Ueber das Beduerfnis und die Richtigkeit einer Medizin vom mechanischen Standpunkt’ [On the need and correctness of a Medicine based on a mechanistic approach] (Virchow, 1907b). In this he outlined the three basic principles he believed were essential to ongoing medical progress: clinical observation, animal experimentation (to determine causes of diseases and the effects of drugs) and pathological anatomy, particularly at the microscopic level. He went further and stated that the cell was the basic unit of the body that had to be studied to understand disease.

These concepts from such a junior doctor were inflammatory. The audience would have been made up of eminent doctors, many of who would have believed in humoral theory, vitalism and empiricism. Although the term ‘cell’ had been coined in the 1600s, the building blocks of life was still considered to be the 21 tissues of Bichat, a concept described by Marie Bichat, a young French physician, at the turn of the nineteenth century (Porter, 1997). Virchow, however, seemed to have great faith in his ideas but little in his peers. In letters to his father at the time he stated:

‘…with real knowledge and a determined language, one can today impress everybody, even in the highest ranks because everything is hollow and rotten up the top.’ (Virchow, 1907a)

After passing his licensing examinations in 1846, Virchow became successor to Froriep. However, his writings were not receiving favourable attention in medical circles and he remained unpublished, despite or because of his far-reaching speech in 1845. Showing great strength of character and tremendous ability, he founded his own journal in 1846 at the age of only 25, ‘Archiv fuer pathologische Anatomie und Physiologie und fuer klinische Medizin’ [Archives for Pathological Anatomy and Physiology and Clinical Medicine]. He founded this with the pathologist Enno Ernst Heinrich Reinhardt who, after dying in 1852, left Virchow the sole editor until his own death 50 years later. This journal began publishing high level contributions based on the criterion that no papers would be published which contained outdated, untested, dogmatic or speculative ideas.

Early in his medical career, he joined liberal medical societies, full of young men who wanted to see change in medicine as well as society. These men were living in an age of social change. The French Revolution was only fifty years old and with the death of the King of Prussia in 1840, political unrest was occurring across Europe. Virchow saw himself as part of this wave of free thinkers and challengers of society. In 1847, he travelled extensively throughout Germany, Belgium and Holland. He appears to have been favourably accepted throughout the medical circles of these countries and was not unaware of his impact:

‘I know now almost all German Universities and most of the German medical big shots, and, what is no less important, they know me. Our ‘Archives’ has thus gained in distribution and influence, and I will be able to consciously pursue my goal of becoming the representative of a certain trend in medicine.’ (Virchow, 1907a)

He was radicalised still further in his social and medical views when he was asked to investigate an epidemic of typhus in the poverty stricken area of Upper Silesia by the Prussian government in 1848. The government hoped they would be provided with guidelines of hygiene and medicine by their government-employed doctor but Virchow’s solution was very different. He stated that the epidemic was due to the poor living conditions of the population, which could only be improved by ‘full and unlimited democracy’ and ‘education, freedom and prosperity’ (Virchow, 1849). These were radical statements. In the mid-nineteenth century, universal suffrage and education were not values widely held across any area of Europe. However, Virchow believed that ‘physicians are the natural attorneys of the poor’ (Virchow, 1879) and even published a weekly newspaper, ‘Die Medizinische Reform’ [The Medical Reformation] from 1848–9, continuing to advocate general reform of German medicine.

Virchow, perhaps unsurprisingly, became part of the wider revolution that occurred during 1848 in Berlin and throughout Prussia. The Industrial Revolution had resulted in poor living and working conditions with associated poor health. Such a situation was an anathema to Virchow and he gladly joined the barricades in Berlin. In a letter to his father:

‘My own share in the uprising was relatively minor. I helped build a few barricades, but then, as I could get hold of only a pistol, I could not do much more.’ (Virchow, 1907a)

He started to become an embarrassment for his tutors such as Mueller but this did not deter him in his beliefs:

‘the few young men who have found real recognition from the administration are therewith personally indebted to certain officials. But this does not mean that they have surrendered their good right to oppose the administration as a body and its principles.’ (Virchow, 1879)

He eventually became intolerable to the establishment and was suspended from the Charité hospital, although within a year was reinstated as prosector ‘on probation’. However as soon as a post became available in the more provincial setting of Wuerzburg, he was encouraged to leave Berlin. He left for Wuerzburg in 1849, having become engaged to Rose Mayer, a liberal’s daughter, just prior to his departure. She joined him a year later for their marriage and together they were to have six children. At the medical school in Wuerzburg, he was employed as chair of pathological anatomy (Fig 4). It was during his 6-year period here that he concentrated on his scientific work, including detailed studies on venous thrombosis and cellular theory.

Figure 4.

 Rudolf Virchow during his period in Wuerzburg (1849–1856) (Adapted from: http://commons.wikimedia.org/wiki/Image:Rudolf_Virchow.jpg).

Virchow, the scientist and his work on venous thrombosis

By 1856, Virchow was asked to return from Wuerzburg to the Charité Hospital in Berlin, mainly at the instigation of his old mentor, Mueller. Such a reinstatement was evidence of the name he was achieving for himself in scientific and medical circles. He became Director of the Pathological Institute and remained in charge of the clinical section of the hospital for the next twenty years.

In 1856, he published a collection of ten years of work entitled ‘Gesammelte Abhandlungen zur Wissenschaftlichen Medicine’ [Collective treatises on Scientific Medicine], that included his detailed studies of thrombosis, which were collated into a single work ‘Thrombosis und Embolie’ in 1910 and eventually translated into English in 1998. This work probably resulted from a challenge laid down to Virchow during his very early career by his professor Robert Froriep; to rebuke the claim made by the eminent French pathologist, Cruveilhier, that ‘La phlebite domine toute la pathologie’ [Phlebitis dominates all pathology] (Cruveilhier, 1829–42). Cruveilhier claimed that he had frequently seen thrombus in inflamed vessels, containing pus at its centre. In turn, he deduced that it was the pus that had led to clot development and therefore coagulation was the main consequence of venous inflammation. It was a view held by many during the nineteenth century.

However, Virchow was incensed by the idea that inflammation caused thrombosis as there was no evidence for such:

‘ [which has been] introduced by French investigators, and which says that coagulation is caused by the absorption of inflammatory products into the blood, though up to now there is no fact to prove this hypothesis.’ (Virchow, 1856)

Virchow’s personal experience of thrombosis had been via the numerous autopsies he had performed at the Charité hospital in Berlin. It was this work that first demonstrated to him that inflammation and infection occurred after the thrombus had formed and not before, as Cruveilhier proposed. To improve understanding of the process underlying thrombogenesis, Virchow had a clear opinion on how further information could be obtained:

‘The only chance for a more exact understanding [of thrombosis] was the pathological experiment. I like this very important methodology of pathological study, which in Germany is unfortunately almost never used.’ (Virchow, 1856)

To refute Cruveilhier’s claims, he concentrated his efforts on investigating thrombosis development in the pulmonary vasculature. He had determined that this was a common condition through his own postmortem work, where he demonstrated the frequency of pulmonary thrombosis to be 8–10% (Virchow, 1856).

It was his observations at autopsy that provided him with the first evidence that thrombosis in the lung might originate from alternative vessels in the circulation, in particular those in the leg. He discovered that thromboses in the lung and leg usually occurred concurrently and, in particular, these thrombi were so shaped that they could be neatly fitted together as though one had broken off the other;

‘…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.’ (Virchow, 1856)

His theory was that part of the thrombus contained in the leg had broken off as a result of turbulent blood flow around its proximal tip and then travelled to the lungs.

Having made these initial discoveries, he proceeded to put forward a scientific hypothesis; that pulmonary thrombi are transported from the veins of the leg and that the blood has the ability to carry such an object. He then proceeded to prove this hypothesis through well designed experiments, repeated numerous times to consolidate evidence, and with meticulously detailed methodology.

He inserted different types of foreign bodies into the jugular veins of dogs to represent a thrombus travelling from the leg. These included cadaveric venous thrombi, coagulated blood from living patients, and various seeds and berries. The dogs frequently developed symptoms of respiratory distress a few days following the procedure and then either died naturally or were euthanized. On every occasion, the foreign body in the jugular vein had travelled to the lung, proving that blood had the capacity to transport thrombi from the peripheral circulation to the lung vasculature and in turn demonstrating that peripheral venous thrombi were the likely source of thrombi in the lung. Two engravings he made clearly demonstrated this theory (Figs 5 and 6).

Figure 5.

 Autochthonous and prolonged thrombi c, c’. Smallish, varicose, lateral branches (circumflex veins of the thigh), filled with autochthonous thrombi which project beyond the orifices into the trunk of the femoral vein. t. Prolonged thrombus produced by concentrically apposed deposits from the blood. t’. Prolonged thrombus, as it appears after fragments (emboli) have become detached from it. Engraving from; Virchow R.L.K Cellular Pathology 1863 ed. 2 [F Chance transl.] New York, Dover 1971.

Figure 6.

 Embolia of the pulmonary artery. P. Moderately large branch of the pulmonary artery. E. The Embolus, astride upon the angle (spur-Sporn), formed by the division of the artery. t, t’. The capsulating (secondary) thrombus: t, the portion in front of the embolus reaching to the next highest collateral vessel c; t’, the portion behind the embolus, in a great measure filling up the diverging branches r, r’, and ultimately terminating in the form of a cone. Engraving from; Virchow R.L.K. Cellular Pathology 1863 ed. 2 [F Chance transl.] New York, Dover 1971. Note Virchow omitted to add the labels t' and r'. These would be represented by the t and r on the right hand side of the diagram.

The results of his experiments made it clear to Virchow that Cruveilhier’s proposal was ridiculous. He believed his work showed, through well designed experimentation, that lung thrombi resulted from clots originally formed in the legs and therefore inflammation was excluded as a cause of pulmonary thrombosis. Moreover, as a result of his earlier autopsy work, Virchow viewed inflammation as a consequence of thrombus in the vessel. In an attempt to remove once and for all the association of inflammation with thrombus development, he coined the term, thrombosis:

‘If we therefore leave inflammation on one side and confine our attention simply to the coagulation of the blood, the formation of the clot (thrombus), it seems most convenient to comprehend the whole of this process under the term thrombosis.’ (Virchow, 1863)

He also coined a further term for thromboses found in the lung vessels, which he had demonstrated arose and broke off from a thrombus in the leg;

‘This gives rise to the very frequent process upon which I have bestowed the name embolia.’ (Virchow, 1863)

Virchow’s writings therefore reveal that his main work on thrombosis involved proving that pulmonary emboli arose in the legs and not in situ and that inflammation played no role in this process. It was not an investigation to prove that stasis, endothelial damage and hypercoagulability lead to thrombosis and then create a triad associated with his name.

However, a secondary finding of Virchow’s experimental work, as shown by his engravings, was thrombus formation occurring in situ in association with the foreign bodies he was introducing indirectly into the lungs. This led him to make the following statement:

‘In all cases the blood formed more or less extensive clots around the introduced body’. ‘…the list of possible consequencesof the obstruction could be grouped into three categories;

Phenomena due to the irritation of the vessel and its surroundings;

Phenomena due to blood coagulation;

Phenomena due to the interruption of the blood-stream’

(Virchow, 1856)

This summary can easily be interpreted as describing endothelial damage, hypercoagulability and stasis and therefore an illustration of Virchow’s triad. However, on closer inspection, these three factors refer to the ‘consequences’ of the foreign body and as such, the ‘consequences’ of what, in vivo, would be a pulmonary embolus.

What Virchow was in effect describing were the conditions required for clot propagation. He further refers to these conditions throughout the text, always with regard to clot propagation. For example, his autopsy work had demonstrated to him that clot propagation was secondary to stasis and his experimental work in dogs confirmed this further:

‘the reduction in velocity of the blood that passes by the obstruction is the main reason for the formation of the extended plug and that it is not just the presence of the solid foreign body…. that induces secondary coagulation.’ (Virchow, 1856)

Furthermore, the more irritating and damaging a foreign body was to the pulmonary vasculature, the more likely clot propagation was to occur:

‘The only possible way to avoid the direct thrombus-formation inside the pulmonary artery and the heart was to introduce only materials that do not chemically irritate the inner surfaces of the vessels and the heart.’ (Virchow, 1856)

However Virchow never linked the role of endothelial damage to de novo clot formation.

The only theory he appears to have accepted as playing a role in the de novo formation of thrombi was venous stasis. It was in fact this supposition that had initially led him to hypothesise that pulmonary emboli did not arise in situ:

‘when it is true, as stated earlier, that the slowing down of the blood stream is the main cause for spontaneous coagulation of the blood in the body-veins, then this rule should with reason and with due consideration of all facts be applicable to the situation in the pulmonary veins’ [and] ‘The localization of the plugs [in the pulmonary artery] demonstrates very clearly that the cause for the coagulation in situ cannot be found in the venous blood itself nor in the slowing down of its circulation.’ (Virchow, 1856)

However, this was a theory that Virchow himself never went on to prove.

It is through Virchow’s description of the secondary effects of a thrombus on the vessel that one can see how he first became associated with describing a triad of factors linked to venous thrombosis. Nevertheless he clearly states in his text that these three phenomena are the consequences of thrombosis and not the originating cause. It could be argued that causes of thrombus formation and thrombus propagation are one and the same although Virchow appears not to have linked the two. It may be that subsequent reviewers of his work came to the conclusion that he had established the causes of de novo thrombogenesis through his description of the requirements for clot propagation despite this not being the main thrust of his work.

The use of Virchow’s triad

Crediting Virchow with a triad did not occur immediately following the publication and dissemination of his work on thrombosis. Extensive reviews of the literature by others have revealed that there is no mention of Virchow’s triad in book or journal article titles until after the 1950s, nor in the contents of abstracts until the 1980s (Malone & Agutter, 2006). This was 100 years after Virchow’s work on thrombosis.

Virchow is however mentioned throughout those intervening 100 years. The earliest English publication mentioning Virchow, in fact, disparages him, stating that he concentrated on pyaemia as a cause of thrombosis, leading to confusion on contemporary thoughts of thrombogenesis (Savory, 1878). This is not an accurate assessment of Virchow’s writings but it would be fair to acknowledge that English translations of his work would not have been available at this time.

An awareness of Virchow as an important figure in venous thrombosis was also evident at the turn of the twentieth century. In 1909, a paper in the Lancet expressed the opinion that Virchow had provided ‘[us with] all we need to know about emboli’. (Bland-Sutton, 1909). ‘We owe practically the whole theory of embolism [to Virchow]’ was a contemporaneous statement made in Annals of Surgery (Wilson, 1912). However, suggestions that were made in this article as to the possible pathogenesis of thrombosis and embolism do not refer back to the original ideas of Virchow or designate Virchow with a triad.

In 1913, a paper described in detail which conditions lead to the development of venous thrombosis but provided Virchow with no credit:

‘feeble state of the circulation due to cardiac debility; injury to, or alteration of the intima of blood vessels [for which they acknowledge Cruveilhier]; direct blocking of [the venous] lumen by the intrusion of foreign or toxic material.’ (Duckworth, 1913)

Ludwig Aschoff, a Professor of Pathological Anatomy in Germany published ‘Lectures in Pathology’ in 1924. He dedicated some of these pages to thrombosis and its underlying pathophysiology. He listed authors who he believed had provided, ‘the most exhaustive experimental work on thrombosis’ (Aschoff, 1924). Virchow is not mentioned in this eminent list.

Aschoff does however give some recognition to Virchow later in the text:

‘As Virchow pointed out long ago, and is now generally recognised, there are certain situations in the venous systems which are especially predisposed to thrombus formation.’ (Aschoff, 1924)

These situations however do not refer, as might be first thought, to pathological conditions leading to thrombosis but to body locations e.g. femoral veins, the pelvic plexus.

He then criticises Virchow for not promoting endothelial injury as a predisposing condition for thrombosis development. This is ironic given that this is now one of the fundamental parts of Virchow’s triad but perhaps appropriate when, on review of his work, it appears that Virchow believed endothelial damage was only a secondary phenomenon, not a cause, of thrombosis:

‘We have up to this point considered two of the conditions which have to do with the building of thrombi; namely, changes in the blood stream, and qualitative and quantitative alterations in the platelets. We will now take up a third condition, which used to play the chief role in the teaching about thrombosis, but the significance of which was greatly limited by Virchow, [the] alteration of the vessel wall itself’ (Aschoff, 1924)

Aschoff in fact summarises the elements that he believes predispose thrombosis. They are remarkably similar to Virchow’s triad but no recognition to Virchow is given.

‘changes in the blood plasma (diminished or increased coagulability)

changes in blood elements (increased or diminished powers of agglutination)

Changes in the blood flow (slowing and formation of eddies)

Changes in the vessel wall itself (endothelial damage)’ (Aschoff, 1924)

As the century progressed, scientific evidence was gradually accrued that would underpin the triad of Virchow that is quoted today. The First World War provided evidence that endothelial damage was important to the development of thrombosis through the experience of trauma and infection resulting from severe injury. Further experimental evidence on the role of endothelial damage in thrombogenesis was accrued in the 1970s (Stamatakis et al, 1977, 1978). Prolonged bed rest was scientifically proven to cause thrombosis and was linked to stasis (Gibbs, 1957; McLachlin et al, 1960,Wessler, 1962). And in 1965 the first inherited thrombophilia was discovered, antithrombin deficiency, which led to the acknowledgement of inherent hypercoagulability (Egeberg, 1965).

As a result of the accumulating experimental data, two review papers in the early 1960s summarised the triad of factors considered responsible at that time for the development of venous thrombosis; hypercoagulability, stasis and endothelial damage, which was essentially a summary of Virchow’s triad. One paper concentrated in particular on stasis; the other on all causative aspects of venous thrombosis. Despite the similarity to Virchow’s triad, Virchow is mentioned in only one paper:

‘  [Rudolf Virchow] defined the role of circulatory stasis as aetiological factor in intravascular coagulation.’ (Wessler, 1962)

In the other paper he is significant by his absence (Mustard et al, 1962).

In the last two decades of the twentieth century further experimental evidence was accrued on the factors required to promote thrombosis formation, particularly with regard to inherited hypercoagulability: Activated Protein C resistance (Dahlback et al, 1993), Factor V Leiden (Bertina et al, 1994), the prothrombin gene mutation (Poort et al, 1996), and Protein C and S deficiency (Griffin et al, 1981; Comp & Esmon, 1984). Prophylaxis in the form of compression stockings to reduce stasis and the use of heparin to reduce hypercoagulability postsurgery and during high risk pregnancy reduced thrombosis rates and confirmed these risk factors still further.

It is during the second half of the twentieth century, as the three causative factors linked to venous thrombosis development were being elucidated, that the application of Virchow’s name to this triad began to occur (Anning, 1957; Dexter, 1973; Peterson, 1986; Nielsen, 1991; Burroughs, 1999):

‘He [Virchow] had a triad that explained the requirements for the development of thrombosis.’ (Burroughs, 1999)

‘The validity of the three possible mechanisms responsible for venous thromboembolism proposed by Virchow in 1856 has stood the test of time.’ (Nielsen, 1991)

At the beginning of the twenty first century, Virchow and his triad is still prominent and being widely acknowledged (Mannucci, 2002; Pearce, 2002; Blann, 2004; Chung & Lip, 2004; Malone & Agutter, 2006; Safavi-Abbasi et al, 2006), but, for the first time, it is also being challenged (Brotman et al, 2004; Dickson, 2004a,b). These latter works dispute that Virchow put forward a triad of causes for thrombogenesis. They believe the statements he made describing the three conditions that result from the presence of a thrombus in a vein have been misinterpreted. Nevertheless, they continue to acknowledge that Virchow’s work contributed significantly to a better understanding of many aspects of the incidence, development and consequences of venous thrombosis. It is unclear whether these new challenges to Virchow’s triad have resulted from the recent translation of Virchow’s seminal work into English in 1998.

Conclusion

It is quite clear that the foundations upon which Virchow’s triad is based are precarious.

Firstly, it is apparent that many great men before Virchow proposed the causative factors for thrombogenesis that we recognise today, even though these causations were not scientifically proven at the time. Virchow appears to have been aware of these theories but refuted most, despite some literary evidence that he appreciated the role of venous stasis.

To then attempt to credit Virchow with assembling a triad of factors that lead to thrombus development, his work has to be studied in depth. When a triad is eventually found in his work, this refers to the consequences of thrombosis and subsequent thrombus propagation rather than the de novo development of clot. His work concentrated almost entirely on pulmonary embolus and its causes, not the environment in the veins of the leg that generated the source of the embolus.

However, through determining the consequences of thrombus, he did discover the conditions that propagate clots and as a result, indirectly determine the conditions that cause de novo development of clots, even though he did not acknowledge this himself. A lack of acknowledgement from Virchow himself provides quite substantial evidence that Virchow did not assemble a triad as we describe it today, as he was certainly a scientist who was not shy of promoting his own ideas and discoveries!

Whatever the lack of clarity regarding the existence of Virchow’s triad, he must certainly be acknowledged as one of the leading historical authorities on venous thrombosis and emboli. He coined these two terms and his scientific methods were exemplary, meeting many of the high standards today considered crucial to good experimentation, including the disproving of hypotheses, reproducibility of experiments and thorough, clear explanations of methodology.

And what of the delay in crediting Virchow with a triad? As experimentation in the first half of the twentieth century elucidated the three factors that predispose to thrombosis, to review Virchow’s work, see its extensiveness and neatly fit him into context may have been a temptation. Furthermore a misinterpretation of Virchow’s description of the consequences of thrombi is not impossible, particularly by English speaking authors who were denied an English translation until the end of the twentieth century.

Without doubt, Virchow deserves substantial recognition for his contribution to our understanding of venous thrombosis. His close association with the triad should therefore continue as acknowledgment of his pioneering work in the thrombotic process, particularly as the triad remains so clinically relevant today.

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