**3.2 Virchow's** *real* **triad**

Pathophysiology and Clinical Aspects of 134 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

In both *Thrombose und Embolie* (Virchow, 1856) and the relevant lectures in *Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre*  (Virchow, 1858), the focus was on pulmonary embolism, not thrombogenesis. The only passage in *Thrombose und Embolie* that vaguely resembles 'Virchow's triad' (pp. 293-4 of the Matzdorff-Bell translation) states: "*the sequence of the possible stages and consequences of blockage may be classified and studied under three headings: (1) phenomena associated with irritation of the vessel and its vicinity; (2) phenomena of blood-coagulation; and (3) phenomena of interrupted blood-flow*"*.* But as the context makes clear, this refers to the 'blockage' of the pulmonary artery by a metastasised thrombus, not to the formation of that thrombus in a distal vein. The quoted passage from Virchow's classic appears to have been misread and mistranslated during the mid-20th century, perhaps because English-speaking readers found 19th century technical German difficult; there was no full and authoritative English translation of *Thrombose und Embolie* until 1998. Several authors have made this point (Brinkhous, 1969; Brotman *et al.*, 2004; Dickson, 2004; Malone & Agutter, 2006; Bagot & Arya, 2008), but the misinterpretation persists. Some of these authors claim that although 'Virchow's triad' has no basis in what Virchow wrote, it is nevertheless useful in clinical practice (Brotman *et al*., 2004; Bagot & Arya, 2008). That may seem practical, guiding us to deal with injured veins, administer anticoagulants, and maintain a reasonably high venous blood flow rate in the lower limbs; but it is not scientifically honourable to exonerate and even legitimate an accidental and regrettable distortion of Virchow's meticulous observations to the detriment

The truth is that Virchow neither conceived nor wrote 'Virchow's triad'; the phrase first appeared in print following the historical study by Anning (1957), about a century after

In its original form - the statement that DVT is caused by some combination of disturbed blood flow, altered blood composition and vessel wall abnormality - 'Virchow's triad' was unexceptionable though misconceived. It afforded a general view of causation, and it is hard to imagine any contribution to the aetiology other than the three named facets. Moreover, it was one of a line of general points of view about DVT dating from the late 19th and early 20th centuries and thus belonged to an institutionalised tradition. For example, Aschoff (1924) proposed a 'tetrad': that DVT is caused by some combination of changes in the coagulability of the blood, changes in the formed elements of the blood, changes in the circulatory blood flow and changes in the vessel walls. But Virchow did not contribute to that tradition.

However, 'Virchow's triad' underwent mutations early in its history (late 1950s). 'Disturbed blood flow' came to be equated with 'venous stasis' (and to mean slow-flow rather than literally no-flow), just as 'altered blood composition' came to be interpreted as 'hypercoagulability'. It must be emphasised that Virchow never mentioned 'hypercoagulability' and furthermore explicitly rejected the 'doctrine' (*die Lehre*) that stasis has any causal role in thrombosis or embolism. 'Virchow's triad' would have bewildered him. The mutations continued and some authors, contrary to the superb studies by Welch (1887, 1899), have doubted whether vessel injury is causally significant in venous

of our understanding of the aetiology of DVT.

Virchow's seminal works were published.

**3.1.1 Precedents and mutations of 'Virchow's triad'** 

Although Virchow's studies during the decade 1846-56 were motivated by refutation of Cruveilhier's opinions and therefore focused on the causation of pulmonary emboli, not of thrombosis, his observations of venous thrombi were crucially important, thanks to his skilled use of the Lister microscope (invented in 1827). One of these observations was his three-part contrast between a thrombus and an *ex vivo* clot. On pp. 514-5 of the *Gesammelte Abhandlungen* (Virchow, 1862), he recognised that:


This tripartite distinction between 'venous thrombus' and 'clot' has a better claim to be labelled 'Virchow's triad' than the stasis-hypercoagulability-injury mantra, since Virchow actually wrote it. Moreover, it encapsulates common clinical knowledge; for instance, those who have seen a thrombus extracted during a venectomy or an embolism removed at postmortem have had the opportunity to observe the white 'tail' (the *Kopfteil* in the terminology of Aschoff, 1924).

In view of the clarity of Virchow's summary distinction, the now-commonplace tendency to treat 'venous thrombus' as synonymous with 'clot' is surprising. Perhaps we should recall

Aetiology of Deep Venous Thrombosis - Implications for Prophylaxis 137

This observation inspired investigations of venous thrombi over the following seventy years. The elegant and detailed morphological studies of Welch (1887, 1899) highlighted the contributions of leukocytes as well as platelets to thrombus structure, and Aschoff (1924) declared that the causation of DVT would only be understood when the accumulation of white cells was explained: *"Along with the explanation of this marking* [the Lines of Zahn] *stands or falls the whole problem of thrombus formation, so far as consideration of the majority of* 

Hunter realised in 1793, more than 60 years before the germ theory of disease was articulated, that leukocytes swarm to sites of either tissue injury or local infection (a phenomenon more recently termed 'margination of leukocytes'). After Pasteur's work had been accepted, it was widely supposed that infections contribute to the causation of DVT; but when no consistent correlation between thrombosis and infectious agents was established, and antibiotics did not alleviate or prevent DVT, that hypothesis was abandoned during the first half of the 20th century. This aspect of history was reviewed briefly in our monograph (Malone & Agutter, 2008, chapter 7). Once again, Virchow was uncannily prescient on this topic; although unaware of the epoch-making discoveries being made in Pasteur's laboratory while he was writing *Thrombose und Embolie*, he perceptively described the accumulation of white material in thrombi as '*puriform but not purulent'*

For more than a century there has been experimental support for the inference that the cause of leukocyte and platelet margination at the site of venous thrombogenesis is local injury. Welch (1887, 1899) showed that experimental thrombi induced by electrical or other traumatic injury to the venous endothelium morphologically resembled autochthonous thrombi. This established the only valid way of evaluating experimental thrombi; as stated in section 3.2.1, coagula that lack the structure summarised in Virchow's *real* triad are not

The studies of Sandison (1931) and Stewart *et al*. (1974) supported Welch's conclusion: vessel injury (by whatever agency) causes the generation of thrombi indistinguishable from autochthonous ones - dominated by the accumulation of vast numbers of

However, in most DVT cases encountered clinically and viewed microscopically, the venous endothelium appears ostensibly intact. Therefore, the key questions arising from the studies of Virchow and others (notably Welch and Aschoff) are: what causes the putative *subtle* injury to the venous endothelium that could initiate autochthonous thrombogenesis, and is a

These two questions were the points of departure for the VCH hypothesis and their answers are fundamental to the VCH mechanism. However, Virchow's *real* triad does not only concern leukocyte/platelet margination at the site of thrombus formation. Its other

**3.2.3 Why do leukocytes accumulate at sites of venous thrombogenesis?** 

*cases of autochthonous thrombosis goes"*.

sequestrated/marginated white cells.

particular zone or area of venous endothelium involved?

(Virchow, 1856).

'thrombi'.

**3.2.4 A caveat** 

the elementary fact reported by Joseph Lister in his Croonian lecture (Lister, 1863): circulating blood has no inherent tendency to coagulate; coagulation is initiated *only* when blood makes contact with an abnormal surface, i.e. anything other than normal, uninjured vascular endothelium. Haemostasis is a part of normal physiology, initiated when blood leaks from a vessel. Venous thrombogenesis is not normal physiology; it is a pathological process entailing local blood coagulation *in situ*. A venous thrombus is a lesion, in the strict sense of an abnormal change in a tissue caused by injury or disease. Venous thrombi are in many respects *like* clots, but they are not clots, so it is not logical to infer that they are formed in the same way as clots.
