**3.1 The status and provenance of 'Virchow's triad'**

In a generally excellent review, Bovill & van der Vliet (2011) wrote: "In the mid-nineteenth century, Rudolph Virchow described, in a paper on PE, three factors that he felt contributed to thrombogenesis (32). The three factors were blood flow (stasis or impaired flow), composition of the blood (hypercoagulability), and changes in the vessel wall (endothelial activation and or damage). This triad has guided thinking about thrombogenesis for 150 years." Their reference (32) is to a secondary source (Owen, 2001). The quoted passage from Bovill & van der Vliet sums up a common but mistaken belief about Virchow's contribution to the field (e.g. Peterson, 1986; Rosendaal, 2005; Esmon, 2009; Kyrle & Eichinger, 2009; Meetoo, 2010). Virchow wrote no such thing.

Aetiology of Deep Venous Thrombosis - Implications for Prophylaxis 135

thrombosis (Comerota *et al*., 1985; Kyrle & Eichinger, 2009); however, others such as López & Chen (2009) have recognised that events at the vessel wall precede coagulation. Moreover, retarded blood flow or 'stasis' is sometimes viewed as only a 'potentiating influence' because – so it is conjectured - it allows coagulation factors to accumulate locally (Thomas, 1988; Mammen, 1992; Hamby, 2005). Thus, increasing emphasis has been placed on the presumption of abnormally rapid blood coagulation (Thiangarajan, 2002; Bulger *et al*., 2004), i.e. on thrombophilias, fostering the misleading impression that the aetiology of DVT is to be understood within the domain of haematology rather than that of circulatory anatomy and

Interestingly, the invention of 'Virchow's triad' in the late 1950s - and the concomitant assumption that DVT is a haematological disorder - followed in the wake of the FDA's acceptance of anticoagulant therapy and prophylaxis (Cundiff *et al*., 2010). Some connection might be suspected, and was indeed suspected at the time. We have quoted the barbed comments of Pulvertaft (1947) elsewhere (Malone & Agutter, 2008). Robb-Smith (1955) wrote: "*In recent years haematologists have been forced to take an interest in the practical if not the theoretical aspects of thrombosis by the introduction of anticoagulant therapy*." Later in the same article, he observed: "… *the coagulationist, tilting his tubes with stop-watch in hand, appears to have inherited the mantle of druidical haematomancy, like the medieval physician who based his prognosis on the appearance of the buffy coat in the bleeding bowl… one has the feeling that the stockin-trade of reagents and reactions to produce a fibrin clot is remote from a thrombus*". Robb-Smith understood the spirit of Virchow's work. (Of course, he did not use the phrase 'Virchow's

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* 

1. a thrombus, unlike a clot, has a manifestly layered structure, later called the Lines of

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

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

triad', which would not be coined for another two years.)

*Abhandlungen* (Virchow, 1862), he recognised that:

3. the white cell content is vastly greater.

2. the fibrin content is many times denser than is found in a clot;

physiology.

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

Zahn (Zahn, 1876);

of Aschoff, 1924).

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 of our understanding of the aetiology of DVT.

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 Virchow's seminal works were published.
