**1. Introduction**

Clinical research on deep venous thrombosis (DVT) and thromboembolism (VTE) has focused in recent years on the contributions of potentiating factors, alone and in combination, to the risk of contracting these conditions. Many such 'risk factors' have been identified (Geerts *et al*., 2004) and are discussed elsewhere in this book. The National Institute for Clinical Excellence (NICE) in the United Kingdom has exploited this knowledge to make the prevention of DVT its main focus for 2011. In his keynote lecture introducing the policy and procedures adopted by NICE, Arya (2011) described the tools for evaluating risk in various patient groups and emphasised 'anticoagulation' in the design and implementation of evidence-based prophylactic measures. He claimed that the frequency of VTE in hospital patients should be reduced by 2/3 if the agreed protocols are followed. An achievement of that magnitude would be most welcome.

Comparable views have been articulated elsewhere in Europe. Although NICE is distinctive in recommending assessment for thromboprophylaxis for all medical inpatients, the health services of other European Union countries offer broadly similar guidelines, especially for patients with acute medical conditions with expected durations of hospital stay longer than 3-4 days (Khoury *et al*., 2011). Similarly, in the USA, the Surgeon General issued a 'Call to Action to Prevent Deep Venous Thrombosis and Pulmonary Embolism' in 2008 (Sliwka & Fang, 2010), and the Joint Commission on Accreditation of Healthcare Organizations requires prophylaxis for patients at moderate or high risk of VTE (Rothberg *et al*., 2010). In all these cases, the emphasis is on anticoagulation, typically with unfractionated or low molecular weight heparin or with Fondaparinux.

However, despite the progress made in recent decades, the incidences of DVT-associated mortality and morbidity among hospital patients have declined only minimally (Kahn & Ginsberg, 2004; Heit, 2005), perhaps suggesting there is scope for improvement in our understanding of the aetiology of DVT and *a fortiori* our approach to prophylaxis.

Because of the range and variety of established risk factors, there is a widespread view that DVT is 'multifactorial' or 'multicausal' (e.g. Rosendaal, 1999, 2005; Lippi & Franchini, 2008; Khoury *et al.*, 2011). In a substantial minority of DVT patients, no known risk factor can be identified, and those cases are dubbed 'idiopathic'. While 'risk factors' determine the

Aetiology of Deep Venous Thrombosis - Implications for Prophylaxis 133

will become dangerous for the patient *after* it has formed, but it has no effect on the likelihood that thrombogenesis will occur in the first place. That does not diminish the relevance of thrombophilias to the *growth* of thrombi and *ipso facto* the likelihood of VTE, but it marginalises their significance for understanding aetiology and *a fortiori* for designing prophylactic measures. More generally: according to the VCH thesis, the situation or conditions under which venous thrombogenesis may be initiated, i.e. the *aetiology* of DVT, is not a defined haematological issue; no components of the coagulation mechanism are

The introduction of haematological concepts and methods into the study of venous thrombosis is of quite recent origin. No haematological publication prior to the Second World War mentioned thrombosis (for example, see Eagle's excellent review 1938), and landmark studies of DVT made little or no reference to haematology. After 1945, considerations of haematology were only gradually introduced into the study of DVT (Robb-Smith, 1955); in the third edition of the Biggs-MacFarlane monograph on haematology (Biggs & MacFarlane, 1962), thrombosis was mentioned on only six of about

Virchow's seminal work (1856, 1858, 1862) was 'thrombological' not 'haematological', though this is a verbal rather than a clinical medical specification. Investigation of the haemophilia of Queen Victoria's child was already in hand as he organised his knowledge, but that investigation was wholly unrelated to his already-active studies of thrombosis and

Virchow's objective from 1846 to 1856 was to prove that pulmonary 'phlebitis' is actually 'pulmonary embolism' arising from thrombi formed in distal veins, and thus to contradict Cruveilhier. He wrote almost nothing of note about the mechanism(s) of thrombogenesis, but made crucial observations about the morphology of venous thrombi and the sites at which they form. Acceptable accounts of the aetiology of DVT must explain those

Virchow's work on thrombosis and embolism has been widely misunderstood and

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;

involved during the inception of the pathological process.

**3. Virchow's studies of thrombosis and embolism** 

misrepresented during the past half century.

Meetoo, 2010). Virchow wrote no such thing.

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

350 pages of text.

embolism.

observations.

probability that a venous thrombus will become clinically significant and make embolism and/or post-thrombotic syndrome more likely, they have not been experimentally shown to be implicated in the *initiation* of thrombosis (Malone & Agutter, 2008, chapter 3). It is therefore conceivable that venous thrombogenesis *per se* is not multicausal.

The *valve cusp hypoxia* (VCH) *hypothesis* was proposed in the 1970s and was subsequently corroborated by experimental evidence showing that all cases of DVT have a common underlying aetiology (Malone & Agutter, 2006, 2008; Agutter & Malone, 2011). The (empirically validated) VCH thesis of DVT aetiology is rooted in longstanding causal concepts, but since it may be unfamiliar to some readers, it will be summarised in this chapter before we discuss its clinical implications. In section 2 the contrast between VCH and current mainstream views will be highlighted, and in section 3 we will explore its roots in the historical literature, focusing on Virchow's seminal studies of venous thrombi and emboli, which raised key questions that must be answered by a plausible account of their aetiology. Section 4 comprises an overview of the VCH thesis and its experimental validation, and answers those key questions. In section 5 the VCH thesis is extended in the light of recent publications, potentially enriching our understanding of DVT aetiology. Section 6 presents a rational approach to prophylaxis based on our understanding of VCH, and outlines a programme of experimental research leading to clinical trial/s.
