**2. A departure from mainstream views**

The VCH thesis is rooted in and informed by the classical work of Virchow, Welch and Aschoff, and its account of DVT aetiology logically implies a means by which venous thrombogenesis can be anticipated and prevented; i.e. it provides a rational basis for prophylaxis, though not for therapy. The mainstream (consensus) viewpoint, in contrast, emphasises 'risk factors' to provide a basis for preventing or retarding the growth of already-formed thrombi. The two perspectives might therefore be seen as complementary rather than as necessarily conflicting, though they are very different.

For example, it is well established that inherited and acquired thrombophilias are important contributors to the risk for clinically significant DVT. After hereditary antithrombin III deficiency was described almost half a century ago (Egeberg, 1965) a number of thrombophilias were identified, and the molecular bases of many of them are now known. Defects in the protein C pathway are the most common inherited disorders (Lane *et al.*, 1996). Acquired thrombophilias are many and varied; the most widespread is antiphospholipid syndrome (Asherton & Hughes, 1989). There are many reviews of the field, e.g. Mazza (2004), Rosendaal (2005), Hassouna (2009), Anderson & Weitz (2010), and the topic is explored elsewhere in this book. Broadly, the work surveyed in these reviews shows that overactivity of coagulation factors, underactivity of regulatory factors or slow lysis of coagula can increase the risk of clinically significant DVT and embolism. Since a patient with no identifiable thrombophilia might develop DVT, it is supposed that other risk factors must be present to carry such patient over the presumed 'thrombogenic threshold' (Mammen, 1992; Lippi & Franchini, 2008; Anderson & Weitz, 2010).

According to the VCH thesis, however, thrombophilias do not *cause* DVT (Malone & Agutter, 2008, chapter 3). A thrombophilia increases the likelihood that a venous thrombus Pathophysiology and Clinical Aspects of 132 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

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

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,

therefore conceivable that venous thrombogenesis *per se* is not multicausal.

and outlines a programme of experimental research leading to clinical trial/s.

rather than as necessarily conflicting, though they are very different.

(Mammen, 1992; Lippi & Franchini, 2008; Anderson & Weitz, 2010).

The VCH thesis is rooted in and informed by the classical work of Virchow, Welch and Aschoff, and its account of DVT aetiology logically implies a means by which venous thrombogenesis can be anticipated and prevented; i.e. it provides a rational basis for prophylaxis, though not for therapy. The mainstream (consensus) viewpoint, in contrast, emphasises 'risk factors' to provide a basis for preventing or retarding the growth of already-formed thrombi. The two perspectives might therefore be seen as complementary

For example, it is well established that inherited and acquired thrombophilias are important contributors to the risk for clinically significant DVT. After hereditary antithrombin III deficiency was described almost half a century ago (Egeberg, 1965) a number of thrombophilias were identified, and the molecular bases of many of them are now known. Defects in the protein C pathway are the most common inherited disorders (Lane *et al.*, 1996). Acquired thrombophilias are many and varied; the most widespread is antiphospholipid syndrome (Asherton & Hughes, 1989). There are many reviews of the field, e.g. Mazza (2004), Rosendaal (2005), Hassouna (2009), Anderson & Weitz (2010), and the topic is explored elsewhere in this book. Broadly, the work surveyed in these reviews shows that overactivity of coagulation factors, underactivity of regulatory factors or slow lysis of coagula can increase the risk of clinically significant DVT and embolism. Since a patient with no identifiable thrombophilia might develop DVT, it is supposed that other risk factors must be present to carry such patient over the presumed 'thrombogenic threshold'

According to the VCH thesis, however, thrombophilias do not *cause* DVT (Malone & Agutter, 2008, chapter 3). A thrombophilia increases the likelihood that a venous thrombus

**2. A departure from mainstream views** 

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 involved during the inception of the pathological process.

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 350 pages of text.

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 embolism.
