The aetiology of deep venous thrombosis and chronic venous insufficiency

Prof. Alun Davies has written in Venous Times: 

This interesting and small text focuses on numerous aspects of DVT or real venous thromboembolic disease. The authors initially focus on the generalities including Virchow's Triad. They then move on to looking at hypercoagulability and then stasis and the importance of hypoxia. The text and references are very comprehensive and hence the book will be of value to those researching the finer points of DVT/VTE and it is a text that will be a useful addition to any library where clinicians wish to explore some of the fundamental issues behind the aetiological factors involved. I have enjoyed reading this book and recommend it to others who have an interest in the field.

 

Professor A Nicolaides MD FRCS wrote:

 

BOOK REVIEW

 

P. C. Malone and P. S. Agutter.—The Aetiology of Deep Venous Thrombosis". A volume of 144 pages.       Springer, Dordrecht, 2008. $ 149.00

 

I have read some of the chapters and I am most impressed. It is well written, scholarly and deals with the subject in "4-D" i.e. not as we know it now but as knowledge developed in time. For me, who has lived through the development of the subject since the late 1960s and reviewed the literature as far back as Hippocrates, it was like reading a novel that I could not put down.

 

Ideas about the subject we now term 'Deep Venous Thrombosis' {DVT} have grown like a 400 year old tree. Young branches arise from the gnarled trunk and roots ; they appear healthy and active, but they carry many of the parasites that have beset the tree since its sapling years. Old branches may seem dead, but they are not. This volume sets out to trace the tree's history, identifying the directions in which it has grown - and the parasites to which it has fallen and still falls prey - in the hope that a plan for its future well being can be developed.

 

Most accounts of  DVT emphasize the role of  blood coagulation and infer that various forms of 'hypercoagulability’ increase the likelihood of thrombosis. This inference is not in doubt. However, the implicit premise that DVT is caused by a perturbation of the coagulation mechanism can be challenged. Eminent physiologists pondered this matter for some 200 years; in the late 19th and early 20th centuries they demonstrated that changes in 'formed blood elements' precede fibrin formation. Further investigation revealed that the first response to injury in the venous valve pockets (VVP) is the local ‘swarming’ of leukocytes as well as platelets - not a change in coagulation. Coagulation is obviously involved in thrombogenesis, but it is not the initiating event; and most victims of DVT have normally coagulable rather than hyper-coagulable blood.

 

In such ways, the book emphasises historical exegesis; but it does not presume that history is a cure for ignorance. The past is re-examined, not for its own sake, but in order to address modern questions and to envisage possibly new answers.  The starting points are the apparent overthrow of Galenism during the century 1535-1635, the description of venous valves by Fabricius, and Harvey's complete re-think of blood motion. The findings of Fabricius were crucial for Harvey's discovery; they are now shown to be the basis of a new hypothesis of DVT aetiology, the valve cusp hypoxia hypothesis (VCHH). According to the VCHH, thrombi form uniquely in venous valves and VVT and may destroy them, or at least impair their function. Circulation of the blood is a sine qua non of thrombogenesis.

 

But Galenist notions have survived in contemporary as well as older accounts of the causation of DVT.  'Stasis' is a prominent example. Galen's notion of blood movement implied nodes of stasis at the anatomical extrema; Harvey's circulatory theory refuted that inference. Also, there is long-standing experimental evidence that static blood, in situ (i.e. within an uninjured vein) coagulates only verv slowly, if at all, and therefore presumably does not thrombose. Yet the consensus account of DVT claims 'stasis' as a causal or permissive factor, a contention dismissed by Virchow ("the doctrine of stasis rests on manifold misinterpretations") among others. According to the VCHH, only when the inner (parietalis) endothelium of the valve cusp is injured, and living leukocytes and platelets are supplied by the circulating blood, can thrombogenesis be initiated.

 

Another essentially Galenic notion, 'inflammation', was once considered causal in DVT. Certainly, the first visible event in thromogenesis is the local accumulation of colourless corpuscles - hence the white core of a nascent thrombus and the lines of Zahn. Before leukocytes were identified and their functions partially understood, such white semi-solid masses were dubbed 'pus'.  John Hunter advised us to regard 'inflammation' as a healing ('salutory') rather than a pathological process; yet the notion that DVT can have an 'inflammatory' aetiology still persists hidden in the 19th century oxymoron 'thrombophlebitis'.

 

The VCHH is closely related to the concept of ischaemic-reperfusion injury.  Both were adumbrated in concurrent but unconnected publications (1977) and both emphasise vascular endothelial injury and local leukocyte invasion. Nevertheless there are fundamental differences between them; they are two different trees whose limbs have become entangled.

 

The main thrust of the book is to show that ideas springing from the apparently dead roots of the old pathophysiological tradition can throw fresh light on current concerns, and that such ideas can be reconciled productively with the 'mechanistic' studies that dominate the current literature. The history and current status of DVT research constitute a clear justification for this optimistic claim.

 

The book consists of 13 chapters. A general introduction (chapter 1) followed by a review of the blood coagulation mechanism (chapter 2) and "hypercoagulabilty" (chapter 3) as understood today. The historical discoveries that have led to our current knowledge of venous thromboembolism are dealt with in chapters 4-8. Chapters 9-11 focus on the valves and valve pockets and the valve cusp hypoxia hypothesis. In chapter 12 the valve cusp hypoxia hypothesis is supplemented and enriched by recent discoveries in the molecular biology of endothelial cells and their responses to hypoxia. Finally, chapter 13 deals with intravascular coagulation after death (post mortem thrombi or clots). This book is a critical historical and scientific survey of the aetiology of DVT. It is highly recommended to all students, researchers and physicians interested in the subject. It is highly stimulating and informative.              Prof.  A. Nicolaides

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