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Post-mortem blood may be either (a) semi-solidified, resembling clots or thrombi or their combinations, or entirely ‘white' thrombi; or (b), in occasional cases, wholly liquid and incoagulable. Because such variations have confused observers, we will suggest an explanation for them in terms of the valve cusp hypoxia hypothesis (VCHH). The central question is whether it can rightly be imagined that blood coagulates after death. This was intensely debated in the early 20th century but was then resolved ad hoc. To attempt a resolution, the forensic and judicial implications of our account of the states of post-mortem blood will be explored and some clinical inferences drawn. This discussion will highlight the essential value of an a priori account of DVT aetiology. [ABSTRACT FROM AUTHOR]

Gene expression patterns in endothelial cells (EC), presumably including those of the valve cusp parietalis, change in response to hypoxia and other challenges. These changes, the signalling networks involved and the consequences for cell phenotype have been elucidated in considerable detail, providing a mechanistic underpinning for our hypothesis (the VCHH) of the aetiology of DVT. In particular, they define mechanisms for (1) the increased congregation and anchoring of leukocytes and platelets on the hypoxic area, (2) the effects of activated neutrophils on the injured vascular endothelium, and (3) enhanced blood coagulation in the immediate neighbourhood. A significant part of the molecular-biological literature in this field concerns the effects of hypoxia on vasodynamics, which have limited relevance to the aetiology of DVT but may be pertinent to perfusion of the vessel wall via the vasa venarum. Satisfactory assimilation of these ‘mechanistic' findings into the VCHH, as articulated in Chapter 11, exemplifies the reconciliation of approaches to medicine and biology outlined in the preface and discussed further in Chapters 4 and 5. We return to this fundamental point at the end of the present chapter and in the appendix. [ABSTRACT FROM AUTHOR]

This chapter draws together the experimental support for the valve cusp hypoxia hypothesis (VCHH), developed stage by stage in Chapters 8-10, and considers its scientific and clinical significance. The VCHH attributes the aetiology of DVT to (1) underperfusion of venous valve pockets (VVP), (2) consequent hypoxic necrosis of the VVP parietalis endothelium, and (3) active responses by viable leukocytes and platelets to the hypoxic or dead endothelium. Because these events necessarily occur in a reiterated succession, venous thrombogenesis is a gradual, sequential process. The VCHH thus re-deploys ancient and modern knowledge of valve cusp structure and function; it focuses on the precise site of prolonged blood ‘stasis' in venous valve pockets, avoiding the old, imprecise, Galenic usage of ‘stasis'. The crux is why and how blood that entered a VVP ‘alive' may have ‘died' there if not replaced with fresh oxygenated blood for many hours. The VCHH is sharply distinct from the consensus (haematological) model in scientific character, medical implications and philosophical connotations, and these distinctions are briefly discussed. [ABSTRACT FROM AUTHOR]

There is a mid-20th century literature on the relationship between venous endothelial hypoxia and thrombosis, as well as an abundance of more recent cell and molecular biological papers. Discussion of the more recent publications will be deferred until Chapter 12. In the present chapter, the implications of the older literature are discussed in relation to the proposal in Chapter 9: hypoxic death of the parietalis endothelium caused by VVP hypoxaemia during intermittent periods of non-pulsatile (streamline) flow is instrumental in DVT. Published micrographs of venous thrombi are re-evaluated to elaborate this proposal and illustrate the thrombogenic process stage-by-stage. Our account also relates to the induction of DVT-like changes by non-fatal carbon monoxide poisoning, the margination of leukocytes on hypoxic endothelia, Aschoff's autopsies of First World War victims, and recent conflicting evidence about ‘traveller's thrombosis'. [ABSTRACT FROM AUTHOR]

If the first stage in the aetiology of DVT is sustained underperfusion of the valve pockets (VVP) during extended periods of non-pulsatile flow, then the structure, function and pathology of venous valves are of crucial importance. The questions to be answered are: how might underperfusion of a VVP lead to thrombosis, and where in a valve would thrombus formation be initiated? This chapter reviews the accumulated evidence that VVP are indeed the sites of venous thrombogenesis, describes valve morphology and function, and considers how these may be changed under pathological conditions. At the end of the chapter we propose that hypoxaemia in long-underperfused VVP leads to endothelial hypoxia, specifically of the inner (parietalis) surface of the valve cusp(s), and that this may under certain conditions become the prelude to DVT. In the light of this proposal, we calculate the approximate time needed for non-pulsatile venous flow to become pathogenic. [ABSTRACT FROM AUTHOR]

The notion that ‘blood stasis' is a causal or contributory factor in DVT is shown to be problematic: it has Galenic connotations. ‘Stasis' in the literal English sense (absolute cessation of movement) entails local or organismic death; it has been shown experimentally to be anti-coagulatory and therefore antithrombogenic. The use of ‘stasis' to denote ‘retarded flow' or ‘interrupted flow' is confusing not only for semantic and historical reasons, but also because it focuses attention on mean blood velocity in veins rather than on the pulsatility of blood movement. We contend that the (temporary) cessation of pulsatility in venous blood movement is instrumental in DVT. Since the aetiological hypothesis developed in this book focuses on the venous circulation and particularly on the venous valve pockets (VVP), we survey the history of the discovery of venous valves and the establishment of their function by Harvey, and explore the evolution of the ‘stasis' concept against this background. We argue that sustained non-pulsatile (streamline) blood flow in veins results in hypoxaemia in the VVP, and that this initiates a potentially thrombogenic sequence of events. [ABSTRACT FROM AUTHOR]

The words ‘inflammation', ‘phlebitis' and ‘pus' have denoted different entities and carried markedly different connotations at various times in history. These shifts of meaning can hinder 21st-century interpretation of some 18th- or 19th-century publications, and failure to take account of this difficulty has led to persistent misunderstandings. The continuing association of ‘phlebitis' with venous thrombosis is particularly problematic. Discussion of the interpretation problem leads to an evaluation of the possible involvement of leukocytes as well as platelets in the aetiology of DVT and focuses attention on the origin of venous thrombi on the valve cusps. This discussion traces the continuation of the pathophysiological tradition into the 20th century. [ABSTRACT FROM AUTHOR]

Chapter 5 traced the mechanistic materialist tradition of blood coagulation studies through the biomedical schism of 1847. This chapter follows the alternative (pathophysiological or ‘vital-materialist') tradition from the 1830s to the late 19th century, focusing mainly on Virchow's contribution to our understanding of venous thrombosis. The ‘doctrine of Cruveilhier' is discussed and the use of the word ‘phlebitis' is evaluated. Virchow's life, times and philosophy are briefly reviewed, and we emphasise his familiarity with the work of Boerhaave and Hunter as well as Cruveilhier and the early 19th-century microscopists. Virchow effected a synthesis of these contributions to knowledge, demonstrated that pulmonary emboli originate by metastasis1 of distant venous thrombi, proved that thrombi and emboli form in moving not static blood, illustrated thrombi apparently anchored on the cusps of venous valves, distinguished clearly between thrombi and clots, and surmised that oxygen is required for thrombosis. We suggest that the ‘Virchow's triad' concept originated from a misapplication of his work, and we discuss his opposition to Cruveilhier and his philosophy of biology and medicine. [ABSTRACT FROM AUTHOR]

Studies of blood coagulation had originated among the ‘animal chemists' of the 18th and early 19th centuries (Chapter 4), but were placed on a firmer footing in the 1830s by Andral's pioneering compilation of medical knowledge and by Buchanan's experimental studies. The history of blood coagulation research from the time of Andral and Buchanan to the present day can be arbitrarily divided into four phases. The third and fourth phases, covering the period between the Second World War and the present, were explored in Chapter 2. This chapter concerns the first two phases. Phase 1 extended from Buchanan's publications to the maturation of Schmidt's ‘classical hypothesis' : the action of thrombin was identified and the existence of prothrombin and antithrombins was inferred. These advances were underpinned by a philosophical movement; mechanistic materialism marginalised the role of cells in blood function and focused attention on the soluble components of the plasma. Phase 2, covering roughly the first half of the 20th century, saw the identification of prothrombin and an increasing number of coagulation factors, and the discoveries of heparin, vitamin K and dicoumarol. The mechanistic-materialist character of coagulation research became entrenched. At the end of the chapter, we discuss the origin of this philosophical movement in a schism that took place around 1847. This schism primarily involved du Bois Reymond, the leading protagonist of mechanistic materialism, and Virchow, the pioneer of cellular pathology and exponent of the ‘pathophysiological' approach to biomedicine. [ABSTRACT FROM AUTHOR]

Two historically disjoint approaches to biomedical investigation are identified: the ‘(patho)physiological', associated with Harvey and Virchow, and the ‘mechanistic', associated with Boerhaave, du Bois Reymond and the consensus model of DVT. The origins of both traditions are traced to the 17th century, the Scientific Revolution and the dawn of natural philosophy. Their developments into the 18th and early 19th centuries are outlined. The lines of investigation that led on the one hand to the elucidation of the blood coagulation mechanism, and on the other to the seminal contributions of Virchow, are identified. Care is taken to distinguish ideas in both mainstream traditions from belief in a ‘vital force', and other possible sources of semantic confusion are discussed. [ABSTRACT FROM AUTHOR]

The claim that Virchow attributed venous thrombosis to ‘hypercoagulability' is refuted. Two uses of the word ‘hypercoagulability' are distinguished: a general sense, which entails circular reasoning, and a specific sense, for which the synonym ‘thrombophilia' is substituted. Three predictions of the hypothesis that ‘hypercoagulability causes DVT' are identified. One of these is shown to be weakly corroborated by early studies on ‘experimental thrombi'. The others are evaluated through a review of the literature on hereditary and acquired thrombophilias and are shown not to be supported by the available evidence. The conclusion — that thrombophilias increase the likelihood of DVT but cannot be considered ‘causal' — is followed by a critical discussion of the clinical value of laboratory tests for thrombotic tendencies, and the need for an alternative to the consensus model of DVT aetiology is re-emphasised. [ABSTRACT FROM AUTHOR]

The development of the blood coagulation ‘cascade' concept after the Second World War, together with the increasing clinical use of anticoagulant and (later) thrombolytic treatment, is briefly reviewed and related to the origin of the consensus model. It is suggested that the consensus model arose from a research tradition that was essentially unrelated to thrombosis, and that its articulation entailed an effective, if unintended, suppression of Virchow's pathophysiological viewpoint (as defined in the preface to this book) and also marginalised studies of the venous endothelium in relation to DVT. It is notable that Virchow's explicit distinction between ‘clot' and ‘thrombus' was not preserved during this process; Virchow had hypothesised that thrombi are analogous to clots, but he knew the limitations of the analogy. The remainder of the chapter is devoted to a more or less detailed overview of the coagulation cascade as it is understood today. These details are included because no matter how the aetiology of DVT is considered, it is clear that the blood coagulation mechanism is involved at some point in the process. Some brief semantic points are raised for later discussion and development. [ABSTRACT FROM AUTHOR]

The frequency and incidence of deep venous thrombosis (DVT) and the major known predisposing factors are summarised, and ‘traveller's thrombosis' is briefly discussed. The main pathological consequences of the condition are outlined: pulmonary embolism, the main cause of mortality; and post-thrombotic syndrome (a general label for the morbid sequelae, involving valve incompetence and leukocyte infiltration). What we term the ‘consensus model' of DVT, which attributes the condition to some combination of hypercoagulability, stasis and endothelial injury, is introduced; some variants of this model are outlined. A brief critique of the consensus model is given, followed by a conjecture about its sustained prominence in the field, and this is followed by a critical discussion of the phrase ‘Virchow's triad'. An alternative model of DVT is briefly outlined. Because both the consensus model and the alternative viewpoint have deep historical roots, we suggest that historical exegesis is necessary to explain their origins and development and to establish a rational understanding of the aetiology of DVT. [ABSTRACT FROM AUTHOR]