VVP Hypoxaemia and Hypoxic Injury to the Parietalis Endothelium

We propose that under non-pulsatile flow conditions, the valve cycle is interrupted and irrespective of the phase in which it is interrupted, a volume of blood will remain sequestered in the valve sinus, neither evacuated nor replaced for as long as the non-pulsatility persists. We argue that this 'focal stasis' in VVP must result in local hypoxaemia and must predispose towards the formation of a pro-thrombotic white nidus (primarily a congregation of leukocytes and platelets interspersed with...

Endothelial Cell Physiology

The vascular endothelium is a confluent monolayer of thin, flattened, rhomboidal cells that normally prevents the escape of fluid from blood vessels other than capillaries. Endothelial cells (EC) produce enzymes and inhibitors that slowly and continuously remodel the subendothelial extracellular matrix (ECM), a structure consisting mainly of collagen, fibronectin and laminin supplemented with glycosaminoglycans, thrombospondin and von Willebrand factor (vWF) (Jaffe 1984). Although the vascular...

Risk Factors for DVT Reconsidered in the Light of the VCHH

The major known 'risk factors' for DVT were listed in Chapter 1 and were evaluated e.g. by O'Shaughnessy et al. (2005, 2007). We noted (Chapter 3) that an aetiological hypothesis should explain why these factors increase the likelihood of DVT. However, a caveat must be entered it would be both scientifically and philosophically erroneous to confuse factors that predispose towards a condition with causes of that condition. Combinations of the known 'DVT risk factors' certainly increase the...

Buchanan

The revolutionary idea that a specific component of the blood causes or positively initiates coagulation was first advanced by Buchanan (1835) when he was a junior surgeon at Glasgow Royal Infirmary. He published a second and more detailed paper (Buchanan 1845) when he was Professor of the Institutes of Medicine in Glasgow. Essentially, his experimental model was to mix blood and water in vitro and allow them to clot he then strained the clot through a linen cloth and called the strained...

Leukocytes Phagocytosis and Thrombosis

The source of 'pus' and its relationship to leukocytes was intensely debated during the 1840s, after the dawn of cell theory. The English microscopists Addison (1842, 1846) and Waller (1846) concluded that 'pus globules' and 'leukocytes' were i dentical, and that pus was normally formed by diapedesis of leukocytes from the blood vessels rather than the other way round. Remarkably, Virchow didactically denied this thesis. Having perceived the admixture of white material in the interstices of red...

Testing for Thrombophilias

These arguments are widely ignored testing for hereditary thrombophilias has become almost routine in hospitals. Some 25,000 tests for factor V Leiden alone are conducted in the UK every year, and wider population screening has been mooted (Keeling 1998). On the face of it, the mortality risk associated with DVT (perhaps 2 in younger patients and 10 or more in older ones) might seem to justify the expense of testing and perhaps prophylaxis. However, there is little evidence that such...

Thrombophilia and DVT

Most studies suggest that antithrombin III, protein C and protein S deficiencies increase the incidence of DVT about 25-fold compared to the general population (Ely and Gill 2005). Factor V Leiden (APC resistance) elevates the incidence less than 10-fold, but it frequently occurs in combination with other defects and aggravates them (Gomez and Laffan 2004). However, there is no simple, regular correspondence between any thrombophilia (inherited or acquired) and DVT or other pathological sequel....

Crucifixion

We now offer a speculation that is, fortunately, unsupported by empirical evidence the cause of death by crucifixion was ruthless extinction of the venous return. Special cruelties were not necessary to ensure slow death, it sufficed to suspend victims from trees in the erect position, with the soles of their feet clear of the ground, either unsupported or with nails driven through their heels into the sides of the tree. The ancient practice inevitably prevented the blood that had been pumped...

Carbon Monoxide Poisoning and Anaemia

The role of oxygen-lack in the aetiology of DVT is singularly well illustrated by its known complication of carbon monoxide poisoning (in cases that survive for long enough). As we recounted earlier, O'Neill (1947) acknowledged Drinker's (1938) suggestion, which was based on his finding of quasi-thrombi in (chronically) carbon monoxide-poisoned human blood vessels. When coal gas was widely used for illumination and heating, CO poisoning, accidental and suicidal, was common. Haldane (1895)...

Introduction

Virchow (1821-1902) passed his student years in Berlin during an exciting period in both European history and the history of biology. The 18th-century Enlightenment fashion for 'experimental philosophy' had spread not only to the study of life, fostering inter alia the mechanism-vitalism debate, but also further into political and religious affairs (Merz 1928 Temkin 1946). The theory of 'transformation' (later to be dubbed 'evolution') was proposed in the early 1800s 1 This was...

The Specific Involvement of the Valve Cusp Parietalis Endothelium

The parietalis and luminalis epithelia of valve cusps are histologically similar (Chapter 9), but whereas the latter is bathed by oxygenated blood in the vein lumen under both pulsatile and streamline flow conditions, the former depends on pulsatile flow, which empties and refills the valve sinuses. Thus, whereas only the whole-body hypoxaemia of gross circulatory failure threatens the survival of the luminalis, the parietalis endothelium suffers oxygen lack each time the peripheral venous...

Molecular Changes in the Hypoxic Endothelium

Abstract 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...

Interrupted Circulation The Stasis Hypothesis and the Significance of Venous Valves

Abstract 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 anti-thrombogenic. 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...

The Debate Reconsidered in the Light of the VCHH

The VCHH predicts that neither clots, coagula nor thrombi can form in corpses after death. Every such structure found in blood vessels after death is a thrombus, either old or agonal, but not formed post-mortem. In short, we agree with Rost and Ribbert as opposed to Aschoff, Marchand and modern orthodoxy. But the question remains why is the blood of some cadavers littered with coagula while others show a complete dearth We must not lose sight of the obvious fact that 'normal', fresh blood shed...

Compression of Veins in the Soles of the Feet

When a foot is lifted from the ground, so that it is not supporting the body weight, the veins in the sole can fill with blood. When the next step is taken and the weight of the body is taken on that foot, blood must be squeezed from the veins of the sole into those atop the metatarsals and forefoot around the ankle, much as water can be 19 'Pumping' is of course metaphorical. What is commonly called the 'calf muscle pump' is not literally a pump. wrung from a wet towel. Centrifugal reflux...

Endothelial Hypoxia and Thrombus Formation in VVP

These studies established empirically that hypoxic injury to the venous endothelium is thrombogenic, but they did not specify the relevant part of the endothelium. The central point is that since valve cusps are avascular, the parietalis endothelium of the cusp must necessarily obtain all its normal nutriment oxygen from the blood within the VVP only. The luminalis endothelium may remain oxygenated by the (still-circulating) luminal blood. Consequently, should the VVP not be regularly evacuated...

Implications for the Formation of Pro Thrombotic Nidi

When the valve cusp pathologies associated with so-called 'venous valvulitis' and ageing (Saphir and Lev 1952a, b) are reviewed in the light of these studies, further inferences about DVT may be drawn. The thickening of the cusp described by Saphir and Lev presumably attenuates the oscillations observed by Lurie et al. (2002, 2003b) in normal younger subjects during the equilibrium phase, with implications for Venturi effect, i.e. the stability of the vortices that are instrumental in...

The Coagulation Cascade and the Consensus Model of DVT

Abstract 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...

Oxygen the Venous Endothelium and Thrombosis

In Chapters 8 and 9 it was proposed that DVT may follow sustained non-pulsatile flow in under- or non-perfused venous valve pockets (VVP), which entails severe hypoxaemia in those pockets and, perhaps, suffocated hypoxic death of valve cusp parietalis endothelium. This hypothesis seems compatible with recent publications on vascular endothelial hypoxia (Chapter 12), extending into the vast literature on ischaemia-reperfusion injury. However, it is rooted in a considerably older literature that...

Virchows Triad

It is trivially true, and has long been recognised, that DVT must entail some combination of malfunctions in 'vessel wall, blood movement and blood coagulation'. However, it is curious that this truism has come to be labelled 'Virchow's triad'. The eponym has become prominent in clinical, pathological and thrombosis research circles, but there are several reasons to consider it problematical. First, its origin is obscure, because it was unquoted (and presumably unknown) in textbooks or research...

A23 Hume The Achilles Heel of Empiricism

David Hume (1711-1776) lived through the Enlightenment era. He inherited the Lockean tradition, but - paradoxically - undermined the certainties of that classical empiricism (Russell 1946 Kemp Smith 2005). What he wrote remains disconcerting today, but few of his contemporaries grasped its implications. Classical empiricism focused on inductive reasoning the path to knowledge was considered to depend on generalisation from repeated instances of the same 'association of ideas'. (In contrast,...

Elk1 and SRF

A ternary complex between the serum response element (SRE Qureshi et al. 1991), serum response factor (SRF) and the receptor tyrosine kinase elk-1 (Hipskind et al. 1994) appears to be required for Egr-1 expression. Hypoxia activates elk-1 via a PKC isoform and other receptor tyrosine kinases (Lo et al. 2001). The SRE is a 20 kb promoter region associated with immediate-early and actin genes (Mohun et al. 1987) as well as with Egr-1. SRF is a 67 kDa protein required for transcription of these...

Simpsons Cases

Simpson (1940) presented a famous case-series of elderly persons who, having slept overnight ( 10 h) in deck-chairs on London Underground station platforms during the Blitz, died of pulmonary embolism in surprising numbers afterwards. He conjectured that the cross-bar beneath their knees obstructed the venous return blood flow from the legs. This was considered a reasonable supposition, and his solution - to replace deck chairs with bunk beds in the Underground - was brilliantly successful his...

Preface

What we now call 'deep venous thrombosis' (DVT) has been studied in diverse ways during the last 200-300 years. Each of these approaches contributes to a full modern understanding of aetiology. Therefore, much of this book is a historical survey of the field. However, our remit is broader than the title might suggest the evolution of ideas about DVT is typical in many ways of medical biology as a whole. Thus, although the aetiology of DVT may seem a narrow topic for a monograph - it implicitly...

A21 The Aftermath of the Scientific Revolution

The fundamental transformation of European thought often ascribed to the publications of Copernicus and Vesalius in 1543 had been adumbrated in the nascent theory of impetus developed in Merton College, Oxford, in the 14th century and in the contributions of Buridan, Oresme, Nicholas of Cusa and other late mediaeval scholars (Hall 1954 Claggett 1959 Boas 1962 Butterfield 1965b). It had far-reaching cultural consequences. The three most venerated prophets of the succeeding age, Francis Bacon3...

Published Travellers Thrombosis Data

The above conclusion seems to be supported by the finding (Lapostolle 2004) that the numbers of passengers affected by DVT rises exponentially with the time distance they have flown. It may be that the duration of VVP hypoxaemia required to cause the margination of the second and subsequent layers of blood cells on the parietalis shortens progressively with each successive cycle. The effect may depend not only on geometrical considerations (the volume of the VVP sinus must decrease as the layer...

Endothelial Hypoxia and Leukocyte Margination

Endothelial lesions are characteristically followed by local margination of leukocytes and platelets (Chapter 7), whether the lesion be caused by experimental vessel wall injury, hypoxaemic endothelial injury or CO toxicity. This recalls the 19th century microscopic descriptions of 'stasis' in small vessels (Chapter 8). Because CO poisoning causes tissue and venous endothelial hypoxia, identical in effect to underperfusion, it causes leukocyte margination and diapedesis identical to that seen...

Listers Experience

Lister was asked to see a young patient who, following an injury, had had a tourniquet applied to an arm for a day. Custom at the time directed that such limbs should be amputated, but Lister, informed by his experimental studies, pondered whether to take this action. He opted to 'save the limb' and recounted how pleased he was a week or two later to find that the limb had recovered and had remained 'useful'. Presumably, if blood vessels or their endothelial linings are deprived of oxygen for a...

Platelet Congregation and Implications for DVT

Platelets are not uniformly distributed in the veins interestingly, they are less dense in such deep lower-limb vessels as the soleus and femoral vein, which are the most common sites of DVT (Woldhuis et al. 1992 see Chapter 8). Platelets interact with EC when the shear rate is sufficiently low (less than 100 s-1), as in the secondary vortices in VVP during streamline flow (Chapter 9). Weiss et al. (1986) investigated this process by intravital microscopy. They found that calcium secretion...

Virchow on the Structure of a Thrombus

Virchow initially considered the clotting of blood ex vivo as a possible model for and analogue of thrombogenesis a plausible hypothesis, but one that he rejected after critical histological studies. In the Gesammelte Abhandlungen we find his summary of the distinctive 'triad' of distinctions between in vivo thrombi and in vitro clots (pp. 514-515) 1. the structure of the thrombus is in layers i.e. the lines of Zahn 10 2. the fibrin content is denser 3. the population of colourless corpuscles...

Monocytes and Macrophages

Monocytes macrophages accumulate in areas that are likely to be hypoxic, presumably including the hypoxaemically injured valve cusp parietalis. Macrophages in such areas show increased metabolic activity and phagocytosis, altered morphology and cell surface markers, and cytokine production (Lewis et al. 1999). Hypoxic EC produce increased amounts of the monocyte chemoattractant protein JE MCP-1 (Karakurum et al. 1994), which probably recruits monocytes and macrophages to the site as well as...

The Valve Cusp Hypoxia Hypothesis

Abstract 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...

The Tissue Factor Extrinsic System

Tissue factor (TF) is a subendothelial cell-surface glycoprotein with a high affinity for phospholipids (Nemerson and Pitlick 1972). Factor Xa and thrombin activate factor VII, and factor VIIa in conjunction with TF catalyses the activation of factor X (Mariani and Mandelli 1983). This is another positive feedback loop, amplifying the fibrinogenic response. Factor VIIa and TF also activate factor IX another amplification device, and another link between the 'intrinsic' and 'extrinsic' systems...

Buchanans Influence The Impact of Mechanistic Materialism

In his remarkable paper 'On the early stages of inflammation' (1858) and his brilliant Croonian lecture 'On the coagulation of the blood' (1863), J.L. Lister both acknowledged Buchanan's priority and noted the intrinsic difficulty of such work (' has engaged the best energies of very able men'). He repeated and confirmed 4 Most textbooks attribute cell theory to Matthias Schleiden in 1838 and Theodor Schwann in 1839, but the cell concept was established by Fran ois-Vincent Raspail (1794-1878)...

Reflection

Although majority opinion in the field seems to doubt the clinical value of diagnosing particular thrombophilias, the characterisation of these conditions has helped to elucidate several aspects of the coagulation mechanism and its regulation, and has led to the identification of individuals at statistically higher-than-average risk of venous thrombosis. A sound aetiological account of DVT must (inter alia) be able to explain the empirical evidence that has accrued about each type of...

Erg1 Hypoxia and DVT

Among the products of genes up-regulated by Erg-1, TNF-a and IL-10 promote marked changes in cell phenotype (Esmon 1999). In particular, they further stimulate the production and intravascular secretion of TF. Thus, hypoxia increases TF expression in monocytes and subendothelial smooth muscle cells (Lawson et al. 1997) as well as EC (Solovey et al. 2004), with plausible implications for thrombosis as well as vascular development and haemostasis (Morrissey 2004). Under normal physiological...

The Significance of Ostial Valves

No histologist investigating DVT has reported evidence of endothelial injury on the vein wall, despite tedious serial sectioning of thrombus nidi and their environs yet not all venous thrombi originate in parietal valves. That conundrum could be explained if some thrombi form in ostial valves and grow precisely as Virchow depicted in his engraving (Fig. 10.1 see also Figs. 9.5 and 9.6). Consequently, unless histopathologists serially section the mouths of tributaries, and plot the relationship...

Binary Oppositions in 17th18thCentury Medicine

The two contrasting viewpoints we have mentioned have deep historical roots common to many areas of medicine, though they are not evident before the 17 th century. General accounts of history often portray the past in terms of opposed pairs of metaphysical viewpoints5 Galenist versus Harveyan, humoralist versus solidist, vitalist versus mechanist, and so on. We shall follow this practice because it cannot 5 The once-fashionable structuralist Claude L vi-Strauss held that the representation of...

A31 The Mechanism Vitalism Debate and its Implications

Both mechanists and vitalists in the 18th and 19th centuries were committed to 'explaining the cause of life', as opposed to 'considering the effects of life'. The basic distinction between the two camps was simple vitalists posited that a 'vital force' informed living as opposed to non-living matter mechanists held that all components of living matter and all principles underpinning its behaviour were also components and principles of the non-living world. The debate between these two...

The General Aetiological Sequence The Trinity

There is no doubt that the three elements of what is dubbed 'Virchow's triad' (vein wall, blood flow and blood components)1 must enter into an aetiological account of DVT (cf. Brotman et al. 2004) though as we have seen (Chapter 6), Virchow discussed these three general 'phenomena' only in relation to the major pathological effect of DVT (pulmonary embolism), not its cause. After Virchow's death, various attempts were made to list the relevant aetiological factors and some of these were...

Virchow versus Cruveilhier

Virchow's seemingly implacable antipathy to Cruveilhier could have been a reflection of the Francophobia characteristic of many 19th-century German scientists (see Chapter 5). There is no doubt that his work surpassed that of his eminent predecessor. He showed that pulmonary emboli arose from peripheral venous thrombi he changed Cruveilhier's nomenclature he demonstrated that thrombosis required circulating blood and was oxygen dependent and he described the structure of thrombi and their...

Summing up the Argument Judicial Implications

(a) All coagula found in cadavers are either the Kopfteil or the Schwanzteil of agonal ante-mortem thrombi, as Ribbert contended. (b) There is no such entity as post-mortem thrombus, coagulum or clot. 2. Since thrombosis is a living, physiological (albeit pathophysiological) response of living blood to dying or dead vascular container envelope, thrombi cannot form once the circulation stops, and liquid blood stopped in dead vessels will not clot therein. Nor will it coagulate if it is shed...

Can Blood Coagulate in a Cadaver

Scientific medical hypotheses are valuable only in so far as they lead to (a) new directions in therapy, prophylaxis or research and (b) solutions to persistent puzzles. We have already shown that the VCHH has potential applications in prophylaxis against DVT and thromboembolism, and we have outlined some of the novel lines of research to which it could lead. In this final chapter we aim to cast new light on a topic long characterised by confusion and uncertainty the state of the blood in...

Inherent Difficulties in the Stasis Dogma

It might be argued that if biomedical researchers agree to use the word 'stasis' to mean 'retarded circulation', its standard English connotation (i.e. 'absolutely no movement whatever') is irrelevant once everyone in a particular scientific field has consented to a specialised language in which a common word is given a definite nonstandard meaning, semantic cavils become otiose. However, there are three important reasons for rejecting a 'special context' for the term 'stasis' in a private...

Continuation of the Pathophysiological Perspective Welch and Aschoff

Welch (1887) posed a new question 'What is the proper status of experimental throm-bogenesis Are its experimentally produced thrombi analogous to autochthonous thrombogenesis ' His 1887 essay and his entry in Allbutt's System of Medicine (Welch 1899) addressed these important issues and sourced much of the information 11 According to Dickson (2004), Humphry suffered venous thrombosis so he was personally motivated to elucidate its aetiology. He reasoned that eddies created in valve pockets...

Aschoff on Post Mortem Clots

In this context, it is remarkable to see how Aschoff (1924) mixed the 'mechanistic' and 'pathophysiological' approaches without attempting to amalgamate or reconcile them. As we observed in Chapter 7, the conflict between these approaches led to inconsistencies. On the one hand, he agreed that thrombi do not form in stationary blood. He wrote (p. 258) 'We have concluded, then, that the thrombus arising from the blood platelets has its origin in the circulating blood stream', and went on to...

The Endothelium and Coagulation

There is consensus agreement that physiologically normal EC control coagulation, promote anticoagulation, regulate fibrinolysis and produce thromboregulators (Eisenberg 1991 Furie and Furie 1992). Examples of the molecular components involved are summarised in Table 12.2. Collectively, these discoveries may help to explain why blood coagulation remains locally confined blood coagulates only when and where the endothelium loses its structural and functional integrity or, perhaps, when the cell...

Experimental Venous Thrombi Induced by a Non Invasive Technique

Using a non-invasive procedure, Hamer and Malone (1984) generated experimental thrombi in the femoral veins of dogs, some of which occluded the deep femoral 4 See Fig. 9.2. The 'bottom' of the pocket is the 'minimum of the parabola' described by the cusp, not the point adjacent to the agger. Thus, the only endothelial cells close to or perhaps touching the electrode were those of the parietalis. Fig. 11.3 Gradient of hypoxaemia in a valve pocket during non-pulsatile flow. (a) Fig. 1 from Hamer...

Platelet Activation and Congregation Local Vasoconstriction

Although the following events are better established in arteries than in veins, exposure of subendothelial collagens I and III at sites of intimal injury seems to be the general primary trigger for the congregation and attachment of platelets10 (Triplett 2000). Attachment appears to be mediated by tissue fibronectin and by von Willebrand Factor (vWF) (Meyer and Larrieu 1970 Caen and Levy-Toledano 1973), which links the collagen fibrils to platelet receptors (Sixma and Schiphorst 1980). vWF is...

The Ancient World

Investigations into blood, blood-related diseases and what we now call the 'circulation' date back to antiquity. Anning (1957) and Dickson (2004) note that pathological haemostasis was described in China in about 2650 BC. From the many references to 'drinking blood' in ancient testaments, it could seem that the ancients had discovered techniques for anticoagulation. 'Whipping', which removes coagulable material, was perhaps the most likely method. The earliest known European writings to mention...

Aetiology The Consensus Model

Since the early 1960s, most explanations of DVT aetiology have revolved around 'hypercoagulability' and 'stasis'. For example, Sherry (1962) wrote 'For over a century, leading pathologists, investigators and clinicians have continued to emphasize the importance of alterations in blood flow, damage to the vessel wall, and changes to the coagulability of blood as the major factors responsible for thrombus formation in vivo Comerota et al. (1985) commented 'The cause of postoperative DVT is...

Venous Valve Morphology

The remark 'nor have any succeeding anatomists added anything to our knowledge' could, with minor reservations, have been echoed by Franklin (1927, 1937), or by Edwards and Edwards (1939) and Saphir and Lev (1952a), who provided further details. Typically, the vein cross-section near a valve is elliptical and slightly dilated. Also, the wall bounding the valve sinus 'laterally' is thinner than in the rest of the vein, rendering it more distensible (Franklin 1927, 1937 see also Edwards and...

Valve Pathology The Formation of Nascent Thrombi within VVP

Saphir and Lev (1952a) studied femoral valvulitis and found that 'inflammatory injury' to venous valves is common. Since the appearance of an 'inflamed' valve cusp represents margination and sequestration of leucocytes platelets, it could be considered that an 'inflamed valve' is indistinguishable from a 'white thrombus' in its earliest (Kopfteil) phase (cf. Chapter 7). Valve cusps can become necrotic, e.g. after (or perhaps during the pathogenesis of) endocarditis or other heart diseases, and...

Early Evidence for Hypercoagulability Conditions

Familial 'thrombophilia essentialis', predicted by Andral in the 1830s, was recognised later in the 19th century by Armand Trousseau and was independently described by George Elgie Brown and Kaare Kristian Nygaard. However, it remained a medical curiosity until the 1950s. The main symptom is intermittent claudication (i.e. arterial rather than venous occlusion) with reduced bleeding times and in vitro clotting times. The syndrome can progress to thrombosis of the abdominal and pelvic vessels,...

Interrupted Flow and Underperfusion of VVP

Virchow (1856) used the phrase 'interrupted circulation' to refer exclusively to pulmonary arterial obstruction and consequent arrest of the circulation, but this is an entirely different matter from normal 'interrupted circulation' i.e. alternating pulsatile flow in arteries or veins with unobstructed (thrombus-free) lumens (Chapter 8). In normal limb vessels, motor pressures fall when cardiac and or venous valves close during extended diastolic periods, but the reduced rate and volume of...

Reflective Anamnesis

This chapter has been concerned with a century's growth of one strand of knowledge - the mechanistic, haematological strand - which would, after the Second World War, come to be related retrospectively to DVT. As we have seen, a cellular (potentially 'physiological' and 'pathophysiological') dimension to this strand was adumbrated in Buchanan's studies, but was subsequently suppressed because of the academic dominance of mechanistic materialism, which is particularly apparent in the work of...

Varicose Veins

Virchow (1858) accompanied the engraving that we reproduced in Fig. 10.1 by a striking comment in the event of thrombi such as the one illustrated, the tributary 9 A Medical Tribune reporter quoted a comment by L.P. Le Quesne at the Lister Centenary 1967 under the heading 'Safe surgery - Maintain circulating blood volume' ' there are practically no circumstances when a patient's safety is enhanced by undertaking surgery with a depleted blood volume. Critical lesion is a circulating blood volume...

The Unification of Approaches

The molecular and cell biological literature reviewed in this chapter belongs to the mechanistic tradition, so most authors in the field have related their findings to the consensus model of DVT. In general, they have been concerned to show that certain insults to the vascular endothelium - including (particularly) hypoxia - tend to promote coagulation fibrinogenesis or, alternatively, to down-regulate anticoagulatory factors such as thrombomodulin, or to impair fibrinolysis. Much of the...

Intermittent Positive Pressure Compression IPPC of Feet or Legs

The same considerations relate to the prophylactic use of IPPC. The principle is once again to empty 'stale', deoxygenated blood from VVP, mainly in the leg veins.12 So what might be the ideal frequencies, intervals and pressures at which the IPPC apparatus should be operated Patients wearing such devices complain of the disturbing effect of compression. For some people, tight and aggressive13 squeezing 12 Jugular and arm veins do not (commonly) thrombose because they are emptied by gravity and...

The Risks of Sleeping for Long Periods in the Sitting Position

People who have spent much longer than average sitting and sleeping (semi-erect), e.g. in deck-chairs, sofas, computer chairs and commercial airline seats, are more prone to suffer 'idiopathic thromboembolism' (Dalen 2003). However, because the aetiological sequence according to the VCHH is complex, only a minute proportion of 'long-sitters' may develop actual lesions, and then usually after a delay of days or weeks. Moreover, such instances cannot be predicted because different subjects...

Blood Cell Congregation and Blood Coagulation

The assertions of Aschoff (1924) that 'important changes in the morphological blood constituents' preceded fibrinogenesis, and that 'along with the explanation of this marking Kopfteil, Halsteil, the 'coralline' structure of thrombi and the lines of Zahn stands or falls the whole problem of autochthonous thrombosis' were discussed at length in Chapters 7 and 10. We also recalled that Hunter (1793) recognised that the core of what we now call venous thrombi was 'pus', and that Virchow (1856)...

Hunter and Hewson

John Hunter (1728-1793) taught anatomy in London as assistant to his elder brother William, and when he was 40 he received the Diploma of the College of Surgeons. Experience and scientific contacts contributed further to his scholarship. Many of those with whom he fraternised were sceptical of the mechanistic philosophies of Hoffmann, Boerhaave and de la Mettrie.13 His practical experience in the Seven Years War as a naval surgeon treating military casualties made him expert on the subject of...

The Role of Leukocytes Reconsidered

How should thrombosis researchers have reacted to the validation of phagocytosis by Metchnikoff in 1892 Aschoff (1924) wrote, referring to Zahn's markings and his own Kopfsteil Halsteil distinction 'Along with the explanation of this marking stands or falls the whole problem of thrombus formation, so far as consideration of the majority of cases of autochthonous thrombosis goes'. This pronouncement was generally ignored for the reasons discussed earlier the involvement of leukocytes in...

Polarographic Demonstration of VVP Hypoxaemia during Non Pulsatile Flow

Hamer et al. (1981a, b) confirmed the central premise of the VCHH - that un-flapped un-agitated valves in paralysed, severely paretic, anaesthetised animals and patients must come to enfold hypoxaemic blood, and that if the initiating circumstances persist, such hypoxemia must inevitably progress to severe (cytotoxic) levels. In anaesthetised human subjects (in preparation for surgical treatment of their varicose veins), streamline flow in the leg veins was presumed when valve cusps were not...

Thrombi Originate in the Venous Valve Pockets

In the early 1950s, it was explicitly shown - for the first time since Virchow's illustration (Figs. 6.1, 9.1) - that venous thrombi form almost exclusively1 in the VVP (McLachlin and Paterson 1951 Paterson and McLachlin 1954 Paterson 1969).2 These careful studies 'categorically' excluded 'local injury to the vein wall, of an obvious type, and abnormality in those blood coagulation factors that were studied' from the causes of thrombosis, leaving the authors to deduce that 'venous stagnation'3...

The 18th Century Solidism Humoralism and the Work of Boerhaave

Most 18th-century physicians held that diseases arose in the solid tissues of the body, but they ignored the possible involvement of body fluids in pathology. Solidism became the fashionable reference framework, and changes in body fluids were considered symptoms rather than causes of disease. Nevertheless, the traditional beliefs rooted in the teachings and practices of Hippocrates and Galen continued to influence 17th- and 18th-century thoughts. Predominant among these 11 They were largely...

Hypoxic Injury to the VVP Cusp Endothelium Is Potentially Thrombogenic a Proposal

Endothelial Response Venous Injury

The outstanding papers of Lister (1858, 1863), discussed in previous chapters, showed that a wide range of chemical and physical irritants - croton oil, galvanic current, fixative or tissue poison, etc. - caused microvascular thrombosis. Lister presumed, and confirmed experimentally, that these substances caused suspension or loss of what he termed 'vital properties' in the vessel linings, and that margination and sequestration of 'colourless corpuscles' ensued, often obstructing circulation....

A41 The Metaphysical Dichotomy in Early 20thCentury Biology and Medicine

Nevertheless, there was a widespread conviction during the 1920s and 1930s that human physiology had 'outgrown' the mechanistic age. This view was far from universal some writers still extolled the virtues of a physics-based approach to physiology. Thus, two kinds of physiologists were distinguished those who believed that 'vital' processes should be investigated by the reductionist methods of physics and chemistry, and those who believed that the object of their science was the associated form...

Relevance of the Vasa Venarum

Since the 1970s, the mechanisms of control of venous tone have been elucidated Skalak et al. 1981 , and fluid mechanical theory had been extended to variablevelocity flow through collapsible tubes Kamm and Pedley 1989 . An overview of vein physiology and pathology by Monos 1992 took account of these studies and of the effects of various endothelial secretions on the subintimal smooth muscle. There is considerable evidence that venous tone changes in response to hypox-aemia smooth muscle...

The Significance of Venous Valves

The prime significance of venous valves is that they begat the scientific revolution in medicine based on Harvey's conversion of anatomical knowledge into physiological understanding. Unlike his Galenist teachers, Harvey did not 'imagine' his physiological concept he inferred that blood circulates from his failure to pass a probe 'caudad' - the valves did not permit it. This showed that the centrifugal blood motion entertained by Galen was impossible, and Harvey went on to deduce that the...

The Role of Endothelial Hypoxia in DVT

Abstract 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...

Sevitt on the Aetiology of DVT

Sevitt's deployment of the word 'stasis' in a leading article in Lancet Sevitt 1961 indicates how deeply entrenched the usage had then become That venous stasis, another member of Virchow's Triad, also plays a part in the pathogene-sis of thrombosis in the lower limbs and pelvis rests on strong, if circumstantial, evidence. Firstly, the blood may take minutes to pass along the thigh and leg veins when the limbs are supine, horizontal, and immobilised especially in elderly patients secondly,...