Table of Contents

Preface     v
Acknowledgments     vii
Synopsis     ix
Introduction to the Study of Deep Venous Thrombosis     1
Incidence     1
Pathology     3
Aetiology: The Consensus Model     4
The Dominance of the Consensus Model     7
‘Virchow’s Triad’     8
An Alternative Viewpoint     9
The Coagulation Cascade and the Consensus Model of DVT     11
The Cascade Model of Blood Coagulation     11
The Origin of the Consensus Model of DVT     13
The Coagulation Cascade Today     16
Platelet Activation and Congregation: Local Vasoconstriction     17
The Contact (‘Intrinsic’) System     19
The Tissue Factor (‘Extrinsic’) System     20
Fibrinogenesis     20
Fibrinolysis     23
Controlling Coagulation     25
Disorders of Coagulation     27
Hypercoagulability     31
Introduction     31
The ‘General’ Use of the Term ‘Hypercoagulability’     32
Early Evidence for ‘Hypercoagulability’ Conditions     32
Testing the ‘Hypercoagulability’ Hypothesis     33
Inherited Thrombophilias     34
Acquired Thrombophilias     36
Thrombophilia and DVT     37
Testing for Thrombophilias     38
Implications for Prophylaxis and Therapy     39
Reflection     40
Historical Roots     41
Two Approaches to Biomedical Research     41
Semantic Issues     42
The Ancient World     44
‘Binary Oppositions’ in 17th-18th-Century Medicine     45
Harvey and the ‘Physiological’ Approach     48
The 18th Century: Solidism, Humoralism and the Work of Boerhaave     49
Hunter and Hewson     51
Late 18th- and Early 19th-Century Studies of Blood Chemistry     54
The 18th-Century Pioneers of Haemostatics and Haemodynamics     54
Coagulation and its Disorders: A History of Haematological Research     57
Introduction     57
Phase 1: 1835-1893     58
Haemophilia and the Study of Coagulation     59
Buchanan     59
Buchanan’s Influence: The Impact of Mechanistic Materialism     60
The ‘Classical Hypothesis’ of Blood Coagulation     63
Phase 2: 1893-1947     64
Prothrombin and its Conversion to Thrombin     64
Heparin, Vitamin K and the Dominance of In Vitro Studies     65
Philosophical and Semantic Considerations     66
Reflective Anamnesis     67
Virchow and the Pathophysiological Tradition in the 19th Century     71
Introduction     71
Cruveilhier     72
Previous Insights into Thromboembolism     73
Cruveilhier’s Contribution     74
Other Formative Influences on Virchow     75
Resolving the Conflict: Virchow’s Synthesis     77
Virchow on the Structure of a Thrombus     79
Virchow on Oxygen and Thromboembolism     81
Virchow versus Cruveilhier     81
The Possible Source of ‘Virchow’s Triad’     83
Reflective Anamnesis     84
The Pathophysiological Tradition after Virchow     87
Problems of Nomenclature: ‘Phlebitis’ and ‘Inflammation’     87
‘Pus’     89
Leukocytes, Phagocytosis and Thrombosis     91
Platelets     93
The Persistence of the ‘Phlebitis’ Concept     95
Continuation of the Pathophysiological Perspective: Welch and Aschoff     96
The Role of Leukocytes Reconsidered     99
Interrupted Circulation: The ‘Stasis’ Hypothesis and the Significance of Venous Valves      103
Introduction     103
The Maturation of the Circulation Hypothesis     104
Connections with the Revolution in Mechanics     106
The Discovery of Venous Valves     107
The Significance of Venous Valves     109
The Venous Valves and DVT     110
The Persistence and Misleading Character of the ‘Stasis’ Concept     111
Inherent Difficulties in the ‘Stasis’ Dogma     111
The Survival of the ‘Stasis’ Dogma in the 19th Century     112
‘Stasis’ and the Consensus Model of DVT Aetiology     113
Sevitt on the Aetiology of DVT     114
The Consensus Model and the VVP as Sites of Thrombogenesis     115
Is the Current (Mis)Use of ‘Blood Stasis’ Equivalent to Virchow’s ‘Interrupted Circulation’?     116
Pulsatile Blood Movement in Veins     116
Compression of Veins in the Soles of the Feet     117
Effects of Standing, Sitting and Lying on the Dynamics of Lower Limb Veins     118
Towards the Valve Cusp Hypoxia Hypothesis: I – Altered Blood Movement     119
Underperfusion of Valve Pockets and the Initiation of DVT     121
Introduction     121
Thrombi Originate in the Venous Valve Pockets     122
The Morphology and Pathology of Venous Valves      125
Venous Valve Morphology     127
Valve Pathology: The Formation of Nascent Thrombi within VVP     129
Can the Venous Return Circulation and Valve Function be Correlated?     132
The Valve Cycle and the Effects of Non-Pulsatile Flow     133
Relevance of Venous Blood Rheology     134
Relevance of the Vasa Venarum     135
Flow Patterns within VVP     137
Implications for the Formation of Pro-Thrombotic Nidi     137
Implications for Compression Prophylaxis     138
Towards the Valve Cusp Hypoxia Hypothesis: II-VVP Hypoxaemia     139
Hypoxic Injury to the VVP Cusp Endothelium Is Potentially Thrombogenic: a Proposal     139
VVP Hypoxaemia and Hypoxic Injury to the Parietalis Endothelium     143
Testing the Predictions     145
The Lesson of History     145
The Role of Endothelial Hypoxia in DVT     147
Oxygen, the Venous Endothelium and Thrombosis     147
Hypoxaemia, the Vascular Endothelium and Thrombosis     148
Association of DVT with Endothelial Hypoxia     149
Endothelial Hypoxia and Thrombus Formation in VVP     151
The Significance of Ostial Valves     152
Interpreting Micrographs of Venous Thrombi: The Tendency of Thrombi to Embolise     154
Carbon Monoxide Poisoning and Anaemia     162
Endothelial Hypoxia and Leukocyte Margination     164
Aschoff on the Coagulation of Cadaver Blood     165
Hypoxaemia and ‘Traveller’s Thrombosis’     166
Overview: Articulating the Valve Cusp Hypoxia Hypothesis     168
The Valve Cusp Hypoxia Hypothesis     169
Introduction     169
Criteria for an Aetiological Hypothesis     170
The General Aetiological Sequence: The ‘Trinity’     171
‘Interrupted Flow’ and Underperfusion of VVP     172
The Specific Involvement of the Valve Cusp Parietalis Endothelium     173
Blood Cell Congregation and Blood Coagulation     174
Pathological Consequences     177
Experimental Support for the VCHH     178
Polarographic Demonstration of VVP Hypoxaemia during Non-Pulsatile Flow     178
Experimental Venous Thrombi Induced by a Non-Invasive Technique     178
Clinical Implications     183
The Risks of Sleeping for Long Periods in the Sitting Position     183
Simpson’s Cases     185
Anaesthesia     187
Crucifixion     188
Varicose Veins     188
‘Risk Factors’ for DVT Reconsidered in the Light of the VCHH     189
Prophylaxis     190
Our Theory-Based Estimate of 1.5-3 h     191
Lister’s Experience     191
Normal Tourniquet Practice     191
Published Traveller’s Thrombosis Data     192
Intermittent Positive Pressure Compression (IPPC) of Feet or Legs     192
The Animal Experiments of Hamer and Malone (1984)     194
Reflection     194
Molecular Changes in the Hypoxic Endothelium     195
Endothelial Cell Physiology     195
The VCHH and the Molecular Responses of EC to Hypoxia     197
Phenotypic Changes in EC under Hypoxic Conditions     197
Phenotypic Changes Consequent on Egr-1 Induction     199
Elk-1 and SRF     200
Other Regulators of Egr-1 Expression     202
Erg-1, Hypoxia and DVT     204
Thrombin and the PARs     204
Interactions Between Platelets and the Hypoxic Endothelium     206
Platelet Congregation and Implications for DVT     206
Leukocyte-Platelet Complexes in the Circulation and their Association with the Hypoxic Endothelium     207
Endothelial Hypoxia and the Congregation of Leukocytes     208
Monocytes and Macrophages      209
Neutrophils     210
Effects of Leukocytes on Injured Endothelium     211
The Endothelium and Coagulation     212
The Endothelium and Vasomotor Tone     216
A Further Comment on ‘Risk Factors’     218
The Unification of Approaches     218
Cadaver Clots or Agonal Thrombi?     221
Can Blood Coagulate in a Cadaver?     221
An Early 20th-Century Debate     222
Aschoff on ‘Post-Mortem Clots’     224
The Debate Reconsidered in the Light of the VCHH     226
Death from Acute Respiratory Failure     226
Death from Circulatory Failure     227
Summary: The Condition of the Blood Post-Mortem Depends on the Mode of Death     228
Consequences of Positing that All Thrombi Are Agonal     228
Possible Post-Mortem Changes     229
Summing up the Argument: Judicial Implications     229
Therapeutic and Prophylactic Implications     230
Science, Medicine and Philosophy     233
The Two Approaches to Medical Biology     233
The Philosophical Background to the Schism of the 1840s     234
The Aftermath of the Scientific Revolution     235
The Empiricist Tradition     235
Hume: The Achilles’ Heel of Empiricism     236
Kant     237
Naturphilosophie and its Influence on Philosophy and Science     238
Schopenhauer     239
Significance for 19th-Century Physiology and Pathology     239
The Opening of the Schism     240
The Origin and Development of Mechanistic Materialism     241
Mechanism Versus Vitalism: The Distinctiveness of Vital-Materialism     243
The Mechanism-Vitalism Debate and its Implications     243
Alternatives to Mechanism are Often Misrepresented     245
‘Extreme’ Mechanism: The 19th-Century German Materialists     245
The Modern Dominance of the Mechanistic Approach     247
The Metaphysical Dichotomy in Early 20th-Century Biology and Medicine     247
Some Contributing Factors to the Hegemony of Mechanism     248
Molecular Motion Versus Bulk Transport: The ‘Newtonianism’ of Biochemistry     249
Rapprochement between the Mechanistic and Vital-Materialist Approaches     251
References     255
Author Index     295
Subject Index     305

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