The aetiology of deep venous thrombosis and chronic venous insufficiency

 

Deep venous thrombosis

 

Our account of the aetiology of deep venous thrombosis (DVT), the valve cusp hypoxia hypothesis (VCHH), derives from the pathophysiological tradition of research extending from Harvey and Hunter to Virchow, Welch and Aschoff, but it also assimilates recent discoveries about the molecular biology of the vascular endothelium. We have extended the account to an explanation of chronic venous insufficiency (CVI). The main publications are our book:

 

Malone, PC & Agutter, PS (2008) The Aetiology of Deep Venous Thrombosis, Springer, Dordrecht.

 

and the following papers:

 

Malone, PC & Agutter, PS (2006) The aetiology of deep venous thrombosis. Quart J Med 99, 581-593. PMID: 16905749

 

Malone, PC & Agutter, PS (2009) To what extent might deep venous thrombosis and chronic venous insufficiency share a common aetiology? Int Angiol 28, 254-268. PMID: 19648868

 

Malone, PC & Agutter, PS (2009) Is ‘Virchow’s Triad’ useful? Br J Haematol 145, 839. PMID: 19344411

 

Cundiff, DK, Agutter, PS, Malone, PC & Pezzullo, J (2010) Diet as prophylaxis and treatment for venous thromboembolism? Theor Biol Med Model 7, 31. PMID: 20701748

 

Agutter PS & Malone PC (2011) Deep Venous Thrombosis: Hunter, Cruveilhier, Virchow, and present-day understanding and clinical practice. Int J Hist Philos Med 1, 7-14.

 

Under normal (pulsatile) blood flow conditions, the venous valve pockets are emptied and refilled regularly so they do not become hypoxaemic.

 

 

According to the VCHH, DVT may occur if there is sustained non-pulsatile (streamline) venous blood flow. Such flow leads to suffocating hypoxaemia in the venous valve pockets, resulting in hypoxic injury to the inner (parietalis) endothelium of the cusp leaflets.

 

 

This injury activates the elk-1/egr-1 pathway within the endothelial cells, which in turn activates a number of chemoattractant and procoagulant factors. When normal pulsatile blood flow is restored, even transiently, leukocytes and platelets swarm at the site of injury, attracted by these factors, and local blood coagulation may be initiated.

 

 

 

 

Afurther period of non-pulsatile flow kills the accumulated blood cells in the valve pocket. These dead cells may then form the core of a nascent thrombus. If periods of non-pulsatile and pulsatile flow continue to alternate, serial deposition of white cells and fibrin may ensue, resulting in the characteristic Lines of Zahn morphology of a venous thrombus.

 

 

Only the blood cells on the outermost layer of a thrombus are still living.

 

Clinical implications

 

The VCHH explains the risk factors for DVT and accounts for the morphology of thrombi. It also predicts that venous thrombi will readily embolise, because the area of endothelium to which they are anchored, the valve cusp parietalis, is necrotic and is readily detached by the flow of blood past the obstruction.

 

The VCHH is also compatible with accepted approaches to therapy, but it suggests new approaches to mechanical prophylaxis against venous thromboembolism. It implies that the crucial factor is not the rate of venous return flow but the pulsatility of that flow. Thus, a device that ensures pulsatile movement at regular though not necessarily frequent intervals (once every 30 minutes would suffice) will prevent the formation of thrombi in the valve pockets.

 

For some patients, another approach may be possible even if venous blood movement is non-pulsatile. Lying horizontally, the anaesthetised or unconscious patient is at risk of valve cusp hypoxia and ipso facto of DVT, notably in the lower limb veins. However, a slight (say 5 degree) head-downwards tilt of the bed will allow the valve pockets to empty by gravity. To prevent hypoxia and thrombogenesis in the veins of the upper body, the tilt should be reversed at roughly hourly intervals. Again, this should prevent thrombogenesis without recourse to prophylactic anticoagulants.

 

For further details see Reviews of "The Aetiology of Deep Venous Thrombosis" and Synopsis of book.

 

Chronic venous insufficiency

 

Even if alternating non-pulsatile and pulsatile blood flow episodes do not proceed to frank thrombogenesis, the valves may be chronically injured and become incompetent.  Serial incompetence in lower limb valves may then generate ‘passive’ venous hypertension.

 

More radically, should ostial valve thrombosis obstruct venous return from muscles via tributaries draining into the femoral vein, as Virchow illustrated, ‘active’ venous hypertension may supervene: muscle contraction would force the blood in the vessels behind the blocked ostial valves to re-route.

 

'Passive’ or ‘active’ venous hypertension opposes return flow, leading to luminal hypoxaemia and vein wall distension, which in turn may impair vasa venarum perfusion. The resulting mural endothelia hypoxia would lead to leukocyte invasion of the wall and remodelling of the media.

 

We propose that varicose veins result if gross ‘active’ hypertension stretches the valve ‘rings’, rendering attached valves incompetent caudad to obstructed sites, replacing normal centripetal flow in perforating veins with centrifugal flow and over-distending those vessels.

 

Hypoxaemia-related venous/capillary wall lesions may lead to accumulation of leukocytes, progressive blockage of capillary blood flow, lipodermosclerosis and skin ulceration.

 

Main reference:

 

Malone, PC & Agutter, PS (2009) To what extent might deep venous thrombosis and chronic venous insufficiency share a common aetiology? Int Angiol 28, 254-268.