**4.1.2 Resolving the 'stasis' paradox**

Wessler's studies suggested what seemed like a paradoxical conclusion: thrombi can form when blood is flowing (albeit slowly) along a vessel segment, but not when the blood is stationary. But surely the likelihood of hypoxic injury is greater when the flow rate is less, and therefore maximal when the flow rate is zero, i.e. when flow is altogether prevented by double ligation? (Oddly, Wessler scarcely mentioned valves, but as reviewed in the foregoing pages, it was already well established that valves are the sites of venous thrombogenesis.)

As Virchow (1858) remarked, "*the doctrine of stasis rests on manifold misinterpretations*". It is important to re-emphasise his inference that venous thrombi form in *flowing* blood, but not in *static* blood, and that since venous thrombogenesis is a slow process, which may evolve over hours, days or even weeks, the *rate* of blood flow may not be material factor. What matters is that the blood is always 'exchanging', however slowly; moving, rather than stationary for dangerously protracted periods.

Elegant studies on the dynamics of the valve cycle (Lurie *et al.*, 2002, 2003) and the patterns of flow within valve pockets (Karino & Motomiya, 1984; Karino, 1986; Karino & Goldsmith, Pathophysiology and Clinical Aspects of 140 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

By the late 19th century it was clear that paralyzed patients develop DVT and PE (Malpother, 1880), and by the middle of the 20th century it was known that prolonged bed rest, e.g. in spinal injury patients, had the same consequence (Wright & Osborn, 1952; Gibbs, 1957). This association between restricted mobility and DVT was attributed to slowed venous return, i.e. reduced volume per unit time (Ochsner *et al*., 1951; Wright & Osborn, 1952). Thus, by the early 1960s, it was held to be virtually certain that 'venous stasis' contributed to the cause of DVT (Zweifach, 1963); it was imagined to promote local coagulation (Mammen, 1992). The endothelial hypoxia hypothesis (from which the VCH hypothesis was coined) directly supported this premise: if blood were to flow slowly enough to injure some part of the endothelium by hypoxaemia (even to kill that part of the tissue should flow cease altogether in an unflapped, unemptied valve pocket), local leukocyte swarming and margination, and local coagulation, would ensue through the molecular mechanisms discovered by Pinsky

However, that conception seems hard to reconcile with Hewson's (1771) experiment. Hewson doubly-ligated a dog's jugular vein, and the stationary blood between the ligatures failed to coagulate after more than an hour; even after three hours, coagulation was only partial. His finding was so counter-intuitive that Lister (1863) and Baumgarten (1876)

Wessler's findings indicated that double ligation *did* somehow injure the vessel, directly or indirectly, because rapid coagulation followed when he introduced serum containing activated coagulation factors into the ligated portion. Importantly, however, the resulting coagula bore no morphological resemblance to autochthonous venous thrombi, so – as explained in section 3.2.1 – his world-renowned experiments were of limited relevance for

Wessler's studies suggested what seemed like a paradoxical conclusion: thrombi can form when blood is flowing (albeit slowly) along a vessel segment, but not when the blood is stationary. But surely the likelihood of hypoxic injury is greater when the flow rate is less, and therefore maximal when the flow rate is zero, i.e. when flow is altogether prevented by double ligation? (Oddly, Wessler scarcely mentioned valves, but as reviewed in the foregoing pages, it was already well established that valves are the sites of venous

As Virchow (1858) remarked, "*the doctrine of stasis rests on manifold misinterpretations*". It is important to re-emphasise his inference that venous thrombi form in *flowing* blood, but not in *static* blood, and that since venous thrombogenesis is a slow process, which may evolve over hours, days or even weeks, the *rate* of blood flow may not be material factor. What matters is that the blood is always 'exchanging', however slowly; moving, rather than

Elegant studies on the dynamics of the valve cycle (Lurie *et al.*, 2002, 2003) and the patterns of flow within valve pockets (Karino & Motomiya, 1984; Karino, 1986; Karino & Goldsmith,

repeated it in the 19th century and Wessler (1962) in the 20th, with identical results.

**4.1.1 The vagaries of 'venous stasis'** 

and his colleagues.

thrombogenesis.)

understanding the aetiology of DVT.

**4.1.2 Resolving the 'stasis' paradox** 

stationary for dangerously protracted periods.

1987) helped to resolve the seeming paradox. Essentially, these studies showed that when venous blood flow is *non-pulsatile (streamline)*, as when the patient's 'calf muscle pump' is inactive and there is no intermittent (*vis a tergo*) upward pressure on the soles of the feet, as in walking, a significant part of the blood within 'backwater' valve pockets is not exchanged with the luminal blood. Under such non-pulsatile flow conditions the valve does not execute its usual cycle but remains half-open/half-closed indefinitely.

Near the mouth of the valve pocket, the blood is likely to circulate in a spiral vortex, driven by the laminar flow in the vein lumen. Deep in the pocket is a secondary vortex, rotating in the opposite sense to the primary vortex and more slowly (see Fig. 1). Because the blood in this secondary vortex is never evacuated from the valve pocket while flow in the vein remains non-pulsatile, it becomes increasingly hypoxaemic. Therefore, the endothelia lining the depths of the valve pockets are progressively at risk of hypoxic injury when the venous blood flow is non-pulsatile, *irrespective of the flow rate*. This was demonstrated experimentally by Hamer *et al.* (1981), as discussed below. We concur with Schina *et al.*  (1993) that non-pulsatile flow, not slow flow or 'stasis', promotes DVT.

Valve cusp leaflets are avascular (Franklin, 1937; Saphir & Lev, 1952a,b; Sevitt, 1974) - they have no vasa venarum. The outer (medial) endothelial surface (luminalis) is oxygenated by the blood flowing through the vein lumen, irrespective of pulsatility, but the inner, lateral endothelium (parietalis) lining the valve pocket is not (see Fig. 1). Therefore, the parietalis endothelium is at greatest risk of hypoxic injury, and potentially of necrotic cell death, when oxygen-starved during sustained non-pulsatile blood flow.
