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 in non-perfused tissues (Thomas et al. 1983). Van Ottingen (1941; see above) continued:

According to Altschul (192714) the vascular changes leading to thrombosis start with a mobilisation of leukocytes which are concentrated on the vascular walls, penetrate into and accumulate in the walls. Why this infiltration - what is its mechanism? Is it changes in the vessel walls ... fatty degeneration of the vessel wall ... or does parenchymatous change apply an attracting force to the white blood corpuscles?. It is undeniable that there is some connection between the observed infiltration and the CO-poisoning. . Then the apparent closing up of the vessels by the massing of white corpuscles, which, if a fatal outcome had not come so soon, might possibly have given rise to yet other phenomena (thrombosis, necrosis about the site) ..

It seems plausible to answer van Ottingen's questions by proposing that sustained hypoxic or other injury to the endothelium provokes a phagocytic leukocyte response at the site. Sandison (1931) showed that leukocyte margination and 'adhesion' occurred very rapidly and occlusively after the induction of hypoxaemia, suggesting that it was triggered almost instantly by sudden total ischaemia; there was immediate recovery when normal flow in his rabbit ear chamber was restored (Chapter 7). Moreover, a series of papers by Stewart and her colleagues (e.g. Stewart 1975; Stewart et al. 1974, 1978, 1980) showed that plasma protein and leukocyte attachment to, and accumulation on, the endothelium may accompany/ coincide with trauma or surgery at distant sites in the body.15 Lost endothelium is rapidly replaced (within 48 h) by cellular proliferation unless it is very extensive or is impaired by fibrin deposition (Krupski et al. 1979).

We infer that although endothelial hypoxia induces leukocyte infiltration, as shown by Gibbs (1957), such infiltration need not necessarily betoken necrosis. It may indicate that the attractant is dying rather than dead, or in the pre-necrotic phase. In thinking about hypoxic death (as such) it is important to keep in mind that

14 It was during this era (the 1920s) that the physiological effects of CO inhalation were extensively studied in Germany; cf. the citations in the earlier quotation from van Ottingen.

15 This will be discussed further in Chapter 11. Stewart and her colleagues suggested that the leukocytes inflict injury on the endothelium, and other authors have made similar suggestions. Of course, activated leukocytes are likely to remove endothelial cells that are already injured, but if they were to attack normal, uninjured cells then none of us would have any vascular endothelium at all (Chapter 12). Stewart and co-authors did not mention the very considerable 'pooling' of blood in the injured limb, one consequence of which would have been reduced perfusion of the damaged jugular vein and in particular its VVP.

the living state is always 'recoverable' unless a point of no return has been passed; death from oxygen deprivation alone is rarely instantaneous. In short, the aetiology of DVT involves a sequence of events, which could make it naive to imagine a simple/single linear causal chain.

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