**5.2 Cross-talk between leukocyte recruitment and coagulation**

The molecular changes in endothelial cells subjected to valve pocket hypoxaemia were discussed in chapter 12 of Malone & Agutter (2008) and by Bovill & van der Vliet (2011). The generation of reactive oxygen species (ROS) in the hypoxic endothelium is of particular interest because ROS promote both neutrophil recruitment (Millar *et al*., 2007) and the activation of TF (Banfi *et al*., 2009), as well as activating egr-1. This involvement of ROS could support the proposal that a vegan diet has prophylactic value against DVT and VTE (Cundiff *et al.*, 2010), since vegan diets are allegedly rich in antioxidants, though a statistically sound test of this proposal would involve a very large patient cohort. Bovill & van der Vliet note that other hypoxia-related transcription factors such as hypoxia-inducible

Aetiology of Deep Venous Thrombosis - Implications for Prophylaxis 149

From the point of view of patient care, this is not a crucial issue; what is important is to prevent the potential morbidity and mortality associated with DVT, specifically VTE and post-thrombotic syndrome. Therefore, preventing thrombus growth is 'useful'. Nevertheless, it seems inherently more satisfactory to prevent the initiation of thrombosis rather than just thrombus growth. That entails a reconsideration of mechanical rather than

However, current approaches to mechanical prophylaxis are unlikely to achieve the objective of preventing the initiation of thrombogenesis. The NICE website sums up the conventional explanation for the effects of intermittent pneumatic compression, though with a curious use of the word 'theory': "*The theory behind mechanical approaches to thromboprophylaxis is that they increase mean blood flow velocity in leg veins, reducing venous stasis*" (National Institute for Clinical Excellence, 2011). It would be valid to presume that an 'adequate' mean venous blood flow velocity maintains our existence and lives, since an 'inadequate' flow velocity would ultimately be incompatible with life; nevertheless, the 'theory' invoked above in support of intermittent pneumatic compression is not consistent with our experimental proof that *pulsatile* flow maintenance is the true thromboprophylactic. The assumption that venous flow velocity has any significance in

thrombogenesis is unproven, and according to the VCH thesis it is likely to be false.

This widespread misunderstanding about the significance of venous return blood flow velocity may explain why mechanical prophylaxis has remained adjunctive to anticoagulant treatment. Thus, Khoury *et al.* (2011) describe mechanical prophylaxis as 'inappropriate' or 'inadequate' unless anticoagulation is contraindicated (because of a serious bleeding risk), and authoritative sources such as Demtali *et al.* (2007), Geerts *et al*. (2008) and Sliwka & Fang (2010) strongly support the use of anticoagulant "*and to a lesser degree mechanical*" forms of prophylaxis (the quoted phrase is from Sliwka & Fang, 2010). Similarly, we recall that "*Chemoprophylaxis is recommended for medical patients at moderate to high risk of venous thromboembolism (VTE) and is now a requirement of the Joint Commission on Accreditation of Healthcare Organizations*" (Rothberg *et al.*, 2010). Moreover, a very large international survey by Kakkar *et al.* (2010) revealed that "*Anticoagulant therapy was much more frequently used than mechanical devices such as compression stockings or intermittent pneumatic compression, even in* 

However, the truth – revealed explicitly by modern medical/surgical practice - is that anticoagulants and mechanical prophylaxis work hand in hand. Physicians might be more inclined to emphasise pharmacological approaches and surgeons to emphasise mechanical ones, but the difference is not absolute and the methods need not be considered mutually exclusive. Since prompt ambulation of post-operative surgical patients has also become routine in recent decades (Cundiff *et al.*, 2010), this form of mechanical prophylaxis, which ensures pulsatile return blood flow in the legs, has long been valued in reducing the incidence of post-surgical DVT/VTE alongside anticoagulants; yet it might not have been

The VCH thesis does not lead to an argument against anticoagulant prophylaxis. However, long-term anticoagulant use is associated with fatal or disabling bleeding (Cundiff *et al.*, 2010; Cundiff, 2011) and Cochrane reviews make clear that the evidence supporting anticoagulant prophylaxis should be monitored constantly (Cundiff, 2011), and that such prophylaxis against VTE may hypothetically be contraindicated. In a sense, giving a patient

anticoagulant prophylaxis.

*patients at increased risk of bleeding*".

recognised universally as a form of 'mechanical prophylaxis'.

factor-1 are potential targets for ROS in the affected endothelium, though the relevance of this to venous thrombogenesis is uncertain.

In examining the molecular cross-talk between leukocyte recruitment and coagulation during venous thrombogenesis, it is important to distinguish early events from developments associated with the growth of a 'mature' thrombus. For example, TF-bearing microvesicles derived from either monocytes or vein wall pericytes seem to be prominent during the development of thrombi, but are almost certainly not involved during the initiation of venous thrombosis (Bovill & van der Vliet, 2011). More importantly from the practical, clinical standpoint, anticoagulants stop the growth of a thrombus but they do not prevent its initiation. It is therefore not surprising that the decline in incidence of DVT/VTE and post-thrombotic syndrome in hospital patients has been only marginal, notwithstanding recent advances in anticoagulant treatment (Kahn & Ginsberg, 2004; Heit, 2005).
