**6. Implications of the VCH mechanism for prophylaxis**

#### **6.1 The balance between anticoagulant and mechanical prophylaxis should be reconsidered**

Anticoagulants do not prevent the initiation of DVT (section 5.2), in particular the recruitment and margination of leukocytes and platelets to the injured parietalis endothelium, but they prevent the growth of already-formed venous thrombi to clinically significant size. Whether they inhibit the putative local effects of TF (see above) is debatable. Pathophysiology and Clinical Aspects of 148 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

factor-1 are potential targets for ROS in the affected endothelium, though the relevance of

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

The evidence reviewed in section 4 testifies to the correctness of the VCH thesis, but the imaginative reader might raise this question. Sustained non-pulsatile flow in the deep limb veins with short episodes of pulsatile flow are quite common in the daily lives of some humans, and is certainly common among carnivores, which sleep and remain immobile for many hours per day. In this context, the proposal of Brooks *et al.* (2009) that the valve pocket endothelia are more resistant than the luminal endothelium to the induction of coagulation

These authors proposed, on the basis of preliminary evidence, that the levels of von Willebrand factor (vWF), thrombomodulin (TM) and endothelial protein C receptor (EPCR) change with depth in the valve pocket, so that the endothelial cells express less of the procoagulant (vWF) and more of the anticoagulant (TM and EPCR) factors. Trotman *et al.*  (2011) pursued this hypothesis and found that the level of vWF did indeed decrease with depth in the pocket, but so did the level of EPCR; the TM level showed no significant change. There was extensive inter-individual variation in all three of these proteins, so the patterns were not entirely clear, but the hypothesis advanced by these authors could in principle help to explain 'why DVT is not even more common than it is'. In principle, The Brooks *et al.* proposal could be tested critically by a study on a large experimental animal group. The incidence of thrombogenesis under conditions similar to those used by Hamer & Malone (1984) could be correlated with the expression of vWF (and perhaps TM and EPCR), as assessed e.g. by immunostaining in the valve pocket endothelia after the end of the experiment. However, the most important factor in thrombogenesis is without doubt the

recent advances in anticoagulant treatment (Kahn & Ginsberg, 2004; Heit, 2005).

this to venous thrombogenesis is uncertain.

**5.3 Why is DVT not even more common than it is?** 

duration of the valve pocket hypoxaemia.

**6. Implications of the VCH mechanism for prophylaxis** 

**6.1 The balance between anticoagulant and mechanical prophylaxis should be** 

Anticoagulants do not prevent the initiation of DVT (section 5.2), in particular the recruitment and margination of leukocytes and platelets to the injured parietalis endothelium, but they prevent the growth of already-formed venous thrombi to clinically significant size. Whether they inhibit the putative local effects of TF (see above) is debatable.

could be of interest.

**reconsidered** 

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 anticoagulant prophylaxis.

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 patients at increased risk of bleeding*".

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 recognised universally as a form of 'mechanical prophylaxis'.

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

Aetiology of Deep Venous Thrombosis - Implications for Prophylaxis 151

In the absence of contrary evidence, there is a *prima facie* case for using the measures described in section 6.2 throughout the period of bed rest for all acute medical patients and for surgical patients with limited mobility. That would be in line with the recommendations of NICE in the UK, of similar bodies in other European countries, and of the Joint Commission on Accreditation of Healthcare Organizations in the USA (see earlier discussion), except that anticoagulants would be given a less central role in prophylaxis.

One area that might need more or less radical reconsideration is surgery involving general anaesthesia. However, we emphasise that our comments here are conjectural and would require detailed evaluation before they were considered for practical application. Also, they relate to a potential risk associated only with very prolonged anaesthesia, involving

It is self-evident that relaxant anaesthesia is inherently thrombogenic. For short operations, this is unlikely to matter greatly; but for longer operations (say over 100 minutes) during which the patient is totally motionless, there is a major risk that undetectable prothrombogenic nidi will form in valve pockets. The muscular paralysis induced during anaesthesia will therefore cause thrombosis in every case unless the duration of the resultant streamline (non-pulsatile) blood flow in all veins of the body is constantly kept in mind. If the unconscious patient's veins are not squeezed, e.g. by mechanical movement of limbs, then valve pocket hypoxaemia cannot be avoided. In reality, of course, the risk depends on how quickly the patient recovers from the effects of the muscle relaxant so that the skeletal muscles of the limbs start to contract again. It would seem ideal for the state of total muscle paralysis to last only ½ to ¾ of an hour, after which the anaesthetist would have to administer another dose of curare, but that is speculation; confirmation from practice and

All anaesthetists are acutely aware of the respiratory support (sustained oxygen supply) needed for safe anaesthesia, but they are far less likely to be concerned about the restoration of pulsatile blood flow in the patient's legs/ abdomen. Appropriate practice must relate to the acceptability of temporary recovery of patient motion to the surgeon, and of course the delicacy of the operation and the disturbance likely from any change in anaesthetic practice. Besides monitoring relaxant anaesthesia, the practice of end-to-end Trendelenburg/anti-Trendenburg tilting discussed in section 6.2 could be re-employed. However, the number of degrees elevation and reduction would be only 2 x 5% to and fro in 'horizontal patient' operations. Operations performed e.g. in sitting positions would require different manoeuvres appropriate to the particular patient posture. The objective in all cases would be to limit drugged-immobility to a specific duration that must be established by experience

(after an initial informed guess based on e.g. the evidence from Hamer *et al.*, 1981).

The currently prevailing beliefs about the aetiology of DVT arose from the assumption, fostered by the ascent of haematology after the Second World War, that venous thrombogenesis is primarily (or exclusively) a matter of *in situ* blood coagulation. This view became associated with a misreading of Virchow's work that gave rise to 'Virchow's triad';

**6.4 Application of rational mechanical prophylactic measures** 

sustained muscle relaxation, not to surgical operations in general.

experience would be essential before such proposals were applied.

**7. Conclusions** 

(There would be little or no need for any such measures in ambulant patients.)

anticoagulants 'in case' he/she develops DVT might be seen as akin to dosing such patient with chemotherapeutic drugs 'in case' he/she develops a cancer.

That is an extreme view. Nevertheless, the balance between the anticoagulant and mechanical approaches to prophylaxis needs to be re-evaluated in the light of the VCH thesis, since they seem likely in time to perfect a more impartial 'cross-party' view of the aetiology of DVT and of patient management.

## **6.2 Mechanical prophylaxis: a rational approach**

The simple objective of mechanical prophylaxis is to ensure that blood in the valve pockets is exchanged at regular intervals (Malone & Agutter, 2008). Modern surgical prophylaxis could readily be improved if the VCH principle were added to the classical objective: 'regular' (i.e. regular intermittent) pulsation need not necessarily mean '*as frequent as is current practice*'. In chapter 9 of our monograph we calculated that valve pocket hypoxaemia does not become dangerous (i.e. potentially injurious) until non-pulsatile flow has persisted for 1.5-3 hours, an estimate consistent with the empirical data (Hamer *et al.*, 1981). Less frequent, i.e. *relatively infrequent*, artificial pulses (perhaps once per hour, though that would need experiential confirmation) would preclude thrombogenesis, and would be more comfortable for patients than what must seem incessant limb compression at short intervals, day and night.

For patients confined to prolonged bed-rest, insensible, automatic alternate end-to-end Trendelenberg/ anti-Trendelenberg tilting of the bed, through a 5-10 degree angle, every hour or so, should be prophylactic by emptying the valve pockets in the upper and lower parts of the body by gravity, allowing them to refill passively with fresh venous blood at relatively short intervals (as above) and preventing unsuspected but potentially fatal hypoxaemia in unmoved pockets.
