**5.1 Accounting for Virchow's** *real* **triad**

As previously elaborated (Malone & Agutter, 2006, 2008), the VCH explains leukocyte accumulation and the white *Kopfteil*, it accounts for most of the known risk factors such as Pathophysiology and Clinical Aspects of 146 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

Fig. 4. When sustained non-pulsatile flow resumes after a pulsatile episode, any white cells that have swarmed over the necrotic parietalis endothelium die likewise as a result of valve pocket hypoxaemia. Meanwhile, coagulation can continue. With further episodes of pulsatile flow, the process will be repeated, generating successive layerings of dead cells interspersed with fibrin, accounting for the Lines of Zahn morphology. The necrotic parietalis is fragile and is liable to dehisce (see illustrations in Malone & Agutter, 2008, chapter 10), particularly when the nascent thrombus outgrows the valve pocket and

protrudes into the vein lumen, where it is subjected to tension by the flowing blood after the resumption of pulsatility. This may explain the tendency of venous thrombi to embolise.

As previously elaborated (Malone & Agutter, 2006, 2008), the VCH explains leukocyte accumulation and the white *Kopfteil*, it accounts for most of the known risk factors such as

**5. Extending the VCH thesis of aetiology** 

**5.1 Accounting for Virchow's** *real* **triad** 

the effect of ageing (cf. Saphir & Lev, 1952b; Van Langevelde *et al*., 2010), and it is consistent with the readiness of venous thrombi to embolise. However, though it is consistent with them, some might reserve judgment as to whether it accounts fully and explicitly for (1) the high density of the fibrin around the *Kopfteil* and (2) the Lines of Zahn. These observations need further clarification.

The dense fibrin in nascent thrombi was likewise described by Sevitt (1974). Bovill & van der Vliet (2011) pointed out that it is consistent with tissue factor (TF)-induced coagulation, but they suggested that coagulation is initiated on the vein wall not the parietalis endothelium of the valve pocket. That suggestion would have to be experimentally verified and corroborated before it could be regarded as fact rather than conjecture. Its plausibility depends on the commonly held belief that TF is the primary physiological trigger for coagulation (e.g. Hoffman & Monroe, 2001); also, TF is one of the many targets of activation by egr-1 (Mechtcheriakova *et al.*, 1999) so it is expected that valve pocket hypoxaemia will activate it. Primary involvement of TF in coagulation during venous thrombogenesis could explain why anticoagulants are allegedly more effective for prophylaxis than are platelet inhibitors.

A possible difficulty with this explanation for the high fibrin density is that heparin does not inhibit the initiation of thrombi on hypoxic venous endothelium (Samuels & Webster, 1952), and heparin is known to inhibit TF directly and by activating tissue factor promoting inhibitor (e.g. Lupu *et al*., 1999; Ettalaie *et al*., 2011). Alternative explanations should therefore be considered. For instance, the inception and growth of a venous thrombus are slow processes, characterised by the serial margination of successive layers of platelets and leukocytes on the hypoxia-induced lesion of the valve pocket endothelium as blood continues to circulate past the site. This results in a much denser crowding of platelets (as well as leukocytes) than is likely in a haemostatic plug or during the coagulation of shed blood, and densely crowded platelets will generate a dense fibrin mesh.

No matter whether coagulation is TF-induced by the luminal endothelial cells of the valve pocket, as Bovill & van der Vliet speculate, or whether the crowded platelets on and around the injured/ necrotic parietalis endothelium spin out the dense fibrin, logical extension of the VCH thesis provides an explanation for that facet of Virchow's *real* triad. As for the Lines of Zahn, the serial deposition described earlier is the critical factor; but the slow secondary vortex in the depths of the valve pocket (Karino, 1986) will also contribute by weaving the leukocyte/platelet-rich and dense fibrin layers around each other.

Thus, the extended VCH mechanism accounts for all three aspects of Virchow's *real* triad.
