**3.3 Thrombi are formed in venous valves**

Virchow (1856, 1858) showed that venous thrombi are formed in the valves, including the (usually monocuspid) valves that control vein junctions, which Franklin (1937) termed 'ostial valves'. The formation of thrombi in valves was mentioned in *Thrombose und Embolie*  and two thrombi arising from two ostial valves were illustrated in *Die Cellularpathologie*. It is worth recalling that even the smallest veins have valves (Phillips *et al.*, 2004), which *ipso facto*  are potential sites of thrombogenesis.

Although Virchow was the first investigator to make the critical role of valves in venous thrombosis explicit, thanks to his use of the microscope, both Hunter and Cruveilhier had probably suspected the same thing. Hunter (1793) was explicit in associating the 'inflammation' ('pus accumulation', i.e. thrombogenesis) with the 'internal coats' of veins, but he too was surprised that the structures he observed were formed in mid-lumen, not on the walls. Likewise, Cruveilhier was puzzled by the formation of 'phlebitis' in mid-lumen. Both these antecedents of Virchow held now-defunct views about what they were looking at: they believed that the 'pus' originated from outside the vessel, which made the observation of a notably centralised coagulum especially difficult to explain in contemporaneous terms. Hunter did not state explicitly that thrombi are initiated on the valves. He considered the microscope an unreliable instrument in his day and eschewed its use, and without the microscope it was/is impossible to see a valve smothered by a large thrombus. However, he was familiar with Harvey's (1628) essay on the circulation of the blood, in which the valves were described as *'eminences'* on the *'internal lining (tunicula intima)'* of the vein. Hence, we suggest, the title of Hunter's treatise ('*inflammation of the internal coats*…') suggests that he, Cruveilhier and Virchow had observed that venous thrombi are 'anchored' – and probably initiated – on/in valve pockets.

A number of detailed studies during the third quarter of the 20th century confirmed Virchow's observation that thrombi are formed in venous valves (e.g. McLachlin & Paterson, 1951; Sevitt, 1974). One of us (PCM) inherited many micrographs of venous thrombi from Simon Sevitt after his death, some of which we used to illustrate our monograph (Malone & Agutter, 2008; see especially the photographs in Fig. 10.5). All his Pathophysiology and Clinical Aspects of 138 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

two microscopic facets should not be overlooked: the remarkably high density of fibrin in those parts of a thrombus that are formed first, in the *Kopfteil*; and the extraordinary morphology of the Lines of Zahn. These observations remind us that despite the importance of leukocytes in thrombogenesis, their swarming around the site coincides with, and is often preceded by, local coagulation. In the tenth lecture in *Die Cellularpathologie*, Virchow (1858) overtly attacked Cruveilhier but made this exception: *"Cruveilhier was right... that the so-called pus in the veins never, in the first instance, lies against the wall of the vein, but is always seen first in the centre of a previously existing coagulum which* 

This observation indicates that the subtle endothelial injury inducing local leukocyte/platelet swarming and margination also initiates local coagulation, which may proceed rapidly. But though Virchow did not speculate about the cause or nature of that

Virchow (1856, 1858) showed that venous thrombi are formed in the valves, including the (usually monocuspid) valves that control vein junctions, which Franklin (1937) termed 'ostial valves'. The formation of thrombi in valves was mentioned in *Thrombose und Embolie*  and two thrombi arising from two ostial valves were illustrated in *Die Cellularpathologie*. It is worth recalling that even the smallest veins have valves (Phillips *et al.*, 2004), which *ipso facto* 

Although Virchow was the first investigator to make the critical role of valves in venous thrombosis explicit, thanks to his use of the microscope, both Hunter and Cruveilhier had probably suspected the same thing. Hunter (1793) was explicit in associating the 'inflammation' ('pus accumulation', i.e. thrombogenesis) with the 'internal coats' of veins, but he too was surprised that the structures he observed were formed in mid-lumen, not on the walls. Likewise, Cruveilhier was puzzled by the formation of 'phlebitis' in mid-lumen. Both these antecedents of Virchow held now-defunct views about what they were looking at: they believed that the 'pus' originated from outside the vessel, which made the observation of a notably centralised coagulum especially difficult to explain in contemporaneous terms. Hunter did not state explicitly that thrombi are initiated on the valves. He considered the microscope an unreliable instrument in his day and eschewed its use, and without the microscope it was/is impossible to see a valve smothered by a large thrombus. However, he was familiar with Harvey's (1628) essay on the circulation of the blood, in which the valves were described as *'eminences'* on the *'internal lining (tunicula intima)'* of the vein. Hence, we suggest, the title of Hunter's treatise ('*inflammation of the internal coats*…') suggests that he, Cruveilhier and Virchow had observed that venous

A number of detailed studies during the third quarter of the 20th century confirmed Virchow's observation that thrombi are formed in venous valves (e.g. McLachlin & Paterson, 1951; Sevitt, 1974). One of us (PCM) inherited many micrographs of venous thrombi from Simon Sevitt after his death, some of which we used to illustrate our monograph (Malone & Agutter, 2008; see especially the photographs in Fig. 10.5). All his

thrombi are 'anchored' – and probably initiated – on/in valve pockets.

*marks the start of the process".* 

subtle injury, he did pin-point its location.

**3.3 Thrombi are formed in venous valves** 

are potential sites of thrombogenesis.

micrographs showed thrombi seated in the valve pockets. In some, the exact site of attachment to the endothelium is not clear because the entire pocket is filled with the thrombus, but in several images the thrombus is evidently attached to the inner (parietalis) face of the valve cusp leaflet, not to the outer (luminalis) face, and not to the vein wall. This recurrent observation played a crucial part in the formulation of the VCH hypothesis.

Bovill & van der Vliet (2011), examining the small sample of micrographs in Sevitt (1974), inferred instead that the thrombi were attached to the vein wall endothelium within the valve pocket. We shall discuss this divergence of opinion later; but it seems improbable that a thrombus perceived as 'anchored' in mid-lumen could be attached to the vein wall endothelium.
