**3.2.2 Leukocytes and venous thrombogenesis**

Nowadays, notwithstanding Virchow's observations, it seems to be tacitly assumed that leukocytes have no aetiological significance and are concentrated in the *Kopfteil* of a thrombus only because they are adventitiously trapped in the fibrin mesh. But adventitious trapping cannot explain the segregated whiteness of the *Kopfteil*; erythrocytes are also adventitiously trapped by the fibrin and they outnumber leukocytes in the circulating blood by many orders of magnitude, hence the redness of the subsequent, more newly-formed, *Schwansteil* of a thrombus.

Virchow's key insight was that the leukocytes concentrated in a venous thrombus (as distinct from a clot) originate from within the blood stream, not from outside (migrating through the vessel wall) as previously supposed. *A fortiori*, they must form while the blood is *flowing*, since such an excess of leukocytes over erythrocytes can be provided only from a large volume of circulating blood. However, he was not the first investigator to recognise that white material is a primary constituent of what we now call 'venous thrombi'. Hunter (1793) wrote about the 'inflammation of the internal coats of veins', describing a lesion of the kind we now call 'venous thrombosis' as a local accumulation of 'pus'. Similarly, Cruveilhier focused on the accumulation of 'inflammatory' material, denoting the process by the term 'phlebitis' (Talbott, 1970). Unlike Hunter and Cruveilhier, who denounced the 'magnifying glasses' of their day, Virchow used the microscope, so he was able to see that the white material in a venous thrombus was not amorphous but comprised a mass of cells. Two decades later, the improved Zeiss microscope made platelets readily visible as obviously copious blood elements.

Pathophysiology and Clinical Aspects of 136 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

the elementary fact reported by Joseph Lister in his Croonian lecture (Lister, 1863): circulating blood has no inherent tendency to coagulate; coagulation is initiated *only* when blood makes contact with an abnormal surface, i.e. anything other than normal, uninjured vascular endothelium. Haemostasis is a part of normal physiology, initiated when blood leaks from a vessel. Venous thrombogenesis is not normal physiology; it is a pathological process entailing local blood coagulation *in situ*. A venous thrombus is a lesion, in the strict sense of an abnormal change in a tissue caused by injury or disease. Venous thrombi are in many respects *like* clots, but they are not clots, so it is not logical to infer that they are

The morphological characterization of venous thrombi encapsulated in Virchow's

First, an account of the aetiology of DVT must include a causal explanation for all three

Second, Virchow's *real* triad constitutes a triple criterion for assessing experimental thrombi. Any coagulum or other structure produced in an experimental setting that does not display Lines of Zahn, dense fibrin and a white *Kopfteil* cannot be regarded as a thrombus, and the experimental model that generates such a structure cannot be considered a model for

Nowadays, notwithstanding Virchow's observations, it seems to be tacitly assumed that leukocytes have no aetiological significance and are concentrated in the *Kopfteil* of a thrombus only because they are adventitiously trapped in the fibrin mesh. But adventitious trapping cannot explain the segregated whiteness of the *Kopfteil*; erythrocytes are also adventitiously trapped by the fibrin and they outnumber leukocytes in the circulating blood by many orders of magnitude, hence the redness of the subsequent, more newly-formed,

Virchow's key insight was that the leukocytes concentrated in a venous thrombus (as distinct from a clot) originate from within the blood stream, not from outside (migrating through the vessel wall) as previously supposed. *A fortiori*, they must form while the blood is *flowing*, since such an excess of leukocytes over erythrocytes can be provided only from a large volume of circulating blood. However, he was not the first investigator to recognise that white material is a primary constituent of what we now call 'venous thrombi'. Hunter (1793) wrote about the 'inflammation of the internal coats of veins', describing a lesion of the kind we now call 'venous thrombosis' as a local accumulation of 'pus'. Similarly, Cruveilhier focused on the accumulation of 'inflammatory' material, denoting the process by the term 'phlebitis' (Talbott, 1970). Unlike Hunter and Cruveilhier, who denounced the 'magnifying glasses' of their day, Virchow used the microscope, so he was able to see that the white material in a venous thrombus was not amorphous but comprised a mass of cells. Two decades later, the improved Zeiss microscope made platelets readily visible as

morphological features. That is the critical test of any aetiological hypothesis.

formed in the same way as clots.

**3.2.1 The importance of Virchow's** *real* **triad** 

venous thrombogenesis (cf. Welch, 1887, 1899).

*Schwansteil* of a thrombus.

obviously copious blood elements.

**3.2.2 Leukocytes and venous thrombogenesis** 

publication is important in two respects:

This observation inspired investigations of venous thrombi over the following seventy years. The elegant and detailed morphological studies of Welch (1887, 1899) highlighted the contributions of leukocytes as well as platelets to thrombus structure, and Aschoff (1924) declared that the causation of DVT would only be understood when the accumulation of white cells was explained: *"Along with the explanation of this marking* [the Lines of Zahn] *stands or falls the whole problem of thrombus formation, so far as consideration of the majority of cases of autochthonous thrombosis goes"*.
