Unraveling the Silent Threat: New Insights into Venous Thrombosis Risk Factors Discovered
Published: 1 September 2023
A recently published report by Professor Lowe and colleagues in Glasgow University (Professor of Health Economics Olivia Wu; Visiting Professor Mark Woodward) and other universities has confirmed these findings in a collaborative systematic review and meta-analysis of population-based studies.
Thrombosis in the leg veins is common, and if it travels to the lungs (pulmonary embolism) it can be fatal. Venous thromboembolism (VTE) is the third commonest cause of cardiovascular death, after coronary heart disease and stroke. Unlike coronary heart disease and stroke, prediction of VTE in the general population is not well established.
The potential role of high blood clotting factor levels in VTE was reported by Professor of Vascular Medicine Gordon Lowe and colleagues in 1991 for Factor VIII (1), then in 2000 for Factor IX (2). Patients with VTE had higher levels than controls of these two factors, low levels of which cause lifelong excessive bleeding (haemophilias).
A recently published report by Professor Lowe and colleagues in Glasgow University (Professor of Health Economics Olivia Wu; Visiting Professor Mark Woodward) and other universities has confirmed these findings in a collaborative systematic review and meta-analysis of population-based studies (3). This included more than 5000 thousand persons who developed VTE, compared to controls who did not. Persons with levels in the top 10 percent of Factor IX levels had almost twice the risk of VTE compared to those with lower levels. Persons in the top 10 percent of Factor VIII levels had three times the risk of VTE. Persons in the top 10 percent of both Factor VIII and Factor IX levels had almost five times the risk of VTE.
While the association of Factors VIII and IX with VTE risk is potentially causal (as suggested by genetic studies including of ABO blood group, which is a determinant of Factor VIII levels), population screening for Factor VIII and Factor IX levels is not feasible, as assays are expensive and not widely available. However, another recently published report by Professor Lowe (in collaboration with Professor Goya Wannamethee, Royal Free Hospital, University of London) confirmed that VTE risk in the British Regional Heart Study was associated not only with Factor VIII and Factor IX levels; but also with two cheaper and widely available blood tests: the activated partial thromboplastin time (APTT), which captures the effect of both Factor VIII and Factor IX; and fibrin D-dimer, which is a measure of activated blood coagulation (4). They suggested that a combination of these two tests may be a more feasible predictor of VTE risk in the population: a hypothesis which can be tested in further population studies.
On a historical note, Professor Lowe, in a recent review of thrombosis in Scotland, records that Joseph Lister, University of Glasgow Professor of Surgery, reported in 1863 that there were two pathways of blood coagulation: the short-acting extrinsic system, activated by exposure of blood to tissues outwith the blood vessels; and the intrinsic system, initiated within the blood over a longer time period. This discovery led to the introduction in the twentieth century of the APTT, as a screening test for Factor VIII and Factor IX deficiencies (5).
References
1. Balendra R, Rumley A, Orr M, Lennie SE, McColl P, Lowe GDO. Blood lipids, coagulation, fibrinolysis and rheology in spontaneous proven deep vein thrombosis. Br J Haematol 1991; 77 (Suppl. 1): 83.
2. Lowe G, Woodward M, Vessey M, Rumley A, Gough P, Daly E. Thrombotic variables and risk of idiopathic venous thromboembolism in women aged 45-64 years. Relationships to hormone replacement therapy. Thromb Haemost 2000; 95: 3678-82.
3. Lowe G, Wu O, van Hylckama Vlieg A, Folsom A, Rosendaal F, Woodward M. Plasma levels of coagulation factors VIII and IX and risk of venous thromboembolism: systematic review and meta-analysis. Thromb Res 2023; 229: 31-39.
4. Wannamethee SG, Papacosta O, Lennon L, Whincup PH, Rumley A, Lowe GDO. Haematological variables and risk of future venous thromboembolism in the British Regional Heart Study on men. Combined D-dimer and APTT as a predictive test for thromboembolism? Br J Haematol 2022; 198: 587-94.
5. Lowe GDO, Thrombosis in Scotland, 1800-1960. J Roy Coll Phys Edinb 2022; 52: 153-58.
First published: 1 September 2023