Venous thrombosis
Thrombi which form in the venous system do so under low shear. Thus von Willebrand factor and platelet tethering seem to be less important, and activation of the coagulation system takes a leading role to produce a fibrin-rich clot.8
Risk factors
Alterations in blood flow (venous stasis, turbulence) and in the coagulability of blood seem to be particularly important in disposing to venous thromboembolism (VTE). This is reflected in acknowledged risk factors for its development. For example, surgery can lead to immobility, venous stasis and an inflammatory response, which includes an increase in factor VIII levels. High levels of oestrogen (as in pregnancy, the oral contraceptive pill and hormone replacement therapy), lead to a prothrobotic state by a rise in clotting factors and a fall in natural anticoagulants. A number of inherited defects of the natural anticoagulant system can predispose to thrombosis, such as deficiencies of protein C, protein S, or antithrombin, or factor V Leiden (an inherited reduction in sensitivity of factor Va to deactivation by protein C). A current area of much active research is the risk of venous thrombosis associated with malignancy. Malignancy predisposes to thrombosis by a number of mechanisms, including expression of tissue factor by tumour cells, pro-thrombotic mucin production, and release of microparticles containing tissue factor into the circulation.9
Pathophysiology
The majority of deep vein thromboses occur in the deep veins of the lower limb. It is thought that venous stasis leads to endothelial hypoxia – and hence activation and adoption of a pro-coagulant state as described above – leading to local activation of the coagulation system.10 Many deep vein thromboses (DVTs) are thought to form in the valve pockets and then to grow by elongation, spiralling up the vein. However, the tip of the thrombus can break off (embolise) and be driven up the venous circulation.
Such an embolus will eventually become lodged in the pulmonary circulation, causing a pulmonary embolus (PE). If large, or if added to by local growth or additional emboli, PEs can cause serious haemodynamic complications, such as pulmonary hypertension, right-sided heart disease, and death.
Treatment
Just as arterial thrombosis is treated and prevented with antiplatelets, VTE is treated and prevented with anticoagulants. Heparin and warfarin were the first anticoagulants to be developed and are remarkably successful in preventing the development of a VTE, be it after a major risk event such as orthopaedic surgery, or in preventing a second VTE. Unfortunately, their use requires close laboratory monitoring and considerable expertise in dosing. Heparin has largely been superseded by a ‘cleaner’ variant, low molecular weight heparin (LMWH). More recently, direct oral anticoagulants (DOACs – previously known as NOACS11) have been developed which offer the prospect of equivalent, or better, efficacy and safety without the need for monitoring. These will be discussed in module 3.
A note about atrial fibrillation
Embolic stroke is one of the most devastating consequences of atrial fibrillation. The mechanism of thrombus formation in atrial fibrillation is thought to be very similar to that in VTE: stasis of blood, with possible contributions from endothelial dysfunction and/or a hypercoagulable state.12 This is further supported by the fact that anticoagulants are more effective at stroke prevention in AF than antiplatelet agents, as will be discussed further in module 3.
VTE prevention
The Royal College of Physicians, in a position statement13 said that there is significant evidence to support the view that hospital-acquired VTE can be prevented through a combination of two simple, safe and effective steps:
- a risk assessment of patients for their VTE and bleeding risk, to identify those at risk of VTE and those for whom preventative treatment is appropriate; and
- administering preventative treatment for those identified as being at risk of VTE, in the form of pharmacological prophylaxis and/or mechanical prophylaxis.
Current NICE guidance14 on reducing the risk of VTE says VTE prevention is a cost-effective measure for national health boards to implement. NICE has calculated that compliance with their guidance to prevent hospital-acquired VTE saves money, over and above the cost of managing VTE once it has developed.
Following the publication of this guideline, NICE placed VTE prevention within its list of top 10 cost-effective guidelines. NICE estimated that effective VTE prevention would cost the NHS in the UK an additional £21.9 million nationally, but this figure is more than offset by the anticipated reductions in DVT and PE. In 1993, the Office for Healthcare Economics estimated that the annual cost of treating patients who developed post-surgical DVT and PE alone was in the region of £204.7 to £222.8 million in the UK.
These figures clearly demonstrate that compliance with best practice in VTE prevention (that is, risk assessment of patients for VTE on admission and the administration of appropriate prophylaxis) makes financial sense for the NHS at a time when there are significant pressures to manage costs. VTE prevention is a simple, effective, and cost-efficient measure to save lives.
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References
1. Gomez K, Tuddenham E, McVey J. Normal haemostasis. In: Hoffbrand et al (Ed), Postgraduate haematology, 6th Edition. London: Wiley Blackwell, 2010. http://dx.doi.org/10.1002/9781444323160.ch39
2. Chan MY, Andreotti F, Becker RC. Hypercoagulable states in cardiovascular disease. Circulation 2008;118:2286–97. http://dx.doi.org/10.1161/CIRCULATIONAHA.108.778837
3. Lancé MD. A general review of major global coagulation assays: thrombelastography, thrombin generation test and clot waveform analysis. Thrombosis J. 2015;13:1. http://dx.doi.org/10.1186/1477-9560-13-1
4. Kaplan ZS, Jackson SP. The role of platelets in atherothrombosis. Hematology Am Soc Hematol Educ Program 2011;2011:51–61. http://dx.doi.org/10.1182/asheducation-2011.1.51
5. Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in hemostasis. Physiological Rev 2013;93:327–58. http://dx.doi.org/10.1152/physrev.00016.2011
6. Blann AD, Landray MJ, Lip GY. ABC of antithrombotic therapy: An overview of antithrombotic therapy. BMJ 2002;325:762–5. http://dx.doi.org/10.1136/bmj.325.7367.762
7. Badimon L, Vilahur G. Thrombosis formation on atherosclerotic lesions and plaque rupture (Review). J Intern Med 2014;276:618–32. http://dx.doi.org/10.1111/joim.12296
8. Aleman MM, Walton BL, Byrnes JR, Wolberg AS. Fibrinogen and red blood cells in venous thrombosis. Thrombosis Res 2014;133:S38–S40. http://dx.doi.org/10.1016/j.thromres.2014.03.017
9. Geddings JE, Mackman N. Tumor-derived tissue factor–positive microparticles and venous thrombosis in cancer patients. Blood 2013;122:1873–80. http://dx.doi.org/10.1182/blood-2013-04-460139
10. López JA, Kearon C, Lee AY. Deep venous thrombosis. Hematology 2004;2004:439–56. http://dx.doi.org/10.1182/asheducation-2004.1.439
11. Barnes GD, Ageno W, Ansell J, Kaatz S, for the Subcommittee on the Control of Anticoagulation. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost 2015;13:1154–6. http://dx.doi.org/10.1111/jth.12969
12. Iwasaki Y, Nishida K,Kato T, Nattel S. Atrial fibrillation pathophysiology: Implications for management. Circulation. 2011;124:2264–74. http://dx.doi.org/10.1161/CIRCULATIONAHA.111.019893
13. Royal College of Physicians press release. Prevention of venous thromboembolism. London: Royal College of Physicians, Academy of Medical Royal Colleges, Royal College of Midwives, Royal College of Nursing and Royal Pharmaceutical Society, 2012. Available from: http://www.rcplondon.ac.uk/press-releases/royal-colleges-advise-professions-cost-effective-prevention-vte
14. National Institute for Health and Clinical Excellence. Venous thromboembolism – reducing the risk (CG92). London: NICE, January 2010. Available from: http://publications.nice.org.uk/venous-thromboembolism-reducing-the-risk-cg92
Further reading
Hicks T, Stewart F, Eisinga A. NOACs versus warfarin for stroke prevention in patients with AF: a systematic review and meta-analysis. Open Heart 2016;3:e000279. http://dx.doi.org/10.1136/openhrt-2015-000279
Messner B, Bernhard D. ATVB in focus: tobacco-related cardiovascular diseases in the 21st century: smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler Thromb Vasc Biol 2014;34:509–15. http://dx.doi.org/10.1161/ATVBAHA.113.300156
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