The post thrombotic syndrome (PTS) is a chronic condition that develops in 20%–40% of deep vein thrombosis (DVT) patients. While risk factors that predispose to the development of venous thromboembolism (VTE) are widely known, factors that influence the development of PTS after DVT have not been well elucidated. Over 10% of the general population is affected by one or more identifiable inherited thrombophilias which have been shown to underlie at least 1/3 of cases of VTE. The various thrombophilias are important risk factors for VTE, but it is unknown whether they also increase the risk for development of PTS. We performed a review of studies that have reported on the association between thrombophilia and the development of PTS in populations of patients with DVT and with chronic venous ulcers. Studies vary with regards to the definition of PTS, study design, follow-up period, and present conflicting results. Based on these results, the question of whether thrombophilia predisposes to the development of PTS remains unanswered. 1. Introduction The post thrombotic syndrome (PTS) is a chronic condition that develops in 20%–40% of patients within 1-2 years after symptomatic deep venous thrombosis (DVT) [1]. There is no gold standard test for the diagnosis of PTS and the diagnosis is primarily based on clinical features. Patients with PTS experience pain, heaviness, and swelling in the affected limb which tend to be aggravated by standing or walking and improved with rest and recumbency. Edema, venous ectasia, hyperpigmentation, eczema, and varicose collateral veins may be apparent. In severe cases, leg ulceration can occur [2]. While hereditary and acquired risk factors that predispose to the development of venous thromboembolism (VTE) are widely known [3], factors that influence the development of PTS after DVT have not been well elucidated. One reason for the lack of understanding of PTS risk factors could be that most investigations have been limited to small retrospectively studied groups, with only a limited number of studies being prospectively undertaken over the long term [4–6]. Furthermore, great differences exist between studies regarding the definition of PTS, study design, follow-up period, and the possibility of bias when the effects of recurrent DVT cannot be clearly distinguished from PTS [7, 8]. Some papers use the clinical classification (clinical, aetiological, anatomical, and pathological (CEAP classification)) recommended by the International Consensus Committee on Chronic Venous Disease for evaluation of PTS [9], while others have used
References
[1]
S. R. Kahn, “The post-thrombotic syndrome: progress and pitfalls,” British Journal of Haematology, vol. 134, no. 4, pp. 357–365, 2006.
[2]
X. Kurz, S. R. Kahn, L. Abenhaim, et al., “Chronic venous disorders of the leg: epidemiology, outcomes, diagnosis and management—summary of an evidence-based report of the VEINES task force,” International Journal of Angiology, vol. 18, no. 2, pp. 83–102, 1999.
[3]
F. A. Anderson Jr. and F. A. Spencer, “Risk factors for venous thromboembolism,” Circulation, vol. 107, no. 23, supplement 1, pp. I9–I16, 2003.
[4]
J. A. Heit, M. D. Silverstein, D. N. Mohr et al., “The epidemiology of venous thromboembolism in the community,” Thrombosis and Haemostasis, vol. 86, no. 1, pp. 452–463, 2001.
[5]
R. B. Rutherford, F. T. Padberg, A. J. Comerota, R. L. Kistner, M. H. Meissner, and G. L. Moneta, “Venous severity scoring: an adjunct to venous outcome assessment,” Journal of Vascular Surgery, vol. 31, no. 6, pp. 1307–1312, 2000.
[6]
M. V. Huisman, “Recurrent venous thromboembolism: diagnosis and management,” Current Opinion in Pulmonary Medicine, vol. 6, no. 4, pp. 330–334, 2000.
[7]
S. R. Kahn and J. S. Ginsberg, “The post-thrombotic syndrome: current knowledge, controversies, and directions for future research,” Blood Reviews, vol. 16, no. 3, pp. 155–165, 2002.
[8]
J. D. Douketis, M. A. Crowther, G. A. Foster, and J. S. Ginsberg, “Does the location of thrombosis determine the risk of disease recurrence in patients with proximal deep vein thrombosis?” The American Journal of Medicine, vol. 110, no. 7, pp. 515–519, 2001.
[9]
J. M. Porter and G. L. Moneta, “Reporting standards in venous disease: an update. International consensus committee on chronic venous disease,” Journal of Vascular Surgery, vol. 21, no. 4, pp. 635–645, 1995.
[10]
S. Villalta, P. Bagatella, A. Piccioli, A. W. A. Lensing, M. H. Prins, and P. Prandoni, “Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome,” Haemostasis, vol. 24, p. 158A, 1994.
[11]
S. R. Kahn, A. Hirsch, and I. Shrier, “Effect of postthrombotic syndrome on health-related quality of life after deep venous thrombosis,” Archives of Internal Medicine, vol. 162, no. 10, pp. 1144–1148, 2002.
[12]
S. R. Kahn, H. Partsch, S. Vedantham, P. Prandoni, and C. Kearon, “Definition of post-thrombotic syndrome of the leg for use in clinical investigations: a recommendation for standardization,” Journal of Thrombosis and Haemostasis, vol. 7, no. 5, pp. 879–883, 2009.
[13]
D. P. M. Brandjes, H. R. Büller, H. Heijboer et al., “Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis,” Lancet, vol. 349, no. 9054, pp. 759–762, 1997.
[14]
D. N. Mohr, M. D. Silverstein, J. A. Heit, T. M. Petterson, W. M. O'Fallon, and L. J. Melton, “The venous stasis syndrome after deep venous thrombosis or pulmonary embolism: a population-based study,” Mayo Clinic Proceedings, vol. 75, no. 12, pp. 1249–1256, 2000.
[15]
J. S. Ginsberg, J. Hirsh, J. Julian et al., “Prevention and treatment of postphlebitic syndrome: results of a 3-part study,” Archives of Internal Medicine, vol. 161, no. 17, pp. 2105–2109, 2001.
[16]
K. A. Bauer, “The thrombophilias: well-defined risk factors with uncertain therapeutic implications,” Annals of Internal Medicine, vol. 135, no. 5, pp. 367–373, 2001.
[17]
U. Seligsohn and A. Lubetsky, “Genetic susceptibility to venous thrombosis,” The New England Journal of Medicine, vol. 344, no. 16, pp. 1222–1231, 2001.
[18]
V. de Stefano, E. Rossi, K. Paciaroni, and G. Leone, “Screening for inherited thrombophilia: indications and therapeutic implications,” Haematologica, vol. 87, no. 10, pp. 1095–1108, 2002.
[19]
S. Middeldorp and A. van Hylckama Vlieg, “Does thrombophilia testing help in the clinical management of patients?” British Journal of Haematology, vol. 143, no. 3, pp. 321–335, 2008.
[20]
P. W. Kamphuisen, R. Lensen, J. J. Houwing-Duistermaat et al., “Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia,” British Journal of Haematology, vol. 109, no. 3, pp. 519–522, 2000.
[21]
J. O'Donnell, E. G. D. Tuddenham, R. Manning, G. Kemball-Cook, D. Johnson, and M. Laffan, “High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction,” Thrombosis and Haemostasis, vol. 77, no. 5, pp. 825–828, 1997.
[22]
P. A. Kyrle, E. Minar, M. Hirschl et al., “High plasma levels of factor VIII and the risk of recurrent venous thromboembolism,” The New England Journal of Medicine, vol. 343, no. 7, pp. 457–462, 2000.
[23]
E. Lindhoff-Last and B. Luxembourg, “Evidence-based indications for thrombophilia screening,” Journal of Vascular Diseases, vol. 37, no. 1, pp. 19–30, 2008.
[24]
P. Prandoni, A. W. A. Lensing, A. Cogo et al., “The long-term clinical course of acute deep venous thrombosis,” Annals of Internal Medicine, vol. 125, no. 1, pp. 1–7, 1996.
[25]
P. Prandoni, S. Villalta, P. Bagatella et al., “The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients,” Haematologica, vol. 82, no. 4, pp. 423–428, 1997.
[26]
P. Prandoni, A. W. A. Lensing, M. H. Prins et al., “Below-knee elastic compression stockings to prevent the post-thrombotic syndrome. A randomized, controlled trial,” Annals of Internal Medicine, vol. 141, no. 4, pp. 249–256, 2004.
[27]
S. Schulman, P. Lindmarker, M. Holmstr？m et al., “Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months,” Journal of Thrombosis and Haemostasis, vol. 4, no. 4, pp. 734–742, 2006.
[28]
M. Stain, V. Schonauer, E. Minar, et al., “The post-thrombotic syndrome: risk factors and impact on the course of thrombotic disease,” Journal of Thrombosis and Haemostasis, vol. 3, no. 12, pp. 2671–2676, 2005.
[29]
L. W. Tick, M. H. H. Kramer, F. R. Rosendaal, W. R. Faber, and C. J. M. Doggen, “Risk factors for post-thrombotic syndrome in patients with a first deep venous thrombosis,” Journal of Thrombosis and Haemostasis, vol. 6, no. 12, pp. 2075–2081, 2008.
[30]
E. Biguzzi, E. Mozzi, A. Alatri, E. Taioli, M. Moia, and P. M. Mannucci, “The post-thrombotic syndrome in young women: retrospective evaluation of prognostic factors,” Thrombosis and Haemostasis, vol. 80, no. 4, pp. 575–577, 1998.
[31]
S. R. Kahn, C. Kearon, J. A. Julian, et al., “Predictors of the post-thrombotic syndrome during long-term treatment of proximal deep vein thrombosis,” Journal of Thrombosis and Haemostasis, vol. 3, no. 4, pp. 718–723, 2005.
[32]
S. R. Kahn, I. Shrier, J. A. Julian et al., “Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis,” Annals of Internal Medicine, vol. 149, no. 10, pp. 698–707, 2008.
[33]
L. Spiezia, E. Campello, E. Giolo, S. Villalta, and P. Prandoni, “Thrombophilia and the risk of post-thrombotic syndrome: retrospective cohort observation,” Journal of Thrombosis and Haemostasis, vol. 8, no. 1, pp. 211–213, 2010.
[34]
L. F. Bittar, E. V. de Paula, S. A. L. Montalv？o, T. B. T. Mello, and J. M. Annichino-Bizzacchi, “Severe post-thrombotic syndrome is associated with higher levels of factor VIII,” Clinical and Applied Thrombosis/Hemostasis, 2012.
[35]
M. Zutt, U. Kruger, A. Rosenberger, et al., “Thrombophilia in patients with chronic venous leg ulcers-a study on patients with or without post-thrombotic syndrome,” Journal of the European Academy of Dermatology and Venereology, vol. 25, no. 12, pp. 1432–1439, 2011.
[36]
J. Hafner, A. Kuhne, B. Schar, et al., “Factor V Leiden mutation in post-thrombotic and nonpost-thrombotic venous ulcers,” Archives of Dermatology, vol. 137, no. 5, pp. 599–603, 2001.
[37]
A. Wiszniewski, K. Bykowska, R. Bilski, W. Jaskowiak, and J. Proniewski, “Prevalence rate for inherited thrombophilia in patients with chronic and recurrent venous leg ulceration,” Wound Repair and Regeneration, vol. 19, no. 5, pp. 552–558, 2011.
[38]
M. B. Maessen-Visch, K. Hamulyak, D. J. Tazelaar, N. Crombag, and H. A. Martino Neumann, “The prevalence of factor V Leiden mutation in patients with leg ulcers and venous insufficiency,” Archives of Dermatology, vol. 135, no. 1, pp. 41–44, 1999.
[39]
Y. Gaber, H. J. Siemens, and W. Schmeller, “Resistance to activated protein C due to factor V Leiden mutation: high prevalence in patients with post-thrombotic leg ulcers,” British Journal of Dermatology, vol. 144, no. 3, pp. 546–548, 2001.
[40]
R. K. MacKenzie, C. A. Ludlam, C. V. Ruckley, P. L. Allan, P. Burns, and A. W. Bradbury, “The prevalence of thrombophilia in patients with chronic venous leg ulceration,” Journal of Vascular Surgery, vol. 35, no. 4, pp. 718–722, 2002.
[41]
F. Ribeaudeau, P. Senet, J. M. Cayuela et al., “A prospective coagulation study including resistance to activated protein C and mutations in factors V and II in venous leg ulcers,” British Journal of Dermatology, vol. 141, no. 2, pp. 259–263, 1999.
[42]
H. Bounameaux, “Factor V Leiden paradox: risk of deep vein thrombosis but not of pulmonary embolism,” Lancet, vol. 356, no. 9225, pp. 182–183, 2000.
[43]
O. Bj？rgell, P. E. Nilsson, J. A. Nilsson, and P. J. Svensson, “Location and extent of deep vein thrombosis in patients with and without FV:R, 506Q mutation,” Thrombosis and Haemostasis, vol. 83, no. 5, pp. 648–651, 2000.
[44]
A. Y. Nossent, V. van Marion, N. H. van Tilburg et al., “von Willebrand factor and its propeptide: the influence of secretion and clearance on protein levels and the risk of venous thrombosis,” Journal of Thrombosis and Haemostasis, vol. 4, no. 12, pp. 2556–2562, 2006.
[45]
M. V. Huisman, F. A. Klok, R. K. Djurabi, D. Tormene, P. Simioni, and P. Prandoni, “Factor V Leiden is associated with more distal location of deep vein thrombosis of the leg,” Journal of Thrombosis and Haemostasis, vol. 6, no. 3, pp. 544–545, 2008.
[46]
A. A. Milne and C. V. Ruckley, “Venous insufficiency following deep vein thrombosis,” Vascular Medicine Review, vol. 5, no. 3, pp. 241–248, 1994.
[47]
A. W. Bradbury, R. K. MacKenzie, P. Burns, and C. Fegan, “Thrombophilia and chronic venous ulceration,” European Journal of Vascular and Endovascular Surgery, vol. 24, no. 2, pp. 97–104, 2002.
[48]
A. W. Bradbury, “Epidemiology and aetiology of C4-6 disease,” Phlebology, vol. 25, supplement 1, pp. 2–8, 2010.
