Management of Venous Disease in Patients with Thrombophilia

VASCULAR DISEASE MANAGEMENT 2011;8(11):E182–E186

Abstract

Venous disease encompasses a wide spectrum of clinical pathology. Thrombophilias are acquired and inherited hypercoagulable conditions that are prevalent among patients with various manifestations of venous disease. However, treatment guidelines often do not investigate the effect of thrombophilia on treatment outcomes. We aim to review the evidence for the relationship between thrombophilias and venous disease, and highlight situations in which the presence of thrombophilia may affect treatment options and outcomes.

Introduction

The management of venous disease has undergone many recent advances. The emergence of new treatment modalities such as radiofrequency ablation (RFA) and endovenous laser treatment for venous reflux disease spurred a surge in research on the management of venous disease and its complications. Concomitantly, recent advances in the hematologic field have led to a better understanding of many coagulation disorders, such as activated protein C resistance in the factor V Leiden mutation and the prothrombin 20210A mutation. Synergy between scientific and technological advances has led to a better understanding of the pathophysiology of venous reflux, deep venous thrombosis (DVT), chronic venous ulcers (CVU), varicose veins, and superficial venous thrombosis (SVT).

It is clear that there is a link between several, if not all, of the venous disorders and abnormalities of coagulation. Both acquired and inherited coagulation disorders seem to be overrepresented in patients with venous disease as opposed to population controls.¹ Causality of venous disease is a result of abnormal coagulation. However, it is more controversial and there are very few management guidelines for venous disease in patients with thrombophilia. The high prevalence of coagulation disorders in patients with venous disease mandates that physicians who treat venous disorders have an understanding of the detection, relative risk, and management of these different thrombophilias in the setting of venous disease. Tailoring treatments and interventions by stratifying patient risk will allow physicians to minimize adverse effects and deliver high-quality, cost-effective care by minimizing non-indicated treatments in low-risk groups while appropriately treating high-risk groups.

Deep Venous Thrombosis and Thrombophilia

The incidence of deep venous thrombosis ranges from 5-10 per 10,000 and the incidence of pulmonary embolism and deep venous thrombosis together is approximately 14 per 10,000 patient years.^2,3,4 Risk factors for venous thromboembolism (VTE) include a mix of environmental factors, acquired and transient prothrombotic states, and inherited abnormalities of coagulation. Environmental and acquired prothrombotic states include: advanced age, hospitalization, immobilization, pregnancy and recent post-partum state, trauma, previous history of DVT, major surgery, long haul travel (>6 H), nephrotic syndrome, and obesity. Inherited risk factors include factor V Leiden mutation, prothrombin 20210 variant, antithrombin III deficiency, protein C and S deficiencies, and dysfibrinogenemia.⁵ Certain prothrombotic states actually have heritable and acquired components such as homocysteinemia, factor VII, VIII, IX, and XI elevation, and hyperfibrinogenemia.

Large retrospective and prospective trials have been conducted to evaluate the relative risk of these different risk factors in the development of venous thrombosis.^6,7 Table 1 summarizes some of the more common risk factors for the development of venous thrombosis and the approximate relative risk of each factor.⁵

Multiple risk factors for venous thrombosis can often be present within the same individual, and the effects can be synergistic. For example, patients who are heterozygous for factor V Leiden mutation and receiving oral contraceptive therapy have a 35-fold increased risk of venous thromboembolism.⁵ Factor V Leiden also interacts synergistically with advancing age and obesity.⁸

Surgical Prophylaxis

There are no specific guidelines for pharmacologic prophylaxis against VTE in asymptomatic patients with thrombophilia. Venous reflux surgery is generally considered minor surgery and not an indication for pharmacologic prophylaxis. However, several studies, including a systematic review of the literature, have shown that the annual risk for VTE in asymptomatic individuals with thrombophilia ranges from 0.5%-4% per year depending on the specific coagulation abnormality.^9-11 Greater than 50% of these VTE events occurred at high-risk periods (i.e., perioperative), and patients with thrombophilia not receiving prophylaxis were at twice the risk of developing VTE (21.7% vs 9.1%).¹⁰ Therefore, screening of high-risk patients for thrombophilia or routine perioperative DVT prophylaxis for patients undergoing venous surgery may be warranted. While there are no official screening guidelines for thrombophilia, Table 2 provides a list of conditions associated with high rates of thrombophilia.^1,5,32,33

Recurrent DVTs

DVTs can be idiopathic or associated with an acquired and transient state, such as post-surgical or trauma-associated DVTs. Furthermore, DVTs can be divided into first events and recurrent. Recurrent refers to any DVT in a patient with previous history of DVT that occurs greater than 3 months after the first event (events that occur in the same limb prior to 3 months are generally considered to be failure of medical therapy). The level of investigation for thrombophilia, as well as duration of therapy, depends on which category the thrombotic event falls into. Generally, at least 4 groups of patients who develop DVTs should be screened for thrombophilia:⁵

1. Idiopathic first event;
2. Secondary first event that is not cancer related, in patients under age 50 years;
3. Recurrent idiopathic or secondary events that are not cancer related;
4. Thrombosis at an unusual site such a cerebral, renal, portal, or hepatic veins.

Overall, the recurrence rates for VTE are quite high. After standard anticoagulation therapy for 3-6 months, 21%-23% of patients will have a recurrence at 4-5 years and as high as 40% at 10 years.^12,13 Many of the same risk factors that increase occurrence of first event DVTs also increase risk for recurrent DVTs as well. However, the biggest risk factors for recurrent DVTs are: idiopathic first event, cancer, proximal extension of DVT, and shorter duration of anticoagulation.^12,13

The presence of thrombophilia does not seem to affect recurrent VTE events as strongly as it does primary VTE events. Some studies show that the risk of VTE recurrence is about twice that for patients without thrombophilia, but this is smaller than the association with first event DVTs.¹³ However the increased risk of recurrent DVT has not been clearly demonstrated for all thrombophilias, and some studies suggest that the presence of thrombophilias does not increase the risk of recurrent VTE at all.^14,15 Several explanations exist for these findings. First, the most common thrombophilias infer relatively small risks of developing DVTs. For example, the risk ratios for the 2 most common thrombophilias associated with DVT, factor V Leiden heterozygosity and prothrombin gene variant, are 1.39-2.0 and 1.20 respectively.¹⁶ Second, identification of patients with thrombophilia often leads to improved prophylaxis of these patients during high-risk situations, which has also been shown to reduce recurrent DVTs.^9,10 Thirdly, many idiopathic DVTs may likely represent uncharacterized hypercoagulable states that increase the risk of recurrent VTEs as much as known thrombophilias.

There are several special considerations regarding treatment of DVTs in the presence on thrombophilias. The current CHEST guidelines recommend at least 3 months of treatment with a vitamin K antagonist (VKA) for treatment of a first episode of unprovoked DVT.¹⁷ After the initial 3 months, patients with proximal DVTs as well as other high-risk patients should have a risk-benefit evaluation for long-term anticoagulation. However, no specific recommendations for such an evaluation exist. Therefore, more objective measures of risk of recurrence could aid in tailoring duration of anticoagulation. A study by Santamaria et al¹⁸ showed that thrombophilia is indeed associated with recurrent episodes of VTE in patients with first episode unprovoked DVT (35% vs 21%, p =0.046).¹⁸ This study further showed that while there was no benefit to extending anticoagulation beyond 3 months in patients without thrombophilia, patients with thrombophilia who received 3 months of anticoagulation were at a 3 times greater risk of recurrent VTE at 4 years than those treated with a VKA for 12 months. Elevated levels of factor VIII and D-dimer have also been shown in another study to correlate with a 2-3 times greater risk of DVT recurrence and that VKA therapy is efficacious in decreasing this recurrence rate.¹⁹ Therefore, in cases of unprovoked DVTs, recurrent DVTs, venous thrombosis in unusual sites, or DVT at a young age (younger than 50 years), screening for thrombophilias and D-dimer levels could help identify patients that would benefit from extended therapy and alleviate treating low-risk individuals that only require 3 months of therapy.

Thrombophilia and Chronic Venous Ulcers

CVUs are a prevalent and potentially debilitating complication of venous disease. The most widely recognized etiology of venous ulcers is that of ambulatory venous hypertension secondary to incompetent valves in the deep and superficial venous systems of the lower extremities, which allow reflux of venous blood.

Chronic venous reflux and venous hypertension promote inflammation and skin changes of the lower extremity that predispose the skin to ulceration. Lymphatic destruction, excessive colloid filtration resulting in regional edema, fibrin deposition, a diffusion barrier to oxygen, and infiltration of lymphocytes and neutrophils have all been shown to occur in the setting of elevated lower extremity venous pressure.²⁰

A history of DVT and subsequent post-thrombotic venous insufficiency is a major cause of venous ulceration.²¹ However, only recently has the direct relationship between thrombophilia and chronic venous ulceration been studied without DVT as an intervening confounder. Hyperhomocysteinemia and elevated factor VIII, IX, and XI levels have all been shown to occur with greater prevalence in patients with CVUs than in age-matched controls without venous disease, with odds ratios ranging from 2.0 to 5.4.^1,21 Other studies have shown that in patients with CVUs there is a 41% chance of concomitant thrombophilia, which is 30 times higher than patients without CVUs. Furthermore, the presence of thrombophilia was not associated with increased rates of clinical DVTs or increased severity of reflux.²² This association between thrombophilia and chronic venous ulceration may enhance the way we understand the pathology of venous ulcer disease. Many of the microvascular and cellular changes of the tissues surrounding ulcer disease have been attributed to ambulatory venous hypertension, but without always having a well-defined mechanism. The lack of correlation of some thrombophilic states with a clinical history of DVT in patients with CVU, and yet their increased prevalence within the CVU population, suggests that thrombophilia may cause progression to CVU through mechanisms other than just DVT formation. One potential mechanism of disease progression may be via microvascular thromboses that progress to skin changes and surrounding inflammation. There have been some small case series using anticoagulation as treatment for CVU refractory to other treatments.^23,24 However, there are no prospective trials to evaluate the use of anticoagulation to prevent progression of venous disease to the more advanced stages of soft tissue changes and ulceration, or as a therapy for venous ulcers. However, such a trial may indeed show some benefit in patients with thrombophilia. It is also possible that many patients with thrombophila develop subclinical DVTs and subsequent reflux that leads the CVUs.

Compression therapy is the mainstay of treatment for CVUs with up to 96% of ulcers healing.²⁵ The current CHEST guidelines based on randomized control trials show a significant benefit to the use of 30 mmhg-40 mmhg compression stockings for at least 2 years in decreasing progression of venous disease after an episode of DVT. Surgical correction of venous reflux does not seem to aid in ulcer healing of primary CVUs; however, it does seem to reduce ulcer recurrence rates.²⁶ A recent prospective randomized control trial also showed increased CVU healing rates in patients with recurrent CVUs who were treated with surgical correction of superficial venous reflux and compression versus compression therapy alone.²⁷ Other treatments, identified by the CHEST guidelines, showing some benefit in the healing of venous ulcers are pentoxifylline and rutosides.¹⁷ There is currently no evidence for modifying these recommendations in patients with thrombophilia.

Thrombophilia and Varicose Veins

Studies have shown that thrombophilias are more prevalent amongst patients with uncomplicated varicose vein disease (CEAP grade C2-C3) compared to healthy controls.¹ However this correlation is not as strong as the correlation between thrombophilia and chronic venous ulceration. Furthermore, it is not clear why certain patients with varicose veins will progress to chronic venous ulceration while others will not. Attempts have been made to identify predictors of progression to CVUs in patients with varicose veins. Presence of skin changes, reflux in deep veins, history of DVT, elevated BMI, and smoking have all been shown to predict progression of venous disease to ulcer formation.²¹ Strong ankle dorsiflexion with preservation of the calf muscle pump is a protective factor.^21,28 No studies have investigated thrombophilia in patients with varicose veins as a potential risk factor for disease progression and development of CVU. If such a relationship truly exists, patients with varicose veins and concomitant thrombophilia may represent a group in which more aggressive control of venous reflux and outcomes should be investigated.

The current treatment options for patients with varicose veins and thrombophilia do not differ from patients without thrombophilia. There is no evidence to suggest that open surgery or endovenous techniques differ in outcomes in patients with thrombophilia, and the safety of radiofrequency endovenous ablation in patients with previous DVTs has been demonstrated.²⁹ Furthermore, the EVOLVeS prospective randomized control trial of RFA vs open saphenous surgery showed no difference in thrombotic complication rates and showed a shorter return to normal activity time in the RFA group, which may be of benefit to patients with underlying thrombophilia.³⁰

Thrombophilia and Superficial Venous Thrombosis

SVT is a relatively common disorder that affects 3%-11% of the population.³¹ The condition has previously been regarded as benign and treatment has been targeted toward alleviating symptoms, mainly with nonsteroidal antiinflammatory drugs and heat packs. However, studies show that there is a strong correlation between SVT and thrombophilic states^32,33 and that thrombophilias are more common when SVTs occur in non-varicosed segments of vein.³⁴

The progression of SVT to DVT varies widely between different studies from the range of 4%-44%.^32-34 Furthermore, the progression to DVTs varies depending on location of the SVTs. For example, SVT of the proximal saphenous trunk is generally considered most prone to progress to DVT with rates greater than 27%.³⁵ However, perforating veins can also provide a route for thrombus extension to deep veins.

The presence of thrombophilia and spontaneous SVT seems to correlate with progression of SVT to DVT. Studies have also shown that in patients with SVT, there will be a significantly higher incidence of thrombophilias in patients with SVTs that propagate to the deep veins than in patients with SVTs that do not extend to the deep veins.³⁴ Further, patients with SVT and hypercoagulable states are much more likely to develop new DVTs on prospective follow-up (41.7% vs 4.2% in one study).³²

Prior to 2010, there had been 5 randomized trials of treatment of SVT with mixed results.^36-40 However, a newer randomized control trial of over 3000 patients showed that anticoagulation for 45 days resulted in a significant reduction of PE, DVT, and recurrent SVT compared to treatment with placebo.⁴¹

As of yet there have been no studies that look at the effect of thrombophilia in the treatment of patients with SVT. There also aren’t any studies of the rate of PEs in patients with SVT as a function of presence of thrombophilia. These are 2 important areas that mandate investigation. Current CHEST guidelines support the use of low or intermediate LMWH, intermediate dose UFHR, or LMWH as a bridge to VKA for 4 weeks as treatment in most cases of spontaneous SVT. However, SVT is still managed conservatively in most cases and its true potential for thromboembolic complications may be underestimated. Randomized studies of anticoagulation versus observation in patients with SVT and concomitant thrombophilia may identify a patient group that would have a greater benefit from anticoagulation after SVT.

A history of spontaneous SVT is an important consideration when planning venous surgery for reflux or varicose veins. At least one study has shown that previous SVT correlates with development of DVT after RFA of the greater saphenous vein.²⁹ This correlation suggests that SVT patients may likely benefit from perioperative pharmacologic DVT prophylaxis, as well as early mobilization and compression wraps. However, the efficacy of these interventions in these patients requires prospective analysis. Furthermore, patients with spontaneous SVTs may also represent a group in which testing for a thrombophilia may be of benefit.

Conclusion

Venous disease represents a wide spectrum of disorders ranging from SVT and varicose veins to debilitating ulcers and potentially fatal thromboembolic events. The role of many thrombophilias as risk factors for VTE is becoming well elucidated. Further investigations in this area will help to stratify risk patients in order to deliver treatments in the most efficient and effective manner. Recent evidence also shows a relationship between thrombophilias, CVU, and SVTs. There is growing evidence for the use of anticoagulation in treatment of SVTs. Further investigation is needed to clarify the role of thrombophilia in venous disease pathophysiology and progression. Scientific and technological advances in the area of venous disease are likely to create new treatment options and better management of an old disease.

From the Oregon Health and Sciences University, Vascular Surgery, Portland, Oregon.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted May 26, 2011, provisional acceptance given August 18, 2011, final version accepted August 18, 2011.

Address for correspondence: Dr. Amir F. Azarbal, MD, Oregon Health and Sciences University, Vascular Surgery, Mail Code OP11, 3181 S.W. Sam Jackson Park Rd, Portland, OR 97239 E-mail: azarbala@ohsu.edu

REFERENCES

1. Darvall KA, Sam RC, Adam DJ, Silverman SH, Fegan CD, Bradbury AW. Higher prevalence of thrombophilia in patients with varicose veins and venous ulcers than controls. J Vasc Surg. 2009 May;49(5):1235-1241.
2. Fowkes FJ, Price JF, Fowkes FG. Incidence of diagnosed deep vein thrombosis in the general population: Systematic review. Eur J Vasc Endovasc Surg. 2003 Jan;25(1):1-5.
3. Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrøm J. Incidence and mortality of venous thrombosis: A population-based study. J Thromb Haemost. 2007Apr;5(4):692-699.
4. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT study. Arch Intern Med. 1991 May;151(5):933-938.
5. Liem TK, DeLoughery TG. First episode and recurrent venous thromboembolism: Who is identifiably at risk? Semin Vasc Surg. 2008 Sep;21(3):132-138.
6. Rosendaal F. Risk factors for venous thrombotic disease. Thromb Haemost. 1999 Aug; 82(2):610-619.
7. Cushman M, Tsai AW, White RH, et al. Deep vein thrombosis and pulmonary embolism in two cohorts: The longitudinal investigation of thromboembolism etiology. Am J Med. 2004 Jul;117(1):19-25.
8. Cushman M, Kuller LH, Prentice R, et al; for Women’s Health Initiative Investigators. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004 Oct;292(13):1573-1580.
9. Wells PS, Louzada ML, Taljaard M, et al. A pilot study to assess the feasibility of a multicenter cluster randomized trial for the management of asymptomatic persons with thrombophilia. J Genet Couns. 2009 Oct;18(5):475-482.
10. Langlois NJ, Wells PS. Risk of venous thromboembolism in relatives of symptomatic probands with thrombophilia: A systematic review. Thromb Haemost. 2003 Jul;90(1):17-26.
11. Middeldorp S, Meinardi JR, Koopman MM, et al. A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism. Ann Intern Med. 2001 Sep;135(5):322-327.
12. Hansson PO, Sörbo J, Eriksson H. Recurrent venous thromboembolism after deep venous thrombosis: Incidence and risk factors. Arch Intern Med. 2000 Mar;160(6):769-774.
13. Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk or recurrent venous thromboembolism after discontinuing of anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica. 2007 Feb;92(2):199-205. 
14. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2005 May;293(19):2352-2361.
15. Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: Prospective cohort study. Lancet. 2003 Aug;362(9383):523-526.
16. Marchiori A, Mosena L, Prins MH, Prandoni P. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies. Haematologica. 2007 Aug;92(8):1107-1114.
17. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; for the American College of Chest Physicians. Anthithrombotic therapy of venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2008 Jun;133(6 Suppl):454S-545S.
18. Santamaria MG, Agnelli G, Taliani MR, et al; for the Warfarin Optimal Duration Italian Trial (WODIT) Investigators. Thrombophilic abnormalities and recurrence of venous thromboembolism in patients treated with standardized anticoagulant treatment. Thromb Res. 2005;116(4):301-306.
19. Shrivastava S, Ridker PM, Glynn RJ, et al. D-dimer, factor VIII coagulant activity, low-intensity warfarin and the risk of recurrent venous thromboembolism. J Thromb Haemost. 2006 Jun;4(6):1208-1214.
20. Mayberry J, Moneta G, Taylor L. Nonoperative treatment of venous stasis ulcers. In: Venous Disorders. Philadelphia: W.B. Saunders Company; 1991: pp.381-395.
21. Robertson L, Lee AJ, Gallagher K, et al. Risk factors for chronic ulceration in patients with varicose veins: A case control study. J Vasc Surg. 2009 Jun;49(6):1490-1498.
22. Mackenzie RK, Ludlam CA, Ruckley CV, Allan PL, Burns P, Bradbury AW. The prevalence of thrombophilia in patients with chronic venous leg ulceration. J Vasc Surg. 2002 Apr;35(4):718-722.
23. Kolbach DN, Veraart JC, Hamulyák K, Spaapen LJ, Neumann HA. Recurrent leg ulcers in a young man with hyperhomocysteinemia, factor V Leiden and impaired fibrinolysis. Acta Derm Venereol. 2002;82(1):52-54.
24. Clivati Brandt HR, de Lorenzo Messina MC, Belda Júnior W, Costa Martins JE, Criado PR. Leg ulcers associated with factor V Leiden and prothrombin G20210A and methyltetrahydrofolate reductase mutations: Successful treatment with warfarin. Int J Dermatol. 2007 Dec;46(12):1319-1320.
25. Marston WA, Carlin RE, Passman MA, Farber MA, Keagy BA. Healing rates and cost efficacy of outpatient compression treatment for leg ulcers associated with venous insufficiency. J Vasc Surg. 1999 Sep;30(3):491-498.
26. Goehl MS, Barwell JR, Taylor M, et al. Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): Randomized controlled trial. BMJ. 2007 Jul;335(7610):83.
27. van Gent WB, Hop WC, van Praag MC, Mackaay AJ, de Boer EM, Wittens CH. Conservative versus surgical treatment of venous leg ulcers: A prospective, randomized, multicenter trial. J Vasc Surg. 2006 Sep;44(3):563-571.
28. Milic DJ, Zivic SS, Bogdanovic DC, Karanovic ND, Golubovic ZV. Risk factors related to the failure of venous leg ulcers to heal with compression treatment. J Vasc Surg. 2009 May;49(5):1242-1247.
29. Puggioni A, Marks N, Hingorani A, Shiferson A, Alhalbouni S, Ascher E. The safety of radiofrequency ablation of the great saphenous vein in patients with previous venous thrombosis. J Vasc Surg. 2009 May;49(5):1248-1255.
30. Lurie F, Creton D, Eklof B, et al. Prospective randomized study of endovenous radiofrequency obliteration (closure procedure) versus ligation and stripping in a selected patient population (EVOLVeS Study). J Vasc Surg. 2003 Aug;38(2):207-214.
31. Leon LR Jr, Labropoulos N. Superficial vein thrombosis and hypercoagulable states: The evidence. Perspect Vasc Surg Endovasc Ther. 2005;17(1):43-46.
32. Gorty S, Patton-Adkins J, DaLanno M, Starr J, Dean S, Satiani B. Superficial venous thrombosis of the lower extremities: Analysis of risk factors, and recurrence and role of anticoagulation. Vasc Med. 2004 Feb;9(1):1-6.
33. Quenet S, Laporte S, Décousus H, Leizorovicz A, Epinat M, Mismetti P; for the STENOX Group. Factors predictive of venous thrombotic complications in patients with isolated superficial vein thrombosis. J Vasc Surg. 2003 Nov;38(5):944-949.
34. Milio G, Saragusa S, Minà C, et al. Superficial venous thrombosis: Prevalence of common genetic risk factors and their role on spreading to deep veins. Thromb Res. 2008;123(2):194-199.
35. Chengelis DL, Bendick PJ, Glover JL, Brown OW, Ranval TJ. Progression of superficial venous thrombosis to deep vein thrombosis. J Vasc Surg. 1996 Nov;24(5):745-749.
36. Superficial Thrombophlebitis Treated by Enoxaparin Group. A pilot randomized double-blind comparison of a low-molecular-weight heparin, a nonsteroidal anti-inflammatory agent, and placebo in the treatment of superficial vein thrombosis. Arch Intern Med. 2003 Jul;163(14):1657-1663.
37. Titon JP, Auger D, Grange P, et al. Therapeutic management of superficial venous thrombosis with calcium nadroparin. Dosage testing and comparison with a non-steroidal anti-inflammatory agent. Ann Cardiol Angeiol (Paris). 1994 Mar;43(3):160-166.
38. Belcaro G, Nicolaides AN, Errichi BM, et al. Superficial thrombophlebitis of the legs: A randomized controlled follow-up study. Angiology. 1999 Jul;50(7):523-529.
39. Marchiori A, Verlato F, Sabbion P, et al. High versus low doses of unfractionated heparin for the treatment of superficial thrombophlebitis of the leg. A prospective, controlled, randomized study. Haematologica. 2002 May;87(5):523-527.
40. Lozano FS, Almazon A. Low-molecular-weight heparin versus saphenofemoral disconnection for the treatment of above-knee greater saphenous thrombophlebitis: A prospective study. Vasc Endovascular Surg. 2003 Nov-Dec;37(6):415-420.
41. Decousus H, Prandoni P, Mismetti P, et al; for the CALISTO Study Group. Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Eng J Med. 2010 Sep;363(13):1222-1232.