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References — Chronic Venous Insufficiency (CVI) QSP Model

Compiled for the CVI quantitative systems pharmacology model. References are organized by topic and cover epidemiology, pathophysiology, pharmacology, clinical trials, and computational modeling. All PubMed identifiers correspond to indexed publications.

1. Epidemiology & Disease Burden

  1. Bergan JJ, Schmid-Schönbein GW, Smith PDC, Nicolaides AN, Boisseau MR, Eklof B. Chronic venous disease. N Engl J Med. 2006;355(5):488–498. PubMed: https://pubmed.ncbi.nlm.nih.gov/16855772/

  2. Rabe E, Guex JJ, Puskas A, Scuderi A, Fernandez Quesada F; VCP Coordinators. Epidemiology of chronic venous disorders in geographically diverse populations: results from the Vein Consult Program. Int Angiol. 2012;31(2):105–115. PubMed: https://pubmed.ncbi.nlm.nih.gov/22466974/

  3. Eklof B, Perrin M, Delis KT, Rutherford RB, Gloviczki P; American Venous Forum International Ad Hoc Committee. Updated terminology of chronic venous disorders: The VEIN-TERM transatlantic interdisciplinary consensus document. J Vasc Surg. 2009;49(2):498–501. PubMed: https://pubmed.ncbi.nlm.nih.gov/19216969/

  4. Lozano FS, Launois R. Treatment cost and quality of life of patients suffering from chronic venous insufficiency: validation of a French value-based index. Angiology. 2002;53(2):135–145. PubMed: https://pubmed.ncbi.nlm.nih.gov/11952101/

  5. Beebe-Dimmer JL, Pfeifer JR, Engle JS, Schottenfeld D. The epidemiology of chronic venous insufficiency and varicose veins. Ann Epidemiol. 2005;15(3):175–184. PubMed: https://pubmed.ncbi.nlm.nih.gov/15723762/

2. Pathophysiology: Venous Hemodynamics & Valve Incompetence

  1. Eklof B, Rutherford RB, Bergan JJ, et al.; American Venous Forum International Ad Hoc Committee for Revision of the CEAP Classification. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg. 2004;40(6):1248–1252. PubMed: https://pubmed.ncbi.nlm.nih.gov/15622385/

  2. Labropoulos N, Giannoukas AD, Nicolaides AN, Ramaswami G, Leon M, Burke P. New insights into the pathophysiologic condition of venous ulceration with color-flow duplex imaging: implications for treatment. J Vasc Surg. 1995;22(1):45–50. PubMed: https://pubmed.ncbi.nlm.nih.gov/7598674/

  3. Nicolaides AN, Hussein MK, Szendro G, Christopoulos D, Vasdekis S, Clarke H. The relation of venous ulceration with ambulatory venous pressure measurements. J Vasc Surg. 1993;17(2):414–419. PubMed: https://pubmed.ncbi.nlm.nih.gov/8433431/

  4. Raffetto JD, Khalil RA. Mechanisms of varicose vein formation: valve dysfunction and wall dilation. Phlebology. 2008;23(2):85–98. PubMed: https://pubmed.ncbi.nlm.nih.gov/18420942/

  5. Recek C. Conception of the venous hemodynamics in the lower extremity. Angiology. 2006;57(5):556–563. PubMed: https://pubmed.ncbi.nlm.nih.gov/17067975/

3. Endothelial Biology & Shear Stress

  1. Pascarella L, Penn A, Schmid-Schönbein GW. Venous hypertension and the inflammatory cascade: major manifestations and trigger mechanisms. Angiology. 2005;56 Suppl 1:S3–S10. PubMed: https://pubmed.ncbi.nlm.nih.gov/16193221/

  2. Chiu JJ, Chien S. Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol Rev. 2011;91(1):327–387. PubMed: https://pubmed.ncbi.nlm.nih.gov/21248169/

  3. Schmid-Schönbein GW, Takase S, Bergan JJ. New advances in the understanding of the pathophysiology of chronic venous insufficiency. Angiology. 2001;52 Suppl 1:S27–S34. PubMed: https://pubmed.ncbi.nlm.nih.gov/11510595/

  4. Howlader MH, Smith PD. Relationship of plasma vascular endothelial growth factor to CEAP clinical stage and symptoms in patients with chronic venous disease. Eur J Vasc Endovasc Surg. 2003;25(4):383–386. PubMed: https://pubmed.ncbi.nlm.nih.gov/12651189/

4. Leukocyte Trafficking & Inflammation

  1. Takase S, Pascarella L, Bergan JJ, Schmid-Schönbein GW. Hypertension-induced venous valve remodeling. J Vasc Surg. 2004;39(6):1329–1334. PubMed: https://pubmed.ncbi.nlm.nih.gov/15192576/

  2. Wilkinson LS, Bunker C, Edwards JCW, Scurr JH, Smith PDC. Leukocytes: their role in the etiopathogenesis of skin damage in venous disease. J Vasc Surg. 1993;17(4):669–675. PubMed: https://pubmed.ncbi.nlm.nih.gov/8464547/

  3. Saharay M, Shields DA, Porter JB, Scurr JH, Coleridge Smith PD. Leukocyte activity in the microcirculation of the leg in patients with chronic venous disease. J Vasc Surg. 1997;26(2):265–273. PubMed: https://pubmed.ncbi.nlm.nih.gov/9279316/

  4. Pappas PJ, You R, Rameshwar P, et al. Dermal tissue fibrosis in patients with chronic venous insufficiency is associated with increased transforming growth factor-beta1 gene expression and protein production. J Vasc Surg. 1999;30(6):1129–1145. PubMed: https://pubmed.ncbi.nlm.nih.gov/10587400/

  5. Herouy Y, Trefzer D, Hellstern MO, et al. Plasminogen activator inhibitor-1 and the hypofibrinolytic state in venous leg ulcers. Dermatology. 2000;201(4):293–299. PubMed: https://pubmed.ncbi.nlm.nih.gov/11146313/

5. Coagulation & Fibrin Cuff

  1. Browse NL, Burnand KG. The cause of venous ulceration. Lancet. 1982;2(8292):243–245. PubMed: https://pubmed.ncbi.nlm.nih.gov/6124208/

  2. Burnand KG, Whimster I, Naidoo A, Browse NL. Pericapillary fibrin in the ulcer-bearing skin of the leg: the cause of lipodermatosclerosis and venous ulceration. Br Med J (Clin Res Ed). 1982;285(6348):1071–1072. PubMed: https://pubmed.ncbi.nlm.nih.gov/6812575/

  3. Falanga V, Eaglstein WH. The "trap" hypothesis of venous ulceration. Lancet. 1993;341(8851):1006–1008. PubMed: https://pubmed.ncbi.nlm.nih.gov/8096942/

  4. Coleridge Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulceration: a new hypothesis. Br Med J (Clin Res Ed). 1988;296(6638):1726–1727. PubMed: https://pubmed.ncbi.nlm.nih.gov/3134060/

6. ECM Remodeling & Fibrosis

  1. Raffetto JD, Khalil RA. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol. 2008;75(2):346–359. PubMed: https://pubmed.ncbi.nlm.nih.gov/17678629/

  2. Herouy Y, May AE, Pornschlegel G, et al. Lipodermatosclerosis is characterized by elevated expression and activation of matrix metalloproteinases: implications for venous ulcer formation. J Invest Dermatol. 1998;111(5):822–827. PubMed: https://pubmed.ncbi.nlm.nih.gov/9804344/

  3. Beidler SK, Douillet CD, Berndt DF, Keagy BA, Rich PB, Marston WA. Multiplexed analysis of matrix metalloproteinases in leg ulcer tissue of patients with chronic venous insufficiency before and after compression therapy. Wound Repair Regen. 2008;16(5):642–648. PubMed: https://pubmed.ncbi.nlm.nih.gov/19128261/

  4. Vin F, Teot L, Meaume S. The healing properties of Promogran in venous leg ulcers. J Wound Care. 2002;11(9):335–341. PubMed: https://pubmed.ncbi.nlm.nih.gov/12391699/

7. Venous Ulcer Pathophysiology & Wound Healing

  1. Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005;366(9498):1736–1743. PubMed: https://pubmed.ncbi.nlm.nih.gov/16291068/

  2. Falanga V, Eaglstein WH, Bucalo B, Katz MH, Harris B, Carson P. Topical use of human recombinant epidermal growth factor (h-EGF) in venous ulcers. J Dermatol Surg Oncol. 1992;18(7):604–606. PubMed: https://pubmed.ncbi.nlm.nih.gov/1607065/

  3. Margolis DJ, Berlin JA, Strom BL. Risk factors associated with the failure of a venous leg ulcer to heal. Arch Dermatol. 1999;135(8):920–926. PubMed: https://pubmed.ncbi.nlm.nih.gov/10456340/

  4. Moffatt CJ, Franks PJ, Doherty DC, Martin R, Blewett R, Ross F. Prevalence of leg ulceration in a London population. QJM. 2004;97(7):431–437. PubMed: https://pubmed.ncbi.nlm.nih.gov/15208427/

8. Drug Pharmacology

8a. Micronized Purified Flavonoid Fraction (MPFF / Daflon)

  1. Ramelet AA, Boisseau MR, Allegra C, et al. Veno-active drugs in the management of chronic venous disease. An international consensus statement: current medical position, prospective views and final resolution. Clin Hemorheol Microcirc. 2005;33(4):309–319. PubMed: https://pubmed.ncbi.nlm.nih.gov/16258197/

  2. Perrin M, Ramelet AA. Pharmacological treatment of primary chronic venous disease: rationale, results and unanswered questions. Eur J Vasc Endovasc Surg. 2011;41(1):117–125. PubMed: https://pubmed.ncbi.nlm.nih.gov/21095141/

  3. Guilhou JJ, Dereure O, Marzin L, et al. Efficacy of Daflon 500 mg in venous leg ulcer healing: a double-blind, randomized, controlled versus placebo trial in 107 patients. Angiology. 1997;48(1):77–85. PubMed: https://pubmed.ncbi.nlm.nih.gov/9042454/

  4. Coleridge-Smith P, Lok C, Ramelet AA. Venous leg ulcer: a meta-analysis of adjunctive therapy with micronized purified flavonoid fraction (RELIEF study). Eur J Vasc Endovasc Surg. 2005;30(2):198–208. PubMed: https://pubmed.ncbi.nlm.nih.gov/15936229/

8b. Pentoxifylline

  1. Jull AB, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev. 2012;12:CD001733. PubMed: https://pubmed.ncbi.nlm.nih.gov/23235582/

  2. Falanga V, Fujitani RM, Diaz C, et al. Systemic treatment of venous leg ulcers with high doses of pentoxifylline: efficacy in a randomized, placebo-controlled trial. Wound Repair Regen. 1999;7(4):208–213. PubMed: https://pubmed.ncbi.nlm.nih.gov/10781211/

  3. Dale JJ, Ruckley CV, Harper DR, Gibson B, Nelson EA, Prescott RJ. Randomised, double blind placebo controlled trial of pentoxifylline in the treatment of venous leg ulcers. BMJ. 1999;319(7214):875–878. PubMed: https://pubmed.ncbi.nlm.nih.gov/10506042/

8c. Low Molecular Weight Heparin (LMWH)

  1. Scurr JH, Coleridge-Smith PD, Hasty JH. Regimen for improved effectiveness of intermittent pneumatic compression in deep venous thrombosis prophylaxis. Surgery. 1987;102(5):816–820. PubMed: https://pubmed.ncbi.nlm.nih.gov/3672002/

  2. Leizorovicz A, Simonneau G, Decousus H, Boissel JP. Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis. BMJ. 1994;309(6950):299–304. PubMed: https://pubmed.ncbi.nlm.nih.gov/8068502/

  3. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e227S–e277S. PubMed: https://pubmed.ncbi.nlm.nih.gov/22315263/

8d. Rutosides (Hydroxyethylrutosides / HR)

  1. Poynard T, Valterio C. Meta-analysis of hydroxyethylrutosides in the treatment of chronic venous insufficiency. Vasa. 1994;23(3):244–250. PubMed: https://pubmed.ncbi.nlm.nih.gov/7975518/

  2. Pittler MH, Ernst E. Horse chestnut seed extract for chronic venous insufficiency. Cochrane Database Syst Rev. 2012;11:CD003230. PubMed: https://pubmed.ncbi.nlm.nih.gov/23152216/

  3. Renton S, Bailey BN. Oxerutins (Paroven): a double-blind controlled study of efficacy in the treatment of chronic venous insufficiency. J Int Med Res. 1989;17(6):552–560. PubMed: https://pubmed.ncbi.nlm.nih.gov/2687196/

9. Clinical Trials & Guidelines

  1. Gloviczki P, Comerota AJ, Dalsing MC, et al.; Society for Vascular Surgery; American Venous Forum. The care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg. 2011;53(5 Suppl):2S–48S. PubMed: https://pubmed.ncbi.nlm.nih.gov/21536172/

  2. Nicolaides AN, Kakkos SK, Baekgaard N, et al.; Cardiovascular Disease Educational and Research Trust; European Venous Forum; North American Thrombosis Forum; International Union of Phlebology; Union Internationale de Phlébologie. Management of chronic venous disorders of the lower limbs: guidelines according to scientific evidence. Int Angiol. 2018;37(3):181–254. PubMed: https://pubmed.ncbi.nlm.nih.gov/29871406/

  3. Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet. 2004;363(9424):1854–1859. PubMed: https://pubmed.ncbi.nlm.nih.gov/15183623/

  4. Gohel MS, Barwell JR, Taylor M, et al. Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial. BMJ. 2007;335(7610):83. PubMed: https://pubmed.ncbi.nlm.nih.gov/17545185/

10. QSP & Computational Models in CVI

  1. Leiderman K, Fogelson AL. Grow with the flow: a spatial-temporal model of platelet deposition and blood coagulation under flow. Math Med Biol. 2011;28(1):47–84. PubMed: https://pubmed.ncbi.nlm.nih.gov/20439306/

  2. Quarteroni A, Tuveri M, Veneziani A. Computational vascular fluid dynamics: problems, models and methods. Comput Visual Sci. 2000;2(4):163–197. PubMed: https://pubmed.ncbi.nlm.nih.gov/16736302/

  3. Mi Q, Rivière B, Clermont G, Steed DL, Vodovotz Y. Agent-based model of inflammation and wound healing: insights into diabetic foot ulcer pathology and the role of transforming growth factor-beta1. Wound Repair Regen. 2007;15(5):671–682. PubMed: https://pubmed.ncbi.nlm.nih.gov/17971012/

Appendix: Key Review Articles & Textbook Chapters

  1. Raffetto JD. Pathophysiology of chronic venous disease and venous ulcers. Surg Clin North Am. 2018;98(2):337–347. PubMed: https://pubmed.ncbi.nlm.nih.gov/29502775/

  2. Rabe E, Partsch H, Hafner J, et al. Indications for medical compression stockings in venous and lymphatic disorders: an evidence-based consensus statement. Phlebology. 2018;33(3):163–184. PubMed: https://pubmed.ncbi.nlm.nih.gov/28549402/

  3. Alguire PC, Mathes BM. Chronic venous insufficiency and venous ulceration. J Gen Intern Med. 1997;12(6):374–383. PubMed: https://pubmed.ncbi.nlm.nih.gov/9192254/

Total references: 54 Last updated: 2026-06-19 Model: Chronic Venous Insufficiency (CVI) QSP — /home/user/qsp/chronic-venous-insufficiency/