Therapeutic use of lowmolecular weight heparin for capillaritis alba

G. Hesse; H. Kutzner

doi:10.1055/s-0037-1622240

Phlebologie, Inhaltsverzeichnis

Phlebologie 2008; 37(05): 259-265
DOI: 10.1055/s-0037-1622240

Original Article

Schattauer GmbH

Therapeutic use of lowmolecular weight heparin for capillaritis alba

Niedermolekulares Heparin zur Therapie der ulzerierten Capillaritis albaUsage thérapeutique des héparines à bas poids moléculaire pour l’atrophie blanche ulcérée

Authors

G. Hesse

¹Hautarztpraxis München, Germany
H. Kutzner

²Hautarztpraxis Friedrichshafen, Germany

Abstract

Summary

The reason of the so called ulcerated capillaritis alba or idiopathic atrophie blanche is vasculopathy caused by severe venous hypertension. Thrombosed and rarificated vessels worsen the oxygenation, increase permanent inflammation and impede the necessary compression therapy. The anti-inflammatory effects of heparin alleviate pain and being independent from the antithrombotic ones it needs much lower doses for treatment. This anti-inflammatory effect is now becoming more important in clinical phlebology. Case studies of more than 50 patients and one prospective randomized study of 87 patients clearly demonstrate the ameliorated healing of ulcerated atrophie blanche. In our office we could document this positive effect with 22 patients. We present the pathophysiology of low molecular heparins for ulcerated capillaritis alba and our own experiences with it.

Zusammenfassung

Die ulzerierte Capillaritis alba wird durch eine Livedovaskulopathie im Korium verursacht, die im Rahmen einer ausgeprägten venösen Hypertonie auftritt. Die thrombosierten und rarefizierten Gefäße verschlechtern die Oxygenation, erschweren die Kompression und führen zu einer andauernden schmerzhaften Entzündung. Die Anwendung von niedermolekularem Heparin führt zu Schmerzlinderung durch antientzündliche Heparinwirkungen. Diese antiinflammatorischen Wirkungen, neben den antithrombotischen Wirkungen der Heparine, treten heute in den Vordergrund der Grundlagenforschung und finden langsam auch Berücksichtigung in phlebologischen Studien. Arbeiten mit klinischen Beobachtungen bei über 50 Patienten und eine prospektiv randomisierte Studie mit 87 Teilnehmern belegen eindrucksvoll die verbesserte Ulkusheilung unter Heparin.

In der eigenen Praxis konnte diese positive Wirkung bei 22 Patienten dokumentiert werden. Nach Darstellung der Grundlagen und der eigenen Erfahrungen wird die Anwendung von niedermolekularem Heparin bei der ulzerierten Capillaritis alba diskutiert.

Résumé

L’étiologie de la lésion nommée atrophie blanche idiopathique avec ulcération est une vasculopathie causée par une hypertension veineuse sévère. Des vaisseaux thrombosés et raréfiés diminuent l’oxygénation, accroissent une inflammation permanente et gênent la compression thérapeutique nécessaire. L’effet anti-inflammatoire de l’héparine diminue la douleur et, indépendamment de son effet anti-thrombotique, nécessite de très faibles doses pour le traitement. Cet effet anti-inflammatoire est actuellement reconnu en phlébologie clinique. Une casuistique de plus 50 patients et une étude prospective randomisée de 87 patients démontrent clairement l’amélioration de la cicatrisation de l’atrophie blanche ulcérée. Dans note consultation, nous pouvons documenter cet effet positif avec 22 patients. Nous présentons le traitement par des héparines à bas poids moléculaire pour l’atrophie blanche avec ulcération, ainsi que le résultat de notre expérience.

Keywords

Ulcerated capillaritis alba - vasculopathy - low molecular weight heparin - protective effects of heparin

Schlüsselwörter

Ulzerierte Capillaritis alba - Vaskulopathie - niedermolekulares Heparin - protektive Heparinwirkung

Mots clés

Dermite blanche atrophique ulcérée - vasculopathie - héparine à bas poids moléculaire - effet protecteur de l’héparine

Volltext

Referenzen

References
1 Amirkhosravi A, Mousa SA, Amaya M, Francis JL. Antimetastatic effect of tinzaparin, a low-molecular-weight heparin. J Thromb Haemost 2003; 1: 1972-1976.
2 Berthold H, Schott G, Müller-Orlinghausen B. Pharmakovigilanz: Empfehlungen zur Meldung unerwünschter Arzneimittelwirkungen durch die Ärzteschaft. Arzneiverordnung in der Praxis 2005; 32: 25-26.
3 Bick RL, Scott RG. Stasis ulcers refractory to therapy--accelerated healing by treatment with clopidogrel +/- dalteparin: a preliminary report. Clin Appl Thromb Hemost 2001; 7: 21-24.
4 Biedermann T, Flaig MJ, Sander CA. Livedoid vasculopathy in a patient with factorV mutation (Leiden). J Cutan Pathol 2000; 27: 410-412.
5 Biegeleisen K, Neilsen RD, O’Shaughnessy A. Inadvertent intra-arterial injection complicating ordinary and ultrasound-guided sclerotherapy. J Dermatol Surg Oncol 1993; 19: 953-938.
6 Bloom S, Kiilerich S, Lassen MR, Forbes A, Leiper K, Langholz E, Irvine EJ, O’Morain C, Lowson D, Orm S. Low molecular weight heparin (tinzaparin) vs. placebo in the treatment of mild to moderately active ulcerative colitis. Aliment Pharmacol Ther 2004; 19: 871-878.
7 Bollinger A, Herrig I, Fischer M, Hoffmann U, Franzeck UK. Intravital capillaroscopy in patients with chronic venous insufficiency and lymphoedema: relevance to Daflon 500 mg. Int J Microcirc Clin Exp 1995; 15 (Suppl. 01) 41-44.
8 Boyvat A, Kundakçi N, Babikir MOA, Gürgey E. Livedoid vasculopathy associated with heterozygous protein C deficiency. Br J Dermatol 2000; 143: 840-842.
9 Brem H, Kirsner RS, Falanga V. Protocol for the successful treatment of venous ulcers. Am J Surg 2004; 188: 1-8.
10 Caillé JP. (Hrsg). Phlebologie en pratique quotidienne. Paris: Expansion Scientifique Francaise; 1982
11 Cooper JC, Griffiths AB, Jones RB, Raftery AT. Accidental intra-arterial injection in drug addicts. Eur J Vasc Surg 1992; 6: 430-433.
12 Cowin AJ, Hatzirodos N, Holding CA, Dunaiski V, Harries RH, Rayner TE, Fitridge R, Cooter RD, Schultz GS, Belford DA. Effect of healing on the expression of transforming growth factor beta(s) and their receptors in chronic venous leg ulcers. J Invest Dermatol 2001; 117: 1282-1289.
13 Deichmann B. Heparin bei Ulcus cruris. Phlebologie und Proktologie 1984; 13: 187-188.
14 Dissemond J, Goos M, Wagner SN. The role of oxidative stress in the pathogenesis and therapy of chronic wounds. Hautarzt 2002; 53: 718-723.
15 Ekre HP, Fjellner B, Hagermark O. Inhibition of complement dependent experimental inflammation in human skin by different heparin fractions. Int J Immunopharmacol 1986; 8: 277-286.
16 Falanga A, Piccioli A. Effect of anticoagulant drugs in cancer. Curr Opin Pulm Med 2005; 11: 403-407.
17 Gallenkemper G, Bulling BJ, Kahle B, Klüken N, Lehnert W, Rabe E, Schwahn-Schreiber Chr. Leitlinien zur Diagnostik und Therapie des Ulcus cruris venosum. AWMF-Leitlinien-Register Nr 037/009 Entwicklungsstufe 3. Phlebologie 1996; 25: 254-258.
18 Gibson GE, Li H, Pittelkow MR. Homocysteinemia and livedoid vasculitis. J AmAcad Dermatol 1999; 40: 279-281.
19 Gogly B, Hornebeck W, Groult N, Godeau G, Pellat B. Influence of heparin(s) on the interleukin-1-beta-induced expression of collagenase, stromelysin-1, and tissue inhibitor of metalloproteinase-1 in human gingival fibroblasts. Biochem Pharmacol 1998; 56: 1447-1454.
20 Gogly B, Dridi M, Hornebeck W, Bonnefoix M, Godeau G, Pellat B. Effect of heparin on the production of matrix metalloproteinases and tissue inhibitors of metalloproteinases by human dermal fibroblasts. Cell Biol Int 1999; 23: 203-209.
21 Gray HR, Graham JH, Johnson W, Burgoon CF. Atrophie blanche: periodic painful ulcers of lower extremities. Arch Dermatol 1966; 93: 187-193.
22 Grob JJ, Bonerandi JJ. Thrombotic skin disease as a marker of the anticardiolipin syndrome. J Am Acad Dermatol 1989; 20: 1063-1069.
23 Grulich-Henn J, Preissner KT, Muller-Berghaus G. Heparin stimulates fibrinolysis in mesothelial cells by selective induction of tissue-plasminogen activator but not plasminogen activator inhibitor-1 synthesis. Thromb Haemost 1990; 64: 420-425.
24 Hayward R, Scalia R, Hopper B, Appel 3^rd JZ, Lefer AM. Cellular mechanisms of heparinase III protection in rat traumatic shock. Am J Physiol 1998; 275: H23-30.
25 Heine KG, Davis GW. Idiopathic atrophie blanche: treatment with low-dose heparin. Arch Dermatol 1986; 122: 855-856.
26 Hoppensteadt D, Walenga JM, Fareed J, Bick RL. Heparin, low-molecular-weight heparins, and heparin pentasaccharide: basic and clinical differentiation. Hematol Oncol Clin North Am 2003; 17: 313-341.
27 Hsiao G-H, Chiu H-C. Livedoid vasculitis. Response to low-dose danazol. Arch Dermatol 1996; 132: 749-751.
28 Jetton RL, Lazarus GS. Minidose heparin therapy for vasculitis of atrophie blanche. J Am Acad Dermatol 1983; 8: 23-26.
29 Johnson Z, Proudfoot AE, Handel TM. Interaction of chemokines and glycosaminoglycans: a new twist in the regulation of chemokine function with opportunities for therapeutic intervention. Cytokine Growth Factor Re 2005; 16: 625-636.
30 Jorizzo JL. Livedoid vasculopathy. What is it?. Arch Dermatol 1998; 134: 491-493.
31 Jorneskog G, Brismar K, Fagrell B. Lowmolecular weight heparin seems to improve local capillary circulation and healing of chronic foot ulcers in diabetic patients. Vasa 1993; 22: 137-142.
32 Kainulainen V, Wang H, Schick C, Bernfield M. Syndecans, heparan sulfate proteoglycans, maintain the proteolytic balance of acute wound fluids. J Biol Chem 1998; 273: 11563-11569.
33 Kalani M, Apelqvist J, Blomback M, Brismar K, Eliasson B, Eriksson JW, Fagrell B, Hamsten A, Torffvit O, Jorneskog G. Effect of dalteparin on healing of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease: a prospective, randomized, double-blind, placebo-controlled study. Diabetes Care 2003; 26: 2575-2580.
34 Keeling D, Davidson S, Watson H. the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The management of heparin-induced thrombocytopenia. Br J Haematol 2006; 133: 259-269.
35 Klein KL, Pittelkow MR. Tissue plasminogen activator for treatment of livedoid vasculitis. Mayo Clin Proc 1992; 67: 923-933.
36 Koenig A, Norgard-Sumnicht K, Linhardt R, Varki A. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and lowmolecular weight heparins as therapeutic agents. J Clin Invest 1998; 101: 877-889.
37 Leu HJ. Morphology of chronic venous insufficiency – light and electron microscopic examinations. Vasa 1991; 20: 330-342.
38 Levine A, Kenet G, Bruck R, Avni Y, Avinoach I, Aeed H, Matas Z, David M, Yayon A. Effect of heparin on tissue binding activity of fibroblast growth factor and heparin-binding epidermal growth factor in experimental colitis in rats. Pediatr Res 2002; 51: 635-640.
39 Ludwig RJ, Alban S, Bistrian R, Boehncke WH, Kaufmann R, Henschler R, Gille J. The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo. Thromb Haemost 2006; 95: 535-540.
40 Maessen-Visch MB, Hamulyak K, Tazelaar DJ, Crombag NH, Neumann HA. The prevalence of factor V Leiden mutation in patients with leg ulcers and venous insufficiency. Arch Dermatol 1999; 135: 41-44.
41 Margolis DJ, Kruithof EKO, Barnard M. et al. Fibrinolytic abnormalities in two different cutaneous manifestations of venous disease. J Am Acad Dermatol 1996; 34: 204-208.
42 McCalmont CS, McCalmont TH, Jorizzo JL. et al. Livedo vasculitis: vasculitis or thrombotic vasculopathy?. Clin Exp Dermatol 1992; 17: 4-8.
43 Meiss F, Marsch WC, Fischer M. Livedoid vasculopathy The role of hyperhomocysteinemia and its simple therapeutic consequences. Eur J Dermatol 2006; 16: 159-162.
44 Miller SJ, Hoggat AM, Faulk WP. Heparin regulates ICAM-1 expression in human endothelial cells: an example of non-cytokine-mediated endothelial activation. Thromb Haemost 1998; 80: 481-487.
45 Milstone LM, Braverman IM, Lucky P, Fleckman P. Classification and therapy of atrophie blanche. Arch Dermatol 1983; 119: 963-969.
46 Milstone LM, Braverman IM. PURPLE (oops! atrophie blanche) revisited. Arch Dermatol 1998; 134: 1634.
47 Murphy MA, Joyce WP, Condron C, Bouchier-Hayes D. A reduction in serumcytokine levels parallels healing of venous ulcers in patients undergoing compression therapy. Eur J Vasc Endovasc Surg 2002; 23: 349-352.
48 Nelson EA, Cullum N, Jones J. Venous leg ulcers. Clin Evid 2005; 13: 2507-2526.
49 Papi M, Didona B, De Pità O. et al. Livedo vasculopathy vs small vessel cutaneous vasculitis. Arch Dermatol 1998; 134: 447-452.
50 Peplow PV. Glycosaminoglycan: a candidate to stimulate the repair of chronic wounds. Thromb Haemost 2005; 94: 4-16.
51 Peschen M, Rogers AA, Chen WY, Vanscheidt W. Modulation of urokinase-type and tissue-type plasminogen activator occurs at an early stage of progressing stages of chronic venous insufficiency. Acta DermVenereol 2000; 80: 162-166.
52 Pizzo SV, Murray JC, Gonias SL. Atrophie blanche. A disorder associated with defective release of tissue plasminogen activator. Arch Pathol Lab Med 1986; 110: 517-519.
53 Salim AS. The role of oxygen-derived free radicals in the management of venous (varicose) ulceration: a new approach. World J Surg 1991; 15: 264-269.
54 Schroeter AL, Diaz-Perez JL, Winkelmann RK, Jordon RE. Livedo vasculitis (the vasculitis of atrophie blanche). Immunohistopathologic study. Arch Dermatol 1975; 111: 188-193.
55 Schultz GS, Mast BA. Molecular analysis of the environment of healing and chronic wounds: cytokines, proteases, and growth factors. Wounds 1998; 10: 1-9.
56 Shirakata Y, Kimura R, Nanba D, Iwamoto R, Tokumaru S, Morimoto C, Yokota K, Nakamura M, Sayama K, Mekada E, Higashiyama S, Hashimoto K. Heparin-binding EGF-like growth factor accelerates keratinocyte migration and skin wound healing. J Cell Sci 2005; 118: 2363-2370.
57 Shornick JK, Nicholas BK, Bergstresser PR, Gilliam JN. Idiopathic atrophie blanche. J Am Acad Dermatol 1983; 8: 792-798.
58 Siegel-Axel DI, Gawaz M. Platelets and endothelial cells. Semin Thromb Hemost 2007; 33: 128-135.
59 Sternbergh 3^rd WC, Makhoul RG, Adelman B. Heparin prevents postischemic endothelial cell dysfunction by a mechanism independent of its anticoagulant activity. J Vasc Surg 1993; 17: 318-327.
60 Stevenson JL, Choi SH, Varki A. Differential metastasis inhibition by clinically relevant levels of heparins--correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res 2005; 11: 7003-7011.
61 Sudhalter J, Folkman J, Svahn CM, Bergendal K, D’Amore PA. Importance of size, sulfation, and anticoagulant activity in the potentiation of acidic fibroblast growth factor by heparin. J Biol Chem 1989; 264: 6892-6897.
62 Thanawiroon C, Rice KG, Toida T, Linhardt RJ. Liquid chromatography/mass spectrometry sequencing approach for highly sulfated heparin-derived oligosaccharides. J Biol Chem 2004; 279: 2608-2615.
63 Trengove NJ, Stacey MC, MacAuley S, Bennett N, Gibson J, Burslem F, Murphy G, Schultz G. Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors. Wound Repair Regen 1999; 7: 442-452.
64 Wagner DD. New links between inflammation and thrombosis. Arterioscler Thromb Vasc Biol 2005; 25: 1321-1324.
65 Williams D, Enoch S, Miller D, Harris K, Price P, Harding KG. Effect of sharp debridement using curette on recalcitrant nonhealing venous leg ulcers: a concurrently controlled, prospective cohort study. Wound Repair Regen 2005; 13: 131-137.
66 Yang LJ, Chan HL, Chen SY, Kuan YZ, Chen MJ, Wang CN, Chen WJ, Kuo TT. Atrophie blanche. A clinicopathological study of 27 patients. Changgeng Yi Xue Za Zhi 1991; 14: 237-245.