American Journal of Therapeutics 0, 1–7 (2015)
Low-Molecular-Weight Heparins as Immunomodulators in Dermatology Practice Berna Solak, MD*
Low-molecular-weight heparins (LMWHs) have some effects on cell proliferation and inflammation beyond mere anticoagulation. They have been tried on treatment of a few dermatological disorders such as lichen planus, skin wound healing, recurrent aphtous stomatitis, chronic urticaria, and contact hypersensitivity. LMWHs are generally well-tolerated drugs, rarely can lead to severe reactions. In this article, we will review the novel indications of LMWHs in dermatology practice and common skin reactions associated with their use. Keywords: low-molecular-weight heparin, heparin, lichen planus, recurrent aphtous stomatitis, enoxaparin
INTRODUCTION Use of low-molecular-weight heparins (LMWHs) in dermatology is mainly limited to liken planus and recurrent aphtous stomatitis (RAS). First, Hodak et al1 showed efficacy of enoxaparin, an LMWH type, in widespread lichen planus (LP) in a preliminary small study. The authors hypothesized that LMWHs can be efficacious considering previous studies reporting importance of cell-mediated immunity in LP and immunomodulatory effects of low-dose LMWHs. Since then, a number of small and uncontrolled studies demonstrated relative efficacy and safety of LMWH use in the treatment of LP. Mostly, other reports regarding the use of LMWHs in dermatology are related to adverse events manifested in skin, which occurred after use of LMWHs in a variety of conditions other than dermatological disease. In this review, we will discuss the rationale in the use of LMWHs in LP with a special emphasis on underlying pathophysiology. We will also summarize potential adverse effects of LMWH use on skin.
Department of Dermatology, School of Medicine, Sakarya University, Sakarya, Turkey. The author has no conflicts of interest to declare. *Address for correspondence: Sakarya Universitesi, Tıp Fakültesi, Dermatoloji Ana Bilim Dalı, Sakarya, Turkey 54000. E-mail: [email protected]
Low-molecular-weight heparins LMWHs are produced by depolymerization of unfractionated heparin.1 Their average molecular weight is below 8000 Da.2 LMWHs are commonly used in clinical practice to prevent and treat venous thromboembolism. They are preferable to unfractionated heparin because they have some advantages such as longer half-life, more predictable anticoagulant response, easier dosage adjustment, no requirement for monitoring except special circumstances, and less bleeding risk. LMWHs have also less effect on the activated partial thromboplastin time and microvascular bleeding than unfractionated heparin.3 They exert antithrombotic effect by inhibiting activated factor X (Xa). The ratio of their anti-Xa to anti-IIa activity is greater than 1.2 LMWHs treatment in dermatologic disorders It has been reported that LMWHs have some actions beyond mere anticoagulation such as regulation of cell proliferation and inflammation, inhibition of neutrophil chemotaxis, and accumulation of eosinophils.4 LMWHs have been tried on treatment of only a few dermatological disorders to date, and the majority of these studies have been conducted on lichen planus.5–11 Additionally, there are a few other studies on skin wound healing, RAS, chronic urticaria, and contact hypersensitivity (Table 1). Lichen planus is an inflammatory disorder affecting skin, mucous membranes, and hair follicles and may
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Copyright Ó 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
First author
Disease
Study design
Iraji et al5
Lichen planus
Open-label, parallel, randomized clinical study
Ghaffari et al8
RAS
Open-label, uncontrolled interventional clinical study
Open-label, uncontrolled interventional clinical study
Femiano and Scully12
Oral lichen planus
Open-label, uncontrolled interventional clinical study
Akdeniz et al13
Lichen planus
Open-label, uncontrolled interventional clinical study
48 (25 patients were Enoxaparin subcutaneously, treated with 5 mg, once enoxaparin and a week 23 patients with prednisone orally)
30
Enoxaparin subcutaneously, 3 mg, once a week
Duration of treatment/ Follow-up
Outcomes (results)
Side effects
Up to 8-wk/6- The effectiveness No/minimal of enoxaparin is mo followlower than that up of prednisone. The relapse rate between 2 groups was statistically insignificant No/minimal 8-wk/3-mo Reduction of follow-up number, size, intensity and duration of pain, and recurrence intervals of aphtae in all patients No/minimal 2 wk Marked improvement in 5 of 8 patients
8 patients who did Nadroparin, subcutaneously, not give response 11.40 IU once to systemic a day and prednisone and tranexamic acid, cetirizine orally, 1 g, 3 times a day 20 Soludexide, orally, First 40 d 18 patients Treatment was 250 units twice responded aborted in 2 a day, then favorable. patients once a day Twelve of 18 because of 40-d/1-yr patients showed dizziness, follow-up no recurrence vomiting, and hot flushes No/minimal Up to 14 wk/ Complete 24 Enoxaparin, 12–14 mo recovery in 20 of subcutaneously, 24 patients with mg once a week no recurrence (Continued on next page)
Solak
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Asero et al11 Chronic urticaria
No. patients treated Medication/Dosage
2
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Table 1. Reported studies on low-molecular-weight heparins in dermatological diseases.
First author
Disease
Study design
Ferahbas‚ et al7
Lichen planus
Case series
Femiano et al14
RAS
Double-blind controlled clinical study
Rai et al15
Lichen planus
Open-label, uncontrolled interventional clinical study
Case series
Stefanidou et al9
Open-label, uncontrolled interventional clinical study
Lichen planus
7
Outcomes (results)
Side effects
Enoxaparin, 6 wk subcutaneously, 5 mg once a week 2 mo/2 mo Sulodexide ULS 250, orally twice daily for 1 mo, and then once daily for another month
Mild clinical No/minimal improvement only in 1 patient The effectiveness No/minimal 30 (10 patients of sulodexide on received number of sulodexide, 10 aphtha and patients received duration of pain oral prednisone, and and 10 patients epithelialization received placebo) is less than prednisone, but better than control Skin necrosis 6 wk None of the 10 Enoxaparin, (treatment was patients showed subcutaneously, stopped), complete 3 mg once a week lichen nitidusclinical like lesions remission (treatment was stopped) 8 wk to 6 mo Marked No/minimal 7 Enoxaparin, improvement in subcutaneously, 5 of 7 patients 30 mg once a day to a week No/minimal 6 to 13 wk/no Complete 18 Enoxaparin, remission or or subcutaneously, marked maximum 3 mg once a week improvement in 26-mo 13 of 18 follow-up patients. Recurrence in only 1 patient (Continued on next page)
3
American Journal of Therapeutics (2015) 0(0)
Pacheco and Lichen planus Kerdel16
No. patients treated Medication/Dosage
Duration of treatment/ Follow-up
LMWHs in Dermatology
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Table 1. (Continued) Reported studies on low-molecular-weight heparins in dermatological diseases.
First author
Disease
Study design
Hodak et al1 Lichen planus
Open-label, uncontrolled, interventional clinical study
Ingber et al10
Open-label, uncontrolled, interventional clinical study
Contact hypersensitivity
Yasar et al17 Palmoplantar Case report (2 hyperkeratotic type cases) of lichen planus Case report Cholongitas Generalized lichen nitidus et al18 Neville et al19
Cutaneous ulcerative Case report lichen planus in a patient with hepatitis C
No. patients treated Medication/Dosage 10
11 patients, 21 positive patch testing reaction
2
1
1
Duration of treatment/ Follow-up
4–6 wk Enoxaparin, subcutaneously, 3 mg once a week
Enoxaparin, subcutaneously, 3 mg
Single injection
4
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Outcomes (results) Improvement in 9 of 10 patients. Seven patients were on remission for at least 5 mo 4 of 21 positive reactions abated. Notable improvement in 3 patients with chronic allergic contact dermatitis Complete healing/ no recurrence
Enoxaparin, 12 wk/1 yr subcutaneously, 3 mg once a week Enoxaparin, 12 wk/32 mo Improvement/no subcutaneously, recurrence 3 mg once a week 4 wk/18 mo Notable Enoxaparin, improvement/ subcutaneously, no recurrence 30 mg biweekly for first 2 wk, then 30 mg biweekly for 2 wk
Side effects No/minimal
No/minimal
No/minimal
No/minimal
No/minimal
Solak
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Table 1. (Continued) Reported studies on low-molecular-weight heparins in dermatological diseases.
LMWHs in Dermatology
represent a type IV (delayed-type) hypersensitivity reaction to an antigenic stimulus residing within the epithelium.9 It has been shown that LMWHs inhibit T-cell migration and delayed-type hypersensitivity response at a very low dose through competitively inhibiting the activity of heparinase in T lymphocytes. Heparinase is released from activated T lymphocytes at the site of inflammation and related to the ability of activated T lymphocytes to penetrate the extracellular matrix and migrate to the target tissue. Beside this, heparin may inhibit the production of tumor necrosis factor alpha, which has a key role in inflammation.1,9 It was shown that heparin also exhibits antiproliferative effects through interaction with keratinocytegenerated, heparin-binding autocrine growth factors.20 Only 2 studies evaluated the effects of LMWHs in RAS patients.8,14 These studies generally found LMWHs treatment effective in reducing number and size of the lesion, pain intensity in patients with RAS probably owing to its anti-inflammatory properties. It has been reported that low-dose heparin inhibits allograft rejection and autoimmune diseases in mice. It is advantageous that heparin is more effective in inhibiting immune response at lower doses in avoiding potential adverse events such as bleeding.21 Another less studied area in which LMWHs used is allergic contact dermatitis. Ingber et al10 showed that LMWHs can diminish the severity of the patch test reactions and relieve the chronic allergic contact dermatitis. Durmaz et al6 compared the efficacy of LMWHs and unfractionated heparin in an experimental study in rats. The authors found that LWMH is superior than heparin on skin wound healing. It is supposed that LMWH inhibits proliferation of fibroblasts, endothelial cells, osteoblasts, and angiogenesis as well as increases the rate of reepithelialization. In the literature, enoxaparin is the most common form of LMWHs for wound healing, and the preferred dose was 1 mg/kg per day.6 Kalani et al22 evaluated dalteparin on healing of chronic foot ulcers in patients with diabetes with peripheral arterial occlusive disease in their prospective, randomized, double-blind, placebo-controlled study. They showed that dalteparin improves the chronic foot ulcer better than placebo.22 Serra et al23 showed that long-term use of LWMHs improved early and late results of skin grafting applied to chronic venous ulcers. The mechanism of LMWHs in wound healing is not exactly known, but it is suggested that it exerts anti-inflammatory and angiogenetic effects and also regulates the proinflammatory cytokines.23 In an uncontrolled study by Asero et al,11 chronic urticaria patients with elevated D-dimer and unresponsive to antihistamines and systemic prednisone www.americantherapeutics.com
5
were treated with nadroparin and tranexamic acid. The authors observed marked improvement of symptoms over half the patients (5 of 8 patients).11 Adverse effects on skin associated with LMWH use Although LMWHs are generally well-tolerated drugs and have minor side effects, they occasionally can lead to severe reactions. Before the commencement of the treatment, patients should be checked for platelet counts and creatinine clearance. Owing to the relatively long half-life of elimination of LMWHs and the lack of a specific antidote, it is difficult to reverse its anticoagulant action.2 It has been shown that there is no need of monitoring in follow-up of LMWH treatment, but in some patient groups including obese persons, children, pregnant women, and the patients with renal insufficiency, monitoring with factor Xa levels is recommended.2 Reported side effects of LMWHs manifested as dermatologic or systemic are listed in Table 2.24–33 LMHWs have a lower risk of heparin-induced thrombocytopenia compared with unfractionated heparin because of less interaction with platelet factor 4.2 The cutaneous side effects Table 2. Reported side effects of LMWHs manifested as dermatological disease and other systemic side effects.
Cutaneous side effects Acral edema Acute generalized exanthematous pustulosis Allergic reactions Alopecia Angioedema Bullous hemorrhagic dermatosis Delayed-type hypersensitivity DRESS syndrome Ecchymosis Erythema Erythematous maculopapular rash Fat necrosis Nail discoloration Pruritus Purpura Pyoderma gangrenosum-like skin changes Skin necrosis Urticarial rash
Other systemic side effects Anaphylactic reactions Bleeding Heparin induced thrombocytopenia Hyperkalemia Hypoaldosteronism Osteoporosis
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6
of LMWHs are various but most of the time not lifethreatening. In systematic reviews about LMWHinduced skin necrosis, researchers-explained necrosis is usually benign and uncommon, rarely surgical treatment may be necessary.28 Skin necrosis may be caused by vasculitis (type III Arthus reaction) or heparin-induced thrombocytopenia.24 Although it has been shown that LMWHs inhibit delayed-type hypersensitivity reaction, there are some studies regarding delayed-type hypersensitivity reactions may be caused by LMWHs as well.26,27
CONCLUSIONS In conclusion, LMWHs have a limited use in dermatology practice, mainly restricted to lichen planus. Considering immunomodulatory effects of low-dose LMWHs, it may have a broader list of indications in the future particularly in immunological and inflammatory dermatological disorders. To date, almost all studies used enoxaparin, and we do not know with certainty that whether beneficial effects of LMWHs are a class effect or not. Low-dose application of LMWHs in aforementioned dermatological disorders make untoward adverse events more unlikely in contrast to other indications in which they are used with an intent to provide systemic anticoagulation. Futuremore, studies are clearly needed to establish their place in various dermatological disorders.
REFERENCES 1. Hodak E, Yosipovitch G, David M, et al. Low-dose lowmolecular-weight heparin (enoxaparin) is beneficial in lichen planus: a preliminary report. J Am Acad Dermatol. 1998;38:564–568. 2. Gray E, Mulloy B, Barrowcliffe TW. Heparin and lowmolecular-weight heparin. Thromb Haemost. 2008;99:807–818. 3. Hirsh J, Levine MN. Low molecular weight heparin. Blood. 1992;79:1–17. 4. Martinez-Salas J, Mendelssohn R, Abraham WM, et al. Inhibition of allergic airway responses by inhaled lowmolecular-weight heparins: molecular-weight dependence. J Appl Physiol (1985). 1998;84:222–228. 5. Iraji F, Asilian A, Saeidi A, et al. Comparison of therapeutic effect of low-dose low-molecular-weight heparin (enoxaparin) vs. oral prednisone in treatment of patients with lichen planus; a clinical trial. Adv Biomed Res. 2013;2:76. 6. Durmaz CE, Ozkan A, Senel B, et al. Comparison of effects of unfractionated heparin and low molecular weight heparin on skin wound healing of rats. Acta Cir Bras. 2012;27:639–644. 7. Ferahbas A, Uksal U, Kutlugun C, et al. Low-molecularweight heparin (enoxaparin) in the treatment of lichen planus. J Eur Acad Dermatol Venereol. 2003;17:604–605. American Journal of Therapeutics (2015) 0(0)
Solak 8. Ghaffari S, Barikbin L, Ashnagar S, et al. Enoxaparin for the treatment of recurrent aphthous stomatitis: a pilot exploratory clinical trial. Minerva Stomatol. 2013;62:281–287. 9. Stefanidou MP, Ioannidou DJ, Panayiotides JG, et al. Low-molecular-weight heparin; a novel alternative therapeutic approach for lichen planus. Br J Dermatol. 1999; 141:1040–1045. 10. Ingber A, Trattner A, Cohen IR, et al. Low doses of lowmolecular-weight heparin in vivo inhibits the elicitation of contact hypersensitivity. Acta Derm Venereol. 1994;74: 454–456. 11. Asero R, Tedeschi A, Cugno M. Heparin and tranexamic acid therapy may be effective in treatment-resistant chronic urticaria with elevated D-dimer: a pilot study. Int Arch Allergy Immunol. 2010;152:384–389. 12. Femiano F, Scully C. Oral lichen planus: clinical and histological evaluation in an open trial using a lowmolecular-weight heparin (sulodexide). Int J Dermatol. 2006;45:986–989. 13. Akdeniz S, Harman M, Atmaca S, et al. The management of lichen planus with low-molecular-weight heparin (enoxaparin). Int J Clin Pract. 2005;59:1268–1271. 14. Femiano F, Gombos F, Scully C. Recurrent aphthous stomatitis unresponsive to topical corticosteroids: a study of the comparative therapeutic effects of systemic prednisone and systemic sulodexide. Int J Dermatol. 2003;42:394–397. 15. Rai R, Kaur I, Kumar B. Low-dose low-molecular-weight heparin in lichen planus. J Am Acad Dermatol. 2002;46: 141–143. 16. Pacheco H, Kerdel F. Successful treatment of lichen planus with low-molecular-weight heparin: a case series of seven patients. J Dermatolog Treat. 2001;12:123–126. 17. Yasar S, Serdar ZA, Goktay F, et al. The successful treatment of palmoplantar hyperkeratotic lichen planus with enoxaparin. Indian J Dermatol Venereol Leprol. 2011;77: 64–66. 18. Cholongitas E, Kokolakis G, Giannikaki E, et al. Persistent generalized lichen nitidus successfully treated with enoxaparin sodium. Am J Clin Dermatol. 2008;9:349–350. 19. Neville JA, Hancox JG, Williford PM, et al. Treatment of severe cutaneous ulcerative lichen planus with lowmolecular-weight heparin in a patient with hepatitis C. Cutis. 2007;79:37–40. 20. Pillai S, Gilliam L, Conrad HE, et al. Heparin and its nonanticoagulant analogues inhibit human keratinocyte growth without inducing differentiation. J Invest Dermatol. 1994;103:647–650. 21. Lider O, Baharav E, Mekori YA, et al. Suppression of experimental autoimmune diseases and prolongation of allograft survival by treatment of animals with low doses of heparins. J Clin Invest. 1989;83:752–756. 22. Kalani M, Apelqvist J, Blomback M, et al. 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. 23. Serra R, Buffone G, de Franciscis A, et al. Skin grafting followed by low-molecular-weight heparin long-term www.americantherapeutics.com
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LMWHs in Dermatology
24.
25.
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27.
therapy in chronic venous leg ulcers. Ann Vasc Surg. 2012;26:190–197. Wutschert R, Piletta P, Bounameaux H. Adverse skin reactions to low molecular weight heparins: frequency, management and prevention. Drug Saf. 1999; 20:515–525. Bassas P, Bartralot R, Garcia-Patos V. Anticoagulation and antiplatelet therapy in dermatology [in Spanish]. Actas Dermosifiliogr. 2009;100:7–16. Koch P, Munssinger T, Rupp-John C, et al. Delayed-type hypersensitivity skin reactions caused by subcutaneous unfractionated and low-molecular-weight heparins: tolerance of a new recombinant hirudin. J Am Acad Dermatol. 2000;42:612–619. Grims RH, Weger W, Reiter H, et al. Delayed-type hypersensitivity to low molecular weight heparins and heparinoids: cross-reactivity does not depend on molecular weight. Br J Dermatol. 2007; 157:514–517.
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7 28. Handschin AE, Trentz O, Kock HJ, et al. Low-molecularweight heparin-induced skin necrosis-a systematic review. Langenbecks Arch Surg. 2005;390:249–254. 29. Sobieszczanska M, Tubek S, Kura I. Pyoderma gangrenosum-like skin changes after subcutaneous administration of low molecular weight heparin. Hum Vaccin Immunother. 2014;10:968–969. 30. Ozturk S, Can I, Erden I, et al. Enoxaparin-induced hemorrhagic bullous dermatosis in a leprosy patient. Cutan Ocul Toxicol. September 8, 2014. doi:10.3109/15569527. 2014.950381. 31. Komericki P, Grims R, Kranke B, et al. Acute generalized exanthematous pustulosis from dalteparin. J Am Acad Dermatol. 2007;57:718–721. 32. Takci Z, Ozoguz P. Nail discoloration due to tinzaparin sodium. Cutan Ocul Toxicol. 2012;31:332–334. 33. Ronceray S, Dinulescu M, Le Gall F, et al. Enoxaparininduced DRESS syndrome. Case Rep Dermatol. 2012;4: 233–237.
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Low-Molecular-Weight Heparins as Immunomodulators in Dermatology Practice Berna Solak, MD*
Low-molecular-weight heparins (LMWHs) have some effects on cell proliferation and inflammation beyond mere anticoagulation. They have been tried on treatment of a few dermatological disorders such as lichen planus, skin wound healing, recurrent aphtous stomatitis, chronic urticaria, and contact hypersensitivity. LMWHs are generally well-tolerated drugs, rarely can lead to severe reactions. In this article, we will review the novel indications of LMWHs in dermatology practice and common skin reactions associated with their use. Keywords: low-molecular-weight heparin, heparin, lichen planus, recurrent aphtous stomatitis, enoxaparin
INTRODUCTION Use of low-molecular-weight heparins (LMWHs) in dermatology is mainly limited to liken planus and recurrent aphtous stomatitis (RAS). First, Hodak et al1 showed efficacy of enoxaparin, an LMWH type, in widespread lichen planus (LP) in a preliminary small study. The authors hypothesized that LMWHs can be efficacious considering previous studies reporting importance of cell-mediated immunity in LP and immunomodulatory effects of low-dose LMWHs. Since then, a number of small and uncontrolled studies demonstrated relative efficacy and safety of LMWH use in the treatment of LP. Mostly, other reports regarding the use of LMWHs in dermatology are related to adverse events manifested in skin, which occurred after use of LMWHs in a variety of conditions other than dermatological disease. In this review, we will discuss the rationale in the use of LMWHs in LP with a special emphasis on underlying pathophysiology. We will also summarize potential adverse effects of LMWH use on skin.
Department of Dermatology, School of Medicine, Sakarya University, Sakarya, Turkey. The author has no conflicts of interest to declare. *Address for correspondence: Sakarya Universitesi, Tıp Fakültesi, Dermatoloji Ana Bilim Dalı, Sakarya, Turkey 54000. E-mail: [email protected]
Low-molecular-weight heparins LMWHs are produced by depolymerization of unfractionated heparin.1 Their average molecular weight is below 8000 Da.2 LMWHs are commonly used in clinical practice to prevent and treat venous thromboembolism. They are preferable to unfractionated heparin because they have some advantages such as longer half-life, more predictable anticoagulant response, easier dosage adjustment, no requirement for monitoring except special circumstances, and less bleeding risk. LMWHs have also less effect on the activated partial thromboplastin time and microvascular bleeding than unfractionated heparin.3 They exert antithrombotic effect by inhibiting activated factor X (Xa). The ratio of their anti-Xa to anti-IIa activity is greater than 1.2 LMWHs treatment in dermatologic disorders It has been reported that LMWHs have some actions beyond mere anticoagulation such as regulation of cell proliferation and inflammation, inhibition of neutrophil chemotaxis, and accumulation of eosinophils.4 LMWHs have been tried on treatment of only a few dermatological disorders to date, and the majority of these studies have been conducted on lichen planus.5–11 Additionally, there are a few other studies on skin wound healing, RAS, chronic urticaria, and contact hypersensitivity (Table 1). Lichen planus is an inflammatory disorder affecting skin, mucous membranes, and hair follicles and may
1075–2765 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright Ó 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
First author
Disease
Study design
Iraji et al5
Lichen planus
Open-label, parallel, randomized clinical study
Ghaffari et al8
RAS
Open-label, uncontrolled interventional clinical study
Open-label, uncontrolled interventional clinical study
Femiano and Scully12
Oral lichen planus
Open-label, uncontrolled interventional clinical study
Akdeniz et al13
Lichen planus
Open-label, uncontrolled interventional clinical study
48 (25 patients were Enoxaparin subcutaneously, treated with 5 mg, once enoxaparin and a week 23 patients with prednisone orally)
30
Enoxaparin subcutaneously, 3 mg, once a week
Duration of treatment/ Follow-up
Outcomes (results)
Side effects
Up to 8-wk/6- The effectiveness No/minimal of enoxaparin is mo followlower than that up of prednisone. The relapse rate between 2 groups was statistically insignificant No/minimal 8-wk/3-mo Reduction of follow-up number, size, intensity and duration of pain, and recurrence intervals of aphtae in all patients No/minimal 2 wk Marked improvement in 5 of 8 patients
8 patients who did Nadroparin, subcutaneously, not give response 11.40 IU once to systemic a day and prednisone and tranexamic acid, cetirizine orally, 1 g, 3 times a day 20 Soludexide, orally, First 40 d 18 patients Treatment was 250 units twice responded aborted in 2 a day, then favorable. patients once a day Twelve of 18 because of 40-d/1-yr patients showed dizziness, follow-up no recurrence vomiting, and hot flushes No/minimal Up to 14 wk/ Complete 24 Enoxaparin, 12–14 mo recovery in 20 of subcutaneously, 24 patients with mg once a week no recurrence (Continued on next page)
Solak
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Asero et al11 Chronic urticaria
No. patients treated Medication/Dosage
2
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Table 1. Reported studies on low-molecular-weight heparins in dermatological diseases.
First author
Disease
Study design
Ferahbas‚ et al7
Lichen planus
Case series
Femiano et al14
RAS
Double-blind controlled clinical study
Rai et al15
Lichen planus
Open-label, uncontrolled interventional clinical study
Case series
Stefanidou et al9
Open-label, uncontrolled interventional clinical study
Lichen planus
7
Outcomes (results)
Side effects
Enoxaparin, 6 wk subcutaneously, 5 mg once a week 2 mo/2 mo Sulodexide ULS 250, orally twice daily for 1 mo, and then once daily for another month
Mild clinical No/minimal improvement only in 1 patient The effectiveness No/minimal 30 (10 patients of sulodexide on received number of sulodexide, 10 aphtha and patients received duration of pain oral prednisone, and and 10 patients epithelialization received placebo) is less than prednisone, but better than control Skin necrosis 6 wk None of the 10 Enoxaparin, (treatment was patients showed subcutaneously, stopped), complete 3 mg once a week lichen nitidusclinical like lesions remission (treatment was stopped) 8 wk to 6 mo Marked No/minimal 7 Enoxaparin, improvement in subcutaneously, 5 of 7 patients 30 mg once a day to a week No/minimal 6 to 13 wk/no Complete 18 Enoxaparin, remission or or subcutaneously, marked maximum 3 mg once a week improvement in 26-mo 13 of 18 follow-up patients. Recurrence in only 1 patient (Continued on next page)
3
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Pacheco and Lichen planus Kerdel16
No. patients treated Medication/Dosage
Duration of treatment/ Follow-up
LMWHs in Dermatology
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Table 1. (Continued) Reported studies on low-molecular-weight heparins in dermatological diseases.
First author
Disease
Study design
Hodak et al1 Lichen planus
Open-label, uncontrolled, interventional clinical study
Ingber et al10
Open-label, uncontrolled, interventional clinical study
Contact hypersensitivity
Yasar et al17 Palmoplantar Case report (2 hyperkeratotic type cases) of lichen planus Case report Cholongitas Generalized lichen nitidus et al18 Neville et al19
Cutaneous ulcerative Case report lichen planus in a patient with hepatitis C
No. patients treated Medication/Dosage 10
11 patients, 21 positive patch testing reaction
2
1
1
Duration of treatment/ Follow-up
4–6 wk Enoxaparin, subcutaneously, 3 mg once a week
Enoxaparin, subcutaneously, 3 mg
Single injection
4
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Outcomes (results) Improvement in 9 of 10 patients. Seven patients were on remission for at least 5 mo 4 of 21 positive reactions abated. Notable improvement in 3 patients with chronic allergic contact dermatitis Complete healing/ no recurrence
Enoxaparin, 12 wk/1 yr subcutaneously, 3 mg once a week Enoxaparin, 12 wk/32 mo Improvement/no subcutaneously, recurrence 3 mg once a week 4 wk/18 mo Notable Enoxaparin, improvement/ subcutaneously, no recurrence 30 mg biweekly for first 2 wk, then 30 mg biweekly for 2 wk
Side effects No/minimal
No/minimal
No/minimal
No/minimal
No/minimal
Solak
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Table 1. (Continued) Reported studies on low-molecular-weight heparins in dermatological diseases.
LMWHs in Dermatology
represent a type IV (delayed-type) hypersensitivity reaction to an antigenic stimulus residing within the epithelium.9 It has been shown that LMWHs inhibit T-cell migration and delayed-type hypersensitivity response at a very low dose through competitively inhibiting the activity of heparinase in T lymphocytes. Heparinase is released from activated T lymphocytes at the site of inflammation and related to the ability of activated T lymphocytes to penetrate the extracellular matrix and migrate to the target tissue. Beside this, heparin may inhibit the production of tumor necrosis factor alpha, which has a key role in inflammation.1,9 It was shown that heparin also exhibits antiproliferative effects through interaction with keratinocytegenerated, heparin-binding autocrine growth factors.20 Only 2 studies evaluated the effects of LMWHs in RAS patients.8,14 These studies generally found LMWHs treatment effective in reducing number and size of the lesion, pain intensity in patients with RAS probably owing to its anti-inflammatory properties. It has been reported that low-dose heparin inhibits allograft rejection and autoimmune diseases in mice. It is advantageous that heparin is more effective in inhibiting immune response at lower doses in avoiding potential adverse events such as bleeding.21 Another less studied area in which LMWHs used is allergic contact dermatitis. Ingber et al10 showed that LMWHs can diminish the severity of the patch test reactions and relieve the chronic allergic contact dermatitis. Durmaz et al6 compared the efficacy of LMWHs and unfractionated heparin in an experimental study in rats. The authors found that LWMH is superior than heparin on skin wound healing. It is supposed that LMWH inhibits proliferation of fibroblasts, endothelial cells, osteoblasts, and angiogenesis as well as increases the rate of reepithelialization. In the literature, enoxaparin is the most common form of LMWHs for wound healing, and the preferred dose was 1 mg/kg per day.6 Kalani et al22 evaluated dalteparin on healing of chronic foot ulcers in patients with diabetes with peripheral arterial occlusive disease in their prospective, randomized, double-blind, placebo-controlled study. They showed that dalteparin improves the chronic foot ulcer better than placebo.22 Serra et al23 showed that long-term use of LWMHs improved early and late results of skin grafting applied to chronic venous ulcers. The mechanism of LMWHs in wound healing is not exactly known, but it is suggested that it exerts anti-inflammatory and angiogenetic effects and also regulates the proinflammatory cytokines.23 In an uncontrolled study by Asero et al,11 chronic urticaria patients with elevated D-dimer and unresponsive to antihistamines and systemic prednisone www.americantherapeutics.com
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were treated with nadroparin and tranexamic acid. The authors observed marked improvement of symptoms over half the patients (5 of 8 patients).11 Adverse effects on skin associated with LMWH use Although LMWHs are generally well-tolerated drugs and have minor side effects, they occasionally can lead to severe reactions. Before the commencement of the treatment, patients should be checked for platelet counts and creatinine clearance. Owing to the relatively long half-life of elimination of LMWHs and the lack of a specific antidote, it is difficult to reverse its anticoagulant action.2 It has been shown that there is no need of monitoring in follow-up of LMWH treatment, but in some patient groups including obese persons, children, pregnant women, and the patients with renal insufficiency, monitoring with factor Xa levels is recommended.2 Reported side effects of LMWHs manifested as dermatologic or systemic are listed in Table 2.24–33 LMHWs have a lower risk of heparin-induced thrombocytopenia compared with unfractionated heparin because of less interaction with platelet factor 4.2 The cutaneous side effects Table 2. Reported side effects of LMWHs manifested as dermatological disease and other systemic side effects.
Cutaneous side effects Acral edema Acute generalized exanthematous pustulosis Allergic reactions Alopecia Angioedema Bullous hemorrhagic dermatosis Delayed-type hypersensitivity DRESS syndrome Ecchymosis Erythema Erythematous maculopapular rash Fat necrosis Nail discoloration Pruritus Purpura Pyoderma gangrenosum-like skin changes Skin necrosis Urticarial rash
Other systemic side effects Anaphylactic reactions Bleeding Heparin induced thrombocytopenia Hyperkalemia Hypoaldosteronism Osteoporosis
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of LMWHs are various but most of the time not lifethreatening. In systematic reviews about LMWHinduced skin necrosis, researchers-explained necrosis is usually benign and uncommon, rarely surgical treatment may be necessary.28 Skin necrosis may be caused by vasculitis (type III Arthus reaction) or heparin-induced thrombocytopenia.24 Although it has been shown that LMWHs inhibit delayed-type hypersensitivity reaction, there are some studies regarding delayed-type hypersensitivity reactions may be caused by LMWHs as well.26,27
CONCLUSIONS In conclusion, LMWHs have a limited use in dermatology practice, mainly restricted to lichen planus. Considering immunomodulatory effects of low-dose LMWHs, it may have a broader list of indications in the future particularly in immunological and inflammatory dermatological disorders. To date, almost all studies used enoxaparin, and we do not know with certainty that whether beneficial effects of LMWHs are a class effect or not. Low-dose application of LMWHs in aforementioned dermatological disorders make untoward adverse events more unlikely in contrast to other indications in which they are used with an intent to provide systemic anticoagulation. Futuremore, studies are clearly needed to establish their place in various dermatological disorders.
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