Abstract
In the present report, we would like to comment a case of patient with diabetes mellitus type 2 manifesting the rare complication of heparin subcutaneous administration in a form of pyoderma gangrenosum-like skin changes which were induced probably by an immune-modulating activity of heparin.
Keywords: :
A 61-y female patient with insulin-dependent type 2 diabetes mellitus, polyneuropathy and diabetic retinopathy, after amputation of the left lower limb for diabetic foot complications, presenting III/IV NYHA chronic cardiac failure and aortic defect with prevailing stenosis, after myocardial infarction and episode of pulmonary embolism, was transferred from Internal Diseases Department of Opole Provincial Medical Centre to Dermatology Department of Opole Voivodship Hospital with suspected gangrenous pyoderma (PG) for clinical diagnostics and adequate therapy. The following cutaneous changes were stated at admission: ulceration of the skin and the subcutaneous tissue on both sides of the navel—they occurred approximately three months before admission to the hospital, predominantly at sites of subcutaneously administered low molecular weight heparin (LMWH) (Clexane—enoxaparin sodium of Sanofi Aventis; 80 mg/0.8 ml) applied during a patient’s hospitalization in the cardiology ward for acute coronary syndrome.
Description of skin changes: the observed skin changes were local in character and occurred mainly on hypogastric skin and the skin of the right crus. Regarding the hypogastric skin, numerous ulcerations, surrounded by an inflammatory wall, were found. There was one extensive ulceration on the skin of the right crus, with morphology as that on the hypogastrium. Till hospital admission, the skin changes had been treated with gentamicin ointment, yet, without any visible improvement.
In the course of hospitalization, additional examinations were performed, revealing urinary tract infection (the patient was catheterized before for infection of the urinary tract with Escherichia coli). Urinary tract infection was treated according to urine culture results. Cyclosporine (Eqoral of TEVA) was administered as part of the hospital therapy in the oral dose of 500 mg/ day, under control of renal parameters and arterial pressure, together with local Flucinar N administration, which resulted in regression of the skin changes. Neither oral nor intravenous steroids were applied for advanced diabetic changes. The patient was discharged home in generally good condition.
In our opinion, the skin changes described might be the consequences of immune-modulating action of heparin being of immunotherapeutic properties.
PG-like skin changes have rarely been reported in literature before, usually after subcutaneous injections, among others, after the administration of interferon-alpha2b,Citation1 interferon-beta1b,Citation2 recombinant human erythropoietinCitation3 or ketobemidone.Citation4
In some reports regarding Clexane, single cases of skin necrosis and ulceration have been described after injections of heparins, including low molecular weight ones (LMWHs)Citation5 but they were not diagnosed as PG, just the opposite – heparin used to be applied as an adjunctive therapy of the diseaseCitation6,Citation7 and other ulcers.Citation8-Citation10
Occurrence of skin changes of PG features is considered to be associated with cellular immunity disorders.Citation11,Citation12
Heparin reveals an immune-modulating and immunotherapeutic activity with regards to cellular and humoral immunity,Citation13-Citation17 similar as the above-mentioned interferon and this mechanism could have been probably a cause of the PG-like skin changes found in the presented patient. An effective and quick reaction to treatment with cyclosporine additionally supports this mechanism.
In our opinion, glycation of systemic proteins, typical for advanced diabetes mellitus, is another possible element that could have induced such an immune response to heparin injection. Possibly X-ray contrast medium action as immunogenic factor may play a role, too.
In literature, as for now, only one case of pyoderma gangrenosum-like changes related to the heparin administration after a cardiac surgery procedure has been reported.Citation18
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
References
- Mir-Bonafé JM, Blanco-Barrios S, Romo-Melgar A, Santos-Briz A, Fernández-López E. Photoletter to the editor: Localized pyoderma gangrenosum after interferon-alpha2b injections. J Dermatol Case Rep. 2012 Sep 28;6(3):98-9. doi: http://dx.doi.org/10.3315/jdcr.2012.1113.
- Wells J, Kossard S, McGrath M. Abdominal wall ulceration and mucinosis secondary to recombinant human interferon-beta-1b. Australas J Dermatol 2005; 46:202 - 4; http://dx.doi.org/10.1111/j.1440-0960.2005.00181.x; PMID: 16008658
- Park CW, Shin YS, Shin MJ, Koh SH, Chang KU, Ahn YB, Chang YS, Bang BK. Pyoderma gangrenosum and spinal epidural abscess after subcutaneous administration of recombinant human erythropoietin. Nephrol Dial Transplant 1997; 12:1506 - 8; http://dx.doi.org/10.1093/ndt/12.7.1506; PMID: 9249800
- Danielsen AG, Hultberg IB, Weismann K. [Skin lesions after injection abuse. Chronic changes caused by ketobemidone (Ketogan)]. Ugeskr Laeger 1994; 156:162 - 4; PMID: 7905216
- http://www.sanofi-aventis.com.pl
- Dwarakanath AD, Yu LG, Brookes C, Pryce D, Rhodes JM. ‘Sticky’ neutrophils, pathergic arthritis, and response to heparin in pyoderma gangrenosum complicating ulcerative colitis. Gut 1995; 37:585 - 8; http://dx.doi.org/10.1136/gut.37.4.585; PMID: 7489951
- Chaudhry SI, George ML, Madans B, Black MM. Anticoagulant-responsive pyoderma gangrenosum associated with an underlying prothrombotic dysfibrinogenaemia. Br J Dermatol 2005; 153:1081 - 3; http://dx.doi.org/10.1111/j.1365-2133.2005.06918.x; PMID: 16225639
- Angiò LG, Pirrone G, Rivoli G, Fracassi MG, Rosato A, Piazzese E, Pacilé V, Sfuncia G, Fiumara F. Pyoderma gangrenosum of the “sinus mammarum” in ulcerative colitis. [Review] G Chir 2003; 24:247 - 54; PMID: 14569923
- Jörneskog G, Brismar K, Fagrell B. Low molecular weight heparin seems to improve local capillary circulation and healing of chronic foot ulcers in diabetic patients. Vasa 1993; 22:137 - 42; PMID: 8391741
- Serra R, Buffone G, Molinari V, Montemurro R, Perri P, Stillitano DM, Amato B, de Franciscis S. Low molecular weight heparin improves healing of chronic venous ulcers especially in the elderly. Int Wound J 2013; Forthcoming http://dx.doi.org/10.1111/iwj.12071; PMID: 23517508
- Hod T, Lazarov A, Edelstein E, Levy Y. A huge pyoderma gangrenosum-like lesion as a presenting sign of antiphospholipid antibody syndrome. J Rheumatol 2009; 36:1557 - 9; http://dx.doi.org/10.3899/jrheum.081182; PMID: 19567641
- Norris DA, Weston WL, Thorne G, Humbert JR. Pyoderma gangrenosum. Abnormal monocyte function corrected in vitro with hydrocortisone. Arch Dermatol 1978; 114:906 - 11; http://dx.doi.org/10.1001/archderm.1978.01640180040010; PMID: 666327
- Wasik M, Górski A. Heparin enhances generation of natural killer activity in vitro. Arch Immunol Ther Exp (Warsz) 1994; 42:73 - 6; PMID: 7503640
- Zheng Y, Yu M, Podd A, Yuan L, Newman DK, Wen R, Arepally G, Wang D. Critical role for mouse marginal zone B cells in PF4/heparin antibody production. Blood 2013; 121:3484 - 92; http://dx.doi.org/10.1182/blood-2013-01-477091; PMID: 23460609
- Harr T, Scherer K, Tsakiris DA, Bircher AJ. Immediate type hypersensitivity to low molecular weight heparins and tolerance of unfractioned heparin and fondaparinux. Allergy 2006; 61:787 - 8; http://dx.doi.org/10.1111/j.1398-9995.2006.01063.x; PMID: 16677252
- Chudasama SL, Espinasse B, Hwang F, Qi R, Joglekar M, Afonina G, Wiesner MR, Welsby IJ, Ortel TL, Arepally GM. Heparin modifies the immunogenicity of positively charged proteins. Blood 2010; 116:6046 - 53; http://dx.doi.org/10.1182/blood-2010-06-292938; PMID: 20852126
- Rouanet C, Debrie AS, Lecher S, Locht C. Subcutaneous boosting with heparin binding haemagglutinin increases BCG-induced protection against tuberculosis. Microbes Infect 2009; 11:995 - 1001; http://dx.doi.org/10.1016/j.micinf.2009.07.005; PMID: 19635582
- Luthra S, Theodore S, Liava’a M, Atkinson V, Tatoulis J. Cutaneous microangiopathic thrombosis complicated by pyoderma gangrenosum in post-cardiac surgery heparin-induced thrombocytopaenia. Heart Lung Circ 2009; 18:307 - 10; http://dx.doi.org/10.1016/j.hlc.2007.12.007; PMID: 18375181