Treatment of Livedoid Vasculopathy with Low-Molecular-Weight Heparin Report of 2 Cases
Total Page：16
File Type：pdf, Size：1020Kb
THE CUTTING EDGE SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: DEE ANNA GLASER, MD; ELAINE SIEGFRIED, MD Treatment of Livedoid Vasculopathy With Low-Molecular-Weight Heparin Report of 2 Cases Bethany R. Hairston, MD; Mark D. P. Davis, MD; Lawrence E. Gibson, MD; Lisa A. Drage, MD; Mayo Clinic, Rochester, Minn The Cutting Edge: Challenges in Medical and Surgical Therapeutics REPORT OF CASES left ankle was notable for hyalinization of dermal blood vessels in the papillary and superficial reticular dermis CASE 1 and minimal perivascular lymphocytic infiltrate (Figure 2). Direct immunofluorescence study showed A 23-year-old man who was otherwise healthy had a superficial vessel deposition of IgG, IgM, and C3 conju- 5-year history of recalcitrant ulcers of the lower extremi- gates with patchy deposition of fibrin. Results of labo- ties. The ulcers worsened in warm weather and during ratory studies, including an extensive screen for coagu- periods of increased physical activity. The ulcers were lation abnormalities, were normal. Taken together, these painful and interfered with his participation in sports, findings were consistent with a diagnosis of livedoid vas- including soccer and basketball. Shallow ulcers and crust- culopathy. Several treatment approaches had been inef- ing with stellate, porcelain-white scarring and surround- fective in controlling ulceration. These approaches in- ing hyperpigmentation on the lower extremities and dor- cluded topical corticosteroids, compression therapy, sal feet were noted on examination (Figure 1). stanozolol, and a triple regimen of pentoxifylline (400 Noninvasive vascular testing, including continuous- mg, 3 times daily for 29 months), nifedipine (30 mg/d wave venous Doppler imaging and measurements of the for 21 months), and aspirin (81 mg/d for 29 months). ankle-brachial index and transcutaneous oximetry (TcPO2), revealed moderately to severely reduced TcPO2 CASE 2 levels but no evidence of venous insufficiency. Histo- pathologic analysis of a skin biopsy specimen from the A 59-year-old man had been treated for seasonal, pain- ful ulcers of the lower extremities for 4 years. His his- tory was also notable for a low-grade B-cell lymphopro- Figure 2. Histopathologic analysis of lower extremity lesions showing hyalinized, fibrinoid change with thrombosis of vessels in the papillary and Figure 1. Shallow ulcers of the dorsal feet with postinflammatory superficial reticular dermis (patient 1 before treatment) (hematoxylin-eosin, hyperpigmentation and stellate scarring (patient 1 before treatment). original magnification ϫ400). (REPRINTED) ARCH DERMATOL / VOL 139, AUG 2003 WWW.ARCHDERMATOL.COM 987 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 ment in physical manifestations and alleviation of the pain associated with the ulcers. SOLUTION A trial of subcutaneous injectable enoxaparin, a low- molecular-weight heparin, was initiated in our patients after patient education in self-administration. In both cases, the patients were maintained on their current oral regimens (pentoxifylline, extended-release nifedipine, and aspirin in case 1; extended-release niacin, pentoxifyl- line, and aspirin in case 2). Two dosing regimens were used. Patient 1 received enoxaparin, 1 mg/kg by subcu- taneous injection every 12 hours, which is the dosage of enoxaparin used to treat active thrombosis.1 Patient 2 was treated with 30 mg by subcutaneous injection every 12 Figure 3. Marked improvement in the ulcers of the dorsal feet (patient 1 after 4 months of treatment with enoxaparin). hours, which is the perioperative prophylactic dose against deep venous thrombosis.1 Patient 1 noted no further ul- liferative disorder (IgG monoclonal protein) previously ceration after initiating the injections and had dramatic treated with rituximab. The ulcerative disease did not im- healing of his ulcers within 4 months (Figure 3). Re- prove during the course of rituximab treatment. Physi- peated TcPO2 measurements of the lower extremities 9 cal examination revealed shallow, crusted ulcers and sur- months after initiation of therapy revealed marked im- rounding stellate white scars with telangiectases and provement in oxygenation with normalization of previ- hyperpigmentation on the anterior shins and dorsal feet. ously reduced levels. His discomfort also was controlled Noninvasive vascular testing, including continuous- on the regimen without further need for daily pain medi- wave venous Doppler imaging and measurements of the cations. After 6 months of therapy, his dosage was de- ankle-brachial index and TcPO2, showed moderately to se- creased to 1 mg/kg once daily with continued benefit. Pa- verely reduced TcPO2 of the arterior part of both legs and tient 2 also had improvement in his ulcers in his 7 months the left dorsal foot. A skin biopsy specimen from the lower on the enoxaparin regimen. extremity revealed ulceration with hyalinizing, fibrinoid changes of the small to medium dermal blood vessels with- COMMENT out marked inflammation. A direct immunofluorescence study of the skin specimen demonstrated vascular stain- Livedoid vasculopathy, or livedoid vasculitis, is a dis- ing with C3 and fibrinogen. Taken together, these find- ease characterized by ulceration of the lower extremi- ings were consistent with a diagnosis of livedoid vascu- ties. Smooth, ivory-white plaquelike areas with sur- lopathy. An extensive coagulation screen and polymerase rounding telangiectases and hyperpigmentation chain reaction analysis revealed heterozygosity for the fac- (atrophie blanche) are commonly identified. The histo- tor V R506Q (Leiden) mutation. pathologic features are distinctive, although not patho- Because of the refractory nature of his active ulcer- gnomonic, and analysis usually reveals a segmental ations and secondary pain, the patient was hospitalized hyalinizing vascular pattern involving the dermal blood on the inpatient dermatology service and treated with topi- vessels, with vessel thickening, endothelial prolifera- cal corticosteroids, topical antibiotics, and wet dress- tion, and focal thrombosis without leukocytoclasis.2 Di- ings. Initially after hospitalization, his condition im- rect immunofluorescence staining typically demon- proved while receiving a regimen of niacin (500 mg, 3 strates immunoglobulin and complement components times daily for 8 months), pentoxifylline (400 mg, 3 times in the superficial, mid-dermal, and deep dermal vascu- daily for 8 months), and aspirin (81 mg/d for 8 months). lature.3 The underlying cause is not yet fully under- Treatment with these medications was discontinued by stood; however, the disease has been reported in indi- the patient, who continued topical corticosteroid therapy. viduals with altered coagulation, including factor V However, the ulcers recurred within 6 months and were Leiden mutation,4 protein C deficiency,5 antiphospho- recalcitrant to reintroduction of his previous regimen. lipid antibody syndrome,6 increased plasma homocys- Warfarin was considered; however, it was not an appro- teine levels,7 abnormalities in fibrinolysis,8 and in- priate therapy for him because his residence in a rural creased platelet activation.9 area had previously made it difficult to maintain a thera- Because potential thrombogenic mechanisms may peutic international normalized ratio. be involved in the disease pathogenesis,10,11 anticoagu- lant therapy is often tried. The Table lists anticoagu- THERAPEUTIC CHALLENGE lant and fibrinolytic therapies that have been reported in the English-language medical literature as treatments As outlined in the clinical cases, numerous therapies had for livedoid vasculopathy.12-24 Anticoagulant therapy with been undertaken without success in healing the exten- warfarin is another option. Treatment at our institution sive, painful, and scarring ulcers of livedoid vasculopa- has shown nicotinic acid to be helpful.25 Psoralen plus thy. Our challenge was to treat these recalcitrant lesions UV-A has also been reported as an effective treatment mo- with an alternative agent that would lead to improve- dality.26,27 (REPRINTED) ARCH DERMATOL / VOL 139, AUG 2003 WWW.ARCHDERMATOL.COM 988 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Anticoagulant and Fibrinolytic Therapies Used for Livedoid Vasculopathy Therapy Delivery Source No. of Patients Minidose heparin 5000 U by SC injection BID Jetton and Lazarus,12 1983 1 Heine and Davis,13 1986 1 Pentoxifylline 400 mg BID to TID Sauer,14 1986 6 Sams,15 1988 8 Combination antiplatelet therapy 1. Therapeutic doses of aspirin and dipyridamole 1. Drucker and Duncan,16 1982 7 Kern,17 1982 2 2. Ticlopidine hydrochloride, dipyridamole, and aspirin 2. Yamamoto et al,18 1988 2 Tissue plasminogen activator 10 mg by IV infusion over 4 h for 14 d Klein and Pittelkow,19 1992 6 Danazol 200 mg QD Hsiao and Chiu,20 1996 2 Hsiao and Chiu,21 1997 7 Wakelin et al,22 1998 1 Prostacyclin platelet aggregation inhibition 1. Prostacyclin infusion 1. Hoogenberg et al,23 1992 1 2. Beraprost sodium (prostaglandin analogue) 2. Tsutsui et al,24 1996 4 Abbreviations: BID, twice daily; IV, intravenous; QD, daily; SC, subcutaneous; TID, 3 times per day. Our cases illustrate the use of enoxaparin as a poten- nial bleeding) and thrombocytopenia. However, a weight- tial therapy for livedoid vasculopathy. Patient 1 is an oth- adjusted dosage of enoxaparin is as efficacious as erwise healthy young man