Treatment of Livedoid Vasculopathy with Low-Molecular-Weight Heparin Report of 2 Cases

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, painful ulcers of the lower extremities for 4 years. His history 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

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, pentoxifylline, and aspirin in case 2). Two dosing regimens were used. Patient 1 received enoxaparin, 1 mg/kg by subcutaneous 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 anticoagulant 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

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 with ulcers refractory to stan- unfractionated heparin in the treatment of deep venous dard therapies. He has had dramatic and sustained clinical thrombosis and is more convenient for patients to use29; improvement as he continues with the subcutaneous in- monitoring of the activated partial thromboplastin time jections. Levels of TcPO2, once moderately to severely re- is not necessary. Similarly, enoxaparin does not require duced, are within the normal range. His pain manage- monitoring of the therapeutic international normalized ment has been markedly improved as well. Patient 2 may ratio, as does warfarin. However, patients should be coun- have an underlying thrombotic diathesis with the factor seled regarding the risks of hemorrhage while they are V Leiden mutation, in addition to his chronic low-grade receiving enoxaparin, and contraindications to antico- B-cell lymphoproliferative disorder. This patient was main- agulation should be fully reviewed before therapy is ini- tained on the therapy during the summer months, when tiated. Candidates also should be screened for risk of os- his disease was usually more severe, and had an im- teoporosis, a potential complication of heparin therapy, proved response compared with that obtained with pre- and considered for calcium supplementation. Our pa- vious treatments. His lymphoproliferative process was tients were started on an aggressive regimen of enoxa- stable during the heparin therapy. He had flaring of his parin in combination with their previous medications, disease in the late summer months because of increased including aspirin. Although the concomitant use of as- activity and bacterial impetiginization, and his course was pirin and anticoagulants is usually avoided because of the discontinued at that time. Patient 1, who received 1 mg/kg increased risk of bleeding, the severity of the disease in of enoxaparin twice daily, had a more effective and pro- our patients warranted aggressive therapy; potential risks longed response to the medication. Benefits continued with were appropriately reviewed with the patients before treat- a decrease in dosage to 1 mg/kg each day. Neither patient ment. had any adverse effects or difficulties in compliance while Low-molecular-weight heparin is expensive com- receiving the enoxaparin regimen. pared with other therapies discussed in the treatment of Enoxaparin is widely used perioperatively in the pre- this disease. However, for the patient with disease recal- vention of deep venous thrombosis in patients having or- citrant to other therapies, the benefits of treatment with thopedic surgery28; it is also used as treatment of acute low-molecular-weight heparin outweigh the costs by pro- deep venous thrombosis.29 Enoxaparin has been proven viding the potential for increased occupational produc- effective in the prevention of ischemic complications of tivity, decreased need for inpatient or wound care therapy, unstable angina and non–Q-wave myocardial infarc- and improved quality of life. tion.30 It acts by neutralizing factor Xa activity, assays of Our cases demonstrate that enoxaparin may be which may be monitored if necessary.1 Enoxaparin therapy considered a viable alternative in the treatment of live- may be an acceptable alternative for the patient with li- doid vasculopathy. It may be of particular advantage in vedoid vasculopathy whose disease is refractory to other treating patients with documented coagulation abnor- therapies, the patient in whom appropriate anticoagula- malities. It should be included on the list of potential tion cannot be maintained with use of warfarin, or the anticoagulant therapies for patients with treatment- patient who is hesitant to initiate advanced therapy such resistant livedoid vasculopathy. as the use of tissue plasminogen activator. The optimal dosage of low-molecular-weight heparin for treatment and Accepted for publication March 18, 2003. management of livedoid vasculopathy has not been de- The authors have no relevant financial interest in this termined. article. The adverse effects of enoxaparin are similar to those Corresponding author and reprints: Lisa A. Drage, MD, of unfractionated heparin. They include minor and ma- Department of Dermatology, Mayo Clinic, 200 First St SW, jor hemorrhages (including retroperitoneal or intracra- Rochester, MN 55905.

(REPRINTED) ARCH DERMATOL / VOL 139, AUG 2003 WWW.ARCHDERMATOL.COM 989

©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 21. Hsiao GH, Chiu HC. Low-dose danazol in the treatment of livedoid vasculitis. Der- REFERENCES matology. 1997;194:251-255. 22. Wakelin SH, Ellis JP, Black MM. Livedoid vasculitis with anticardiolipin antibod- 1. PDR.net. Available at: http://www.pdr.net/HomePage_template.jsp. Accessed 2002. ies: improvement with danazol. Br J Dermatol. 1998;139:935-937. 2. Bard JW, Winkelmann RK. Livedo vasculitis: segmental hyalinizing vasculitis of 23. Hoogenberg K, Tupker RA, van Essen LH, Smit AJ, Kallenberg CG. Successful the dermis. Arch Dermatol. 1967;96:489-499. treatment of ulcerating livedo reticularis with infusions of prostacyclin. Br J Der- 3. Schroeter AL, Diaz-Perez JL, Winkelmann RK, Jordan RE. Livedo vasculitis (the matol. 1992;127:64-66. vasculitis of atrophie blanche): immunohistopathologic study. Arch Dermatol. 24. Tsutsui K, Shirasaki F, Takata M, Takehara K. Successful treatment of livedo vas- 1975;111:188-193. culitis with beraprost sodium: a possible mechanism of thrombomodulin up- 4. Calamia KT, Balabanova M, Perniciaro C, Walsh JS. Livedo (livedoid) vasculitis regulation. Dermatology. 1996;192:120-124. and the factor V Leiden mutation: additional evidence for abnormal coagulation. 25. Winkelmann RK, Schroeter AL, Kierland RR, Ryan TM. Clinical studies of livedoid J Am Acad Dermatol. 2002;46:133-137. vasculitis: (segmental hyalinizing vasculitis). Mayo Clin Proc. 1974;49:746-750. 5. Boyvat A, Kundakci N, Babikir MO, Gurgey E. Livedoid vasculopathy associated 26. Choi HJ, Hann SK. Livedo reticularis and livedoid vasculitis responding to PUVA with heterozygous protein C deficiency. Br J Dermatol. 2000;143:840-842. therapy. J Am Acad Dermatol. 1999;40:204-207. 6. Acland KM, Darvay A, Wakelin SH, Russell-Jones R. Livedoid vasculitis: 27. Lee JH, Choi HJ, Kim SM, Hann SK, Park YK. Livedoid vasculitis responding to a manifestation of the antiphospholipid syndrome? Br J Dermatol. 1999;140: PUVA therapy. Int J Dermatol. 2001;40:153-157. 131-135. 28. LeizoroviczA,HaughMC,ChapuisFR,SamamaMM,BoisselJP.Lowmolecularweight 7. Gibson GE, Li H, Pittelkow MR. Homocysteinemia and livedoid vasculitis. JAm heparin in prevention of perioperative thrombosis. BMJ. 1992;305:913-920. Acad Dermatol. 1999;40:279-281. 29. Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous throm- 8. Pizzo SV, Murray JC, Gonias SL. Atrophie blanche: a disorder associated with bosis with low-molecular-weight heparins: a meta-analysis. Arch Intern Med. 1995; defective release of tissue plasminogen activator. Arch Pathol Lab Med. 1986; 155:601-607. 110:517-519. 30. Goodman SG, Barr A, Sobtchouk A, et al. Low molecular weight heparin de- 9. Papi M, Didona B, DePita O, et al. Livedo vasculopathy vs small vessel cutane- creases rebound ischemia in unstable angina or non-Q-wave myocardial infarc- ous vasculitis: cytokine and platelet P-selectin studies. Arch Dermatol. 1998; tion: the Canadian ESSENCE ST segment monitoring substudy. J Am Coll Car- 134:447-452. diol. 2000;36:1507-1513. 10. Jorizzo JL. Livedoid vasculopathy: what is it? Arch Dermatol. 1998;134: 491-493. 11. McCalmont CS, McCalmont TH, Jorizzo JL, White WL, Leshin B, Rothberger H. Submissions Livedo vasculitis: vasculitis or thrombotic vasculopathy? Clin Exp Dermatol. 1992; 17:4-8. 12. Jetton RL, Lazarus GS. Minidose heparin therapy for vasculitis of atrophie blanche. Clinicians, local and regional societies, residents, and fel- J Am Acad Dermatol. 1983;8:23-26. lows are invited to submit cases of challenges in man- 13. Heine KG, Davis GW. Idiopathic atrophie blanche: treatment with low-dose hep- agement and therapeutics to this section. Cases should arin. Arch Dermatol. 1986;122:855-856. follow the established pattern. Submit 4 double-spaced 14. Sauer GC. Pentoxifylline (Trental) therapy for the vasculitis of atrophie blanche. copies of the manuscript with right margins nonjusti- Arch Dermatol. 1986;122:380-381. fied and 4 sets of the illustrations. Photomicrographs and 15. Sams WM Jr. Livedo vasculitis: therapy with pentoxifylline. Arch Dermatol. 1988; illustrations must be clear and submitted as positive color 124:684-687. transparencies (35-mm slides) or black-and-white prints. 16. Drucker CR, Duncan WC. Antiplatelet therapy in atrophie blanche and livedo vasculitis. J Am Acad Dermatol. 1982;7:359-363. Do not submit color prints unless accompanied by origi- 17. Kern AB. Atrophie blanche: report of two patients treated with aspirin and di- nal transparencies. Material should be accompanied by pyridamole. J Am Acad Dermatol. 1982;6:1048-1053. the required copyright transfer statement, as noted in “In- 18. Yamamoto M, Danno K, Shio H, Imamura S. Antithrombotic treatment in livedo structions for Authors.” Material for this section should vasculitis. J Am Acad Dermatol. 1988;18:57-62. be submitted to George J. Hruza, MD, Laser and Der- 19. Klein KL, Pittelkow MR. Tissue plasminogen activator for treatment of livedoid matologic Surgery Center Inc, 14377 Woodlake Dr, Suite vasculitis. Mayo Clin Proc. 1992;67:923-933. 111, St Louis, MO 63017. 20. Hsiao GH, Chiu HC. Livedoid vasculitis: response to low-dose danazol. Arch Der- matol. 1996;132:749-751.

CME Announcement

In fall 2003, online CME will be available for JAMA/Archives and will offer many enhancements: • Article-specific questions • Hypertext links from questions to the relevant content • Online CME questionnaire • Printable CME certificates and ability to access total CME credits We apologize for the interruption in CME and hope that you will enjoy the improved online features that will be available in fall 2003.

(REPRINTED) ARCH DERMATOL / VOL 139, AUG 2003 WWW.ARCHDERMATOL.COM 990