1. health and fitness
2. therapy

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
CASE 1
A 23-year-old man who was otherwise healthy had a
5-year history of recalcitrant ulcers of the lower extremities. The ulcers worsened in warm weather and during
periods of increased physical activity. The ulcers were
painful and interfered with his participation in sports,
including soccer and basketball. Shallow ulcers and crusting with stellate, porcelain-white scarring and surrounding hyperpigmentation on the lower extremities and dorsal feet were noted on examination (Figure 1).
Noninvasive vascular testing, including continuouswave venous Doppler imaging and measurements of the
ankle-brachial index and transcutaneous oximetry
(TcPO2), revealed moderately to severely reduced TcPO2
levels but no evidence of venous insufficiency. Histopathologic analysis of a skin biopsy specimen from the
Figure 1. Shallow ulcers of the dorsal feet with postinflammatory
hyperpigmentation and stellate scarring (patient 1 before treatment).
(REPRINTED) ARCH DERMATOL / VOL 139, AUG 2003
987
left ankle was notable for hyalinization of dermal blood
vessels in the papillary and superficial reticular dermis
and minimal perivascular lymphocytic infiltrate
(Figure 2). Direct immunofluorescence study showed
superficial vessel deposition of IgG, IgM, and C3 conjugates with patchy deposition of fibrin. Results of laboratory studies, including an extensive screen for coagulation abnormalities, were normal. Taken together, these
findings were consistent with a diagnosis of livedoid vasculopathy. Several treatment approaches had been ineffective in controlling ulceration. These approaches included topical corticosteroids, compression therapy,
stanozolol, and a triple regimen of pentoxifylline (400
mg, 3 times daily for 29 months), nifedipine (30 mg/d
for 21 months), and aspirin (81 mg/d for 29 months).
CASE 2
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
superficial reticular dermis (patient 1 before treatment) (hematoxylin-eosin,
original magnification ⫻400).
WWW.ARCHDERMATOL.COM
©2003 American Medical Association. All rights reserved.
Downloaded From: http://jamanetwork.com/ on 10/21/2014
ment in physical manifestations and alleviation of the pain
associated with the ulcers.
SOLUTION
Figure 3. Marked improvement in the ulcers of the dorsal feet (patient 1 after
4 months of treatment with enoxaparin).
liferative disorder (IgG ␭ monoclonal protein) previously
treated with rituximab. The ulcerative disease did not improve during the course of rituximab treatment. Physical examination revealed shallow, crusted ulcers and surrounding stellate white scars with telangiectases and
hyperpigmentation on the anterior shins and dorsal feet.
Noninvasive vascular testing, including continuouswave venous Doppler imaging and measurements of the
ankle-brachial index and TcPO2, showed moderately to severely reduced TcPO2 of the arterior part of both legs and
the left dorsal foot. A skin biopsy specimen from the lower
extremity revealed ulceration with hyalinizing, fibrinoid
changes of the small to medium dermal blood vessels without marked inflammation. A direct immunofluorescence
study of the skin specimen demonstrated vascular staining with C3 and fibrinogen. Taken together, these findings were consistent with a diagnosis of livedoid vasculopathy. An extensive coagulation screen and polymerase
chain reaction analysis revealed heterozygosity for the factor V R506Q (Leiden) mutation.
Because of the refractory nature of his active ulcerations and secondary pain, the patient was hospitalized
on the inpatient dermatology service and treated with topical corticosteroids, topical antibiotics, and wet dressings. Initially after hospitalization, his condition improved while receiving a regimen of niacin (500 mg, 3
times daily for 8 months), pentoxifylline (400 mg, 3 times
daily for 8 months), and aspirin (81 mg/d for 8 months).
Treatment with these medications was discontinued by
the patient, who continued topical corticosteroid therapy.
However, the ulcers recurred within 6 months and were
recalcitrant to reintroduction of his previous regimen.
Warfarin was considered; however, it was not an appropriate therapy for him because his residence in a rural
area had previously made it difficult to maintain a therapeutic international normalized ratio.
THERAPEUTIC CHALLENGE
As outlined in the clinical cases, numerous therapies had
been undertaken without success in healing the extensive, painful, and scarring ulcers of livedoid vasculopathy. Our challenge was to treat these recalcitrant lesions
with an alternative agent that would lead to improve(REPRINTED) ARCH DERMATOL / VOL 139, AUG 2003
988
A trial of subcutaneous injectable enoxaparin, a lowmolecular-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
hours, which is the perioperative prophylactic dose against
deep venous thrombosis.1 Patient 1 noted no further ulceration after initiating the injections and had dramatic
healing of his ulcers within 4 months (Figure 3). Repeated TcPO2 measurements of the lower extremities 9
months after initiation of therapy revealed marked improvement in oxygenation with normalization of previously reduced levels. His discomfort also was controlled
on the regimen without further need for daily pain medications. After 6 months of therapy, his dosage was decreased to 1 mg/kg once daily with continued benefit. Patient 2 also had improvement in his ulcers in his 7 months
on the enoxaparin regimen.
COMMENT
Livedoid vasculopathy, or livedoid vasculitis, is a disease characterized by ulceration of the lower extremities. Smooth, ivory-white plaquelike areas with surrounding telangiectases and hyperpigmentation
(atrophie blanche) are commonly identified. The histopathologic features are distinctive, although not pathognomonic, and analysis usually reveals a segmental
hyalinizing vascular pattern involving the dermal blood
vessels, with vessel thickening, endothelial proliferation, and focal thrombosis without leukocytoclasis.2 Direct immunofluorescence staining typically demonstrates immunoglobulin and complement components
in the superficial, mid-dermal, and deep dermal vasculature.3 The underlying cause is not yet fully understood; however, the disease has been reported in individuals with altered coagulation, including factor V
Leiden mutation,4 protein C deficiency,5 antiphospholipid antibody syndrome,6 increased plasma homocysteine levels,7 abnormalities in fibrinolysis,8 and increased platelet activation.9
Because potential thrombogenic mechanisms may
be involved in the disease pathogenesis,10,11 anticoagulant therapy is often tried. The Table lists anticoagulant and fibrinolytic therapies that have been reported
in the English-language medical literature as treatments
for livedoid vasculopathy.12-24 Anticoagulant therapy with
warfarin is another option. Treatment at our institution
has shown nicotinic acid to be helpful.25 Psoralen plus
UV-A has also been reported as an effective treatment modality.26,27
WWW.ARCHDERMATOL.COM
©2003 American Medical Association. All rights reserved.
Downloaded From: http://jamanetwork.com/ on 10/21/2014
Anticoagulant and Fibrinolytic Therapies Used for Livedoid Vasculopathy
Therapy
Delivery
Source
Minidose heparin
5000 U by SC injection BID
Pentoxifylline
400 mg BID to TID
Combination antiplatelet therapy
1. Therapeutic doses of aspirin and dipyridamole
Tissue plasminogen activator
Danazol
2. Ticlopidine hydrochloride, dipyridamole, and aspirin
10 mg by IV infusion over 4 h for 14 d
200 mg QD
Prostacyclin platelet aggregation inhibition
No. of Patients
12
1. Prostacyclin infusion
2. Beraprost sodium (prostaglandin analogue)
Jetton and Lazarus, 1983
Heine and Davis,13 1986
Sauer,14 1986
Sams,15 1988
1. Drucker and Duncan,16 1982
Kern,17 1982
2. Yamamoto et al,18 1988
Klein and Pittelkow,19 1992
Hsiao and Chiu,20 1996
Hsiao and Chiu,21 1997
Wakelin et al,22 1998
1. Hoogenberg et al,23 1992
2. Tsutsui et al,24 1996
1
1
6
8
7
2
2
6
2
7
1
1
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 potential therapy for livedoid vasculopathy. Patient 1 is an otherwise healthy young man with ulcers refractory to standard therapies. He has had dramatic and sustained clinical
improvement as he continues with the subcutaneous injections. Levels of TcPO2, once moderately to severely reduced, are within the normal range. His pain management has been markedly improved as well. Patient 2 may
have an underlying thrombotic diathesis with the factor
V Leiden mutation, in addition to his chronic low-grade
B-cell lymphoproliferative disorder. This patient was maintained on the therapy during the summer months, when
his disease was usually more severe, and had an improved response compared with that obtained with previous treatments. His lymphoproliferative process was
stable during the heparin therapy. He had flaring of his
disease in the late summer months because of increased
activity and bacterial impetiginization, and his course was
discontinued at that time. Patient 1, who received 1 mg/kg
of enoxaparin twice daily, had a more effective and prolonged response to the medication. Benefits continued with
a decrease in dosage to 1 mg/kg each day. Neither patient
had any adverse effects or difficulties in compliance while
receiving the enoxaparin regimen.
Enoxaparin is widely used perioperatively in the prevention of deep venous thrombosis in patients having orthopedic surgery28; it is also used as treatment of acute
deep venous thrombosis.29 Enoxaparin has been proven
effective in the prevention of ischemic complications of
unstable angina and non–Q-wave myocardial infarction.30 It acts by neutralizing factor Xa activity, assays of
which may be monitored if necessary.1 Enoxaparin therapy
may be an acceptable alternative for the patient with livedoid vasculopathy whose disease is refractory to other
therapies, the patient in whom appropriate anticoagulation cannot be maintained with use of warfarin, or the
patient who is hesitant to initiate advanced therapy such
as the use of tissue plasminogen activator. The optimal
dosage of low-molecular-weight heparin for treatment and
management of livedoid vasculopathy has not been determined.
The adverse effects of enoxaparin are similar to those
of unfractionated heparin. They include minor and major hemorrhages (including retroperitoneal or intracra(REPRINTED) ARCH DERMATOL / VOL 139, AUG 2003
989
nial bleeding) and thrombocytopenia. However, a weightadjusted dosage of enoxaparin is as efficacious as
unfractionated heparin in the treatment of deep venous
thrombosis and is more convenient for patients to use29;
monitoring of the activated partial thromboplastin time
is not necessary. Similarly, enoxaparin does not require
monitoring of the therapeutic international normalized
ratio, as does warfarin. However, patients should be counseled regarding the risks of hemorrhage while they are
receiving enoxaparin, and contraindications to anticoagulation should be fully reviewed before therapy is initiated. Candidates also should be screened for risk of osteoporosis, a potential complication of heparin therapy,
and considered for calcium supplementation. Our patients were started on an aggressive regimen of enoxaparin in combination with their previous medications,
including aspirin. Although the concomitant use of aspirin and anticoagulants is usually avoided because of the
increased risk of bleeding, the severity of the disease in
our patients warranted aggressive therapy; potential risks
were appropriately reviewed with the patients before treatment.
Low-molecular-weight heparin is expensive compared with other therapies discussed in the treatment of
this disease. However, for the patient with disease recalcitrant to other therapies, the benefits of treatment with
low-molecular-weight heparin outweigh the costs by providing the potential for increased occupational productivity, decreased need for inpatient or wound care therapy,
and improved quality of life.
Our cases demonstrate that enoxaparin may be
considered a viable alternative in the treatment of livedoid vasculopathy. It may be of particular advantage in
treating patients with documented coagulation abnormalities. It should be included on the list of potential
anticoagulant therapies for patients with treatmentresistant livedoid vasculopathy.
Accepted for publication March 18, 2003.
The authors have no relevant financial interest in this
article.
Corresponding author and reprints: Lisa A. Drage, MD,
Department of Dermatology, Mayo Clinic, 200 First St SW,
Rochester, MN 55905.
WWW.ARCHDERMATOL.COM
©2003 American Medical Association. All rights reserved.
Downloaded From: http://jamanetwork.com/ on 10/21/2014
REFERENCES
1. PDR.net. Available at: http://www.pdr.net/HomePage_template.jsp. Accessed 2002.
2. Bard JW, Winkelmann RK. Livedo vasculitis: segmental hyalinizing vasculitis of
the dermis. Arch Dermatol. 1967;96:489-499.
3. Schroeter AL, Diaz-Perez JL, Winkelmann RK, Jordan RE. Livedo vasculitis (the
vasculitis of atrophie blanche): immunohistopathologic study. Arch Dermatol.
1975;111:188-193.
4. Calamia KT, Balabanova M, Perniciaro C, Walsh JS. Livedo (livedoid) vasculitis
and the factor V Leiden mutation: additional evidence for abnormal coagulation.
J Am Acad Dermatol. 2002;46:133-137.
5. Boyvat A, Kundakci N, Babikir MO, Gurgey E. Livedoid vasculopathy associated
with heterozygous protein C deficiency. Br J Dermatol. 2000;143:840-842.
6. Acland KM, Darvay A, Wakelin SH, Russell-Jones R. Livedoid vasculitis:
a manifestation of the antiphospholipid syndrome? Br J Dermatol. 1999;140:
131-135.
7. Gibson GE, Li H, Pittelkow MR. Homocysteinemia and livedoid vasculitis. J Am
Acad Dermatol. 1999;40:279-281.
8. 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.
9. Papi M, Didona B, DePita O, et al. Livedo vasculopathy vs small vessel cutaneous vasculitis: cytokine and platelet P-selectin studies. Arch Dermatol. 1998;
134:447-452.
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.
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.
J Am Acad Dermatol. 1983;8:23-26.
13. Heine KG, Davis GW. Idiopathic atrophie blanche: treatment with low-dose heparin. Arch Dermatol. 1986;122:855-856.
14. Sauer GC. Pentoxifylline (Trental) therapy for the vasculitis of atrophie blanche.
Arch Dermatol. 1986;122:380-381.
15. Sams WM Jr. Livedo vasculitis: therapy with pentoxifylline. Arch Dermatol. 1988;
124:684-687.
16. Drucker CR, Duncan WC. Antiplatelet therapy in atrophie blanche and livedo vasculitis. J Am Acad Dermatol. 1982;7:359-363.
17. Kern AB. Atrophie blanche: report of two patients treated with aspirin and dipyridamole. J Am Acad Dermatol. 1982;6:1048-1053.
18. Yamamoto M, Danno K, Shio H, Imamura S. Antithrombotic treatment in livedo
vasculitis. J Am Acad Dermatol. 1988;18:57-62.
19. Klein KL, Pittelkow MR. Tissue plasminogen activator for treatment of livedoid
vasculitis. Mayo Clin Proc. 1992;67:923-933.
20. Hsiao GH, Chiu HC. Livedoid vasculitis: response to low-dose danazol. Arch Dermatol. 1996;132:749-751.
21. Hsiao GH, Chiu HC. Low-dose danazol in the treatment of livedoid vasculitis. Dermatology. 1997;194:251-255.
22. Wakelin SH, Ellis JP, Black MM. Livedoid vasculitis with anticardiolipin antibodies: improvement with danazol. Br J Dermatol. 1998;139:935-937.
23. Hoogenberg K, Tupker RA, van Essen LH, Smit AJ, Kallenberg CG. Successful
treatment of ulcerating livedo reticularis with infusions of prostacyclin. Br J Dermatol. 1992;127:64-66.
24. Tsutsui K, Shirasaki F, Takata M, Takehara K. Successful treatment of livedo vasculitis with beraprost sodium: a possible mechanism of thrombomodulin upregulation. Dermatology. 1996;192:120-124.
25. Winkelmann RK, Schroeter AL, Kierland RR, Ryan TM. Clinical studies of livedoid
vasculitis: (segmental hyalinizing vasculitis). Mayo Clin Proc. 1974;49:746-750.
26. Choi HJ, Hann SK. Livedo reticularis and livedoid vasculitis responding to PUVA
therapy. J Am Acad Dermatol. 1999;40:204-207.
27. Lee JH, Choi HJ, Kim SM, Hann SK, Park YK. Livedoid vasculitis responding to
PUVA therapy. Int J Dermatol. 2001;40:153-157.
28. LeizoroviczA,HaughMC,ChapuisFR,SamamaMM,BoisselJP.Lowmolecularweight
heparin in prevention of perioperative thrombosis. BMJ. 1992;305:913-920.
29. Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins: a meta-analysis. Arch Intern Med. 1995;
155:601-607.
30. Goodman SG, Barr A, Sobtchouk A, et al. Low molecular weight heparin decreases rebound ischemia in unstable angina or non-Q-wave myocardial infarction: the Canadian ESSENCE ST segment monitoring substudy. J Am Coll Cardiol. 2000;36:1507-1513.
Submissions
Clinicians, local and regional societies, residents, and fellows are invited to submit cases of challenges in management and therapeutics to this section. Cases should
follow the established pattern. Submit 4 double-spaced
copies of the manuscript with right margins nonjustified and 4 sets of the illustrations. Photomicrographs and
illustrations must be clear and submitted as positive color
transparencies (35-mm slides) or black-and-white prints.
Do not submit color prints unless accompanied by original transparencies. Material should be accompanied by
the required copyright transfer statement, as noted in “Instructions for Authors.” Material for this section should
be submitted to George J. Hruza, MD, Laser and Dermatologic Surgery Center Inc, 14377 Woodlake Dr, Suite
111, St Louis, MO 63017.
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
990
WWW.ARCHDERMATOL.COM
©2003 American Medical Association. All rights reserved.
Downloaded From: http://jamanetwork.com/ on 10/21/2014