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THE CUTTING EDGE: CHALLENGES IN MEDICAL AND SURGICAL THERAPIES

SECTION EDITOR: EDWARD W. COWEN, MD, MHSc;


ASSISTANT SECTION EDITORS: MURAD ALAM, MD; WILLIAM D. AUGHENBAUGH, MD

Retiform Purpura and Digital Gangrene Secondary


to Antiphospholipid Syndrome Successfully Treated
With Sildenafil
Mercedes E. Gonzalez, MD; Philip Kahn, MD; Harper N. Price, MD; Hideko Kamino, MD; Julie V. Schaffer, MD;
Departments of Dermatology (Drs Gonzalez, Price, Kamino, and Schaffer), Pediatrics (Drs Kahn and Schaffer),
and Pathology (Dr Kamino), New York University School of Medicine, New York;
and Phoenix Childrens Hospital, Phoenix, Arizona (Dr Price)
REPORT OF A CASE

A 16-year-old African American female adolescent with


a 2-year history of systemic lupus erythematosus (featuring a malar erythema, photosensitivity, arthritis, and
anemia in the setting of high-titer antinuclear, anti
double-strand DNA, anti-Smith, and anti-Ro antibodies) and Raynaud phenomenon presented with persistently painful and dusky toes since wearing a new pair
of boots 2 weeks previously. She also noted an increased frequency of Raynaud episodes. Her dose of nifedipine was increased (from 30 mg/d to 60 mg/d) because of the latter, and she continued her baseline regimen
of prednisone (5 mg/d), mycophenolate mofetil (1500
mg, twice daily), hydroxychloroquine (400 mg/d), and
indomethacin (75 mg, twice daily). Despite this, she experienced worsening pain and progressive necrosis of her
toes and was hospitalized for evaluation and treatment
of impending digital gangrene.
On physical examination, retiform purpura was evident on the left first and second toes. There was a hemorrhagic bulla on the distal left first toe, and the left second toenail was absent, replaced by a necrotic ulcer
(Figure 1). Milder purpura on a background of dusky
reticulated erythema was present on the left medial sole,
A

left third through fourth toes, and right first through fourth
toes. Dorsalis pedis pulses were diminished, more so on
the left foot than the right foot. Findings from arterial
Doppler studies showed a complete absence of blood flow
in all the digits of the left foot and in the second through
fourth digits of the right foot.
A biopsy specimen from the peripheral portion of the
purpuric area on the left first toe revealed thrombi in the
lumens of small and medium-sized blood vessels throughout the mid and deep reticular dermis (Figure 2). There
was no inflammatory infiltrate or fibrin deposition in the
vessel walls. Partial necrosis of the eccrine glands and the
overlying epidermis was apparent.
Laboratory evaluation revealed elevated anticardiolipin IgM antibody levels, which had also been elevated
in laboratory testing performed 10 months prior, and presence of the lupus anticoagulant. Anticardiolipin IgG and
anti-2 glycoprotein I antibodies were not identified. There
were no abnormalities found in the remainder of an extensive evaluation for thrombophilia, which included protein C and S levels and activity, antithrombin III activity, homocysteine levels, and testing for factor V Leiden
and prothrombin gene mutations.
The clinical, histologic, and laboratory findings confirmed a diagnosis of thrombotic vasculopathy secondB

Figure 1. Clinical photographs of hemorrhagic bulla and retiform purpura. A, Hemorrhagic bulla on the distal left first toe and necrotic ulcer with loss of the nail on
the second toe. B, Retiform purpura on the left first and second toes, and dusky reticular erythema on the third and fourth toes.

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Figure 2. Fibrin thrombi in the lumens of small and medium-sized blood vessels throughout the mid and deep reticular dermis, with partial necrosis of eccrine
glands and the overlying epidermis. A, Hematoxylin-eosin, original magnification 10; B, hematoxylin-eosin, original magnification 40.

ary to antiphospholipid antibody syndrome (APS).1 Treatment was initiated with enoxaparin (80 mg, twice daily),
intravenous methylprednisolone (1 g/d), and topical nitroglycerin paste under occlusion to the feet and toes; in
addition, the dose of nifedipine was doubled (60 mg, twice
daily) and the patient wore 3 layers of socks to keep her
toes warm. Despite these interventions, the pain and necrosis progressed.
THERAPEUTIC CHALLENGE

Vascular thrombosis with resultant cutaneous necrosis


and digital gangrene can occur in the setting of APS. Extensive cutaneous necrosis associated with APS is typically treated with anticoagulation and systemic corticosteroids, sometimes in combination with plasmapheresis,
intravenous immunoglobulins, and/or fibrinolytic
agents.2-5 Similarly, digital gangrene from APS has been
effectively managed with anticoagulation and fibrinolytic therapy.6 However, therapy with enoxaparin, methylprednisolone, and nifedipine did not halt the progression of our patients cutaneous necrosis and digital
gangrene.
SOLUTION

On the third hospital day, nifedipine therapy was discontinued and treatment with sildenafil (20 mg, 3 times
daily) was initiated. The patient had rapid pain relief, and

within 24 to 48 hours there was a marked increase in the


dorsalis pedis pulses and fading of the reticular erythema. The gangrene stabilized, and the patient went on
to lose only the tips of her left first and second toes
(Figure 3). Sildenafil treatment was maintained for 14
months.
COMMENT

Antiphospholipid antibody syndrome is an acquired systemic autoimmune disorder characterized by vascular


thrombosis (venous, arterial, or small vessel thrombosis) and/or pregnancy complications (unexplained miscarriage or premature delivery) associated with the presence of antiphospholipid antibodies (lupus anticoagulant,
anticardiolipin antibodies, or anti-2 glycoprotein I antibodies). Diagnostic criteria for APS require the laboratory abnormalities to be detected on 2 or more occasions, at least 12 weeks apart.1 In recent years, APS has
been increasingly recognized as a cause of recurrent
thromboses in pediatric patients. Childhood APS does
not have the marked female predominance that is observed in adults with APS (female to male ratio approximately 1:1 in children, compared with approximately 5:1
in adults).7
In both pediatric and adult APS cohorts, approximately half of patients had an underlying connective tissue disease (most often systemic lupus erythematosus),
and deep venous thrombosis of the lower extremities was

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Figure 3. Three months after presentation, the patient had lost only the second toenail (A) and a small amount of tissue from the tips of her first and second toes (B).

the most common clinical presentation (30%-40% of


patients).7,8 Small-vessel occlusion (partial or complete) is thought to underlie many of the cutaneous manifestations of APS, which include livedo reticularis, retiform purpura progressing to cutaneous necrosis, leg
ulcers, livedoid vasculopathy, nail bed infarcts, and superficial thrombophlebitis.9,10 Livedo reticularis is the most
frequent skin finding and was a presenting sign in 204
of 1000 adults (20%) and 7 of 121 children (7%) in 2
APS case series; Raynaud phenomenon was also noted
at the time of diagnosis in 7 of 121 affected children
(6%).7,8 Digital gangrene was documented in 3% or fewer
patients in these series.7,8
The precise pathogenic mechanism by which antiphospholipid antibodies lead to thrombosis is not known.
It is thought that these antibodies bind to and activate
platelets and endothelial cells by up-regulating expression of adhesion molecules and tissue factor, thereby leading to a procoagulant state.5,11 This process is amplified
by activation of the complement cascade and inhibition
of proteases that promote fibrinolysis. In addition, vascular injury from atherosclerosis, inherited thrombophilia (present in 13 of 29 children [45%] with APS in
one series7), or precipitating factors such as infections,
immobilization, trauma, and surgery may provide a second hit that is necessary for thrombus development.5,11
Vasospasm related to Raynaud syndrome and trauma
caused by her new boots may have exacerbated our patients thrombotic vasculopathy.
Sildenafil, a selective phosphodiesterase-5 (PDE5) inhibitor, is currently approved by the US Food and Drug
Administration for the treatment of erectile dysfunction and
pulmonary hypertension. In addition to the corpus cavernosum, PDE5 is found in vascular smooth muscle and platelets. Phosphodiesterase-5 normally degrades intracellular
cyclic guanosine monophosphate (cGMP), a second messenger that mediates the vasodilatory and antiplatelet effects of nitric oxide. Inhibition of PDE5 by sildenafil leads
to an increased intracellular level of cGMP, resulting in a
decreased intracellular concentration of calcium, smooth
muscle relaxation, and vasodilatation. Furthermore, sildenafils inhibition of PDE5 in an endoplasmic reticulum
signaling complex within platelets leads to a localized increase in cGMP, which blocks thrombin-induced calcium
release and thereby prevents platelet activation.12
Accumulating data indicate that inhibition of PDE5
has therapeutic potential extending beyond erectile dys-

function and pulmonary hypertension. In a randomized, double-blind, placebo-controlled trial, patients with
secondary Raynaud phenomenon who received sildenafil experienced statistically significant reductions in
the frequency and duration of attacks compared with the
control group.13 In this study and other case reports and
series, sildenafil therapy was also associated with increased capillary blood flow to the fingers and healing
of digital ulcers in individuals with Raynaud phenomenon.13-16 In addition, treatment with sildenafil led to improvement of digital ischemia in 3 patients who had autoimmune connective tissue diseaseassociated Raynaud
phenomenon plus severe tuberculosis or disseminated
malignant disease.17
Healing of chronic, livedoid vasculopathylike leg ulcers within 3 months of initiating sildenafil therapy was
described in a 57-year-old man with APS that was also
associated with deep venous thrombosis and cerebral infarctions.18 The patient had a 10-year history of the recalcitrant leg ulcers, which had never been biopsied. The
lesions had not responded to a regimen including local
wound care, aspirin, and warfarin, and they resolved but
recurred after previous treatment with intravenous tissue plasminogen activator and heparin.
Our patient had acute onset of a biopsy-proven, APSrelated thrombotic vasculopathy that presented as retiform purpura and digital gangrene, which progressed despite medical therapy including standard anticoagulant,
anti-inflammatory, and vasodilator agents. However, sildenafil led to an immediate decrease in pain and arrest
of necrosis. We postulate that both the vasodilatory and
antiplatelet effects of sildenafil contributed to our patients improved distal blood flow. To our knowledge, this
represents the first report of successful treatment of APSrelated retiform purpura or digital gangrene with sildenafil. Further studies are needed to determine the
potential roles of sildenafil and other PDE5 inhibitors in
cutaneous and extracutaneous vascular thrombosis associated with APS.
Accepted for Publication: August 26, 2010.
Correspondence: Julie V. Schaffer, MD, Department of
Dermatology, New York University School of Medicine,
560 First Ave, Ste H-100, New York, NY 10016 (julie
.schaffer@nyumc.org).
Author Contributions: All authors had full access to all
the data in the study and take responsibility for the in-

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tegrity of the data and the accuracy of the data analysis.


Study concept and design: Gonzalez, Kahn, Price, and Schaffer. Acquisition of data: Gonzalez, Kahn, Price, Kamino,
Schaffer. Analysis and interpretation of data: Gonzalez,
Kahn, Price, Kamino, and Schaffer. Drafting of the manuscript: Gonzalez and Schaffer. Critical revision of the manuscript for important intellectual content: Gonzalez, Kahn,
Price, Kamino, and Schaffer. Administrative, technical, and
material support: Gonzalez, Kahn, Kamino, and Schaffer. Study supervision: Schaffer.
Financial Disclosure: None reported.
Additional Contributions: Carina Rizzo, MD, took the
clinical photographs.

7.

8.

9.
10.
11.

12.

REFERENCES
1. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on
an update of the classification criteria for definite antiphospholipid syndrome (APS).
J Thromb Haemost. 2006;4(2):295-306.
2. Abernethy ML, McGuinn JL, Callen JP. Widespread cutaneous necrosis as the
initial manifestation of the antiphospholipid antibody syndrome. J Rheumatol.
1995;22(7):1380-1383.
3. Paira S, Roverano S, Zunino A, Oliva ME, Bertolaccini ML. Extensive cutaneous
necrosis associated with anticardiolipin antibodies. J Rheumatol. 1999;26(5):
1197-1200.
4. Asherson RA, Francs C, Iaccarino L, et al. The antiphospholipid antibody syndrome: diagnosis, skin manifestations and current therapy. Clin Exp Rheumatol.
2006;24(1)(suppl 40):S46-S51.
5. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med.
2002;346(10):752-763.
6. Jicha DL, Caty MG, Lillehei CW. Primary antiphospholipid syndrome in a child

13.

14.
15.

16.
17.
18.

(REPRINTED) ARCH DERMATOL/ VOL 147 (NO. 2), FEB 2011


167

with lower extremity arterial thrombosis. J Pediatr Surg. 1994;29(12):15191520.


Avcin T, Cimaz R, Silverman ED, et al. Pediatric antiphospholipid syndrome: clinical and immunologic features of 121 patients in an international registry. Pediatrics.
2008;122(5):e1100-e1107.
Cervera R, Piette JC, Font J, et al; Euro-Phospholipid Project Group. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46(4):
1019-1027.
Gibson GE, Su WPD, Pittelkow MR. Antiphospholipid syndrome and the skin.
J Am Acad Dermatol. 1997;36(6, pt 1):970-982.
Weinstein S, Piette W. Cutaneous manifestations of antiphospholipid antibody
syndrome. Hematol Oncol Clin North Am. 2008;22(1):67-77.
Pierangeli SS, Chen PP, Raschi E, et al. Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms. Semin Thromb Hemost. 2008;
34(3):236-250.
Wilson LS, Elbatarny HS, Crawley SW, Bennett BM, Maurice DH. Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows
selective cGMP-mediated regulation of platelet functions. Proc Natl Acad Sci U
S A. 2008;105(36):13650-13655.
Fries R, Shariat K, von Wilmowsky H, Bhm M. Sildenafil in the treatment of
Raynauds phenomenon resistant to vasodilatory therapy. Circulation. 2005;
112(19):2980-2985.
Lichtenstein JR. Use of sildenafil citrate in Raynauds phenomenon: comment
on the article by Thompson et al. Arthritis Rheum. 2003;48(1):282-283.
Gore J, Silver R. Oral sildenafil for the treatment of Raynauds phenomenon and
digital ulcers secondary to systemic sclerosis. Ann Rheum Dis. 2005;64(9):
1387.
Heymann WR. Sildenafil for the treatment of Raynauds phenomenon. J Am Acad
Dermatol. 2006;55(3):501-502.
Kumana CR, Cheung GTY, Lau CS. Severe digital ischaemia treated with phosphodiesterase inhibitors. Ann Rheum Dis. 2004;63(11):1522-1524.
Gertner E. Treatment with sildenafil for the healing of refractory skin ulcerations
in the antiphospholipid syndrome. Lupus. 2003;12(2):133-135.

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