A 57-year-old male presented to our clinic with pain and blue discoloration to his right hallux of one month’s duration. The patient, a mechanic, noted that the pain was greatest at night and improved slightly when he was ambulating at work. The patient denied any symptoms of intermittent claudication but noted a past medical history of gout and diabetes mellitus that had been diagnosed six months ago. He also had a previous history of tobacco use but quit using tobacco 26 years ago. The patient could not identify any trauma or triggering event for his current symptoms.
In regard to the clinical exam, the patient had palpable pedal pulses. He had a dark blue discoloration of his distal right hallux extending to the distal interphalangeal joint with dried eschar at the proximal nail fold. The left hallux had subtle cyanotic discoloration. Both digits were painful to palpation. The halluces were cool to the touch and had absent capillary refill. The remaining digits were warm with normal capillary refill. Digital hair growth was present and there were no atrophic skin changes. Protective sensation was intact to the digits and there were no gross musculoskeletal deformities.
Initial screening radiographs were negative for any bony abnormalities. We suspected an arterial embolism and initial treatment consisted of topical Nitro-Bid and aspirin. We referred the patient to an interventional cardiovascular specialist. The vascular workup showed normal non-invasive vascular studies and a normal computed tomography (CT) angiogram.
The patient developed increasing pain, progressive ulceration surrounding his right hallux nail and further blue discoloration to his right hallux. He continued to have blue discoloration of his left hallux and also developed cyanotic mottling of the tip of his second and third digits. Given the negative vascular evaluation, we suspected an inflammatory etiology, placed the patient on prednisone and prescribed acetaminophen/hydrocodone for pain management. The patient noted some improvement in pain with prednisone and Vicodin. However, he did continue to have progression with cyanosis and mottling of the first through fourth digits on the right foot, and the first and third digits on the left foot.
1. What is the most likely diagnosis?
2. What are the main characteristics of this condition?
3. What are other manifestations of this disorder?
4. What is the treatment?
Answering The Key Diagnostic Questions
1. Antiphospholipid syndrome
2. Recurrent arterial and venous thrombosis, and/or pregnancy-related complications with associated, persistently elevated antiphospholipid antibodies
3. Cutaneous manifestations of antiphospholipid syndrome include livedo reticularis, livedo vasculopathy, atrophie blanche, cutaneous necrosis and necrotic skin ulcerations.
4. The standard anticoagulation regimen is intravenous or subcutaneous heparin followed by warfarin.
What You Should Know About Antiphospholipid Syndrome
The patient got a subsequent referral to hematology. An extensive workup revealed antiphospholipid syndrome with positive antiphospholipid antibody titers, a positive skin biopsy for thrombosis and clinical findings of digital necrosis and necrotic ulceration. Subsequent treatment included enoxaparin (Lovenox, Sanofi) injections and warfarin (Coumadin, Bristol-Myers Squibb). The treating physician discontinued the enoxaparin injections when the patient reached the therapeutic international normalized ratio (lNR) with warfarin. With anticoagulation therapy, the patient noted gradual wound healing, pain resolution and discoloration of his digits. The patient will maintain lifetime anticoagulation therapy for management of his antiphospholipid syndrome.
Antiphospholipid syndrome is a systemic autoimmune disorder characterized by recurrent arterial and venous thrombosis, and/or pregnancy-related complications with associated, persistently elevated antiphospholipid antibodies. Numerous organ systems and tissues are affected by the hypercoagulable state and resulting thrombosis caused by antiphospholipid syndrome.
There are primary and secondary forms of antiphospholipid syndrome. Primary antiphospholipid syndrome has no associated disease and secondary antiphospholipid syndrome occurs in association with other diseases, most often systemic lupus erythematosus but other autoimmune or rheumatic disorders as well. Cutaneous manifestations are very common and frequently are the initial presenting symptom of antiphospholipid syndrome.1
Due to the difficulty of diagnosing the condition and many suspected undiagnosed cases, the true prevalence of antiphospholipid syndrome is unknown.2 Up to 5 percent of healthy adults carry antiphospholipid antibodies with no known clinical significance.3 Approximately half of the cases of antiphospholipid syndrome are primary and are not associated with another autoimmune or rheumatic disease.4 The majority of patients with antiphospholipid syndrome are between the ages of 15 and 50, and primary antiphospholipid syndrome occurs more frequently in females.5,6 A 2013 study found that antiphospholipid syndrome plays a significant role in thrombotic disease, citing it as the cause of 14 percent of all strokes, 11 percent of myocardial infarctions, 10 percent of deep vein thrombosis, 6 percent of pregnancy morbidity and 9 percent of pregnancy losses.6
The diagnosis of antiphospholipid syndrome requires meeting a minimum of one clinical criterion and one laboratory criterion. Clinical criteria include vascular thrombosis and pregnancy morbidity. Vascular thrombosis includes at least one episode of thrombosis in any tissue or organ confirmed by histopathology or imaging studies, and without evidence of inflammation of the vessel wall.7 Pregnancy morbidity includes at least one unexplained death of a normal fetus beyond the 10th week of gestation; premature birth or a normal neonate before 34 weeks gestation due to eclampsia; severe preeclampsia or placental insufficiency; and three or more unexplained, consecutive spontaneous abortions before the 10th week of gestation.7 Laboratory criteria require the presence of medium to high titers and antiphospholipid antibodies including anti-cardiolipin antibodies, lupus anticoagulant and anti-beta 2-glycoprotein on at least two occasions at least 12 weeks apart.1
A Closer Look At Cutaneous Manifestations Of Antiphospholipid Syndrome
While not included in the classification criteria, cutaneous manifestations of antiphospholipid syndrome are common and are frequently the initial presenting symptom of this syndrome. In a study of 295 patients, Alegre and colleagues found 41 percent had skin lesions as the first sign of disease and nearly 40 percent had thrombotic events throughout the course of their disease.8 Several authors emphasize that skin disease can serve as a marker for diagnosis and an indicator of future thrombotic events.1,9 The most common cutaneous manifestations of antiphospholipid syndrome include livedo reticularis, livedo vasculopathy, atrophie blanche, cutaneous necrosis and necrotic skin ulceration.1
Livedo reticularis is a persistent mottled discoloration of the skin that appears in a reticular pattern with reddish blue discoloration surrounding central pale skin. Livedo reticularis is the most common cutaneous manifestation of antiphospholipid syndrome but does occur with several other physiologic and pathologic states.10 There are variations of livedo reticularis including livedo racemosa, which is characterized by irregular, broken circles and associated with a higher risk of thrombosis.5,11 Livedo vasculitis and atrophie blanche are associated with livedo reticularis and antiphospholipid syndrome.12,13 Livedo vasculitis is a rare, chronic disorder characterized by painful purpuric lesions localized to the lower leg and foot that progress to irregular ulcerations. The ulcerations heal but leave atrophie blanche skin lesions, which are white atrophic scars surrounded by telangiectasia, hyperpigmentation and hemosiderin deposits.14
Digital gangrene is the second most common cutaneous finding in antiphospholipid syndrome with an overall prevalence as high as 7.5 percent.5,15 Digital gangrene is preceded by symptoms of ischemia including pain, pallor and cyanosis, and occasional ulceration. Due to its potential to lead to amputation, digital gangrene is considered a major thrombotic event and requires management with lifetime anticoagulation agents. Necrotic skin ulcerations, typically located on the extremities and manifesting early in the disease, are another common cutaneous manifestation of antiphospholipid syndrome with a prevalence of 5.5 percent.5,11 Cutaneous necrosis, characterized by black, necrotic plaques with purpuric borders, is another common skin finding with antiphospholipid syndrome.16
What Are The Treatment Options?
There is no cure for antiphospholipid syndrome but one can manage the disorder and prevent thrombotic events with anticoagulant treatments. The standard anticoagulation regimen is intravenous or subcutaneous heparin followed by warfarin. Treatment regimens are individualized based on the patient’s history and current clinical symptoms. Most commonly, the international normalized ratio (INR) remains between 2.0 and 3.0 for venous thrombosis, around 3.0 for arterial thrombosis and potentially between 3.0 and 4.0 for recurrent thrombotic events.17,18 There is currently no data for the use of new direct thrombin inhibitors and factor Xa inhibitor oral anticoagulants in the management of patients with antiphospholipid syndrome. Currently, one should reserve these agents for patients who are intolerant of warfarin.19,20
Dr. Hoffman is a Fellow of the American College of Foot and Ankle Surgeons, and is in private practice in Boulder, Colo.
Dr. Weber is a Fellow of the American College of Foot and Ankle Surgeons, and a Diplomate of the American Board of Podiatric Surgery. She is in private practice in Boulder, Colo.
- Pinto-Almeida T, Caetano M, Alves R, Selores M. Cutaneous lesions and finger clubbing uncovering hypocomplementemic urticarial vasculitis and hepatitis C with mixed cryoglobulinemia. An Bras Dermatol. 2013;88(6):973-976.
- Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med. 2002;346(10):752-763.
- Petri M. Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun. 2000;15(2):145-151.
- Lockshin MD. Update on antiphospholipid syndrome. Bull NYU Hosp Jt Dis. 2008;66(3):195-197.
- Cervera R, Piette JC, Font J, et al. 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.
- Jara LJ, Medina G, Vera-Lastra O, Barile L. The impact of gender on clinical manifestations of primary antiphospholipid syndrome. Lupus. 2005;14(8):607-612. 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.
- Alegre VA, Gastineau DA, Winkelmann RK. Skin lesions associated with circulating lupus anticoagulant. Br J Dermatol. 1989;120(3):419-429.
- Gibson GE, Su WP, Pittelkow MR. Antiphospholipid syndrome and the skin. J Am Acad Dermatol. 1997;36(6 Pt 1):970-982.
- Gibbs MB, English JC, 3rd, Zirwas MJ. Livedo reticularis: an update. J Am Acad Dermatol. 2005;52(6):1009-1019.
- Frances C, Niang S, Laffitte E, Pelletier F, Costedoat N, Piette JC. Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases. Arthritis Rheum. 2005;52(6):1785-1793.
- Acland KM, Darvay A, Wakelin SH, Russell-Jones R. Livedoid vasculitis: a manifestation of the antiphospholipid syndrome? Br J Dermatol. 1999;140(1):131-135.
- Grasland A, Crickx B, Blanc M, Pouchot J, Vinceneux P. [Livedoid vasculopathy (white atrophy) associated with anticardiolipin antibodies]. Ann Med Interne (Paris). 2000;151(5):408-410.
- Maessen-Visch MB, Koedam MI, Hamulyak K, Neumann HA. Atrophie blanche. Int J Dermatol. 1999;38(3):161-172.
- Asherson RA, Khamashta MA, Ordi-Ros J, et al. The “primary” antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore). 1989;68(6):366-374.
- Sharkey MP, Daryanani, II, Gillett MB, Jones SK. Localized cutaneous necrosis associated with the antiphospholipid syndrome. Australasian J Dermatol. 2002;43(3):218-220.
- Khamashta MA. [Hughes syndrome: anticardiolipin or antiphospholipid]. Rev Clin Esp. 1995;195(1):5-7.
- Krnic-Barrie S, O’Connor CR, Looney SW, Pierangeli SS, Harris EN. A retrospective review of 61 patients with antiphospholipid syndrome. Analysis of factors influencing recurrent thrombosis. Arch Intern Med. 1997;157(18):2101-2108.
- Barbhaiya M, Erkan D. Top 10 clinical research developments in antiphospholipid syndrome. Curr Rheumatol Rep. 2013;15(10):367.
- Erkan D, Aguiar CL, Andrade D, et al. 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev. 2014;13(6):685-696.