Necrotic skin ulcers in association with a LA have been reported since 1963 [
12]. However, non-vasculitic skin ulcers are an uncommon manifestation of APS and a recent study in France suggested that the prevalence of necrotic skin ulcers was only 3.5% in APS [
9]. These skin lesions are usually painful, small, surrounded by a purple halo and purpura, and are located usually around the ankles. These ulcers are usually associated with livedo reticularis on the legs, which is the most common dermatologic manifestation of APS. Healing is usually associated with white atrophic scars with a dark pigmented halo resembling livedoid vasculitis [
13]. The histopathology reveals fibrin deposition often with hyalinization within the walls and lumina of affected superficial vessels. Thrombi within the lumen and blood extravasation may be present but the absence of perivascular infiltrate excludes true vasculitis [
3,
4]. In this patient, the skin biopsy findings excluded vasculitis as a cause of non-healing skin ulcers. Furthermore, laboratory evidence did not support a diagnosis of an active lupus as reflected by: normal complement levels, negative anti-dsDNA antibody, and absence of renal involvement as urine analysis was negative for active sediment. Our patient was compliant with anticoagulation as this was reflected by her therapeutic INR levels in the months prior to the development of skin ulcers. Livedoid vasculopathy associated with APS was considered a possible differential but was thought to be less likely due to the absence of immunoglobulin and complement deposits on immunofluorescence testing of biopsy samples. Finally, fulminant APS was considered a less likely diagnosis as this patient had no evidence of multiorgan failure with a rapid clinical deterioration.
Differential diagnosis
The differential diagnosis of non-healing skin ulcers is broad. It includes warfarin-induced skin necrosis, although this usually occurs in the setting of protein C deficiency and usually develops within the first few days of starting warfarin [
14]. Alternatively, calciphylaxis can present with necrotic ulcers although this is usually in the setting of end-stage kidney disease and is usually not seen with moderate chronic kidney disease, as in the present case [
15]. Calciphylaxis can be diagnosed from calcium deposits on biopsy [
16]. Vasculitis and pyoderma gangrenosum usually occur in the setting of inflammatory bowel disease although they can be seen in APS and can produce non-healing ulcers [
17]. Other causes of non-healing ulcers in the context of APS can be due to non-compliance of anticoagulation, chronic disseminated intravascular coagulation (DIC), livedoid vasculopathy, and catastrophic APS [
7]. Livedoid vasculopathy usually causes recurrent ulcers around both ankles which may heal slowly over 3–4 months with stellate white scars called
atrophie blanche [
18]. Livedoid vasculopathy may be associated with inherited thrombophilia, hyperhomocysteinemia, and APS [
19]. Histopathology shows intraluminal thrombosis in 97.8% cases while direct immunofluorescence usually reveals immunoglobulins and complement components in blood vessels and the dermis [
19].
Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening variant of APS that is characterized by rapid development of arterial and/or venous thrombosis over a short period of time, usually ending in multiorgan failure [
20]. Most episodes are precipitated by infections, surgery, or malignant diseases. In a majority of cases, small vessels are affected leading to a disseminated microangiopathic syndrome resembling thrombotic thrombocytopenic purpura [
21]. The most frequently involved sites are kidney (73%), lungs (60%), brain (56%), and heart (50%) [
22].
Prolidase deficiency is a rare autosomal recessive disorder, which presents with dysmorphic facies, mental retardation, splenomegaly, respiratory infections, and non-healing lower extremity ulcers [
23]. Recent studies suggest that 10% of patients will develop SLE [
24]. Prolidase deficiency was considered less likely in our patient as this condition usually becomes symptomatic between birth and 22 years of age [
24].
Very few formal, prospective studies have evaluated the pathogenesis and treatment options for non-criteria manifestations of APS including any dermatologic lesions [
25]. These manifestations often develop during, and may not improve with, heparin or warfarin anticoagulation [
3]. Current treatment recommendations from the 13th International Congress on Antiphospholipid Antibodies Task Force, recommend that an INR of between 2 and 3 should be the target for patients who develop venous thrombosis associated with APS [
26]. A higher target of 3.5 is recommended for patients who develop recurrence of thrombosis while on warfarin with an INR of between 2.0 and 3.0 [
27].
It remains a mystery why this patient suffered from APS-related thrombosis after being stable a long time on anticoagulation. Studies have shown minimal likelihood of recurrence of thrombotic events in patients on moderate-intensity treatment with warfarin (with an INR between 2 and 3) [
28]. We did exclude any new thrombotic risk factors as a cause for her microvascular thrombosis. In particular, occult malignancy was excluded in this patient.
Keeping in line with the evidence-based guidelines, we increased her anticoagulation intensity to maintain an INR between 3 and 4 but there was no significant improvement in her symptoms. Other treatment options were to switch from warfarin to therapeutic doses of unfractionated heparin or low molecular weight heparin but our patient refused to accept any injectable treatment options. Furthermore, she had an episode of bleeding per rectum with a significant drop in hemoglobin. We could not find any sinister cause for her bleeding apart from hemorrhoids which were managed with conservative measures.
Due to limited therapeutic options and reluctance on the part of our patient to switch over to injectable heparin, an informal decision was made to try apixaban. ODIs have a potential to be used in APS-related thrombotic events, although there is no concrete evidence supporting such use at the time of writing this report [
29]. The available data from a phase 3 clinical trial suggest that using therapeutic fixed dose dabigatran or rivaroxaban may have a role in the management of patients with thrombotic APS [
29]. Since approximately 10% of the patients who present with acute venous thromboembolism (VTE) have underlying APS, one can assume that ODIs will be effective in this category of patients as well [
30,
31]. A recent randomized controlled trial has suggested that rivaroxaban is non-inferior to warfarin in patients with thrombotic APS (with or without SLE) [
32]. However, this trial was limited to 6 months and it is unknown whether ODIs are effective in patients who develop recurrent thromboembolism while being on warfarin.
Apart from anticoagulation, isolated case reports exist describing other treatment options including the use of plasmapheresis and antifibrinolytics in some patients with APS [
33,
34]. Other case reports have found successful treatment with the use of intravenously administered immunoglobulins [
35], recombinant tissue plasminogen activator [
34], rituximab [
2], and sildenafil [
36]. However, corticosteroids and cytotoxic agents have been found to be ineffective in APS [
3].