Severe cutaneous necrosis in antiphospholipid syndrome

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Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent thrombosis and/or recurrent fetal loss. APS can be primary or secondary to autoimmune disorders such as systemic lupus erythematosus (SLE). It is unique from other thrombophilic disorders in that it predisposes patients to not only venous but also arterial thrombosis through endothelial cell damage and activation of platelets.1 The Sydney Criteria are used for diagnosis of APS and necessitate the presence of one clinical and one laboratory criteria.2 Clinical criteria consist of objectively confirmed venous, arterial or small vessel thrombosis, or pregnancy complications that may be attributed to placental insufficiency, including pre-eclampsia, pregnancy loss, or premature birth. Laboratory criteria consist of a positive laboratory test (lupus anticoagulant, anticardiolipin anticoagulant and/or anti-B2 glycoprotein) found on 2 or more occasions at least 12 weeks apart.2 Management of APS involves the long-term use of vitamin K antagonists. Catastrophic APS (CAPS), as the name implies, is a disastrous complication of APS. The International Congress on aPL has proposed criteria for diagnosis of CAPS; Definite CAPS requires all four of the following criteria: involvement of three or more organs, systems or tissues, manifestations develop simultaneously or in less than 1 week, small vessel occlusion that is confirmed histologically in at least one organ or tissue and presence of antiphospholipid antibodies twice at least 12 weeks apart. Probable CAPS diagnosis requires less stringent criteria (involvement of only two organs or sites of tissue involvement and manifestations of a third event develops between 1 week and 1 month after presentation despite anticoagulation).3 Although CAPS only occurs in less than 1% of patients with APS, when present, it is associated with high morbidity and mortality with the majority of patients requiring ICU admission for multi-organ failure.4 Cutaneous manifestations are recognized in the clinical spectrum of APS and include ulcers, pseudovasculitic skin lesions and digital gangrene.5 Less commonly reported is cutaneous skin necrosis, for which there have only been 14 case reports since the year 2000. We now present a rare case of APS with cutaneous necrosis and summarize clinical presentation and management of previous cases reported in the literature since the year 2000. A 36-year-old obese female patient with past medical history of hypertension, tobacco use, peripheral neuropathy, peripheral vascular disease with previous stents, and APS presented with worsening left lower extremity and perennial wounds. One year prior, she had been given a diagnosis of primary APS when she presented with a small ulcer on her left foot and laboratory testing revealed positive lupus anticoagulant, high titers for anticardiolipin immunoglobulin G (ACL IgG) (>150/mL) and B2-glycoprotein IgG (B2GP IgG) (>150 U/mL). Skin biopsy from the patient's initial presentation at the time with a skin ulcer on her toe revealed thrombotic microangiopathy and she was placed on warfarin (see Figure 1). She then presented 10 months later with a perineal wound and gangrenous toes. This occurred despite being on warfarin with average INR before admission 1.9. She required multiple amputations to all her left toes and surgical debridement leaving a poorly healing lateral wound on the left foot that failed skin graft. She presented to our institution with worsening cutaneous necrosis on the left foot stump, thigh, perineal decubitus ulcer, and fever (Figure 1). Labs revealed microcytic anemia (hemoglobin 6.8 g/dL, mean corpuscular volume 76 fl), thrombocytopenia 81 × 103/μL, and elevated inflammatory markers (erythrocyte sedimentation rate 102 mm/h [normal 0–30 mm/h], C-reactive protein 240 mg/L [normal 0–10 mg/L]). Coagulation profile was significant for PT of 21.6 s (normal 10.2–12.9 s), INR 1.9, PTT 100 s (normal 25.1–36.5 s), and fibrinogen 978. She was also triple positive with positive lupus anticoagulant, ACL IgG titer of 112 U/mL (negative < 20 U/mL) and B2-glycoprotein IgG titer >150 U/mL (negative < 15 U/mL). She had a negative thrombophilia gene workup including factor V Leiden and prothrombin gene mutation. She had polymicrobial growth from her wound culture and her blood cultures were negative. There was no evidence of deep venous thrombosis or osteomyelitis by ultrasound and bone scan respectively. The patient did not have any other organ affection and therefore she did not meet criteria for CAPS. Her warfarin was initially transitioned to low molecular weight heparin in response to her thrombocytopenia. Subsequently, anticoagulation was interrupted briefly as platelet count continued to drop to a nadir of 24 × 103/μL but she continued on half dose LMWH while platelet count was between 25 and 50 × 103/μL and with full dose anticoagulation once her platelet count recovered to >50 × 103/μL. Her rapidly worsening cutaneous necrosis and thrombocytopenia were thought to be a manifestation of severe anti-phospholipid syndrome (though not meeting CAPS criteria) with immune mediated thrombocytopenic flare (as opposed to disseminated intravascular coagulation given elevated fibrinogen without worsening in PT and INR). She was started on aggressive therapy with a quadruple regimen of intravenous immunoglobulin (IVIG), high dose steroids, plasma exchange and rituximab. IVIg infusion was given Day 1 and Day 7 (1 g/kg), methylprednisolone was given on Day 1–3 (500 mg/day), rituximab was given on Day 7 and Day 21 (1 g), and daily plasma exchange was started from Day 1 up to and including Day 7 (Figure 1 shows platelet count trends and timing of therapy). Her platelet count normalized on Day 15, and a heparin infusion was started on Day 3 once platelet counts reached 50 × 103/μL. The patient underwent left below knee amputation and surgical debridement without complications. She was transitioned back to warfarin with a higher INR goal (2.5–3.5). Antiplatelets with aspirin was initiated after the amputation once platelet count recovered. She continued to have stable platelet count and post-operative healing of her wounds (Figure 1). Cutaneous necrosis is a rare presentation of APS. Our case presented with cutaneous necrosis in her left foot, thigh and perineum along with severe thrombocytopenia. She was managed aggressively with IVIg, high dose steroids, plasma exchange and rituximab and required a below knee amputation and cutaneous tissue debridement. Her platelet counts stabilized and the cutaneous lesions resolved with treatment. There are no established standards of care for management of cutaneous necrosis in APS patients with only a few case reports documenting case presentations and management since 20006-16 (with all cases detailed in Supporting Information S1). Table 1 summarizes the characteristics of APS patients who developed cutaneous necrosis in previous case reports since the year 2000. The average age of patients presenting with cutaneous necrosis was 45 years (with median age of 46 years). The majority of patients were female (86.6%) and had primary APS (60.0%). A third of the cases also presented with CAPS. A prospective cohort study by Cervera et al. of 1000 patients with APS showed that the mean age was 34 years with a female to male ratio of 5:1 (83.3% female) similar to that reported for APS patients in a large cohort study.5 That cohort also reported that 53% of APS patients had primary APS and 36% of patients had secondary APS associated with SLE similar to our study. However, Cervera et al.'s cohort only showed 0.8% of patients with CAPS compared to the 33.3% of patients reported here, which suggests that cutaneous necrosis may be a manifestation that accompanies a more severe form of APS that is more likely to be associated with CAPS. The authors of the cohort went on to describe cutaneous manifestations and reported that ulcers occurred i

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