Abstract
Objectives
We discuss two patients with antiphospholipid syndrome (APS) who presented with critical ischemia of both lower extremities due to arterial microthrombi. They received multimodality therapy emergently: anticoagulation, immunosuppression, and therapeutic plasma exchange (TPE). Then they were maintained on anticoagulation with fondaparinux and immunosuppression with mycophenolate mofetil (MMF), and were followed for 4 years.
Methods
Two patients with APS with ischemia and necrosis of their distal lower extremities were treated emergently with anticoagulation (intravenous heparin), immunosuppression (prednisone), and TPE. They were maintained on anticoagulation with fondaparinux and immunosuppression with MMF.
Results
Neither patient had recurrent microthrombotic disease during a 4-year follow-up.
Conclusions
As described in our small cohort, patients with APS who suffer from microthrombotic arterial disease may benefit from maintenance therapy of anticoagulation with fondaparinux and immunosuppression with MMF, an approach which may be worthy of further trial. Fondaparinux does not require attention to diet, monitoring, and cumbersome bridging that is typical of warfarin therapy. MMF provides immunosuppression while sparing the side effects of steroid treatment.
Introduction
Antiphospholipid syndrome (APS) is an autoimmune illness that is characterized by serum positivity for antiphospholipid antibodies (aPLs), recurrent vascular thrombosis, and/or pregnancy morbidity. The aPLs include lupus anticoagulant (LA), anticardiolipins (ACLs), β-2 glycoprotein 1 (β2GP1) antibodies, and antibodies to phosphatidylserine.1,2 APS may be primary or associated with another autoimmune disease, especially systemic lupus erythematosus and rheumatoid arthritis. The incidence of APS is about 5 new cases per 100,000 persons per year, and the prevalence about 40–50 cases per 100,000 persons. 3 Therapy in aggressive disease has included anticoagulation (usually heparin or warfarin) and has been directed toward elimination of the aPLs by immunosuppression (e.g. steroids, rituximab, intravenous immune globulin, sometimes cyclophosphamide, and, most recently, eculizumab) 4 and therapeutic plasma exchange (TPE). Anticoagulants may interfere with clotting-based LA testing, but they are not expected to affect assays of ACLs, β2GP1 antibodies, or antibodies to phosphatidylserine. The decrease or elimination of the aPLs is often temporary, and antibodies frequently return on cessation of treatment. There has not been a consensus regarding optimal maintenance treatment regimens, and despite current recommendations, patients with APS still encounter significant morbidity and mortality. 5
Methods
Under a protocol approved by the University of Chicago Institutional Review Board (IRB, protocol number 18-0014), we discuss two patients with APS who presented with critical ischemia of both distal lower extremities due to arterial microthrombi. The IRB waived patient consent because this was a retrospective chart review of patients who were not identified and who were no longer in the hospital. They were treated emergently with combined anticoagulation with heparin, TPE, and immunosuppression with prednisone. Maintenance treatment included anticoagulation with fondaparinux and immune suppression with mycophenolate mofetil (MMF). The patients were followed for 4 years.
Results
Patient 1
A 45-year-old African American female began experiencing a burning sensation in both feet accompanied by purple discoloration of her toes (more on the left) in 2014. These changes progressed to dry gangrene of the distal left foot. She worked in packaging, occasionally in a freezer, smoked five cigarettes per day for 20 years, and had no family history of a clotting disorder. At presentation she had an LA (both in dilute Russell viper venom time (DRVVT) and partial thromboplastin time-LA (PTTLA) testing) and a β2GP1 IgM antibody titer of 93.2 U/ml (reference range (rr) < 20 U/ml). Other results included elevated C-reactive protein, normal WBC (7.7 K/µL), hemoglobin 11.3 gm/dL, platelet count 327 K/µL, and antinuclear IFA 320 (rr 0–80), but anti-DNA native double-stranded < 10.
A computed tomography angiogram showed patent vasculature in the abdomen, pelvis, and both lower extremities down to the level of the posterior tibial arteries.
Of interest, she had a positive tissue thromboplastin inhibition test 17 years before (no clinical details available) and an elevated β2GP1 IgM antibody (102 U/ml) 11 years before, when she had documented occlusion of an artery of the right great toe. At that time, she was anticoagulated with warfarin for 2 months. She had no other history of peripheral arterial vascular disease and no history of hypertension, diabetes mellitus, vasculitis, or atrial fibrillation.
At presentation in 2014 she was treated with warfarin and aspirin, but she was switched to intravenous heparin once the diagnosis of APS was made to more readily facilitate accurate anticoagulation, especially during the course of TPE. She had three TPE procedures, each approximately one plasma volume, with all or partial plasma fluid replacement. After the third TPE, β2GP1 IgM antibodies were reduced to 42.5 U/ml and the LA was undetectable. A fourth TPE was performed prior to left trans-metatarsal foot amputation for dry gangrene. She was started on maintenance therapy with fondaparinux (7.5 mg/day subcutaneously) and MMF (2 gm/day).
One year post-surgery she was walking with a special boot. She has been followed for 4 years without new thromboembolic events despite persistently positive β2GP1 IgM antibodies fluctuating between 29 and 89 U/ml over the first year. The levels became negative 3 years after presentation when the LA once again became detectable and there was a transient rise in IgM anticardiolipin titer. A switch to enoxaparin was necessitated by insurance constraints, but there was no change in her clinical course thereafter.
Patient 2
A 34-year-old Hispanic man, eighth grade teacher, non-smoker, presented in 2014 with throbbing in his feet and discoloration of the skin of his right great toe, which became mottled and turned black. Subsequently he developed similar changes on his left great toe and left heel. He had no personal or family history of clotting disorders and no history of diabetes mellitus, atrial fibrillation, hypertension, or vasculitis. A leg Doppler arterial ultrasound showed no clots. No angiograms or magnetic resonance angiogram examinations were performed. He was found to have the following: antinuclear IFA level of 2560; anti-DNA titer within rr; Sjogren's SSA antibodies 58 (rr < 20); positive LA (DRVVT and PTTLA); IgG antibodies directed against phosphatidylserine 64.2 U/ml (rr < 11 U/ml); IgG ACL 26.9 GPL units (rr<15, medium positive); IgM ACL 21 MPL units (rr < 12.5, medium positive), and marginally positive IgG anti-β2GP1 titer (21 U/ml, rr < 20 U/ml). Triglyceride level was elevated (485 mg/dL, rr 30–149 mg/dL). Hemoglobin was 12.1 mg/dL, WBC 9.3 K/μL, platelet count 196 K/μL, and remained similar during his course. A diagnosis of APS was made, and an intravenous heparin drip and prednisone (45 mg twice a day) were started. Three TPEs were performed on consecutive days, each one plasma volume, with plasma as the replacement fluid. He was discharged on aspirin 81 mg/day, clopidogrel bisulfate 75 mg/day orally, prednisone 45 mg twice a day, and fondaparinux 7.5 mg/day subcutaneously, which was later increased to 10 mg/day. Although he needed a wheelchair, his pain improved, there was no progression of the necrotic areas on his toes, and his heel demonstrated healing. Prednisone was decreased to 30 mg twice a day. MMF, 500 mg twice a day, was started and subsequently increased to 1500 mg/day, with a decrease in prednisone to 40 mg/day, then 20 mg/day, then 10 mg/day. Hydroxychloroquine, 200 mg twice a day was added. Fondaparinux was decreased to 7.5 mg/day.
The patient's feet continued to heal, and eventually he was able to walk, run errands, climb stairs, and resume work. No surgery was needed. He was later started on Folbee twice daily for an elevated homocysteine level which normalized. He has been followed for 4 years and has had an intermittently positive LA (last in 2017), persistently low titer anti-phosphatidylserine antibody, and negative antibodies to cardiolipin and β2GP1. There have been no clinical complications from APS. Current medications include prednisone (10–20 mg/day), MMF, fondaparinux, and aspirin. Adjustments in prednisone doses prevented progression of occasional episodes of mild ischemic changes in his fingertips.
Discussion
We diagnosed our patients with APS based on their strongly positive serologic findings and the absence of diagnostic criteria for other entities. Limitation of thrombotic changes to distal extremity sites is consistent with the microthrombotic location of the clotting events.
Thrombotic events are the major complications of APS, and long-term anticoagulation is the mainstay of therapy. 6 However, despite anticoagulation, some patients develop a vasculopathy with microthrombi which appears to be mediated by the aPLs interacting with the endothelium.5,7 This phenomenon suggests a rationale for immunosuppressive therapy to reduce antibody titers in addition to overcoming the hypercoagulable state by anticoagulation.
Our patients presented with progressing microthrombotic symptoms for which we initiated multimodality therapy acutely because of progressive limb-threatening changes, similar to that used in catastrophic APS (CAPS), including corticosteroids. Erkan et al. 8 referencing Asherson et al.9, state that “the highest survival rate” in CAPS has been “achieved with the combination of anticoagulation, corticosteroids, and plasmapheresis or intravenous immunoglobulin (IVIG) (70%).” Steroid doses were reduced in our patients and MMF started in hopes of keeping the aPL titers low and reducing long-term vasculopathy complications.
Our patients also received TPE. Through a computer-assisted Medline search of the literature, Uthman et al. 10 found that “TPE has shown reasonable therapeutic benefits and improved survival for patients with CAPS” and that TPE, “along with anticoagulation and if needed pharmacological immunosuppression, should be considered for the acute management of patients who present with this life-threatening condition.” Neuwelt et al. 11 present a case in which repeated TPE over 3 years was the only treatment of multiple therapies that halted the progression of CAPS. They suggest that perhaps “through removal of cytokines or other mediators” TPE may disrupt “the interaction between phospholipid protein complexes and endothelial cells.”
Although it is not clear what role each of the therapeutic modalities played in the subsequent clinical course, there was sustained reduction of the antibody titers long after TPE, and small increases in prednisone dose correlated with reversal of new early evolving skin lesions in Patient 2. Taken together, these observations suggest a contributing role of immunosuppressive therapy in the ongoing control of our patients' microthrombotic APS.
Fondaparinux and MMF were selected for maintenance because of their anticipated favorable side effect profiles. There is little experience with fondaparinux in APS. 12 It provides anticoagulation without the problems of diet, monitoring, and cumbersome bridging typical of warfarin therapy. The use of MMF has been reported previously, though apparently uncommonly, for the treatment of APS. 13 It is helpful in sparing steroid side effects.
Conclusions
We have discussed two patients with APS who presented with microthrombotic-based distal lower extremity ischemia and necrosis. Their acute management included heparin anticoagulation, immunosuppression with prednisone, and TPE. Subsequently they were maintained on anticoagulation with fondaparinux and immune suppression with MMF with good clinical results. They have not had recurrent microthrombotic disease during a 4-year follow-up period.
Because of the known variable features and course of APS, it is difficult to assign proof of efficacy of specific treatments except to observe over an extended period of time. We report our observations of two patients who remained under clinical control without adverse reactions on fondaparinux and MMF. We suggest that this combination might be the subject of future study in a larger cohort of patients with a similar presentation.
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.