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Antiphospholipid antibodies disappearance in primary antiphospholipid syndrome: Thrombosis recurrence
Autoimmunity Reviews 16 (2017) 352–354
Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Antiphospholipid antibodies disappearance in primary antiphospholipid syndrome: Thrombosis recurrence Gabriela Medina a,f, Eduardo Briones-García b, María Pilar Cruz-Domínguez c,f, Oscar I. Flórez-Durante d, Luis J. Jara e,f,⁎ a
Clinical Research Unit, Hospital de Especialidades Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico Universidad de Guadalajara, Guadalajara, Mexico Research Division, Hospital de Especialidades Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico d Escuela Nacional de Ciencias Biológicas Instituto Politécnico Nacional, Mexico e Direction of Education and Research, Hospital de Especialidades Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico f Universidad Nacional Autónoma de México, Mexico City, Mexico b c
a r t i c l e
i n f o
a b s t r a c t Objective: To evaluate the clinical outcome after aPL (antiphospholipid antibodies) disappearance in primary APS patients. Methods: From a cohort of 70 patients with primary APS, we selected patients with positive aPL determinations at onset and ≥2 subsequent negative aPL determinations during the last 5 years. To corroborate the immunologic profile, we determined IgG/IgM aCL antibodies, IgG/IgM antiβ2GPl, anti-annexin A5 antibodies and lupus anticoagulant (LA). All patients continued treatment with oral anticoagulants. Clinical data and aPL determinations at onset/after disappearance were obtained. Statistical analysis: descriptive statistics and Kaplan-Meier analysis. Results: We found 24 patients with persistently negative aPL, including the last immunologic profile, 17 females, 7 males, mean age 51.7, disease evolution 16.3 years, mean of 4 aPL previous positive determinations. aCL was positive at onset in 87.5%, 29% had double aPL positivity at onset (aCL/LA). Deep venous thrombosis (DVT) and ischemic stroke in 33% and pulmonary embolism in 12.5% were the most frequent manifestations at onset. INR range: 2–3. Time with aPL positive 109.4 ± 80.7 months. After 60 months of follow-up since aPL disappearance, 45.8% of patients presented thrombosis recurrence, DVT in 9 patients, ischemic stroke in 1, pulmonary artery hypertension in 1. Other non-thrombotic APS manifestations were chronic ulcers in lower extremities and severe thrombocytopenia. Conclusions: This study suggest, that in primary APS, persistent negative aPL profile is not an indication to interrupt oral anticoagulant therapy. However, there is a subset of patients that remained asymptomatic. Other studies are necessary in order to elucidate this controversy. © 2017 Elsevier B.V. All rights reserved.
Article history: Received 12 December 2016 Accepted 19 December 2016 Available online 13 February 2017 Keywords: Primary antiphospholipid syndrome aPL disappearance Clinical outcome Thrombosis recurrence
Contents 1. 2.
Introduction . . . . . . . . . Patients and methods . . . . . 2.1. Statistical analysis . . . 3. Results . . . . . . . . . . . . 3.1. Before aPL disappearance 3.2. After aPL disappearance . 4. Discussion . . . . . . . . . . 5. Conclusions. . . . . . . . . . References. . . . . . . . . . . . .
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353 353 353 353 353 353 353 354 354
⁎ Corresponding author at: Hospital de Especialidades Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Seris y Zaachila S/N Col. La Raza, 02990 Mexico City, Mexico. E-mail addresses: [email protected] (G. Medina), [email protected] (E. Briones-García), [email protected] (M.P. Cruz-Domínguez), oscar_fl[email protected] (O.I. Flórez-Durante), [email protected] (L.J. Jara).
http://dx.doi.org/10.1016/j.autrev.2017.02.004 1568-9972/© 2017 Elsevier B.V. All rights reserved.
G. Medina et al. / Autoimmunity Reviews 16 (2017) 352–354
1. Introduction Antiphospholipid syndrome (APS) is defined by clinical manifestations including recurrent arterial and/or venous thrombosis and/or pregnancy morbidity in patients with persistence of antiphospholipid antibodies (aPL) (lupus anticoagulant (LA), and/or anticardiolipin (aCL) and anti-β2-glycoprotein 1 antibodies (antiβ2GP1) [1]. In absence of other diseases it is defined as primary APS (PAPS). Despite appropriate anticoagulant treatment, thrombotic recurrence rate in APS has been reported as high as 7.5/100 patient years in the first 5 years after the first thrombotic event [2]. Until now, indefinite anticoagulation remains the mainstay of therapy for thrombotic APS. During the course of the disease, some patients with previously positive aPL profile remain stable for years and may become negative, being a challenge for the clinician to deal with this condition [3]. Factors related to the disappearance of aPL are unknown and there is no evidence of thrombotic risk and the role of prophylactic treatment in this subset of patients. As hemorrhagic complications are associated to long-term anticoagulation therapy, there is uncertainty about the possibility of withdrawing this therapy in patients that lose aPL positivity [4]. At present, little is known about the course of this subset of patients after anticoagulation therapy is discontinued. In fact, only two small case series of APS patients with previously positive aPL profile and subsequent negative aPL determinations have been reported. These studies suggested the possibility of anticoagulation discontinuation in PAPS patients with low-risk and venous thrombosis with a concomitant risk factor that turned persistently aPL negative, once they did not present thrombotic recurrence after a mean follow-up of 20 months [3,5]. Studies with larger number of patients and longer follow-up are lacking. Therefore, the aim of the study was to describe the clinical outcome after aPL profile became negative in patients with PAPS during a 5-year follow-up.
353
10.9 years, disease evolution 16.5 ± 6 years, with a mean of 4 aPL positive determinations performed at least 12 weeks apart. The number of aPL determinations ranged from 2 to 10, and a median of 4 thrombotic events. Two patients had N 10 venous thrombotic events in the four extremities. One of these two patients had other abnormalities such as resistance to activated protein C, moderate increase in plasma concentration of hemostatic factor VIII and hyperhomocysteinemia. 3.1. Before aPL disappearance Antiphospholipid antibodies positivity at disease onset were: aCL IgG or IgM in 21 patients (87.5%), most of the patients presented aCL titers b80 GPL or MPL units. Two patients (8%) had positivity only to antiβ2GPl (this antibody was performed only in a subset of patients that were initially negative to aCL/LA) and one to LA (4%), while 29% had double aPL positivity (aCL/LA). Mean time with positive aPL: 109.4 ± 80 months. Deep venous thrombosis (DVT) in the inferior extremities was the most frequent manifestation at APS onset, followed by ischemic stroke and pulmonary embolism. Other types of venous thrombosis included subclavian and jugular vein thrombosis. Of interest, the initial clinical manifestation in 37.5% of patients was arterial thrombosis, being the clinical presentation stroke and mesenteric thrombosis. (Table 1). Only three patients had history of recurrent abortions before APS diagnosis was made. INR range was maintained between 2 and 3. Cardiovascular risk factors at the time of diagnosis of PAPS were present in 45.8% of patients, 2 patients took oral contraceptives, 2 had dyslipidemia, 2 smoked, 2 had arterial hypertension, 1 had diabetes mellitus, 1 with overweight and 1 had thrombosis after a surgical procedure. After follow-up, cardiovascular risk factors increased in 75% of patients; four patients had N 1 risk factor. The most frequent concomitant cardiovascular risk factors were dyslipidemia (29%), overweight (20.8%) and obesity (16.7%).
2. Patients and methods 3.2. After aPL disappearance From a cohort of 70 patients with established diagnosis of PAPS according to International consensus criteria, [6] we selected patients with positive aPL determinations at onset and ≥2 subsequent negative aPL determinations during the last 5 years. All aPL tests were performed in the same laboratory. Other causes of thrombophilia were ruled out at disease onset. Patients continued treatment with oral anticoagulants (Coumadin) and they were not taking hydroxychloroquine or chloroquine. Clinical charts were reviewed to obtain clinical data, initial aPL determinations, clinical manifestations at onset and posterior to aPL disappearance, mean International Normalized Ratio (INR) as well as the presence of cardiovascular risk factors for thrombosis. To corroborate the negative aPL profile, currently we determined the following plasmatic antibodies: aCL IgG, (normal values b8.4 IU) aCL IgM (normal values b13.1 IU)(INOVA QUANTA Lite ACA); IgG antiβ2GPl (normal values b 8.4 IU) IgM antiβ2GPl (normal values 14.3 IU)(INOVA QUANTA Lite β2GPI); IgG anti-annexin 5 (normal values b 5.6 IU) and IgM anti-annexin 5 (normal values b 4.8 IU) antibodies, (ORGENTEC Diagnostika GmbH) all of them were measured by Enzyme Linked Immunosorbent Assay (ELISA) and LA (Russell viper venom) (IL Diagnostic) (1.2 a 1.5 mild positive), 1.5 a 2 moderate, N 2 highly positive).
After 60 months of follow-up since disappearance of aPL, 7/24 patients remained completely asymptomatic. Survival free of thrombosis recurrence was calculated by Kaplan-Meier analysis revealing that 11/ 24 patients (45.8%) presented thrombosis recurrence despite optimal anticoagulant treatment and aPL disappearance. The most common clinical manifestation in this subset of patients was DVT in 9 patients, one presented pulmonary arterial hypertension, and another one had ischemic stroke (Fig. 1). Other non-thrombotic or non-criteria APS manifestations were chronic skin ulcers in lower extremities in 4 patients, and severe thrombocytopenia in 2. During follow-up two patients developed lupus-like syndrome. 4. Discussion In the present study we found that after long-term follow-up, almost a half of PAPS patients with persistent aPL disappearance had thrombosis recurrence despite optimal anticoagulant treatment. Additionally, a small proportion of patients presented other non-thrombotic APS manifestations. These data also suggest that other risk factors and/or aPL can contribute to recurrence of thrombosis or presentation of other non-
2.1. Statistical analysis Descriptive statistics, frequencies, percentages, mean, standard deviation, median and ranges, and Kaplan Meier analysis. SPSS software, version 20.0 (SPSS, Chicago, IL) was used for the statistical calculations. p values b0.05 were considered statistically significant. 3. Results We found 24/70 patients with persistently negative aPL, including the last immunologic profile, 17 females, 7 males, mean age 51.8 ±
Table 1 Clinical manifestations of PAPS patients at onset. Clinical manifestation at onset
Number of patients (N = 24)
Stroke Mesenteric thrombosis Deep venous thrombosis Pulmonary embolism Subclavian thrombosis Jugular vein thrombosis Optic neuritis
8 (33%) 1 (4%) 8 (33%) 3 (12.5%) 1 (4%) 1(4%) 2 (8%)
354
G. Medina et al. / Autoimmunity Reviews 16 (2017) 352–354
Fig. 1. Kaplan Meier analysis for survival free of thrombosis in patients with aPL disappearance.
thrombotic APS manifestations. Therefore, negative aPL profile is not an indication to discontinue anticoagulant therapy. However, there was a subset of patients that remained asymptomatic. It has been reported a subset of APS patients who initially tested positive for aPL and during evolution became persistently negative for the same antibodies; the factors related to the loss of aPL positivity are unknown [4]. Previous studies about this problem are short series of cases (six and eleven cases respectively) with a shorter follow-up period (mean follow-up 20 months without thromboprophylaxis) after which no new thrombotic episodes were seen [3,5]. Criado Garcia et al. [3] mentioned that from six patients with persistent negative aPL profile, 4 had transient risk factors at the time of first venous thrombotic event. They concluded that anticoagulation could be discontinued especially in those with venous thrombosis and a concomitant transient risk factor. In the second study, DVT was the most common manifestation at APS onset, along with recurrent miscarriage and pulmonary embolism in 2 patients. No patients had arterial thrombosis. In patients with previous thrombosis no new thrombotic episode was seen after 18 months of follow-up [5]. Important differences with our study are that these previous reports have no patients with arterial thrombosis, while we had 9 patients with this type of event, considering this subset of patients in a higher risk category. Furthermore, follow-up time was three times that of previous studies. In our series, only 3 patients had obstetric morbidity, however, diagnosis of APS was made after they presented an arterial thrombotic event. Regarding type and titers of aPL present at disease onset, similar to the Criado-Garcia [3] series, aCL was the most frequent aPL seen at the beginning of the disease, and they also presented low to medium aCL titers. An important consideration is that in the present study the majority of included patients had previous thrombotic event, different to the obstetric events as initial manifestation in one third of the patients from Coloma Bazán et al. [5] This last consideration, knowing that patients that had only obstetric morbidity may have a different risk profile. About risk factors for thrombosis, several papers have shown that cardiovascular disease is associated with aPL, as well as traditional risk factors (hypertension, obesity, dyslipidemia, etc.), and non-traditional risk factors (hyperhomocysteinemia, increased lipoprotein a, autoantibodies, etc.) [7]. Previously, our group found a high prevalence of metabolic syndrome in PAPS patients, similar to other autoimmune diseases [8]. As metabolic syndrome is a constellation of cardiovascular risk factors, patients that had disappearance of aPL also presented these factors during follow-up and they may contribute to thrombosis recurrence. Another point is that some patients with disappearance of aPL, developed APS features different to thrombotic manifestations, considered
as non-thrombotic or non-criteria APS manifestations, such as chronic skin ulcers with difficulty to heal and severe thrombocytopenia. Other studies have addressed the non-criteria manifestations of APS including thrombocytopenia, nephropathy, cardiac valve disease, cognitive dysfunction, skin ulcers, or diffuse pulmonary hemorrhage [9]. They may occur despite full-dose anticoagulation or may not improve if anticoagulation is initiated after their presentation. Non-vasculitic skin ulcers are commonly small and painful, though some lesions may recur and extend. Regarding thrombocytopenia, usually it is not severe, with platelet levels over than 50,000 platelets/μL, however, there is a subset of APS patients that developed severe thrombocytopenia (b 50.,000/μL), and some of them may have hemorrhagic complications or even thrombotic events in spite of severe thrombocytopenia [10]. These non-thrombotic complications were also observed in our patients. Limitations from the present study are retrospective design, small sample size, even though the number of patients included is larger than the other reported series, and lack of evaluation of other aPL after their disappearance. The strength of our study is that disappearance of aPL was confirmed after 5 years of follow-up. In summary, discontinuation of anticoagulation treatment in PAPS patients with subsequent disappearance of aPL is still a matter of debate due to the possibility of recurrence of thrombosis or presentation of other non-criteria clinical manifestations in a subset of patients. Until now, not all risk factors have been understood and identified. In the meantime, integral management of PAPS patients includes close surveillance of risk factors, monitoring fluctuations of INR, drug therapy adjustment, with the possibility of introducing new target therapies, patient education with lifestyle modification and finally, individualization of every case. 5. Conclusions This study suggests that in primary APS, persistent negative aPL profile is not an indication to interrupt oral anticoagulant therapy. Additional risk factors and other aPL can contribute to the recurrence of thrombosis or presentation of non-criteria clinical manifestations revealing clinical disease activity. However, a subset of patients may remain asymptomatic. Other studies with longer follow-up are necessary to clarify this controversy. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Chaturvedi S, McCrae KR. The antiphospholipid syndrome: still an enigma. Hematology Am Soc Hematol Educ Program 2015;2015:53–60. [2] Bazzan M, Vaccarino A, Stella S, Sciascia S, Montaruli B, Bertero MT, et al. Patients with antiphosholipid syndrome and thrombotic recurrences: a real world observation (the Piedmont cohort study). Lupus 2016;25:479–85. [3] Criado-García J, Fernández-Puebla RA, Jiménez LL, Velasco F, Santamaría M, BlancoMolina A. Anticoagulation treatment withdrawal in primary antiphospholipid syndrome when anticardiolipin antibodies become negative. Rev Clin Esp 2008;208: 135–7. [4] Espinosa G, Cervera R. Current treatment of antiphospholipid syndrome: lights and shadows. Nat Rev Rheumatol 2015;11:586–96. [5] Coloma Bazán E, Donate López C, Moreno Lozano P, Cervera R, Espinosa G. Discontinuation of anticoagulation or antiaggregation treatment may be safe in patients with primary antiphospholipid syndrome when antiphospholipid antibodies became persistently negative. Immunol Res 2013;56:358–61. [6] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. [7] da Silva FF, Levy RA, de Carvalho JF. Cardiovascular risk factors in the antiphospholipid syndrome. J Immunol Res 2014;2014:621270. [8] Medina G, Gutiérrez-Moreno AL, Vera-Lastra O, Saavedra MA, Jara LJ. Prevalence of metabolic syndrome in primary antiphospholipid syndrome patients. Autoimmun Rev 2011;10:214–7. [9] Erkan D, Lockshin MD. Non-criteria manifestations of antiphospholipid syndrome. Lupus 2010;19:424–7. [10] Rosa RF, Ugolini-Lopes MR, Zeinad-Valim AK, D'Amico E, Andrade D. Difficult clinical situations in the antiphospholipid syndrome. Curr Rheumatol Rep 2015;17:29.
Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Antiphospholipid antibodies disappearance in primary antiphospholipid syndrome: Thrombosis recurrence Gabriela Medina a,f, Eduardo Briones-García b, María Pilar Cruz-Domínguez c,f, Oscar I. Flórez-Durante d, Luis J. Jara e,f,⁎ a
Clinical Research Unit, Hospital de Especialidades Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico Universidad de Guadalajara, Guadalajara, Mexico Research Division, Hospital de Especialidades Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico d Escuela Nacional de Ciencias Biológicas Instituto Politécnico Nacional, Mexico e Direction of Education and Research, Hospital de Especialidades Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico f Universidad Nacional Autónoma de México, Mexico City, Mexico b c
a r t i c l e
i n f o
a b s t r a c t Objective: To evaluate the clinical outcome after aPL (antiphospholipid antibodies) disappearance in primary APS patients. Methods: From a cohort of 70 patients with primary APS, we selected patients with positive aPL determinations at onset and ≥2 subsequent negative aPL determinations during the last 5 years. To corroborate the immunologic profile, we determined IgG/IgM aCL antibodies, IgG/IgM antiβ2GPl, anti-annexin A5 antibodies and lupus anticoagulant (LA). All patients continued treatment with oral anticoagulants. Clinical data and aPL determinations at onset/after disappearance were obtained. Statistical analysis: descriptive statistics and Kaplan-Meier analysis. Results: We found 24 patients with persistently negative aPL, including the last immunologic profile, 17 females, 7 males, mean age 51.7, disease evolution 16.3 years, mean of 4 aPL previous positive determinations. aCL was positive at onset in 87.5%, 29% had double aPL positivity at onset (aCL/LA). Deep venous thrombosis (DVT) and ischemic stroke in 33% and pulmonary embolism in 12.5% were the most frequent manifestations at onset. INR range: 2–3. Time with aPL positive 109.4 ± 80.7 months. After 60 months of follow-up since aPL disappearance, 45.8% of patients presented thrombosis recurrence, DVT in 9 patients, ischemic stroke in 1, pulmonary artery hypertension in 1. Other non-thrombotic APS manifestations were chronic ulcers in lower extremities and severe thrombocytopenia. Conclusions: This study suggest, that in primary APS, persistent negative aPL profile is not an indication to interrupt oral anticoagulant therapy. However, there is a subset of patients that remained asymptomatic. Other studies are necessary in order to elucidate this controversy. © 2017 Elsevier B.V. All rights reserved.
Article history: Received 12 December 2016 Accepted 19 December 2016 Available online 13 February 2017 Keywords: Primary antiphospholipid syndrome aPL disappearance Clinical outcome Thrombosis recurrence
Contents 1. 2.
Introduction . . . . . . . . . Patients and methods . . . . . 2.1. Statistical analysis . . . 3. Results . . . . . . . . . . . . 3.1. Before aPL disappearance 3.2. After aPL disappearance . 4. Discussion . . . . . . . . . . 5. Conclusions. . . . . . . . . . References. . . . . . . . . . . . .
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353 353 353 353 353 353 353 354 354
⁎ Corresponding author at: Hospital de Especialidades Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Seris y Zaachila S/N Col. La Raza, 02990 Mexico City, Mexico. E-mail addresses: [email protected] (G. Medina), [email protected] (E. Briones-García), [email protected] (M.P. Cruz-Domínguez), oscar_fl[email protected] (O.I. Flórez-Durante), [email protected] (L.J. Jara).
http://dx.doi.org/10.1016/j.autrev.2017.02.004 1568-9972/© 2017 Elsevier B.V. All rights reserved.
G. Medina et al. / Autoimmunity Reviews 16 (2017) 352–354
1. Introduction Antiphospholipid syndrome (APS) is defined by clinical manifestations including recurrent arterial and/or venous thrombosis and/or pregnancy morbidity in patients with persistence of antiphospholipid antibodies (aPL) (lupus anticoagulant (LA), and/or anticardiolipin (aCL) and anti-β2-glycoprotein 1 antibodies (antiβ2GP1) [1]. In absence of other diseases it is defined as primary APS (PAPS). Despite appropriate anticoagulant treatment, thrombotic recurrence rate in APS has been reported as high as 7.5/100 patient years in the first 5 years after the first thrombotic event [2]. Until now, indefinite anticoagulation remains the mainstay of therapy for thrombotic APS. During the course of the disease, some patients with previously positive aPL profile remain stable for years and may become negative, being a challenge for the clinician to deal with this condition [3]. Factors related to the disappearance of aPL are unknown and there is no evidence of thrombotic risk and the role of prophylactic treatment in this subset of patients. As hemorrhagic complications are associated to long-term anticoagulation therapy, there is uncertainty about the possibility of withdrawing this therapy in patients that lose aPL positivity [4]. At present, little is known about the course of this subset of patients after anticoagulation therapy is discontinued. In fact, only two small case series of APS patients with previously positive aPL profile and subsequent negative aPL determinations have been reported. These studies suggested the possibility of anticoagulation discontinuation in PAPS patients with low-risk and venous thrombosis with a concomitant risk factor that turned persistently aPL negative, once they did not present thrombotic recurrence after a mean follow-up of 20 months [3,5]. Studies with larger number of patients and longer follow-up are lacking. Therefore, the aim of the study was to describe the clinical outcome after aPL profile became negative in patients with PAPS during a 5-year follow-up.
353
10.9 years, disease evolution 16.5 ± 6 years, with a mean of 4 aPL positive determinations performed at least 12 weeks apart. The number of aPL determinations ranged from 2 to 10, and a median of 4 thrombotic events. Two patients had N 10 venous thrombotic events in the four extremities. One of these two patients had other abnormalities such as resistance to activated protein C, moderate increase in plasma concentration of hemostatic factor VIII and hyperhomocysteinemia. 3.1. Before aPL disappearance Antiphospholipid antibodies positivity at disease onset were: aCL IgG or IgM in 21 patients (87.5%), most of the patients presented aCL titers b80 GPL or MPL units. Two patients (8%) had positivity only to antiβ2GPl (this antibody was performed only in a subset of patients that were initially negative to aCL/LA) and one to LA (4%), while 29% had double aPL positivity (aCL/LA). Mean time with positive aPL: 109.4 ± 80 months. Deep venous thrombosis (DVT) in the inferior extremities was the most frequent manifestation at APS onset, followed by ischemic stroke and pulmonary embolism. Other types of venous thrombosis included subclavian and jugular vein thrombosis. Of interest, the initial clinical manifestation in 37.5% of patients was arterial thrombosis, being the clinical presentation stroke and mesenteric thrombosis. (Table 1). Only three patients had history of recurrent abortions before APS diagnosis was made. INR range was maintained between 2 and 3. Cardiovascular risk factors at the time of diagnosis of PAPS were present in 45.8% of patients, 2 patients took oral contraceptives, 2 had dyslipidemia, 2 smoked, 2 had arterial hypertension, 1 had diabetes mellitus, 1 with overweight and 1 had thrombosis after a surgical procedure. After follow-up, cardiovascular risk factors increased in 75% of patients; four patients had N 1 risk factor. The most frequent concomitant cardiovascular risk factors were dyslipidemia (29%), overweight (20.8%) and obesity (16.7%).
2. Patients and methods 3.2. After aPL disappearance From a cohort of 70 patients with established diagnosis of PAPS according to International consensus criteria, [6] we selected patients with positive aPL determinations at onset and ≥2 subsequent negative aPL determinations during the last 5 years. All aPL tests were performed in the same laboratory. Other causes of thrombophilia were ruled out at disease onset. Patients continued treatment with oral anticoagulants (Coumadin) and they were not taking hydroxychloroquine or chloroquine. Clinical charts were reviewed to obtain clinical data, initial aPL determinations, clinical manifestations at onset and posterior to aPL disappearance, mean International Normalized Ratio (INR) as well as the presence of cardiovascular risk factors for thrombosis. To corroborate the negative aPL profile, currently we determined the following plasmatic antibodies: aCL IgG, (normal values b8.4 IU) aCL IgM (normal values b13.1 IU)(INOVA QUANTA Lite ACA); IgG antiβ2GPl (normal values b 8.4 IU) IgM antiβ2GPl (normal values 14.3 IU)(INOVA QUANTA Lite β2GPI); IgG anti-annexin 5 (normal values b 5.6 IU) and IgM anti-annexin 5 (normal values b 4.8 IU) antibodies, (ORGENTEC Diagnostika GmbH) all of them were measured by Enzyme Linked Immunosorbent Assay (ELISA) and LA (Russell viper venom) (IL Diagnostic) (1.2 a 1.5 mild positive), 1.5 a 2 moderate, N 2 highly positive).
After 60 months of follow-up since disappearance of aPL, 7/24 patients remained completely asymptomatic. Survival free of thrombosis recurrence was calculated by Kaplan-Meier analysis revealing that 11/ 24 patients (45.8%) presented thrombosis recurrence despite optimal anticoagulant treatment and aPL disappearance. The most common clinical manifestation in this subset of patients was DVT in 9 patients, one presented pulmonary arterial hypertension, and another one had ischemic stroke (Fig. 1). Other non-thrombotic or non-criteria APS manifestations were chronic skin ulcers in lower extremities in 4 patients, and severe thrombocytopenia in 2. During follow-up two patients developed lupus-like syndrome. 4. Discussion In the present study we found that after long-term follow-up, almost a half of PAPS patients with persistent aPL disappearance had thrombosis recurrence despite optimal anticoagulant treatment. Additionally, a small proportion of patients presented other non-thrombotic APS manifestations. These data also suggest that other risk factors and/or aPL can contribute to recurrence of thrombosis or presentation of other non-
2.1. Statistical analysis Descriptive statistics, frequencies, percentages, mean, standard deviation, median and ranges, and Kaplan Meier analysis. SPSS software, version 20.0 (SPSS, Chicago, IL) was used for the statistical calculations. p values b0.05 were considered statistically significant. 3. Results We found 24/70 patients with persistently negative aPL, including the last immunologic profile, 17 females, 7 males, mean age 51.8 ±
Table 1 Clinical manifestations of PAPS patients at onset. Clinical manifestation at onset
Number of patients (N = 24)
Stroke Mesenteric thrombosis Deep venous thrombosis Pulmonary embolism Subclavian thrombosis Jugular vein thrombosis Optic neuritis
8 (33%) 1 (4%) 8 (33%) 3 (12.5%) 1 (4%) 1(4%) 2 (8%)
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Fig. 1. Kaplan Meier analysis for survival free of thrombosis in patients with aPL disappearance.
thrombotic APS manifestations. Therefore, negative aPL profile is not an indication to discontinue anticoagulant therapy. However, there was a subset of patients that remained asymptomatic. It has been reported a subset of APS patients who initially tested positive for aPL and during evolution became persistently negative for the same antibodies; the factors related to the loss of aPL positivity are unknown [4]. Previous studies about this problem are short series of cases (six and eleven cases respectively) with a shorter follow-up period (mean follow-up 20 months without thromboprophylaxis) after which no new thrombotic episodes were seen [3,5]. Criado Garcia et al. [3] mentioned that from six patients with persistent negative aPL profile, 4 had transient risk factors at the time of first venous thrombotic event. They concluded that anticoagulation could be discontinued especially in those with venous thrombosis and a concomitant transient risk factor. In the second study, DVT was the most common manifestation at APS onset, along with recurrent miscarriage and pulmonary embolism in 2 patients. No patients had arterial thrombosis. In patients with previous thrombosis no new thrombotic episode was seen after 18 months of follow-up [5]. Important differences with our study are that these previous reports have no patients with arterial thrombosis, while we had 9 patients with this type of event, considering this subset of patients in a higher risk category. Furthermore, follow-up time was three times that of previous studies. In our series, only 3 patients had obstetric morbidity, however, diagnosis of APS was made after they presented an arterial thrombotic event. Regarding type and titers of aPL present at disease onset, similar to the Criado-Garcia [3] series, aCL was the most frequent aPL seen at the beginning of the disease, and they also presented low to medium aCL titers. An important consideration is that in the present study the majority of included patients had previous thrombotic event, different to the obstetric events as initial manifestation in one third of the patients from Coloma Bazán et al. [5] This last consideration, knowing that patients that had only obstetric morbidity may have a different risk profile. About risk factors for thrombosis, several papers have shown that cardiovascular disease is associated with aPL, as well as traditional risk factors (hypertension, obesity, dyslipidemia, etc.), and non-traditional risk factors (hyperhomocysteinemia, increased lipoprotein a, autoantibodies, etc.) [7]. Previously, our group found a high prevalence of metabolic syndrome in PAPS patients, similar to other autoimmune diseases [8]. As metabolic syndrome is a constellation of cardiovascular risk factors, patients that had disappearance of aPL also presented these factors during follow-up and they may contribute to thrombosis recurrence. Another point is that some patients with disappearance of aPL, developed APS features different to thrombotic manifestations, considered
as non-thrombotic or non-criteria APS manifestations, such as chronic skin ulcers with difficulty to heal and severe thrombocytopenia. Other studies have addressed the non-criteria manifestations of APS including thrombocytopenia, nephropathy, cardiac valve disease, cognitive dysfunction, skin ulcers, or diffuse pulmonary hemorrhage [9]. They may occur despite full-dose anticoagulation or may not improve if anticoagulation is initiated after their presentation. Non-vasculitic skin ulcers are commonly small and painful, though some lesions may recur and extend. Regarding thrombocytopenia, usually it is not severe, with platelet levels over than 50,000 platelets/μL, however, there is a subset of APS patients that developed severe thrombocytopenia (b 50.,000/μL), and some of them may have hemorrhagic complications or even thrombotic events in spite of severe thrombocytopenia [10]. These non-thrombotic complications were also observed in our patients. Limitations from the present study are retrospective design, small sample size, even though the number of patients included is larger than the other reported series, and lack of evaluation of other aPL after their disappearance. The strength of our study is that disappearance of aPL was confirmed after 5 years of follow-up. In summary, discontinuation of anticoagulation treatment in PAPS patients with subsequent disappearance of aPL is still a matter of debate due to the possibility of recurrence of thrombosis or presentation of other non-criteria clinical manifestations in a subset of patients. Until now, not all risk factors have been understood and identified. In the meantime, integral management of PAPS patients includes close surveillance of risk factors, monitoring fluctuations of INR, drug therapy adjustment, with the possibility of introducing new target therapies, patient education with lifestyle modification and finally, individualization of every case. 5. Conclusions This study suggests that in primary APS, persistent negative aPL profile is not an indication to interrupt oral anticoagulant therapy. Additional risk factors and other aPL can contribute to the recurrence of thrombosis or presentation of non-criteria clinical manifestations revealing clinical disease activity. However, a subset of patients may remain asymptomatic. Other studies with longer follow-up are necessary to clarify this controversy. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Chaturvedi S, McCrae KR. The antiphospholipid syndrome: still an enigma. Hematology Am Soc Hematol Educ Program 2015;2015:53–60. [2] Bazzan M, Vaccarino A, Stella S, Sciascia S, Montaruli B, Bertero MT, et al. Patients with antiphosholipid syndrome and thrombotic recurrences: a real world observation (the Piedmont cohort study). Lupus 2016;25:479–85. [3] Criado-García J, Fernández-Puebla RA, Jiménez LL, Velasco F, Santamaría M, BlancoMolina A. Anticoagulation treatment withdrawal in primary antiphospholipid syndrome when anticardiolipin antibodies become negative. Rev Clin Esp 2008;208: 135–7. [4] Espinosa G, Cervera R. Current treatment of antiphospholipid syndrome: lights and shadows. Nat Rev Rheumatol 2015;11:586–96. [5] Coloma Bazán E, Donate López C, Moreno Lozano P, Cervera R, Espinosa G. Discontinuation of anticoagulation or antiaggregation treatment may be safe in patients with primary antiphospholipid syndrome when antiphospholipid antibodies became persistently negative. Immunol Res 2013;56:358–61. [6] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. [7] da Silva FF, Levy RA, de Carvalho JF. Cardiovascular risk factors in the antiphospholipid syndrome. J Immunol Res 2014;2014:621270. [8] Medina G, Gutiérrez-Moreno AL, Vera-Lastra O, Saavedra MA, Jara LJ. Prevalence of metabolic syndrome in primary antiphospholipid syndrome patients. Autoimmun Rev 2011;10:214–7. [9] Erkan D, Lockshin MD. Non-criteria manifestations of antiphospholipid syndrome. Lupus 2010;19:424–7. [10] Rosa RF, Ugolini-Lopes MR, Zeinad-Valim AK, D'Amico E, Andrade D. Difficult clinical situations in the antiphospholipid syndrome. Curr Rheumatol Rep 2015;17:29.