10.4081/btvb.2023.92
The definite diagnosis of antiphospholipid syndrome (APS) depends on the laboratory performance and clinicians’ interpretation. Results from two Italian inception cohort studies of anti-phospholipid antibodies (aPL)-positive subjects, the Italian Survey on ANtiphoSpholipid antibody Positive Individuals Registry (INSPIRE) and the Survey on AnTicoagulated Patients-RegisTry (START) have been compared. Data from INSPIRE were collected by rheumatologists of the FIRMA group while those of START by physicians working in Italian thrombosis centers. Evidence on several, still unraveled, clinical and methodological aspects of ‘real life’ aPL testing and APS diagnosis was collected. In this paper, we report the characteristics of 123 cases enrolled in INSPIRE and 229 in START registries, with particular reference to the reasons why these tests were requested, the obtained aPL profile, and consequent treatment. Laboratory testing for aPL in the absence of clinical criteria defining APS was more frequent in INSPIRE (p&lt;0.0001). The rate of patients in classification category I (more than one aPL test positive) was significantly higher in START (p&lt;0.0001) as well as the use of warfarin. A wide variety of treatments has been observed in patients in classification category II (single aPL positivity). These data indicate that there is a need to harmonize many aspects among the various specialists dealing with APS.
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Descriptive analysis of patients positive for anti-phospholipid antibodies included in two Italian registries
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El Hasbani G, Viola M, Sciascia S, et al. Antiphospholipid Antibodies in Inflammatory and Autoimmune Rheumatic and Musculoskeletal Diseases Beyond Lupus: A Systematic Review of the Available Evidence. Rheumatol Ther. 2021;8:81-94.
Descriptive analysis of patients positive for anti-phospholipid antibodies included in two Italian registries
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                                                                                                           ORIGINAL ARTICLE

Correspondence: Vittorio Pengo, Thrombosis Research Laboratory,
University of Padova, Campus Biomedico ‘Pietro d’Abano’, Via               Descriptive analysis of patients
Orus 2/B, 35129, Padova, Italy.
E-mail: vittorio.pengo@unipd.it                                            positive for anti-phospholipid
Citation: Pengo V, Sarti L, Antonucci E, et al Descriptive analysis
of patients positive for anti-phospholipid antibodies included in          antibodies included in two
two Italian registries. Bleeding, Thrombosis, and Vascular Biology
2023;2:92.                                                                 Italian registries
Key words: antiphospholipid syndrome; registries; classification.
Contributions: VP, substantial contribution to concept and design          Vittorio Pengo,1,2 Luca Sarti,3 Emilia Antonucci,2
of the study and writing of the first draft of the manuscript; LS,         Stefania Di Agostino,3 Elisa Bison,1 Gentian Denas,1
EA, SDA, EB, GD, contributed to analyze and interpret the data;
DP, PLM, RG, AR, GP, substantial contribution to collect data, crit-       Daniela Poli,4 Pierluigi Meroni,5 Roberto Gerli,6
ical writing and revising the intellectual content. All the authors        Antonella Radice,7 and Gualtiero Palareti,2 on behalf of
approved the final version to be published.
                                                                           FIRMA group and START collaborators
Acknowledgments: FIRMA collaborators: Cristiano Alessandri,
Roma-Università La Sapienza-Reumatologia 31; Orietta Borghi,
Roberta Gualtierotti Pierluigi Meroni, Milano-Ospedale Auxologico-         Thrombosis Research Laboratory, University of Padova;
                                                                           1

IRL 29; Elena Bartoloni Bocci, Onelia Bistoni, Giacomo Cafaro,             Arianna Anticoagulation Foundation, Bologna; 3Thrombosis
                                                                           2
Carlo Perricone, Alessia Alunno, Perugia-Università Medicina 18;           Center, Internal Emergency Medicine, Baggiovara Civil
Federica Zunino, Immunologia, Bergamo 16; Laura Andreoli, Angela
Tincani, Reumatologia, Brescia 14; Annamaria Iuliano, Gian-                Hospital,, Modena; 4Thrombosis Center, Careggi University
domenico Sebastiani, Reumatologia, Ospedale San Camillo Roma-              Hospital, Firenze; 5Italian Auxological Institute, IRCCS,




                                                                                             ly
10; Arianna Damiani, Maurizio Benucci, Maria Infantino, Ospedale
San Giovanni di Dio, Firenze 3; Amelia Rigon, Elisabetta Cerchiara         Experimental Laboratory of Immuno-rheumatologic




                                                                                     on
Reumatologia Campus Bio-medico-Roma 2; START-antiphospho-                  Researches, Milano; 6Rheumatology Unit, Department of
lipid register collaborators: Poli Daniela, Lotti Elena, Centro Trom-      Medicine and Surgery, University of Perugia; 7Department of
bosi Firenze (FI) 60; Sivera Piera, Ematologia-Mauriziano Torino
(TO) 29; Barcellona Doris, Centro Emocoagulopatie Monserrato               Microbiology and Virology, ASST Santi Paolo e Carlo, San
(CA) 22; Prisco Domenico, Canfora Maria, SODC Medicina Interna,            Carlo Hospital, Milano, Italy




                                                                               e
Firenze 15; Sarti Luca, Medicina Interna D’urgenza-Modena 14; Vi-
sonà Adriana, Medicina Vascolare, Castelfranco Veneto 13; Chistolini
Antonio, Sez Ematologia, Policlinico Umberto I, Roma (RM) 9; De
Candia Erica, Università Cattolica del Sacro Cuore, Roma (RM) 8;
Falanga Anna, Centro emostasi e trombosi, Bergamo (BG) 8;
                                                                          us
Bucherini Eugenio, Amb. anticoagulanti Faenza - AUSL di Ravenna            ABSTRACT
                                                                          al
(RA) 7; Tufano Antonella, UOC Med Interna, Napoli (NA) 7;Pizzini                The definite diagnosis of antiphospholipid syndrome (APS)
Attilia, UOC Medicina A-OM-Bologna Bologna 6; Oriana Vincenzo,
                                                       ci

Centro Emofilia – Reggio Calabria 5; Cotelli Maria Sophia, SSD             depends on the laboratory performance and clinicians’ interpre-
Neurologia-ASST Valcamonica, Esine (BS) 5; Gresele Paolo, MIV              tation. Results from two Italian inception cohort studies of anti-
                                                     er


Perugia (PG) 4; Toma Andrea, UOC di Patologia Clinica, Arzignano
(VI) 4; Fregoni Vittorio, U.O.C. Medicina Generale, Sondalo (SO)           phospholipid antibodies (aPL)-positive subjects, the Italian
3; Ageno Walter, Medicina d’Urgenza, Varese (VA) 2; Pedrini Si-            Survey on ANtiphoSpholipid antibody Positive Individuals Reg-
                                                    m



mona, Servizio di laboratorio-Fond. Poliambulanza Brescia (BS) 2;          istry (INSPIRE) and the Survey on AnTicoagulated Patients- Reg-
Lodigiani Corrado, Centro Trombosi, Istituto Clinico Humanitas, Mi-
lano 2; Bison Elisa, Laboratorio di ricerca sulla Trombosi, Padova 1;      isTry (START) have been compared. Data from INSPIRE were
                                        om




Spataro Carmine, UOSD SIMT-Treviglio, Treviglio (BG) 1; Hoxha              collected by rheumatologists of the FIRMA group while those of
Ariela, UOC-Med generale 1 Vicenza Vicenza (VI) 1; Banov Laura,
UOC Oncoematologia -IRCCS Gaslini Genova (GE) 1.                           START by physicians working in Italian thrombosis centers. Ev-
                                                                           idence on several, still unraveled, clinical and methodological as-
                                  -c




Conflict of interest: VP received lecture fees from Werfen Group.          pects of ‘real life’ aPL testing and APS diagnosis was collected.
The other authors declare no potential conflict of interest.
                                                                           In this paper, we report the characteristics of 123 cases enrolled
                         on




Funding: none.                                                             in INSPIRE and 229 in START registries, with particular refer-
Ethical approval and consent to participate: APS patients after sign-      ence to the reasons why these tests were requested, the obtained
                   N




ing an informed consent were screened for possible participation           aPL profile, and consequent treatment. Laboratory testing for aPL
in the registries.
                                                                           in the absence of clinical criteria defining APS was more frequent
Availability of data and material: data are available upon reason-         in INSPIRE (p<0.0001). The rate of patients in classification cat-
able request.                                                              egory I (more than one aPL test positive) was significantly higher
Informed consent: all patients enrolled in the study read and signed       in START (p<0.0001) as well as the use of warfarin. A wide va-
the informed consent.                                                      riety of treatments has been observed in patients in classification
Received: 13 July 2023.                                                    category II (single aPL positivity). These data indicate that there
Accepted: 20 September 2023.                                               is a need to harmonize many aspects among the various specialists
                                                                           dealing with APS.
Publisher’s note: all claims expressed in this article are solely those
of the authors and do not necessarily represent those of their affili-
ated organizations, or those of the publisher, the editors and the re-
viewers. Any product that may be evaluated in this article or claim
that may be made by its manufacturer is not guaranteed or endorsed         Introduction
by the publisher.
©
 Copyright: the Author(s), 2023                                                Anti-phospholipid syndrome (APS) is the most studied form
Licensee PAGEPress, Italy                                                  of acquired thrombophilia. It is defined as the concomitant pres-
Bleeding, Thrombosis and Vascular Biology 2023; 2:92
doi:10.4081/btvb.2023.92                                                   ence of thromboembolic events or pregnancy morbidity in patients
                                                                           with persistently positive circulating anti-phospholipid antibodies
This work is licensed under a Creative Commons Attribution-                (aPL).1 Besides thrombosis and pregnancy morbidity, other clinical
NonCommercial 4.0 International License (CC BY-NC 4.0).
                                                                           manifestations affecting every organ are often associated with


                                            Bleeding, Thrombosis and Vascular Biology 2023; 2:92
34                                                                        V. Pengo et al.




APS.2 Therefore, clinicians often prescribe testing for aPL in the                   and testing was repeated after 12 weeks. Demographic and clinical
presence of signs or symptoms unrelated to the classical manifes-                    data (thrombosis, pregnancy complications, non-criteria clinical
tations of the syndrome.3,4 Epidemiological and methodological                       manifestations, systemic autoimmune disease, cardiovascular risk
data on testing for aPL in general and specific laboratories are                     factors and treatment) were entered in a web-based case report
sparse. Reasons for aPL checking are relevant for the appropriate-                   form. All patients enrolled in the study read and signed the in-
ness, cost-effectiveness, and difficult interpretation of positive re-               formed consent. Reasons for testing were grouped according to
sults. In the present report, we evaluate the relation between the                   clinical events that defined or did not define APS (thrombosis and
reasons why aPL was tested, the obtained aPL profile, and the treat-                 pregnancy morbidity) and aPL profiles were classified as category
ment. We explored data from two Italian registries, the INSPIRE                      I (more than one aPL test positive) or category II (only one aPL
which is mainly driven by rheumatologists, and the START which                       test positive), according to Miyakis.1
involves thrombosis centers led by hematologists, internists, or
clinical pathologists. Differences in the type of patients enrolled,
and the aPL profiles are examined. The implications on the inter-                    Results
pretation of abnormal test results and the approach to therapeutic
interventions in the two registries are discussed.                                        In total, 123 patients were recruited in the INSPIRE and 229
                                                                                     in the START registries during a 2-year period. Patients’ charac-
                                                                                     teristics are summarized in Table 1.
Materials and Methods                                                                     Patients were older in START and female gender was more




                                                                                                                ly
                                                                                     frequent in both cohorts, although it was higher in INSPIRE. Car-




                                                                                                        on
    The Interdisciplinary Forum for the Research on Autoimmune                       diovascular risk factors and associated autoimmune diseases were
Diseases (FIRMA), the Italian branch of the European Autoim-                         more frequent in INSPIRE registry. Antithrombotic treatment dif-
munity Standardization Initiative (EASI) founded in the 90s and                      fered importantly in the two registries since warfarin use was by




                                                                                                  e
devoted to standardizing serology in rheumatic diseases, promoted                    far greater in the START registry, which collected data in throm-
the Italian Survey on ANtiphoSpholipid antibody Positive Indi-
viduals Register (INSPIRE), an Italian registry of aPL-positive
individuals. This is an educational program aimed to harmonize
                                                                                            us
                                                                                     bosis centers.
                                                                                          In 54 of 123 cases (44%) in INSPIRE and in 155 of 229 cases
                                                                                     (67%) in START, clinical criteria matched those required in the
                                                                                    al
the way aPL are detected and interpreted. The Survey on AnTi-                        classification criteria for the diagnosis of APS (Table 2). A higher
coagulated Patients- RegisTry (START) aPL register is a prospec-                     rate of venous thromboembolism was recorded in the START
                                                                    ci

tive register of long-term collected data from Centers for the                       compared to the INSPIRE registry (p<0.0001). Conversely, clin-
Diagnosis of Thrombosis and surveillance of antithrombotic ther-                     ical criteria not included in the guidelines were more frequent in
                                                                  er


apies promoted by Arianna Foundation on Anticoagulation. Sub-                        INSPIRE (p<0.0001). The large majority of specialists who re-
jects were recruited when testing positive for one or more criteria                  quested aPL testing are rheumatologists in INSPIRE while hema-
                                                                 m




aPL tests [anti-cardiolipin (aCL) and anti-ß2-Glycoprotein I (anti-                  tologists, internists and clinical pathologists were the more
                                                     om




ß2GPI) antibodies IgG/IgM at any titer, lupus anticoagulant (LA)]                    represented specialists in START registry. Reported reasons for
                                              -c




Table 1. Characteristics of enrolled individuals.
                                     on




                                                        INSPIRE (n=123)                      START (n=229)                             P
Age (yrs)                                                     49.7±14.1                          54.3±16.9                           0.01
                               N




Sex (F)                                                        93 (76)                           145 (63)                            0.02
BMI                                                           25.1±5.2                           25.8±6.8                              -
Ethnicity                                                                                                                              -
 Caucasian                                                    121 (98)                           223 (97)                              -
 Asian                                                           1                                  6                                  -
 Hispanic                                                        1                                  0                                  -
Hypertension                                                   37 (30)                            77 (34)                              -
Diabetes                                                       12 (10)                             19 (8)                              -
Dyslipidemia                                                   36 (29)                            31 (13)                            <0.01
Smoking habit                                                  35 (28)                            37 (16)                            <0.01
Systemic autoimmune diseases                                   36 (29)                            28 (12)                            <0.01
 Systemic lupus erythematosus                                    12                                 24                                 -
 Undifferentiated connective tissue disease                       8                                  -                                 -
 Lupus-like                                                       3                                  -                                 -
 Rheumatoid arthritis                                             2                                  -                                 -
 Sjögren’s syndrome                                              1                                  3                                 -
 Connective tissue disease                                        1                                  -                                 -
 Other                                                            9                                  -                                 -
Data are expressed as mean ± standard deviation or n (%). BMI, body mass index.


                                               Bleeding, Thrombosis and Vascular Biology 2023; 2:92
                 Descriptive analysis of patients positive for anti-phospholipid antibodies included in two Italian registries                                 35



testing in the absence of clinical criteria defining APS are reported                clinical criteria in APS patients in classification category I in IN-
in Table 3 in descending order. Programmed pregnancy, autoim-                        SPIRE (A) and START (B). In both registries, most of the patients
mune diseases, and thrombocytopenia were among the most cited                        with venous thromboembolism (VTE) were treated with warfarin
clinical reasons.                                                                    (73% and 74%, respectively). The majority of patients with arte-
                                                                                     rial thromboembolism (ATE) in INSPIRE are treated with an-
Classification of patients in the registries                                         tiplatelet drugs or a combination of warfarin and aspirin plus
                                                                                     clopidogrel in special situations (myocardial infarction), while in
     Among the 123 subjects enrolled in INSPIRE, the request for
                                                                                     START warfarin was the most used drug (in 51% of cases). The
aPL testing is motivated in 54 cases (43.9%) by clinical criteria
                                                                                     difference in the use of warfarin in ATE among registries is not
of APS. In 27 (50%) of APS patients the aPL profile falls in clas-
                                                                                     statistically significant (p=0.09).
sification category I (more than one positive test among LAC,
IgG/IgM aCL and aβ2GPI), and in the remaining 27 cases in cat-                            Figure 3 reports the antithrombotic treatment in patients with
egory II (single positive test). The distribution of specific aPL pro-               clinical criteria for APS and classification category II (only one
files is shown in Figure 1.                                                          positive test) in INSPIRE (A) and START (B) registries. In the 27
     Of the 229 subjects enrolled in the START registry, 155 (68%)                   patients of INSPIRE, isolated LA is present in 3 patients, isolated
had the clinical criteria for the diagnosis of APS. Of these, 125                    IgG aCL or isolated IgG aβ2GPI in 16, and isolated IgM aCL or
patients had an aPL profile in classification category I and 30 in                   isolated IgM aβ2GPI in 8 patients. The antithrombotic regimen
category II. The distribution of specific profiles is shown in Figure                in VTE patients of this group are quite heterogenous (Figure 3A):




                                                                                                          ly
1B. There was a significant difference in the distribution of clas-                  patients received either warfarin or direct oral anticoagulants
sification categories among the registries (p<0.0001). Indeed,                       (DOACs) and in a few cases other treatment. Patients with ATE




                                                                                                 on
classification category II is more represented in INSPIRE, partic-                   took antiplatelet drugs or a combination of warfarin and an-
ularly isolated aCL.                                                                 tiplatelet drugs in special situations. In the 2 cases of obstetric
     Figure 2 reports the antithrombotic treatment according to                      APS, Aspirin and Aspirin plus LMWH were used.




                                                                                          e
Table 2. Reasons for anti-phospholipid antibodies testing clinical criteria.
                                                                                  us
                                                                         al
Clinical criteria                                     INSPIRE (n=123)                         START (n=229)                                  P
                                                         ci

Included in the guidelines                                   54 (43.9)                            140 (67.7)                             <0.0001
 Venous thromboembolism                                      29 (23.6)                            96 (41.9)                                 -
                                                       er


   Deep vein thrombosis                                         16                                    90
   Pulmonary embolism                                           12                                     6
                                                      m



   Budd Chiari syndrome                                          1                                     -
 Arterial thromboembolism                                    21 (17.1)                             44 (19.2)                                 -
                                          om




   Transient ischemic attack                                     8                                     6
   Ischemic stroke                                               6                                    32
   Acute myocardial infarction                                   3                                     3
   Unspecified arterial thrombosis                               4                                     3
                                    -c




 Miscarriage                                                  4 (3.2)                               15 (6.5)                                 -
                               on




Not included in the guidelines                               69 (56.1)                             74 (32.3)                             <0.0001
Data are expressed as n (%).
                      N




Table 3. Patients tested for anti-phospholipid antibodies without the antiphospholipid syndrome clinical criteria in INSPIRE.
                                                                                            Reasons for testing                        Treatment
Laboratory classification category I                           Triple+                     8 autoimmune diseases                        7 aspirin
                                                                n=17                      4 thrombophilia screening                  5 no treatment
                                                             IgG n=13                        2 thrombocytopenia               4 warfarin (1 SLE, 1 Sjögren,
                                                              IgM n=4                         2 prolonged aPTT                 2 thrombophilia screening)
                                                                                              1 thrombophlebitis                        1 DOAC
                                                             Double+                       10 autoimmune diseases                       23 aspirin
                                                          n=33IgG n=13                    4 programmed pregnancy                        6 warfarin
                                                            IgM n=20                      3 thrombophilia screening                   4 no treatment
                                                                                             3 thrombocytopenia
                                                                                                    9 other
                                                                                                  4 unknown
Laboratory classification category II                        Single+                       11 autoimmune disease                      12 no treatment
                                                               n=19                       4 thrombophilia screening                      6 aspirin
                                                             IgG n=8                      2 programmed pregnancy                         1 DOAC
                                                            IgM n=11                             2 unknown
aPTT, activated partial thromboplastin time; DOAC, direct oral anticoagulants; IgG, immunoglobulin G; IgM, immunoglobulin M; SLE, systemic Lupus Erythematosus.


                                              Bleeding, Thrombosis and Vascular Biology 2023; 2:92
36                                                         V. Pengo et al.




Figure 1. Distribution of anti-phospholipid antibodies profiles among antiphospholipid syndrome patients in INSPIRE (A) and in




                                                                                                ly
START (B) registries.




                                                                                         on
                                                                                   e
                                                                             us
                                                                     al
                                                        ci
                                                      er
                                                     m
                                           om
                                      -c
                              on
                          N




Figure 2. Antithrombotic treatment in patients with antiphospholipid syndrome clinical criteria and laboratory classification category
I (more than one anti-phospholipid antibodies positive test) in INSPIRE (A) and START (B) registries.


                                       Bleeding, Thrombosis and Vascular Biology 2023; 2:92
               Descriptive analysis of patients positive for anti-phospholipid antibodies included in two Italian registries              37



    In the START registry, most patients in classification category      boembolic events or pregnancy morbidity), most of the patients
II were positive for LA (n=24) and positive for aCL in 6 cases           in the laboratory category I receive anticoagulant or antiplatelet
while no patient was positive for isolated aβ2GPI antibodies. In         therapy. In contrast, most patients in laboratory category II did
patients with VTE warfarin is more frequently used, but DOACs            not receive an antithrombotic treatment. In the 61 patients (data
are also prescribed. In patients with ATE, treatment is highly in-       were not available in 13) without clinical criteria in START (Table
homogeneous with a few patients left without anticoagulant drugs.        4), antiplatelet therapy or no treatment was the choice in classifi-
                                                                         cation category I. In contrast, most patients in classification cate-
Laboratory classification category in patients                           gory II did not receive an antithrombotic treatment.
without anti-phospholipid syndrome clinical
criteria (anti-phospholipid antibodies carriers)
                                                                         Discussion and Conclusions
     Among the 69 individuals tested for aPL without the APS
clinical criteria in INSPIRE, 50 are in classification criteria I (17        This report describes patients positive for aPL antibodies in-
are triple positive and 33 are double positive). The reasons for         cluded in the INSPIRE and START registries. The aim of the
testing and antithrombotic treatment are depicted in Table 3. In         study was to compare patients’ characteristics, the reasons for
most cases, specialists prescribe aPL testing in patients with au-       checking aPL and the obtained aPL profiles with consequent treat-
toimmune diseases (n=29). Despite being aPL carriers (no throm-          ment in the setting of rheumatology departments (INSPIRE) and




                                                                                            ly
                                                                                    on
                                                                              e
                                                                        us
                                                                   al
                                                    ci
                                                  er
                                                 m
                                       om
                                 -c
                         on
                   N




Figure 3. Antithrombotic treatment in patients with antiphospholipid syndrome clinical criteria and laboratory classification category
II (only one anti-phospholipid antibodies positive test) in INSPIRE (A) and START (B) registries.


                                          Bleeding, Thrombosis and Vascular Biology 2023; 2:92
38                                                                    V. Pengo et al.




Table 4. Patients tested for anti-phospholipid antibodies without the antiphospholipid syndrome clinical criteria in START.
                                                                                          Reasons for testing                     Treatment
Laboratory classification category I                        Triple+                        8 autoimmune diseases                   10 aspirin
                                                             n=19                             4 prolonged aPTT                   8 no treatment
                                                           IgG n=13                      3 programmed pregnancy                  1 clopidogrel
                                                           IgM n=6                      2 superficial thromboflebitis
                                                                                               1 vasculopathy
                                                                                                  1 epilepsy
                                                            Double+                        9 autoimmune diseases                    8 aspirin
                                                              n=23                       3 thrombophilia screening                1 clopidogrel
                                                            IgG n=8                      2 programmed pregnancy                  14 no treatment
                                                           IgM n=15                     2 superficial thromboflebitis
                                                                                           1 raynaud phenomenon
                                                                                                   3 other
                                                                                                 3 unknown
Laboratory classification category II                       Single+                        6 autoimmune disease                     2 LMWH
                                                             n=19                            6 prolonged aPTT                    17 no treatment




                                                                                                                  ly
                                                                                         3 programmed pregnancy
                                                                                                 1 epilepsy




                                                                                                         on
                                                                                                 1 migraine
                                                                                                2 unknown
aPTT, activated partial thromboplastin time; LMWH, low-molecular-weight heparin; IgG, immunoglobulin G; IgM, immunoglobulin M.




                                                                                                  e
thrombosis centers (START). There was a higher number of car-
                                                                                          us
                                                                                   ratio for recurrent VTE after stopping anticoagulant therapy in
riers (patients without the clinical criteria for APS) in INSPIRE                  patients with an anti-cardiolipin antibody was 1.53 (95% CI,
                                                                                 al
due to aPL testing in a broad way in autoimmune diseases. Indeed,                  0.76-3.11), and with a LA was 2.83 (95% CI, 0.83-9.64). How-
                                                                 ci

rheumatologists request aPL for patients with autoimmune dis-                      ever, all considered studies had important methodologic limita-
eases in the absence of APS clinical criteria as a part of diagnostic              tions. Although a positive aPL test appears to predict an
                                                               er


work-up and because aPL is considered among the lab criteria for                   increased risk of recurrence in patients with a first VTE, the
the diagnosis of systemic lupus erythematosus.5-7 Consequently,                    strength of this association is uncertain because the available ev-
                                                              m



signals for the presence of autoantibodies comprising aPL are                      idence is of very low quality.11 Finally, the absence of specific
sweep-searched in autoimmune disorders. This extensive search                      clinical trials for aPL carriers also determines the great variety
                                                   om




for aPL in INSPIRE results in completely different aPL profiles                    of treatments in both the INSPIRE and START registers. Cer-
from those found in the START register. Isolated positivity (only                  tainly, the increased demand for aPL testing by rheumatologists
one positive test) that is not associated with thromboembolic                      may lead them to prescribe antithrombotic treatments outside
                                            -c




events is more frequent in INSPIRE. In addition, isolated positiv-                 the standard treatment as there are no ad hoc studies. Indeed,
ity deserves attention as the test may be false-positive or con-                   apart from SLE patients, in other autoimmune diseases such as
                                   on




firmed 12 weeks apart in less than 50% of cases (transient                         systemic scleroderma, Sjogren’s syndrome and rheumatoid
antibodies).8 In contrast, profiles that are more likely to be asso-               arthritis the presence of aPL is not associated with an increased
                              N




ciated with thrombosis (positivity in more than one test) are fre-                 risk of thromboembolic events. More studies are needed to de-
quent in START where patients with thromboembolic disease are                      termine whether aPL can predispose patients with autoimmune
more frequently seen. In that registry, the aPL profile was specif-                diseases to manifestations of vascular events other than throm-
ically requested in patients with clinical criteria for APS and in                 bosis, such as renal crisis or pulmonary arterial hypertension.12
half of them the profile fell in the laboratory classification I (more                  Data reported herein enhance the vision of contributors and
than one positive test). Of note, many of them show triple or dou-                 readers leading to a more thoughtful behavior in prescribing and
ble positivity of IgG isotype, which is believed the aPL profile                   treating aPL-positive patients and hopefully contribute to create
most often associated with thromboembolic events.9 In both reg-                    a better connection between clinicians and clinical pathologists
istries, these patients were accurately treated with warfarin in the               for the correct interpretation of laboratory results.
case of VTE, while antiplatelet agents were preferred in the case
of ATE. Recent guidelines point out the need to treat ATE patients
with warfarin or warfarin plus antiplatelet drugs.10 A few APS pa-                 Rerefences
tients in the classification category I are treated with DOACs, a
practice that is not currently recommended.10                                       1. Miyakis S, Lockshin MD, Atsumi T, et al. International con-
     More variability in treatment is observed in APS patients in                      sensus statement on an update of the classification criteria
Classification Category II, where both warfarin or DOACs are                           for definite antiphospholipid syndrome (APS). J Thromb
used in VTE and treatment of ATE is left to the doctor’s discre-                       Haemost 2006;4:295-306.
tion. Indeed, there are no specific clinical trials addressing this                 2. Cecchi I, Radin M, Rubini E, et al. Clinical manifestations
issue. A systematic review by Garcia et al.11 showed that the risk                     in patients with antiphospholipid antibodies: Beyond throm-


                                             Bleeding, Thrombosis and Vascular Biology 2023; 2:92
              Descriptive analysis of patients positive for anti-phospholipid antibodies included in two Italian registries             39



   bosis and pregnancy loss. Lupus 2021:961203321995248.                 8. Pengo V, Ruffatti A, Del Ross T, et al. Confirmation of initial
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                                         Bleeding, Thrombosis and Vascular Biology 2023; 2:92
