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Original article

Investigation of the relation between the type and titer of antiphospholipid antibodies and the clinical manifestations of antiphospholipid syndrome

Dunja Stankić1, Predrag Miljić1,2
  • University of Belgrade, Faculty of Medicine, Belgrade, Serbia
  • University Clinical Center of Serbia, Clinic for Hematology, Belgrade, Serbia

ABSTRACT

Introduction: Antiphospholipid syndrome (APS) is an autoimmune disorder manifested by arterial or venous thromboses and/or spontaneous abortions associated with a persistently elevated level of antiphospholipid antibodies. To date, no clear relationship has been established between levels and types of autoimmune antibodies and clinical manifestations of APS, which can range from mild coagulation disorders to life-threatening conditions.

Aim: The aim of this study is to examine the relation between antiphospholipid antibody type and titer and the most common clinical manifestations of APS.

Materials and methods: The retrospective study included 32 patients with a confirmed laboratory finding of elevated antiphospholipid antibodies, who came for follow-up examinations to the Hemophilia Unit of the University Clinical Center of Serbia, between June 1, 2017 and December 31, 2018. Data on patients were taken from their medical records. Basic demographic data, type and titer of antiphospholipid antibodies, and their association with the present clinical manifestations of APS were analyzed using standard statistical methods.

Results: There was no significant difference regarding the frequency of positive results for lupus anticoagulant, anti-cardiolipin, and anti-beta-2-GP-I antibodies, between the symptomatic and asymptomatic group. The percentage of persons with simultaneous positivity for two or all three antiphospholipid antibodies was the same in both groups of subjects.

Conclusion: As opposed to previous studies, our study did not demonstrate a correlation between the titer of antiphospholipid antibodies and the clinical manifestations of APS. Symptomatic and asymptomatic patients did not significantly differ in the frequency of elevated antibodies. These results indicate that the presence of other factors, which are as yet little-known, is necessary for the clinical manifestations of APS.


INTRODUCTION

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by a persistent presence of increased levels of antiphospholipid antibodies in the blood, which is associated with the development of thromboembolic complications or pregnancy-related complications [1]. Antiphospholipid antibodies are a heterogenous groups of antibodies directed towards different proteins that bind to phospholipids. So far, it has been shown that, out of the antiphospholipid group of antibodies, the following have pathogenetic significance: lupus anticoagulant (LA), anticardiolipin antibodies (ACLA), and anti-beta-2-glycoprotein-I (aβ2GP-I) antibodies belonging to the IgG and IgM classes [2]. The presence of these antibodies is proven with different laboratory methods – the lupus anticoagulant is detected with coagulation methods, while anticardiolipin and anti-beta-2-glycoprotein-I antibodies are detected with immunoassays, most commonly the ELISA method.

With regard to clinical manifestations, antiphospholipid syndrome is quite a heterogenous disease and can manifest in various forms. According to the revised Sapporo criteria, in order to establish the diagnosis of antiphospholipid syndrome, it is necessary that at least one clinical criterion is present, i.e., vascular thrombosis or pregnancy loss, as well as one laboratory test criterion, which entails the persistence of elevated levels of one or more antiphospholipid antibodies over a period of more than 12 weeks [3].

Antiphospholipid syndrome is the most frequent cause of acquired thrombophilia and is responsible for around 15% of all cases of deep vein thrombosis, for one third of all cases of cerebral infarction in persons under 50 years of age, as well as for around 10% – 15% of all cases of repeated pregnancy loss [4]. However, in addition to thrombosis and obstetric complications, antiphospholipid antibodies may be associated with a series of other clinical manifestations, such as thrombocytopenia, and also dermatological or neurological manifestations, which do not enter the criteria for establishing the diagnosis of antiphospholipid syndrome.

Antiphospholipid antibodies can also be proven in a small percentage of healthy people, without any clinical manifestation of antiphospholipid syndrome. According to data found in literature, the frequency of anticardiolipin antibody positivity in the healthy population is 1% – 5%, while the frequency of positive lupus anticoagulant is 0% – 4% [5]. Antiphospholipid antibodies may occur within other autoimmune diseases, such as systemic connective tissue disorders, particularly in patients with systemic lupus erythematosus (SLE). In a study including 1,000 patients with antiphospholipid syndrome, 36% of them also had SLE [6]. If antiphospholipid syndrome is present in patients without other autoimmune diseases, this is then considered the primary form of the disease, while in cases where the patient also suffers from another autoimmune disorder, it is considered as secondary antiphospholipid syndrome.

The exact mechanism of the occurrence of thrombosis or obstetric complications in patients with antiphospholipid antibodies is as yet unclear, although it is believed that platelet activation, fibrinolysis inhibition, endothelial cell activation, the inhibition of natural anticoagulant systems, or complement activation, may play an important part in the pathogenesis of the disease [7]. Also, little is known of the factors which affect the way that antiphospholipid syndrome is clinically manifested. Recognizing these factors is of great significance in identifying asymptomatic individuals with antiphospholipid antibodies, as they are at increased risk of thrombosis or obstetric complications.

In this paper, we analyze the link between the type and titer of antiphospholipid antibodies and the clinical manifestations of antiphospholipid syndrome, in patients in whom the level of these antibodies had been elevated for a longer period of time and who have been regular patients of the Hemophilia Unit of the Clinic for Hematology of the University Clinical Center of Serbia, in Belgrade.

MATERIALS AND METHODS

The study included 32 patients, who came to the Hemophilia Unit of the UCCS for follow-up examinations, between June 1, 2017 and December 31, 2018, because of persistently elevated antiphospholipid antibody levels. The data on the patients were collected through retrospective analysis of their electronic medical records and case histories. All patients had a confirmed elevated level of at least one of the observed phospholipid antibodies: lupus anticoagulant (LA), anticardiolipin antibodies (ACLA), or anti-beta-2-glycoprotein-I (aβ2GP-I). Of the 32 patients, 22 patients had a confirmed diagnosis of APS, according to the revised Sapporo criteria, while there were 10 asymptomatic carriers of elevated antibodies. ACLA and aβ2GP-I values were determined with laboratory blood tests, using the ELISA method, while LA was determined with the coagulation method, according to the ISTH criteria for laboratory diagnostics of the lupus anticoagulant [8]. Depending on the estimation of the clinical criteria, patients were divided into two groups: the first group was made up of patients who fulfilled the clinical criteria for APS (thrombosis or obstetric complication), while the second group was composed of individuals without thrombosis or obstetric complications (asymptomatic carriers).

Standard statistical methods were used to investigate the frequency of elevated antiphospholipid antibodies in the symptomatic and asymptomatic groups. For the purpose of our study, a positive antiphospholipid antibody finding was considered to be any finding above the upper reference limit of the laboratory where the test had been performed. Demographic characteristics of the subjects, the type and titer of antiphospholipid antibodies, as well as the clinical manifestations of APS were included in the analysis. The group of symptomatic subjects included patients with arterial or venous thrombosis, as well as patients with obstetric complications. Finally, groups of patients with the most frequent clinical manifestations of APS were analyzed amongst each other, by sex and age.

Statistical analysis was performed using the IBM SPSS 23 software (IBM Corporation, New York, USA). Descriptive statistical parameters were presented as the mean ± standard deviation or the median (min – max), while the frequency of the categorical variables was expressed in numbers (%). The t-test, Mann-Whitney rank sum test, and the Kruskal-Wallis test were used for the analysis of numerical data. The difference in the frequency of categorical data was tested with Fisher’s exact test. The level of statistical significance was set at p < 0.05.

RESULTS

Demographic data

The study involved 32 patients, of whom 8 (25%) were male and 24 (75%) were female. The average age of all of the patients involved in the study was 43.5 ± 11.3 years, (range: 25 – 71). The average age of the male patients was 50.6 ± 12.3 years (range: 35 – 71), while the average age of the female patients was 41.2 ± 10.2 years (range: 25 – 69). Male patients with APL were statistically significantly older, as compared to female patients (p = 0.039).

Relationship between demographic data and clinical manifestations of APS

The sex distribution of the patients did not show a significant difference between the patients with clinical manifestations of APS and asymptomatic carriers (p = 0.380), and there was also no difference with respect to age (p = 0.360). The clinical and demographic characteristics of patients, according to the assessment of clinical criteria, are shown in Table 1.

Table 1. Clinical and demographic characteristics of patients according to clinical criteria assessment

04 01

Clinical manifestations of APS

Of all the patients involved in the study, 22 (68.8%) patients had a confirmed diagnosis of antiphospholipid syndrome, while 10 (31.2%) patients were without thrombosis or obstetric manifestations (asymptomatic carriers). In patients with confirmed APL diagnosis, 13 (59.1%) patients had thrombosis, while 7 (31.8%) female patients had an obstetric manifestation of APL. Only two (9.1%) patients had more than one clinical manifestation of APL. In patients with thrombosis, 7 (53.38%) were male and 6 (46,0%) were female patients. The age of the patients with confirmed diagnosis of APL did not significantly differ in relation to clinical manifestations (p = 0.333). Table 2 shows clinical and demographic characteristics of the subjects, according to the clinical manifestations of APL.

Table 2. Distribution of clinical manifestations of APS among patients included in the study

04 02

The frequency of the presence of antiphospholipid antibodies and the values of their titer

The greatest number of patients had an elevated LA, 25 (78.1%) of them. Elevated ACLA IgG and IgM antibodies occurred in 11 (34.4%) patients. Elevated levels of aβ2GP-I IgG were present in 8 (25%) patients, while elevated levels of aβ2GP-I IgM were registered in 12 (37.5%) patients. The antiphospholipid antibody titer values did not significantly differ between patients with clinical manifestations of antiphospholipid syndrome (thrombosis and obstetric manifestations) and asymptomatic carriers. The antiphospholipid antibody titer values are shown in Table 3.

Table 3. Mean antibody titer of antiphospholipid antibodies Values of antibody titer of antiphospholipid antibodies, by clinical criteria

04 03

The frequency of positive findings of individual types of antiphospholipid antibodies and the frequency of the presence of clinical manifestations of antiphospholipid syndrome

The comparison of symptomatic and asymptomatic persons did not find a connection between the frequency of a positive finding and the frequency of clinical manifestation of the illness, for any of the individual types of antiphospholipid antibodies. Also, the anticardiolipin antibody titer and the aβ2GP-I antibody titer were similar in symptomatic and asymptomatic subjects. The frequency of a positive result for different types of antibodies in patients with clinically manifest APL and asymptomatic carriers is shown in Table 4.

Table 4. Frequency of positive findings of certain antiphospholipid antibodies in the group of symptomatic and the group of asymptomatic subjects

04 04

Relationship between clinical manifestations of antiphospholipid syndrome and overall test positivity

It was confirmed that, of all the patients involved in the study, 22 (68.75%) patients exhibited clinical manifestations of APL. Amongst symptomatic patients, almost a half of them (45.45%) had only one positive test, every fifth patient (18.18%) had two positive tests, while every third patient (36.37%) had all three positive tests. In keeping with the results, a connection at the level of a statistical trend was found between the occurrence of clinical manifestations of APL and two positive immunological tests (p = 0.096). For details, see Table 5.

Table 5. Frequency of positivity to one, two, or three types of antiphospholipid antibodies

04 05

DISCUSSION

Antiphospholipid antibodies, which are the basic laboratory criterion for antiphospholipid syndrome, are a very heterogenous group of antibodies, since they bind with different phospholipids and are detected with different laboratory methods [9]. The lupus anticoagulant is detected by prolonged phospholipid-dependent coagulation tests, while anticardiolipin and anti-beta-2-glycoprotein-I antibodies are detected with immunological methods. According to previously published data, the presence of all three groups of antibodies causes a pronounced susceptibility to thrombosis or leads to failed pregnancy. However, in the general population, antiphospholipid antibodies can also be detected in a small percentage of completely healthy individuals, which reflects the complex pathogenesis of thrombosis, i.e., of obstetric complications, in antiphospholipid syndrome. If the presence of antiphospholipid antibodies is the dominant mechanism in the development of these complications, one could assume that the type and titer of antiphospholipid antibodies significantly affect their manifestation. However, studies investigating the connection between the type of antiphospholipid antibodies and the occurrence of clinical manifestation of APL did not provide a definitive conclusion and often had contradictory results [10].

In our study, the relation between the presence of different types of antiphospholipid antibodies and the clinical manifestations that enter into the criteria for diagnosing antiphospholipid syndrome, was investigated. The presence of antiphospholipid antibodies was retrospectively analyzed in a total of 32 individuals, of whom 22 had clinical manifestations of antiphospholipid syndrome, while 10 persons, despite clearly proven presence of antiphospholipid antibodies on repeat tests, had no signs of thrombosis or of obstetric complications.

Although the group of subjects was small, our study included persons with both of the manifestations of antiphospholipid syndrome, i.e., persons with thrombosis and persons with obstetric complications, but also an especially interesting group of individuals, who had the presence of antiphospholipid antibodies but displayed no clinical manifestations of APL (asymptomatic persons). It needs to be emphasized that, in a number of cases, the persons in question had been regularly followed up for a longer period of time, sometimes during a period of several years, at a tertiary health institution – teaching hospital, during which time, on several occasions, the persistent presence of antiphospholipid antibodies had been proven, which significantly decreases the possibility of mistake in the selection of patients, according to the diagnosis, which, in phospholipid syndrome, is not always established easily.

Our study did not determine the presence of a difference in the frequency of the presence of lupus anticoagulant in persons who had thrombosis or obstetric complications (symptomatic individuals), as compared to asymptomatic individuals with a persistent presence of antiphospholipid antibodies. Very similar results were obtained with respect to anticardiolipin and anti-beta-2-glycoprotein-I antibodies of the IgG and IgM class. In other words, the presence of each of the observed antiphospholipid antibodies was similar in the symptomatic and asymptomatic groups, which indicates that, for clinical manifestations of antiphospholipid syndrome, in addition to the presence of antiphospholipid antibodies, other, as yet not sufficiently know factors, are also significant. It is known that, in addition to antiphospholipid antibodies, infection, immobilization, tumors, inflammatory states, and other factors, affect the development of clinical manifestations of APL [11].

Our results did not completely correspond with earlier publications, which showed the risk of arterial and venous thrombosis to be the greatest in persons with the presence of lupus anticoagulant (risk increased by 11 times), and to be lesser in persons with positive anticardiolipin antibodies with moderate and high titers (risk increased by 1.6 times) [12].

However, it needs to be highlighted that, in the abovementioned meta-analysis, the analyzed studies investigated the frequency of the lupus anticoagulant and the frequency of anticardiolipin antibodies in a group of patients with thrombosis and compared the results with a healthy control group, while our study had a different design, since the presence of antibodies was analyzed in persons already fulfilling the laboratory criteria for antiphospholipid syndrome. Because of the different design of our study, as compared to the abovementioned studies, our results indicate that the absence of clinical manifestations of APL is not strictly linked to the presence, i.e., absence of a certain type of antiphospholipid antibody. Based on our analysis, it is not possible to conclude whether the absence of a pathogenetic effect of the antiphospholipid antibodies is related to the antibodies themselves or whether it is the result of the characteristics of the individual in whom the antibodies are present, without exhibiting clinical manifestations. In any case, it can be concluded that the phenomenon of “tolerance” of the presence of antiphospholipid antibodies occurs equally frequently for all three types of antibodies, i.e., this phenomenon is not specific to any one type of antibody.

In our study, the titer of anticardiolipin and anti-beta-2-glycoprotein-I antibodies was generally similar in symptomatic patients and individuals without clinical manifestations of APL. This does not correspond with data that can be found in literature, which indicate that the level of antiphospholipid antibody titer correlates with the risk of thrombosis, i.e., the risk of the occurrence of obstetric complications [13]. Also, in our study, we did not find a difference in positivity to two or three antibody types in the same person, between the symptomatic and asymptomatic groups, which has been reported in previous publications [14]. Such a finding is probably linked to the design of our study, where asymptomatic individuals with already confirmed presence of antiphospholipid antibodies were involved.

Our study included a relatively small number of subjects with positive antiphospholipid antibodies, which significantly limits the possibility of generalization of results, but its advantage is reflected in the fact that antibody presence was confirmed several times over. The results indicate no difference between symptomatic and asymptomatic test subjects with respect to the frequency of individual types of antibodies, which leads to an important conclusion that a certain number of persons with antiphospholipid antibodies has protective mechanisms, which protect against the occurrence of clinical manifestations of antiphospholipid syndrome. Identifying these mechanisms would be very important, as it could potentially open the possibility of more effective prevention of clinical complications in persons with a presence of antiphospholipid antibodies. On the other hand, based on the results from our study, it transpires that it is not possible, on the basis of the type of antiphospholipid antibodies, to predict the clinical development in a person in whom these antibodies were detected in the asymptomatic phase.

CONCLUSION

Our study did not prove the relationship between the antiphospholipid antibody titer and the occurrence of clinical manifestations of APL. Symptomatic and asymptomatic patients did not differ significantly with respect to the frequency of elevated antibodies. However, there was a link, at the level of a statistical trend, between the manifestation of APL symptoms and two positive immunological tests.

  • Conflict of interest:
    None declared.

Informations

Volume 3 No 1

Volume 3 No 1

March 2022

Pages 35-44
  • Received:
    28 May 2021
  • Revised:
    22 July 2021
  • Accepted:
    28 February 2022
  • Online first:
    25 March 2022
  • DOI:
Corresponding author

Dunja Stankić
Faculty of Medicine, University of Belgrade, Belgrade, Serbia
8 Dr Subotica Street, 11129 Belgrade, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.



References

1. Lim W. Antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program. 2013;2013:675-80. doi: 10.1182/asheducation-2013.1.675.[CROSSREF]

2. Khamashta MA, Amigo MC. Antiphospholipid syndrome. Rheumatology. 2015;1144–52.[CROSSREF]

3. 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 Feb;4(2):295-306. doi: 10.1111/j.1538-7836.2006.01753.x.[CROSSREF]

4. Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Schur PH, Hennekens CH, et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med. 1992 Dec 15;117(12):997-1002. doi: 10.7326/0003-4819-117-12-997.[CROSSREF]

5. Juby AG, Davis P. Prevalence and disease associations of certain autoantibodies in elderly patients. Clin Invest Med. 1998 Feb;21(1):4-11. PMID: 9512879.

6. Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al.; Euro-Phospholipid Project Group. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002 Apr;46(4):1019-27. doi: 10.1002/ art.10187.[CROSSREF]

7. Urbanus RT, Derksen RH, de Groot PG. Platelets and the antiphospholipid syndrome. Lupus. 2008 Oct;17(10):888-94. doi: 10.1177/0961203308096344.[CROSSREF]

8. Moore GW. Recent guidelines and recommendations for laboratory detection of lupus anticoagulants. Semin Thromb Hemost. 2014 Mar;40(2):163-71. doi: 10.1055/s-0033-1364185.[CROSSREF]

9. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999 Jul;42(7):1309-11. doi: 10.1002/1529-0131(199907)42:7<_x0031_309:_x003a_AID-ANR1>3.0.CO;2-F.[CROSSREF]

10. Chaturvedi S, McCrae KR. Diagnosis and management of the antiphospholipid syndrome. Blood Rev. 2017 Nov;31(6):406-417. doi: 10.1016/j.blre.2017.07.006.[CROSSREF]

11. Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol. 2011 Jun;7(6):330-9. doi: 10.1038/nrrheum.2011.52.[CROSSREF]

12. Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003 Mar 1;101(5):1827-32. doi: 10.1182/blood-2002-02-0441.[CROSSREF]

13. Galli M, Borrelli G, Jacobsen EM, Marfisi RM, Finazzi G, Marchioli R, et al. Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study. Blood. 2007 Aug 15;110(4):1178- 83. doi: 10.1182/blood-2007-01-066043.[CROSSREF]

14. Pengo V, Ruffatti A, Legnani C, Gresele P, Barcellona D, Erba N, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost. 2010 Feb;8(2):237-42. doi: 10.1111/j.1538-7836.2009.03674.x.[CROSSREF]

1. Lim W. Antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program. 2013;2013:675-80. doi: 10.1182/asheducation-2013.1.675.[CROSSREF]

2. Khamashta MA, Amigo MC. Antiphospholipid syndrome. Rheumatology. 2015;1144–52.[CROSSREF]

3. 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 Feb;4(2):295-306. doi: 10.1111/j.1538-7836.2006.01753.x.[CROSSREF]

4. Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Schur PH, Hennekens CH, et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med. 1992 Dec 15;117(12):997-1002. doi: 10.7326/0003-4819-117-12-997.[CROSSREF]

5. Juby AG, Davis P. Prevalence and disease associations of certain autoantibodies in elderly patients. Clin Invest Med. 1998 Feb;21(1):4-11. PMID: 9512879.

6. Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al.; Euro-Phospholipid Project Group. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002 Apr;46(4):1019-27. doi: 10.1002/ art.10187.[CROSSREF]

7. Urbanus RT, Derksen RH, de Groot PG. Platelets and the antiphospholipid syndrome. Lupus. 2008 Oct;17(10):888-94. doi: 10.1177/0961203308096344.[CROSSREF]

8. Moore GW. Recent guidelines and recommendations for laboratory detection of lupus anticoagulants. Semin Thromb Hemost. 2014 Mar;40(2):163-71. doi: 10.1055/s-0033-1364185.[CROSSREF]

9. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999 Jul;42(7):1309-11. doi: 10.1002/1529-0131(199907)42:7<_x0031_309:_x003a_AID-ANR1>3.0.CO;2-F.[CROSSREF]

10. Chaturvedi S, McCrae KR. Diagnosis and management of the antiphospholipid syndrome. Blood Rev. 2017 Nov;31(6):406-417. doi: 10.1016/j.blre.2017.07.006.[CROSSREF]

11. Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol. 2011 Jun;7(6):330-9. doi: 10.1038/nrrheum.2011.52.[CROSSREF]

12. Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003 Mar 1;101(5):1827-32. doi: 10.1182/blood-2002-02-0441.[CROSSREF]

13. Galli M, Borrelli G, Jacobsen EM, Marfisi RM, Finazzi G, Marchioli R, et al. Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study. Blood. 2007 Aug 15;110(4):1178- 83. doi: 10.1182/blood-2007-01-066043.[CROSSREF]

14. Pengo V, Ruffatti A, Legnani C, Gresele P, Barcellona D, Erba N, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost. 2010 Feb;8(2):237-42. doi: 10.1111/j.1538-7836.2009.03674.x.[CROSSREF]


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