This project used qualitative synthesis of the scientific evidence together with consensus techniques which include the agreement of experts based on their clinical experience and scientific evidence.

Preparation of the Recommendations document involved a series of steps, as described below:

• 1.

  Creation of the work group. Preparation of the document commenced with the formation of a panel of experts, composed of four rheumatologists who are members of the SER, a haematologist and a gynaecologist. The rheumatologists were selected by open invitation to all of the members of the SER. The Clinical Practice Guides and Recommendations Commission (CPG) of the SER evaluated the curriculum vitae of all of the applicants according to objective criteria based on their contributions to knowledge about APS. This mainly consisted of their participation in high-impact journals during the past 5 years. The clinical and methodological aspects were coordinated, respectively, by a rheumatologist as the chief researcher and a specialist in methodology, a technician of the SER Research Unit.

• 2.

  Identification of key areas. All of the members of the work group took part in designing the document and establishing its contents and key aspects. First they identified the clinical research questions that could have the most impact in offering information on the management of APS. They then decided which of these required answering in PICO question format (patient, intervention, comparison and outcome). The methodology to be following in the process of drawing up the recommendations was also defined.

• 3.

  Bibliographical search. To answer non-PICO clinical questions a search was undertaken of systematic reviews and updated CPG in Medline and sources that specialise in guides. The other clinical questions were reformulated as four PICO format questions. A search strategy was designed to answer the PICO questions and a review of the scientific evidence in studies published until May 2017 was performed. The following databases were used: Pubmed (Medline), Embase and Cochrane Library (Wiley Online). The process was completed with a manual search of references, posters and conference summaries which the reviewers and experts considered to be of interest.

• 4.

  Analysis and synthesis of the scientific evidence. Systematic reviews and CPGs identified for the non-PICO questions were evaluated by the methodological coordinator. It was agreed that only high quality ones would be considered suitable for inclusion as a source of evidence. Several rheumatologists in the SER evidence reviewers work group systematically reviewed the available scientific evidence for the PICO questions. After the critical reading of the complete text of the selected studies for each review they prepared a summary by using a homogenised formula, including tables and text, to describe the methodology, the results and the quality of each study. They described the reasons for the exclusion of the papers that were not included in the selection. The overall level of scientific evidence was evaluated using the levels of evidence of the Scottish Intercollegiate Guidelines Network (SIGN)9 (see Appendix B).

• 5.

  Preparation of recommendations. After the critical reading, the chief researcher and the members of the group of experts formulated the specific recommendations based on the scientific evidence. This formulation was based on the “formal evaluation” or “reasoned judgement”, having previously summarised the evidence for each one of the clinical questions. The quality, quantity and consistency of the scientific evidence were also taken into account, together with the generality of the results, their applicability and clinical impact. The recommendations were graded using the SIGN9 system (see Appendix B). The recommendations were divided into five main areas: diagnosis and evaluation, primary thromboprophylaxis, treatments of primary APS or secondary thromboprophylaxis, treatment of obstetric APS and special situations.

• 6.

  External review. After the previous phases a final draft version of the document was prepared. This was sent to professionals selected for their knowledge of APS for a phase of independent external revision. The ultimate aim of this was to increase the external validity of the document and ensure the exactitude of its recommendations.

• 7.

  Public exhibition. The draft of the SER Recommendations document was shown to members of the SER and other interested parties (the pharmaceutical industry, other scientific associations and patients’ associations) to gather their opinions and scientific arguments respecting its methodology and recommendations. No statements were received in response to this.

The document contains recommendations which are subdivided into the different areas described above. Treatment algorithms have been prepared on the basis of the recommendations, showing the approach to treating APS in summarised form.

Which of the APA included in the classification criteria (LA, aCL and aβ2GPI) are the ones with the highest risk of developing venous and/or arterial thrombosis and obstetric complications?

Recommendation:in patients with APS it is recommended that all three APA included in the classification criteria should be detected simultaneously (LA, aCL and aβ2GPI) to establish the risk of thrombosis or obstetric complications (grade C recommendation).

Recommendation:there is a higher risk of presenting clinical manifestations of APS when lupus anticoagulant or more than one different APA is detected (double and in particular triple positivity) in the same patient (grade B recommendation).

The clinical manifestations of APS are associated with the detection of APA. APA may be detected by the prolongation of phospholipid dependent coagulation tests, which is denominated lupus anticoagulant (LA), or by solid phase assays such as ELISA for aCL, IgG and/or IgM or aβ2GPI, Ig and/or IgM. APS classification criteria currently only include the detection of these APA. A patient fulfils the laboratory criterion when at least one of these APA is detected in serum or plasma, on two or more occasions at least 12 weeks apart. Nevertheless, the risk of thrombosis or obstetric complications may differ depending on whether one of these antibodies or a combination of the same is detected.

Recurrent abortions occur the most frequently in patients with type IgG and/or IgM aCL10,11(LoE 2++) or AL12,13(LoE 2−). aβ2GPI type IgG and/or IgM antibodies are associated with a higher rate of foetal losses11,14,15 than is the case with aCL and AL,16 and especially with a higher risk of late foetal losses12(2−). The majority of studies find that the detection of more than one APA in the same patient indicates an increased risk of recurring abortions.10,13,15–19(LoE 2++, 2+, 2−, 3)

Recurring venous and/or arterial thromboses are more frequent in patients with AL20–28(LoE 2++, 2+, 2−), aCL antibodies16,21,22,26,29–35(LoE 2++, 2+, 2−, 3) or aβ2GPI antibodies21,22,24,27,28,33,36–39(LoE 2++, 2+, 2−). The detection of more than one APA in the same patient indicates an increased risk of recurring venous and/or arterial thrombosis,24,25,37,39 in particular triple positivity for LA, aCL and aβ2GPI.16,23,24(LoE 2++, 2+)

In the light of these studies the preparatory group considers that in patients with APS the risk recurrent abortions and venous and/or arterial thrombosis is greater when different APA are detected in the same patient. The results of the different studies are consistent, and the majority suggest detection of all the APA included in the classification criteria (LA, aCL and aβ2GPI).

The preparatory group also understands that the results of the studied analysed are directly applicable to our medical system, as it is possible for all hospitals and speciality centres to detect the APA included in the classification criteria (LA, aCL and aβ2GPI).

Detecting more than one APA makes it possible to select the subgroup of patients with APS and the highest risk of recurring abortions and recurring venous and/or arterial thrombosis, with the resulting implications for prognosis and treatment.

When is it necessary to detect the APA that are not included in the current APS classification criteria?

Recommendation:in normal clinical practice, in the general population with the suspicion of APS or in patients already diagnosed with the disease, it is not recommended to detect the APA that are not included in the classification criteria (grade D recommendation).

The Sydney classification criteria only include three of the known APA: LA, the aCL (IgM and IgG) and the aβ2GPI (IgM and IgG). Detection of the other APA is still not indicated in medical care. There is insufficient information about their clinical significance, although many of the new APA described are potentially important in the physiopathology of APS, and currently it is not known whether they should be included in the diagnostic algorithm and routine study of patients with APS.

The most relevant of the new APA are described below, in terms of their involvement in thrombosis or obstetric problems.

Which antiphospholipid antibodies can be used and when for the diagnosis and follow-up of an anticoagulated patient with APS?

Recommendation:the detection of antiphospholipid antibodies is not recommended if the patient is anticoagulated and diagnosed (grade √ recommendation).

Recommendation:in patients with induced thrombosis, a low risk profile for thrombosis and without conventional cardiovascular risk factors, antibody detection test repetition may be considered to evaluate the need for indefinite anticoagulation (grade √ recommendation).

Recommendation:it is recommended to repeat the determination of the antiphospholipid antibodies included in the classification criteria (except for lupus anticoagulant) at least at 12 weeks (grade √ recommendation).

Recommendation:if lupus anticoagulant was positive in the initial diagnosis and confirmation is required, individualising each patient according to their risk of thrombosis, it is recommendable to suspend oral anticoagulation at least 1 or 2 weeks before the determination, using heparin at a therapeutic dose (associated with acetylsalicylic acid at anti-aggregant dose levels in the case of previous arterial thrombosis) and suspending it the night prior to determination to prevent interfering with the laboratory results (grade √ recommendation).

APA is determined at least once for the majority of patients who develop thrombosis. However, once they are anticoagulated the experts agree that it is necessary to perform a new determination at 12 weeks, to comply with the Sydney criteria and ensure that the diagnosis of APS is correct. There is no inference between the aCL and aβ2GPI antibodies and anticoagulants, and tests for them can be repeated under anticoagulation. Nevertheless, in the case of LA there is interference at the level of laboratory testing, and interpretation may be erroneous in the presence of anticoagulants. International agreements therefore recommend determining LA without the presence of anticoagulants, so that anticoagulation in patients taking vitamin K antagonists (VKA) should be suspended during 1–2 weeks, switching to low molecular weight heparin (LMWH) during this time at a therapeutic dose and suspending it 12h before the test.61,62

There are also two studies which were performed to validate LA detection tests in anticoagulated patients. They conclude that in the clinical situation in which an anticoagulated patient at high risk of thrombosis requires confirmation of LA positivity, it is possible to consider using the Taipan snake venom time test with Ecarin time to confirm their positivity and thereby avoid suspending anticoagulation. Nevertheless, in spite of its high specificity its sensitivity is low, and it is not available in all coagulation laboratories for routine determination. In any case, the clinical criterion should prevail, and the panel considers that for a patient at high risk of thrombosis it is not absolutely necessary to confirm LA to diagnose the disease.63,64

It is also important to monitor VKA in patients with APS, as different studies show that in patients with APS there is a phenomenon of warfarin resistance, and that given the interferences at the level of INR detection, it is considered to be important for anticoagulated patients to maintain an INR≥3. This parameter should be determined by using a citrated tube in the laboratory. In the case of recurring thrombosis events the studies conclude that determination of an anti-Xa should be performed to evaluate the real levels of anticoagulation. Moreover, at the current time finger-prick checks are less reliable than those using venous puncture.61,65–69

There is little evidence for the clinical significance of APA in monitoring APS in anticoagulated patients.65–69 A prospective study of patients who were anticoagulated due to arterial disease compared warfarin and aspirin for the prevention of ictus relapse, with a follow-up time of 2 years.69 There were no significant differences between the patients with or without positive APA, although patients with APA have a higher rate of events (31.7%) than those who do not have APA (24%). The authors conclude that although detecting APA without subsequent confirmation does not identify high risk patients, double positivity does identify these high risk patients. They also conclude that APA should be studied for young ictus patients.69

The relevance of these studies is based on improving knowledge about the complexity of monitoring anticoagulation in APS patients. It is not indicated to perform APA tests on anticoagulated patients indefinitely for their follow-up or during anticoagulant treatment. There are no data that would bring about a change of therapeutic attitude: it only identifies the patients who are at a high risk of relapse.70

Nor are there data on the usefulness of determining APA in patients with induced thrombosis, although given the risk of haemorrhage associated with VKA, in some cases monitoring may be individualised to determine whether patients need indefinite anticoagulant treatment or not.71,72

To summarise, some studies show how difficult it is to measure LA in the presence of anticoagulants, for diagnosis as well as when monitoring. Although it is possible to measure the other APA (IgM and IgG), there is no consistent evidence for their usefulness in long-term monitoring or that this gives rise to greater risk or a change of therapeutic attitude.

In patients with APA who do not fulfil APS criteria, which prophylaxis is the most effective?

Recommendation:in patients who are carriers of antiphospholipid antibodies and without symptoms associated with APS, prophylactic treatment is recommended with low molecular weight heparin in situations with a high risk of thrombosis (prolonged immobilisation, recent surgery, during the puerperium or ovary stimulation, etc.) (Grade C recommendation).

Recommendation:in low-risk profile patients prophylactic treatment is only recommended when there are associated cardiovascular risk factors. This should consist of low doses of acetylsalicylic acid and correction or treatment of the cardiovascular risk factors (grade C recommendation).

Recommendation:in patients who are carriers of antiphospholipid antibodies and with associated thrombocytopenia, prophylactic treatment is recommended with low doses of acetylsalicylic acid (grade C recommendation).

Recommendation:in patients with a medium to high risk profile prophylactic treatment is recommended with low doses of acetylsalicylic acid during an indefinite period of time (grade C recommendation).

Recommendation:in patients who are carriers of antiphospholipid antibodies, without symptoms associated with APS and who wish to conceive, it is recommended that prophylactic treatment with low doses of acetylsalicylic acid be considered, according to their risk profile (grade C recommendation).

At the current time, the risk of thrombosis in individuals who are carriers of APA (fulfilling the serological criteria), without associated symptoms, is not well established. The data obtained in series of patients with highly heterogeneous characteristics varies in rates of annual incidence from 0% to 7.4%.6,73 APA are common in the general population, and not all carriers run the same risk of developing manifestations of the disease in the future.74 Of all the risk factors for developing clinical APS, the experts agree that four of them are fundamental, and that these should guide the classification of APA carrier individuals when deciding whether or not primary prophylaxis is necessary.34,74–77 These four factors are the APA profile, the presence of cardiovascular risk factors, the presence of other manifestations associated with APS (and not included in the criteria) and the fact of suffering another associated autoimmune disease, especially SLE (Table 4). While these risk factors have been shown to be of possible use in grading the risk of thrombosis in this group of APA carriers, their role in the risk of developing obstetric manifestations is not equally clear.6

Although controversy clearly exists as to which APA positive patients should receive primary prophylaxis, the majority of experts agree that prophylaxis should be administered to all of these patients during high risk situations for thrombosis (prolonged immobilisation, recent surgery, pregnancy and the puerperium, ovary stimulation and nephrotic syndrome, etc.).6,74 This recommendation is based on the data of two observational studies in which APA positive patients without associated clinical signs showed a significant reduction in thrombosis events during monitoring when they were only given prophylaxis during risk situations (surgery or immobilisation).25,78(LoE 2+)

There is now only one clinical trial that covers primary prophylaxis in APA carrier patients. The clinical trial by Erkan et al.79 included 98 APA positive patients, with or without systemic autoimmune disease, who were randomised and received acetylsalicylic acid (ASA) (81mg/day) or a placebo, before being followed up for 3 years. This trial did not find a favourable result for primary prophylaxis with ASA. Three of the 48 patients with ASA had thrombosis (2.75 cases per 100 patients-years) vs none for the 50 control patients, giving a HR of 1.04 (CI 95%: 0.69–1.56; P=.830) (LoE 1+). Nevertheless, this study has been broadly criticised by experts, and it has numerous limitations. The small number of patients included, the short follow-up of the same, the APA profile of the patients and the high proportion of patients with SLE mean that the results of this work should be interpreted extremely cautiously.6 In spite of its limitations, the majority of experts consider that chronic treatment with prophylactic doses of ASA in APA carrier individuals with a low risk profile is not justified.6,74

Arnaud et al.80 carried out a meta-analysis of observational studies, asking the authors of the studies for the data of individual patients to determine whether ASA has a protective effect against the risk of a first thrombosis in APA positive patients without the clinical criteria for APS. 5 studies of international cohorts were included, with a total of 497 subjects and 79 cases of a first thrombosis (3469 patients-years of follow-up). After adjustment for cardiovascular risk factors, APA profiles and treatment with hydroxychloroquine (HCQ), the HR for a first thrombosis of any type in individuals treated with low doses of ASA vs those who were not treated was 0.43 (CI 95%: 0.25–0.75). Analysis of subgroups according to the type of thrombosis showed that ASA has a protective effect against arterial thrombosis (HR: 0.43; CI 95%: 0.20–0.93) but not venous thrombosis (HR: 0.49; CI 95%: 0.22–1.11). The analysis of subgroups depending on the underlying disease showed that ASA has a protective effect against arterial thrombosis in patients with SLE (HR: 0.43; CI 95%: 0.20–0.94) and in asymptomatic carriers (HR: 0.43; CI 95%: 0.20–0.93) (LoE 2++). In a prospective observational study81 that included asymptomatic individuals who were carriers of APA, and after a 9-year follow-up, the main factors identified as associated with the development of thrombosis were double/triple APA positivity, the presence of classical cardiovascular risk factors (smoking) and the concomitant presence of other autoimmune diseases. In this study prophylaxis during risk situations was associated with less development of thrombosis.81(LoE 3)

Thus although it is not possible to recommend primary prophylaxis for all APA carrier individuals, according to the little evidence that is available, all of the experts agree on the need to grade the risk of thrombosis according to the parameters defined above, as well as the correction and treatment of classical cardiovascular risk factors. They also agree on the need for primary indefinite prophylaxis with antiaggregant doses of ASA in individuals who are considered to be at risk.6,74 This risk group should include patients who have an associated autoimmune disease, especially SLE.74

Thrombocytopenia is the only one of the several clinical manifestations associated with APS but which are not included in the classification criteria for the disease which has been shown most conclusively to be associated with a higher risk of thrombosis.75,82–84 In other manifestations, such as cardiac or cutaneous involvement, it has not been possible to conclusively demonstrate such a clear association with the development of clinical or obstetric thrombosis.

To date no well-designed study has evaluated the efficacy of anticoagulation in APA patients without any associated clinical signs. Only one study conducted in a different population (purely obstetric APS and patients with SLE) compared this treatment with ASA associated with low intensity anticoagulation (INR 1.5) vs antiaggregant doses of ASA for the primary prophylaxis of thrombotic phenomena.73 In spite of the limitations of the study, no significant differences between both treatment groups were found in terms of the prevention of thrombotic events. However, the group that included low intensity anticoagulation had a higher number of episodes of bleeding.

While there is little information about primary thromboprophylaxis in APA carriers, even fewer studies have been published on prophylaxis for obstetric complications. Women with obstetric APS are currently considered to be at greater risk of developing thrombosis in the future.85 While treatment with heparin associated with ASA seems to be effective in the prevention of early foetal loss,86,87 this combination has not been proven to be effective in preventing late complications of the disease.86–88 The clinical situation in question – primary prophylaxis in women who are APA carriers – is hard to define at the current time due to the lack of studies in this population. While on the one hand APA detection is not usually requested for women who have not previously shown clinical signs of obstetric involvement, on the other hand the few studies which are available cover an extremely heterogeneous population, and several studies include patients with SLE and other autoimmune diseases.89(LoE 1+)

The study by Amengual et al.89 was a systematic recent review which analysed 154 pregnancies (92 with a prophylactic treatment and 62 with no treatment). It concluded that there is now no evidence that prove that giving prophylactic doses of ASA is better than a placebo or normal care to prevent unfavourable obstetric results during the first pregnancy of healthy women who are APA carriers.90–92 A recent study that has only been published in abstract form93 reviewed 70 pregnancies in 62 women who are APA carriers. The factors associated with a poorer obstetric prognosis were triple positivity for APA, the presence of acquired risk factors (fundamentally cardiovascular risk factors), the presence of manifestations associated with APS and lupus-like manifestations. Curiously, the patients with the worst obstetric prognosis were also more likely to receive combined therapy of low dose ASA and heparin.

What is the treatment for arterial thromboembolic disease in a patient with APS?

Recommendation:patients with primary APS and previous arterial thrombotic events should be treated with standard anticoagulation (INR 2–3) to prevent recurrences of arterial thrombosis (grade B recommendation).

The treatment of arterial thrombosis in patients with APS is still controversial as to whether it should consist of platelet anti-aggregation, anticoagulation or both. In the case of anticoagulation there is debate about whether a dose to maintain an INR of 2–3 or a stronger dose should be used.

The management of arterial thrombosis and more specifically cerebral ischaemia is highly controversial in APS patients. This difficulty arises due to several factors, including the lack of well-designed randomised prospective studies; the fact that the majority of studies fail to differentiate between venous and arterial thrombosis; methodological and therapeutic heterogeneity, and lastly that the laboratory diagnosis of APS is not always carried out strictly in accordance with the classification criteria. Thus as little scientific evidence is found for this question and no primary studies were identified which were specifically designed to answer it, a parallel search was added to the initial search strategy. However, the papers found in the parallel search also failed to answer the clinical question, so they were not included. In the studies that were found it was impossible to obtain individualised data according to thrombosis type (venous or arterial) as they were designed to evaluate the efficacy of thrombosis treatment in general for patients with primary APS.

Due to the above reason, the preparatory group decided to eventually include studies which either do not distinguish between venous and arterial thrombosis, as well as ones that include only patients with venous thrombosis or with arterial thrombosis, but which do not distinguish between primary APS or APS that is secondary to SLE.70,103,104,124

The Antiphospholipid Antibodies and Stroke Substudy (APASS), conducted in the context of the Warfarin vs Aspirin Recurrent Stroke Study (WARSS) clinical trial, found no significant differences between the use of anti-aggregation with ASA and warfarin in the prevention of thrombotic events, although it did not distinguish between venous and arterial thromboses. Even in this work the authors found that the presence of APA was not a predictive factor for the recurrence of thrombosis.70(LoE 1+)

At first, retrospective studies carried out in patients with APS suggested that intense anticoagulation (INR≥3) is more effective than treatment using lower standard ranges.106 No differences were found between high range anticoagulation with warfarin (for an INR of 3–4) and standard range (INR 2–3) in two clinical trials which did not discriminate between arterial and venous thromboses. These studies also had the limitation that their evidence could not be extrapolated to patients with previous arterial thrombotic events, as they excluded patients with previous ictus and those with recurrent thrombosis while anticoagulated.103,104 A secondary analysis of these trials shows that high range anticoagulation (INR 3–4) may reduce the risk of recurrence of thrombotic events in patients with APS. Nevertheless, this conclusion is controversial. On the one hand, when the results of both unique clinical trials are analysed together103,104 paradoxically a slight increase is observed in recurrences in patients treated using high range anticoagulation (INR 3–4), although this is not statistically significant (LoE 1+). However, the systematic review by Ruiz-Irastorza et al.106 presents a sub-analysis of the INR at the moment of recurrence of the thrombosis in the works that give this datum. These studies are heterogeneous and the author concludes that the majority of recurrences occur at an INR lower than 3, and suggests that intense anticoagulation may be a better option for the prevention of the said recurrences (LoE 1+).

More specifically, the conclusions regarding the management of cerebral ischaemia are based on studies that include patients with ictus of any origin, with overall analysis of the therapy and without distinguishing between primary APS or APS secondary to SLE. In general no significant differences were found between the use of anti-aggregation with ASA and standard range anticoagulation with warfarin. Nevertheless, in patients with primary APS and a history of a previous ischaemic cerebrovascular event, the combined therapy of ASA and standard range anticoagulation (INR 2–3) is effective in the secondary prevention of recurrences.124(LoE 1−)

Although the evidence is limited, the studies also show that the risk of recurrent thrombosis and mortality due to thrombosis is greater than the risk of mortality due to haemorrhaging in patients with APS who receive anticoagulation, even in the range INR 3–4.102–104,106,107,111,116

Lastly, a recommendations document was identified which had been prepared by the American association for the study of ictus.125 Two of the guidelines this gives for patients with ictus or a transitory ischaemic accident include APS criteria: (a) anticoagulation has to be considered, given the risk of recurrence of thrombotic events and bleeding, and (b) when anticoagulation has not yet commenced, treatment with antiaggregants is indicated (LoE 4).

In the light of the results, it is not possible to confirm the efficacy of any specific therapy in patients with primary APS and arterial thrombosis. It has not been possible to prove that any significant differences exist between anti-aggregation and anticoagulation or between using high or standard doses of anticoagulation in the secondary prevention of arterial thrombosis.

As no primary studies which evaluate the efficacy of therapies in patients with primary APS and arterial thrombosis, we cannot extrapolate the results of the studies used as scientific evidence to the target population of our recommendations. Nevertheless, after reviewing the evidence the expert panel considers that in patients with APS defined by clinical and analytical criteria, and particularly those with other vascular risk factors or at high risk due to triple APA positivity, it would be possible to recommend standard range anticoagulation (INR 2–3). Finally, the preparatory group has also decided to issue a recommendation that association with anti-aggregation should be assessed in cases with more than one recurrence or poor anticoagulation control.

• -

  Studies are required which can add to knowledge of the pathogenic power of the APA included in primary APS classification criteria as well as those which are not.

• -

  Studies should be undertaken to make it possible to agree on which techniques are the best for identifying the APA associated with the pathogenesis of thrombosis and morbidity during pregnancy.

• -

  In vitro and in vivo studies are needed to identify the APA which are involved in the pathogenesis of APS, to aid the design of clinical trials in patients without clinical manifestations.

• -

  Additional clinical trials are necessary with DOAC in different clinical situations, to confirm their efficacy and safety in APS.

• -

  New tools or scores have to be developed which make it possible to identify the asymptomatic individuals who are APA carriers at risk of developing thrombotic phenomena and especially obstetric manifestations of the disease.

• -

  Multicentre prospective studies are needed to make it possible to determine which primary prophylaxis is the most effective in asymptomatic carriers of APA, graded according to risk profile.

• -

  Specific studies are necessary in patients with venous and arterial thrombosis that include patients with different risk profiles (triple positivity or the concomitant presence of other prothrombotic risk factors).

• -

  Prospective studies are required to evaluate the possibility of suspending anticoagulation in patients with venous thrombosis at low risk of recurrence (no triple positivity, IgM isotypes or thrombosis coinciding with other risk situations such as taking contraceptives or undergoing surgery, etc.).

• -

  Prospective studies are also needed to compare the efficacy of treating using isolated anticoagulation vs a combination with antiaggregation in patients with arterial thrombosis.