Viewpoint: Provoked thrombosis in antiphospholipid syndrome

Abstract

Unprovoked thrombosis (thrombosis occurring without an established environmental factor favouring the episode) is a classic feature of APS. In the general population, provoked venous thromboembolism (VTE) is clearly defined and has clinical and therapeutic differences compared with unprovoked VTE. Whether provoked VTE in the context of APS may lead to a limited treatment duration is not well established. Therefore, careful clinical and laboratory evaluation is needed to identify patients eligible for a limited duration of anticoagulation treatment after provoked VTE. Given the uncertainties of available data, the risks and benefits of treatment decisions should be clearly explained. Decisions should be shared by both the patient and physician. Cardiovascular risk factors are common in patients with APS with arterial thrombosis. There are insufficient data suggesting that cardiovascular risk factor control would allow the cessation of anticoagulation. In most instances, arterial thrombosis will require prolonged anticoagulants. A careful analysis of clinical characteristics and laboratory evaluation, particularly the aPL antibody profile, is needed to make decisions on a case-by-case basis.

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Introduction

A working group of the International Society of Thrombosis and Haemostasis (ISTH) developed the concept of provoked thrombosis in the general population [1] as an evaluation tool for the risk of recurrent venous thromboembolism (VTE) after an index episode. Identification of an important environmental ‘provoking’ risk factor for the inaugural episode of VTE defines provoked VTE. Conversely, the episode is unprovoked in the absence of any environmental factor favouring the episode.

The ISTH group made a distinction between unprovoked VTE and idiopathic VTE: ‘idiopathic’ suggests that there is no reason for thrombosis (environmental or patient specific). Thus a patient with either provoked or unprovoked VTE still may have inherited or acquired thrombophilia, while the term idiopathic thrombophilia may suggest that no risk factor is present (either inherited or acquired).

There is a clearly demonstrated interaction between provoking environmental factors and inherited thrombophilia as well as with autoimmune thrombophilia induced by aPL antibodies. While data on VTE show that in combined oral contraceptive (COC) users, mild and severe inherited thrombophilia increased the risk of VTE 6-fold and 7-fold, respectively, in the general population [2], in APS the risk for VTE in COC users is not precisely established [3]. Regarding arterial thrombosis in the general population, the absolute risks of thrombotic stroke and myocardial infarction associated with the use of hormonal contraception are low, but the risk is increased up to 2-fold in COC users [4]. In patients with the lupus anticoagulant (LA), the odds ratio (OR) for myocardial infarction was 5-fold, which increased to >20 in women who used oral contraceptives and >30 in those who smoked. In the same group, the OR for ischaemic stroke also increased dramatically in women with LA who used oral contraceptives.

A common assumption is that VTE provoked by a major transient risk factor, such as recent surgery in the general population, has a very low risk of recurrence after stopping therapy and will need a short duration of treatment. In APS, the limited amount of data regarding provoked thrombosis does not allow such firm conclusions at this stage and patient management will require careful individual evaluation and shared decisions until high-quality data from randomized studies are available.

Risk factors

Analysis of risk factors of provoked VTE

Definition of transient risk factors

While unprovoked VTE occurs without any environmental provoking factor, risk factors may be transient or persistent. Within the transient category, it is important to identify major and minor risk factors. Major transient risk factors are paramount for the occurrence of an episode of VTE and the risk of recurrence is low after their resolution in the general population. However, in the context of APS, the risk of recurrence is determined not only by conventional VTE risk factors, but also by aPL profiles and associated conditions.

Common major transient risk factors are surgery with general anaesthesia for >30 min, being confined to bed in a hospital (with only ‘bathroom privileges’) for at least 3 days with an acute illness or caesarean section (Table 1) [1]. Other risk factors are minor risk factors in comparison with those mentioned above, but they are also relevant provoking factors, in particular when combined between them or with inherited thrombophilia (Table 1). In the young APS female population, combined oral contraceptives containing oestrogens are a significant risk factor (all the more important with a high oestrogen dosage or third-generation progestins such as desogestrel). Pregnancy and the post-partum period convey a significant risk for VTE in female patients with aPL antibodies. Other minor transient risk factors include in vitro fertilization hormonal treatment strategies and post-menopausal hormone replacement therapy (HRT). Of note, transdermal HRT conveys a reduced VTE risk compared with oral HRT, modulated by associated progestins [8] and inherited thrombophilia [9] demonstrated in the general population. Obesity, other types of surgery, immobilization in a hospital and central venous catheters are associated with a significant risk for VTE. The strength of association of risk factors related to VTE are well established in the general population but specific data in APS are limited.

Resolution of transient risk factors

The period after which the effect of the risk factor resolves is variable. It is therefore important to assess the resolution of transient risk factors according to their known characteristics. For instance, the risk conveyed by non-cancer general surgery remains high for <2 months [10], while for patients with thrombosis provoked by hormonal contraception, the risk returns to baseline levels within 1–3 months of ending hormone use [11].

Risk of recurrence of provoked VTE

The risk of recurrence for symptomatic provoked VTE depends on the type of transient risk factors. Indeed, a review article showed that the rate of recurrence was 0.7%/patient-year (three studies, 248 patients) in the subgroup with a surgical risk factor and 4.2%/patient-year (three studies, 509 patients) in the subgroup with a non-surgical risk factor [12]. Whether the presence of aPL antibodies increases the risk of recurrence after a first episode of provoked VTE is not known. A systematic review by Garcia et al. [13] showed that the risk ratio for recurrent VTE after stopping anticoagulant therapy in patients with an aCL antibody was 1.53 (95% CI 0.76, 3.11) and with an LA was 2.83 (95% CI 0.83, 9.64). However, considered studies had important methodological limitations. Although a positive aPL test appeared to predict an increased risk of recurrence in patients with a first VTE, the strength of this association seemed uncertain because the available evidence was of low quality [13]. Indeed, there are uncertainties regarding how the APS diagnosis was made and on the confirmation of initial aPL positivity.

In the study of Schulman [14], patients with positive aCL titres had significantly more recurrent events than those with a negative aCL test. However, blood sampling and determination of aCL antibodies were done after 6 months of treatment in all patients randomized to either 6 weeks or 6 months of treatment with warfarin after a first episode of VTE. Problems with this article are the low cut-off for aCL (5 GPL), LA testing performed on oral anticoagulant treatment with possible false-positive results and the absence of confirmation data. In another study [15], aPL was measured at the time of randomization of patients with idiopathic VTE to 3 months or extended anticoagulation. The study concluded that LA but not aCL was a risk factor for recurrence, but confirmation tests at 12 weeks were not performed, therefore the analysis could have included transient positivity. It is now well known that the initial positivity of a single aPL test is confirmed after 12 weeks in <50% of cases [16].

The American College of Chest Physicians guidelines in 2012 [17], citing the articles of Schulman et al. [14] and Kearon et al. [15], concluded that LA but not aCL is a risk factor for recurrence in patients with VTE.

Definition of persistent risk factors

In the general VTE population, the main major persistent risk factor is active cancer. However, in APS patients [18, 19], risk factors differ from those of the general population (Table 2). Chronic inflammatory diseases are present in almost 50% of patients, mainly SLE, but also SS, RA, IBD, SpA, SSc, systemic vasculitis or dermatomyositis [18, 19].

Recent data [20] indicate that lupus flares may be associated with the index VTE event. However, in SLE the risk of VTE recurrence is mainly driven by APS. This was shown in a cohort of SLE patients who had stopped anticoagulation after an index event. The risk of recurrence was the lowest in SLE patients without APS but with a provoking factor (surgery, use of contraception containing oestrogen, pregnancy and/or puerperium, being bedridden for >3 days, immobilization of a lower extremity using a cast, hospital admission or the presence of a central venous catheter). A similar high risk of recurrence was observed in patients with unprovoked VTE and those with APS and provoked VTE. Notably, in patients with both an unprovoked index VTE and APS, the risk of recurrence was the highest, as expected. These results are in line with previous data [21] suggesting that disease activity may be associated with increased rates of arterial thromboembolism and VTE after diagnosis of SLE.

Diabetes is a frequent minor persistent risk factor for VTE, although a potential confounding effect of obesity is possible [22]. Obesity may be a transient, resolving risk factor (especially with modern bariatric care) or a persistent one in many patients.

The combination of aPL antibodies with one or more inherited risk factor significantly increased the risk of VTE in SLE [23].

While active cancer is an established and major risk factor for VTE in the general population, it accounts for a minority of VTE events in aPL when paraneoplastic aPL antibodies are excluded. According to the ISTH proposals, cancer is considered active in the following situations: the disease has not received potentially curative treatment or there is evidence that treatment has not been curative (recurrence or progression) or treatment is still ongoing. In these cases, there is a high risk of recurrent VTE after stopping anticoagulant therapy.

Resolution of persistent RF

While complete remission of chronic systemic autoimmune or inflammatory diseases is difficult to obtain, one could expect a lower risk of VTE recurrence when the disease is stable under treatment meeting criteria of low disease activity. It is unclear whether, in APS patients with stable associated disease, cessation of anticoagulants would be possible.

Cancer may no longer be a risk factor for VTE after curative treatment. However, the duration of the disease-free interval varies according to the type of disease and ongoing treatment (notably prolonged hormone therapy, which conveys an additional VTE risk). Furthermore, there is no single/standardized disease-free interval after which VTE risk resolves.

Prediction scores

Prediction scores for VTE recurrence in patients with previous unprovoked VTE have been developed and validated in the general population, such as the DASH score [5], Vienna prediction model [6] and the HERDOO2 rule [7]. They have not been tested in the context of APS and cannot be used for APS patients.

A composite score, the Global Antiphospholipid Syndrome Score, and its variation, the adjusted Global Antiphospholipid Syndrome Score including the aPL profile and two clinical risk factors (hyperlipidaemia and arterial hypertension), predicted further thrombosis over time in APS [24, 25].

Analysis of provoked arterial thrombosis risk factors

The concept of provoked arterial thrombosis is different from provoked VTE. There is not a consensus definition. However, a common understanding is that arterial thrombosis occurring in the absence of classic or demonstrated risk factors (Table 3) is unprovoked. Despite their clinical significance, the identification of risk factors leading to arterial thrombosis in APS is still challenging. The prevalent APS-related clinical manifestation in the arterial circulation is ischaemic stroke that in many cases is unprovoked ‘cryptogenic’. In a few cases, potential causative disorders can be identified and ‘provoked’ arterial thrombosis is attributed to atherosclerosis, valvular heart disease (Libman–Sacks endocarditis) or patent foramen ovalis (paradoxical embolism). Favouring factors include the classic cardiovascular risk factors such as hypertension, diabetes, obesity, smoking and hyperlipidaemia. Other possible causes have occasionally been identified in selected case reports. Recurrent ischaemic stroke in a 20-year-old triple-positive woman occurred in the same cerebral artery due to a stenosis of the index vessel identified on MRI [26]. In another patient, a thrombotic occlusion of the right deep brachial artery occurred in a patient confined to bed for 2 weeks for sciatica, who kept sleeping in a right lateral decubitus position. Thus, alteration of vessels and stasis of blood can contribute to arterial thrombosis in APS [26] and in these cases the arterial event could be ‘provoked.’ If the resolution of the provoking factor or condition allows for suspension or modification of antithrombotic treatment is unknown. Unprovoked arterial thrombosis may lead to a diagnosis of specific diseases [27], such as medium-sized artery diseases (e.g. fibromuscular dysplasia or other rare inherited diseases of the arteries).

Unprovoked arterial thrombosis is a typical feature of APS. However, in many instances the main classical arterial risk factors play a role in APS, in addition to aPL. This has been documented by the Ratio study [4]. Cardiovascular risk factors should be assessed in patients with aPL detected before the occurrence of thrombosis, in particular patients with obstetric APS, or SLE to implement therapeutic strategies for prevention of arterial thromboses. In patients who experienced a first arterial event, it is paramount to prevent recurrence despite prolonged anticoagulant therapy [19].

In a case–control study, the risk of myocardial infarction (MI) in women with LA was >5-fold higher than in women without LA [4]. The risk of MI increased to >20-fold in women who used oral contraceptives and >33-fold in those who smoked. The risk estimate (OR) for ischaemic stroke was 43-fold higher in women with LA compared with controls, which increased to 87-fold in women who smoked and to 201-fold in those who used oral contraceptives. In addition, in women who had anti-β2-glycoprotein I (aβ2GPI) antibodies, the risk of ischaemic stroke was increased 2-fold.

Together with classical risk factors (current smoking, arterial hypertension, diabetes, obesity, hyperlipidaemia), other risk factors should be considered in the aPL/APS population.

In an observational cohort study [28] including premenopausal women ages 18–45 years enrolled in the SLICC registry, it was found that combined contraceptives containing oestrogens were taken in the presence of one or more possible contraindications, which was the presence of positive aPL in >50% of these cases. Overall, there was a low prevalence of any hormonal contraceptive use in these SLE women (11% at baseline) compared with general population estimates. These results indicate a cautious use of oestrogen-containing pills overall, but also the need to implement safe alternatives (compounds containing progestin only, pills, subcutaneous injections, intrauterine devices with or without levonorgestrel).

In a recent report, out-of-target low-density lipoprotein cholesterol (LDL-C) levels were found in 67.5% of patients, of whom 46% had a history of established cardiovascular disease [29], while another study showed suboptimal cardiovascular risk factor target achievement in APS, especially in high-/very high-risk patients [30], highlighting the need for specific management strategies/programs in APS patients. Together with these risk factors, APS patients frequently have an associated disease and may present with chronic kidney disease (either APS or lupus nephropathy) that also increased the risk of accelerated atheroma. A higher prevalence of classic cardiovascular risk factors [31] and a higher risk for atherosclerosis has been demonstrated in APS compared with healthy controls or other high cardiovascular risk disorders [32, 33].

Cardiovascular risk factors should be assessed in patients with aPL detected before the occurrence of thrombosis, in particular patients with obstetric APS or SLE, to implement therapeutic strategies for primary prevention of arterial thromboses, according to recent EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases, including SLE and APS [34].

APS profile

APS clinical profile

The clinical profile of APS varies from patient to patient. At diagnosis, most patients present with a single index vascular thrombotic or an obstetrical event. In SLE patients, aPL antibodies are often diagnosed in asymptomatic patients by routine evaluation. However, in some cases patients have a complex clinical picture at diagnosis, with additional features of APS. Thrombosis may occur in common sites (VTE, stroke or MI), but also in unusual sites (e.g. splanchnic thromboses such as portal vein thrombosis or Budd–Chiari syndrome, adrenal infarction). The microcirculation may also be involved with various manifestations (livedo racemosa, cardiac microvascular disease, diffuse alveolar haemorrhage or aPL nephropathy). These features may be cardiac valve thickening or vegetations (classical Libman–Sacks endocarditis), moderate thrombocytopaenia or non-vascular neurological manifestations.

Several studies have identified patient clusters with different characteristics [35–37]. Although not strictly identical across studies, these analyses indicate different patient profiles important for treatment decisions. Therapeutic decisions for provoked thrombosis may be different for APS patients with VTE without any associated autoimmune disease or women with SLE, VTE, aPL nephropathy, thrombocytopaenia, haemolytic anaemia or a lupus anticoagulant laboratory profile. Another cluster identified older men whose main clinical manifestations were arterial thrombosis, heart valve disease, livedo, skin ulcers, neurological manifestations and having other cardiovascular disease (CVD) risk factors. The latter group will require prolonged anticoagulants and risk factor control.

APL (laboratory) profile

When considering the aPL antibody profiles generated by testing all three available tests, namely LA, aCL and aβ2GPI), it is clear that the association with thromboembolic events is high in patients with triple positivity [38]. Patients with APS and triple positivity are also at high risk of developing future thromboembolic events. Warfarin significantly reduces the risk, although recurrence of venous and arterial events remains frequent despite anticoagulation [39]. Most of the 74 patients with VTE in the above-mentioned study had associated risk factors for VTE, including recent surgical intervention, perioperative immobilization and contraceptive pills, indicating that their index event of VTE in most cases was provoked. Therefore, testing for aPL should not be limited to unprovoked VTE, but also to young patients with provoked VTE.

LA was always indicated to be a strong risk factor for thrombosis and should be further considered [40–43]. However, isolated LA (negative aCL and aβ2GPI) is due to antibodies different from aβ2GPI and directed toward the complex formed between phosphatidylserine and prothrombin (aPS/PT). Although the incidence of VTE in isolated LA is apparently lower [44], the role of isolated LA and aPS/PT antibodies as risk factors for VTE warrants further study. If single-test positivity or double-test positivity is confirmed positive after 12 weeks, further tests may be useful to improve the APS diagnosis and to assess the risk of recurrence [45]. The reliability and predictive value of single-test positivity for aCL and aβ2GPI is low [46] or absent [47]. Furthermore, isolated aCL antibodies are directed toward antigens different from β2GPI [48]; isolated aβ2GPI are directed towards epitopes of β2GPI different from the clinically relevant domain 1 [49] of β2GPI in different aPL antibody profiles. Alternative tests checking the presence of aPL are currently emerging in the literature [50], namely IgG anti-domain 1 (aDm1) and IgG anti-domain 4/5 (aDm4/5) of β2GPI plus IgG and IgM aPS/PT. These new tools could help to refine the risk of further thromboembolic events in aPL-positive patients.

In case aPL turns negative during the follow-up period, the decision to suspend oral anticoagulant treatment may be considered in provoked VTE. Disappearance of aPL may occur in patients treated with the anti-malarial drug hydroxychloroquine [51]. However, the risk of a new thrombotic event in APS patients who stopped their anticoagulation is high, even in those who showed a long-lasting disappearance of aPL antibodies [52]. This observation could be linked in part to fluctuating aPL, reappearing after transient negativity [53].

Development of new test systems is important to consider for stratification of solid phase antibody tests (low, medium, high). An ISTH report gives indications to correspondences between classic and new-generation tests [54]. Functional tests based on thrombin generation analysis may also improve laboratory risk stratification, but their current availability is limited [50, 55].

Management of provoked thrombosis in APS

When is it possible to stop anticoagulant treatment?

Overall assessment

Management of provoked thrombosis in the context of aPL/APS should be based on a careful evaluation of patient history and significance of risk factors in this particular population. Patients with APS are young (mean age at symptoms onset 34 years in the Euro-Phospholipid cohort). Almost 50% of patients have an associated systemic autoimmune disease [18, 19]. Therefore, analysis of risk factors should be adapted to the characteristics of this patient population. Treatment decisions should be made with a complete overview of clinical and laboratory data and patient preferences.

VTE

Long-term anticoagulant treatment is generally indicated in APS patients after an episode of VTE. This decision is reinforced if VTE was unprovoked in patients with multiple aPL positivity or high titres if the event was PE and in case of associated inherited thrombophilia, in particular in SLE patients [23, 56] or active autoimmune disease (e.g. SLE).

The appropriate anticoagulation duration after provoked aPL-associated VTE is undetermined. In a few cases, the decision to suspend oral anticoagulant treatment after 3–6 months may be considered and, in particular, when VTE was a consequence of a strong risk factor (i.e. major surgery) in patients with an incomplete aPL profile or if the aPL disappeared during the follow-up period.

In the case of VTE after major surgery, therapy should be continued at least for a duration recommended for patients without APS according to the EULAR guidelines [56].

In case of provoked VTE by ‘mild’ (minor) risk factors (e.g. the contraceptive pill), the decision should take into consideration the APS clinical profile, aPL profile, the type of pill used (third-generation drugs confer a higher risk), presence of an underlying disease and patient’s preferences. Longer anticoagulation could be maintained in patients with a high-risk clinical or aPL profile in repeated measurements or in the presence of other risk factors for recurrence.

In summary, in provoked VTE, doctors should make the decision to suspend oral anticoagulant treatment with caution. If shared decision making with the patient is to discontinue anticoagulant treatment, then the prescription of an antiplatelet therapy (i.e. aspirin) is indicated for overall management of APS, in particular prevention of arterial manifestations, notably in the context of SLE [57, 58]. A watchful program including follow-up evaluations, patient education and adequate pharmacological and non-pharmacological prophylaxis in situations at risk (in particular, pregnancy) must be implemented.

‘Provoked’ arterial thrombosis duration of treatment after stroke (secondary prevention)

In patients with arterial thrombosis and APS, the approach is different from VTE and anticoagulants will be continued in most cases, together with management of the risk factors.

The optimal management for stroke prevention in APS patients remains uncertain. Long-term anticoagulation therapy is indicated for people who fulfil the Sydney–Sapporo criteria for APS [56].

In a minority of APS patients, recurrent thromboembolic phenomena occur despite long-term anticoagulation therapy with values in the recommended range (i.e. INR 2–3). In these cases, the addition of an antiplatelet agent to warfarin or anticoagulation with an INR >3 should be considered after the resolution of acute episodes according to guidelines [56].

Recent EULAR guidelines [56] recommend the use of vitamin K antagonists (VKAs) over low-dose aspirin (LDA) as a first-line treatment in patients with arterial thrombosis. In patients with definite APS and a first arterial thrombosis, treatment with VKA with INR 2–3 or INR 3–4 is recommended, considering the patient’s risk of bleeding and recurrent thrombosis. Treatment with VKA with INR 2–3 plus LDA may also be considered. If a patient has recurrent arterial thrombosis despite adequate treatment with VKA, after evaluating for other potential causes, an increase of the INR target to 3–4, addition of LDA or a switch to low molecular weight heparin (LMWH) can be considered according to these guidelines [56].

It has been debated if, for APS patients who have a high-risk aPL profile (i.e. patients with multiple positive antibodies), the high intensity of anticoagulation could be an alternative option in the prevention of recurrent arterial thrombosis [59]. This approach is still considered controversial, although it is difficult to maintain the INR in the correct range (range 3–4), with the risk of increasing major bleeding. Standard intensity of oral anticoagulant treatment (INR 2.0–3.0) was shown to be superior to high-intensity anticoagulation (INR 3.0–4.5) in two randomized controlled trials [60, 61], although these studies did not include the most severe and highest-risk patients for relapse.

In summary (Fig. 1), in APS patients with provoked VTE, a limited duration of anticoagulants can be proposed in selected patients with major transient risk factors. This is in line with the new classification criteria for APS [62, 63] in which provoked events result in a lower score: some patients with a single provoked VTE and a low-risk antibody profile may not be classified as APS.

In APS patients experiencing arterial thromboses, if an additional cause or classical risk factors are present, remove the cause whenever possible and manage the modifiable classical risk factors and underlying conditions, preferably in a structured program. Risk factors should be treated to target: blood pressure, LDL-C (other lipid measures that affect the risk that are not yet considered as treatment targets are triglycerides and lipoprotein (a), but these may be in the near future), diabetes control, complete smoking cessation, weight-reducing regimens, Mediterranean-type nutrition, physical exercise (minimum of 150 min/week of moderate-intensity endurance exercise training should be combined with three weekly sessions of resistance exercise).

If the patient has a high-risk aPL profile (triple positive), continuing long-term treatment with warfarin maintaining an INR 2–3 is mandatory. In case of recurrence, add aspirin 100 mg/day. In other aPL profiles (double or single confirmed, persistent aPL positivity), treat on a case-by-case basis with warfarin, aspirin or both according to the titres and persistence of aPL antibodies after the evaluation of bleeding risk. For instance, in a patient with documented transient risk factors (withdrawal of oestrogen-containing contraception, quitting smoking), a low-risk antibody profile and a high bleeding risk (menorrhagia), without recurrence on aspirin, this treatment could be continued over shifting to anticoagulants.

In other cases, when anticoagulants are continued, the focus should be on management of modifiable risk factors to optimal targets, avoid additional risk factors (such as oral oestrogen-containing contraceptives) and treat to target associated autoimmune systemic diseases. Programmed warfarin interruption requires bridging with unfractionated or LMWH.

Clinical vignettes

The following clinical vignettes are fictional cases constructed specifically for this article.

Patient 1. A 30-year-old female patient was referred for therapeutic advice. She had a caesarean section for foetal malpresentation. Within 48 h she was diagnosed for intermediate- to high-risk pulmonary embolism and iliofemoral deep vein thrombosis. Laboratory workup revealed triple positivity (LA, aCL IgG 140 U/ml, aβ2GPI) IgG 100 U/ml confirmed after 12 weeks. She was treated with LMWH then VKAs. Follow-up echocardiography returned to normal after the acute phase and the patient had clinical signs of post-thrombotic syndrome and significant iliofemoral sequelae on duplex ultrasound. VKA treatment was well tolerated with INRs in the target range. A shared decision was made between the patient and consultant to continue VKAs over the long term.

Patient 2. A 40-year-old female patient with no previous history of thrombosis or obstetric morbidity had distal deep vein thrombosis (isolated thrombus of posterior tibial vein) after 4 weeks of plaster cast immobilization (she had stopped pharmacological prophylaxis after 1 week). After treatment of the acute phase (6 weeks), laboratory workup revealed single positivity of aCL IgG 40 U/ml, confirmed after 12 weeks, with low positivity of 21 U/ml. The patient was asymptomatic and duplex ultrasound did not show any residual thrombus. A shared decision between the patient and consultant was to stop treatment after the acute phase and continue clinical follow-up. The patient was advised to avoid any additional risk factors (e.g. combined contraceptives containing oestrogens) and informed about the situations for risk of VTE requiring pharmacological or non-pharmacological prevention.

These two clinical vignettes show that provoked VTE in the context of APS may have different clinical and laboratory presentations. Decisions shared by the patient and physician should be based on a careful analysis of the clinical event, clinical and laboratory risk factors, medical resources and the patient’s preferences.

Data availability

The authors confirm that the data supporting the findings of this study are available within the article and references.

Authors’ contributions

Denis Wahl and Vittorio Pengo conceived and designed the paper, performed the literature review, analyzed the data, wrote the paper and approved the final version.

Funding

This article received no specific grants from any funding agency in the public, commercial or not-for-profit sector.

Disclosure statement: The authors have no potential conflicts of interest related to this article.

References