Which treatments are the most effective in a patient with obstetric APS?

Recommendation: it is suggested that acetylsalicylic acid be administered prior to conception at a dose of 100mg/day in all patients with obstetric APS who wish to become pregnant, and that this dose be maintained throughout pregnancy (Grade C recommendation).

Recommendation: in patients with obstetric APS it is recommended that low molecular weight heparin (LMWH) be added to acetylsalicylic acid as a secondary prophylactic treatment at the moment pregnancy is confirmed, and this should be maintained throughout the pregnancy. The dose of heparin should be individualised depending on the risk level of each patient (Grade C recommendation).

Only a small percentage of patients with obstetric APS have a good prognosis for pregnancy if they do not take appropriate prophylactic medical treatment during gestation.1 Complications in pregnancy include repeated abortions, foetal death, preeclampsia and premature birth, among others. These are caused by several mechanisms, including placental dysfunction and placental thrombosis and infarct. Due to this the treatment of APS during pregnancy has traditionally been based on attenuating the prothrombotic state of these patients.

Different preventive treatments have been used in recent years. These include ASA, unfractionated heparin, LMWH, prednisone and other glucocorticoids and intravenous immunoglobulin (IVIG), as the sole treatment or combined, with the intention of improving the gestational prognosis. It is therefore relevant to evaluate the efficacy of these drugs to see which treatment is the best for administration to these patients.

In patients with obstetric APS who suffer a new obstetric complication in spite of conventional treatment, what should the therapeutic attitude be?

Recommendation: in refractory obstetric APS it is recommended to add starting hydrochloroquine before pregnancy to the conventional treatment and maintain this throughout gestation, alone or in combination with prednisone or equivalent until the start of pregnancy (≤10mg/day during the first quarter) (Grade D recommendation).

Recommendation: in patients who develop complications associated with placental insufficiency (preeclampsia or delayed intrauterine growth) in spite of conventional treatment, it is recommended that pravastatin be added (20mg/day) from the start of the complication (Grade C recommendation).

Recommendation: the use of IVIG and plasmapheresis is not recommended from the first, although this may be considered in the absence of a response to other treatments (Grade √ recommendation).

The conventional treatment of obstetric APS is the combination of aspirin at an antiaggregant dose and LMWH at a prophylactic dose.5 However, from 20% to 30% of these patients do not achieve the final objective of a live birth.16 The main risk factors associated with failure of conventional treatment are associated with the previous obstetric history and the antibody profile, especially triple positivity for APA.17–19 The identification of these risk factors and better knowledge of the mechanisms of action of LMWH and the use of new drugs have made it possible to design new therapeutic strategies for refractory obstetric APS.20

As well as its antithrombotic effect heparin has a broad range of anti-inflammatory and immunomodulating properties.21 The current attitude of the majority of experts is to use aspirin and heparin at prophylactic doses during the whole pregnancy. When heparin starts to be administered may be decisive for its efficacy, and it should be administered in the first stages of gestation. In patients with obstetric APS it has been observed that better results are obtained by gradually adjusting the prophylactic dose of heparin for patient weight throughout pregnancy better results are obtained compared with maintaining a single dose.22 Nevertheless, in refractory obstetric APS, the results of studies that evaluated the modification of the dose of heparin during pregnancy have not been conclusive.23,24

Hydrochloroquine (HCQ) is commonly used in autoimmune diseases, especially in systemic lupus erythematosus (SLE), where it is recommended during pregnancy.25 Although there is little information on obstetric APS and what there is consists of retrospective studies, its anti-inflammatory, immunoregulating and antiaggregant properties make HCQ a good therapeutic option.26 Moreover, in vitro as well as in several animal models HCQ is able to correct several of the biological functions which are altered by APA.27–30 Several retrospective studies show the efficacy of HCQ in combination with conventional therapy, in patients with obstetric APS as well as in those with refractory obstetric APS.18,26,31–36 A recent retrospective study has therefore shown that use of HCQ at a dose of 400mg, especially when commenced prior to conception, is useful in patients with refractory APS who have suffered no previous thrombotic episodes.36

The glucocorticoids inhibit the complement pathway and reduce the number of NK cells, so that it has been suggested to have a possible beneficial effect in patients with recurrent abortions. In an open study with a limited number of patients, prednisone at a dose of 10mg/day during the first three months of pregnancy significantly increased the rate of live births without increasing side effects in patients with refractory obstetric APS.37 In a recent retrospective multicentre study18 that included 49 patients with refractory obstetric APS, the combination of glucocorticoids or HCQ with conventional treatment was also associated with a significant increase in the number of life births. The beneficial effect of treatment with glucocorticoids was maintained in the multivariable analysis.18

IVIG have been used in obstetric APS with contradictory results. Some studies find no significant differences between patients treated solely with IVIG or in combination with conventional treatment when they are compared with those who only receive the latter.10,38 Other authors have mentioned positive results.39 In spite of the heterogeneous results, IVIG will be reserved for use with selected cases of patients with refractory obstetric APS. At the current time there is no agreement on the duration, frequency or optimum dose of IVIG.40

In cases of obstetric APS with high risk factors such as previous thrombosis, severe complications during pregnancy and lack of response to conventional treatment, together with triple APA positivity, different apheresis procedures have been used, such as plasmapheresis or immunoadsorption.41,42 In a recent study25 14 pregnant patients with high risk APS received conventional treatment with added weekly apheresis and IVIG, giving a 94% success rate. These preliminary results were confirmed recently by a retrospective study that included a higher number of patients with refractory obstetric APS.36

APS is one of the main risk factors for the development of preeclampsia which is, in turn, one of the main maternal complications during pregnancy. On the other hand, prematurity and delayed intrauterine growth are the 2 main foetal complications.43 A recent open prospective study44 described the beneficial effect of associating a 20mg/day dose of pravastatin with conventional treatment in patients with APS who developed preeclampsia or delayed intrauterine growth. In this study association with pravastatin from the start of the said complications improved the figures of arterial blood pressure, increased placental flow and, most importantly, obtained a 100% rate of live births.

How long should thrombotic prophylaxis last postpartum in patients with antiphospholipid syndrome?

Recommendation: in previously anticoagulated patients with thrombotic APS vitamin K antagonists should be reintroduced immediately postpartum (Grade √ recommendation).

Recommendation: in women with obstetric APS thromboprophylaxis is recommended after birth with low molecular weight heparin at a prophylactic dose during at least 6 weeks (Grade √ recommendation).

Recommendation: in patients with thrombotic APS who for some reason are not receiving long-term anticoagulation, thromboprophylaxis with low molecular weight heparin is recommended at intermediate doses and individualising depending on risk, during at least 6–12 weeks after birth (Grade D recommendation).

Although experts have made different recommendations for the prevention of obstetric complications, there is no agreement. In the general population venous thromboembolic disease occurs in 0.5–2.2 per 1000 pregnancies (a risk 15–35 times greater than it is in women who are not pregnant) and it may appear during gestation or the puerperium. Although the absolute number is low, it is still one of the first causes of morbimortality during pregnancy and the puerperium. During the postpartum period the risk of thrombosis is higher in the first 3–6 weeks, although it may persist until week 12.45,46

There is very little evidence on this point. The recommendations published in clinical practice guides on the presence of acquired thrombophilia and APA are inconsistent, as they are based on observational studies and on extrapolation from studies of non-pregnant women. A systematic review by Bain et al. also concluded that they found no sufficiently high quality studies to establish recommendation on the postnatal management of thromboembolic disease.45–51

Taking this lack of evidence into account, different scientific societies and groups of experts have made the following recommendations47–50:

• •

  In women with APS (APA+previous venous thromboembolism and not receiving indefinite anticoagulation) 6 weeks at intermediate or high doses of LMWH are recommended, or switching to a vitamin K antagonist (VKA) (The American Congress of Obstetricians and Gynecologists, ACOG; Societat Catalana d’Obstetrícia i Ginecologia, SCOG; Royal College of Obstetricians and Gynaecologists, RCOG and the American College of Clinical Pharmacy, ACCP).

• •

  In women with thrombotic APS who have previously been anticoagulated, the recommendation is to switch to a therapeutic dose of LMWH during pregnancy and, after birth, to recommence VKA as soon as possible (ACOG, SOGC, RCOG and ACCP).

• •

  Regarding post-Caesarean prevention, they recommend thromboprophylaxis during at least 6 weeks if there is a history of thrombosis, preeclampsia with delayed intrauterine growth, comorbidities such as SLE or known thrombophilia (ACCP).

• •

  As the results of the different studies which were identified are not consistent, the efficacy of the intervention has not been proven by randomised clinical trials, so that it is based on expert recommendations, and in the majority of scenarios they prefer to use thromboprophylaxis during at least 6 weeks.

• •

  Although this subject is controversial, given its clinical importance and in spite of the fact that there are no good quality clinical trials or studies, all of the guides recommend thromboprophylaxis.52–54 Additionally, the opinion of the patient must always be taken into account. The group of panellists considers that, given the high thrombotic risk of women with thrombotic APS or obstetric APS during the puerperium, thromboprophylaxis at a prophylactic or intermediate dose should be administered from 6 to 12 during the postpartum period (Tables 2 and 3).

  Table 2.

  Prophylactic doses of low molecular weight heparin.

  Weight (kg)	Enoxaparin (Clexane©), mg/day	Bemiparin (Hibor©), U/day	Tinzaparin (Innhoep©), U/day
  <50	20	2500	3500
  50–90	40	3500	4500
  91–130	60		7000
  131–170	80		9000
  >170	0.6mg/kg/day		75U/kg/day
  High prophylaxis	40mg/12h		4500U/12h
  Table 3.

  Intermediate doses of low molecular weight heparin.

  Drug	Dosea
  Bemiparin (Hibor©)	5000U/d sc (75UI/d sc approx.)
  Enoxaparin (Clexane©)	1mg/kg/day
  Tinzaparin (Innohep©)	8000UI/d sc

  a

  Estimated and not specified in the technical data sheet.

What should the therapeutic attitude be for women with antiphospholipid syndrome during assisted reproduction techniques?

Recommendation: in patients with APS who are going to perform assisted reproduction techniques it is recommended that risk be individualised by associating prophylactic or therapeutic doses of LMWH as the anticoagulant (Grade D recommendation).

Recommendation: patients with APS and oral anticoagulation will switch to low molecular weight heparin at a therapeutic dose before ovary stimulation, and they will continue to take it throughout pregnancy (Grade D recommendation).

Recommendation: the recommendation for patients with APS who are not taking chronic anticoagulation is treatment with an antiaggregant dose of acetylsalicylic acid and low molecular weight heparin at an individualised dose from the start of ovary stimulation, maintaining this treatment throughout gestation (Grade D recommendation).

Recommendation: in women with antiphospholipid antibodies and triple positivity or high levels of APA, due to the risk of thrombosis as well as the appearance of obstetric complications it is recommended to use low molecular weight heparin plus acetylsalicylic acid (Grade D recommendation).

Recommendation: the recommendation is to avoid ovary hyperstimulation syndrome, which is a risk factor for secondary thrombosis during assisted reproduction techniques, by using low risk hormonal protocols for this complication (Grade D recommendation).

The increase in the concentrations of oestrogens in serum during ovary stimulation or the induction of ovulation when using ART leads to changes in coagulation that induce a state of hypercoagulability. Due to these changes the risk of thrombosis during ART increases slightly in the general population, although the risk is higher in patients with congenital or acquired thrombophilia.55 There is scientific evidence for the safety and efficacy of ART in patients with APS, on condition that suitable antithrombotic treatment is administered.56–60 Although it is complicated to set fixed recommendations for the most suitable antithrombotic treatment during ART in patients with APS, current scientific evidence makes it possible to establish antithrombotic recommendations which must be individualised.

There are too few studies to make it possible to know the prevalence of thrombosis with a high methodological quality. This is also the case for the importance of preventive treatment for thrombosis during ART in patients with APS or who are carriers of APA.56 The only finding here consisted of some series of cases57–60 (LoE 3). Current recommendations are based on the results of these studies and the recommendations in the clinical practice guides published by different scientific societies26,49,61 (LoE 3 and 4). Thus in general the advice is to offer the same treatment as is given to pregnant patients, as prophylaxis for thrombosis and obstetric complications26,49,61–63 (LoE 3 and 4). Nor are the duration and dose of thromboprophylaxis during and after ART well known, although they are similar to those used after other surgical procedures with a low risk of bleeding64,65 (LoE 4). Regarding anticoagulant treatment during follicular puncture, the experts conclude that LMWH should be suspended during at least 12h before performing this procedure, restarting administration 6–12h after puncture, to reduce the risk of bleeding56–60 (LoE 4).

As the different clinical practice guides published recently all agree and recommend the same thromboprophylactic treatment, the preparatory group for this document recognises that these recommendations are directly applicable to our health system and may be extrapolated to all ART. Thus although there is little scientific evidence, and in spite of the risk of haemorrhage, antithrombotic treatment is recommended for patients with APS or who are APA carriers who are going to undergo ART. Nevertheless, it is not recommended that APA be determined for all of the patients who are going to undergo ART.56

In patients with obstetric antiphospholipid syndrome without thrombotic manifestations, should they be monitored outside the period of pregnancy?

Recommendation: in patients with isolated obstetric APS monitoring is recommended after pregnancy and the puerperium, as they have a higher risk of thrombosis than the general population (Grade C recommendation).

Recommendation: in the said monitoring it is recommended that cardiovascular risk be individualised (identifying the presence of arterial hypertension, diabetes mellitus, a sedentary lifestyle, obesity, smoking and dyslipidemia, etc.) and informing about, eliminating or controlling existing cardiovascular risk factors (Grade B recommendation).

Recommendation: during monitoring it is prudent to individualise advice on the use of acetylsalicylic acid at low doses as a primary antithrombotic prophylaxis. There is no conclusive proof that this should only be administered to patients with the highest thrombotic risk (those who are positive for lupus anticoagulant or patients with triple antibody positivity) (Grade B recommendation).

Recommendation: the use of subcutaneous low molecular weight heparin is recommended in situations with a high risk of venous thrombosis (Grade √ recommendation).

There is clear scientific evidence on what should be done in the case of patients with thrombotic APS (thrombosis as the sole manifestation of APS or accompanied by a history of obstetric complications). However, there are still few studies which evaluate what should be done over the long-term in patients with purely obstetric APS but without a history of previous thrombosis. It is necessary to know the thrombotic risk of these patients and evaluate and individualise the use of antithrombotic prophylaxis.

Different prospective and retrospective cohort studies and series of cases43,66–71 show an increase in thrombotic risk during the long-term follow-up of patients with a history of obstetric APS without previous thrombosis (LoE 4). The majority of these studies either fail to supply sufficient data on the use of low-dose ASA or prescribe this treatment for all of their patients, so they do not help to elucidate the protective role of this as a primary antithrombotic prophylaxis. There are 2 retrospective case–control studies54,72 that include patients with APS and repeated abortions or gestational losses, and these too show an increased thrombotic risk in this subgroup of patients with obstetric APS (LoE 3b). All of the studies conclude that it is necessary to perform follow-up and inform these patients about thrombotic risk and the importance of controlling associated cardiovascular risk factors.

The primary long-term prevention of thrombosis by using low-dose ASA in all patients with isolated obstetric APS is controversial. There are no randomised studies that would show the benefit of treatment using low-dose ASA in all such patients, and nor are there any studies that classify and individualise thrombotic risk in these patients. The current recommendation for treatment is based on the results of a recent meta-analysis that evaluated APA carrier patients without previous thrombosis, sub-analysing the group of patients with isolated obstetric APS.73 This study showed a protective effect of low-dose ASA in patients with isolated obstetric APS, in asymptomatic patients who are APA carriers and in patients with SLE (LoE 3). As a result, the authors conclude that during follow-up patients should be advised to use low-dose ASA as a primary antithrombotic prophylaxis if they have isolated obstetric APS. Nevertheless, individualised analysis of these patients depending on their cardiovascular risk, APA positivity profile and treatment with HCQ, published at a later date by the same group, found no protective effect in patients with isolated obstetric APS74 (LoE 3). According to the authors this lack of a relationship was probably due to the limited number of patients with isolated obstetric APS in this last meta-analysis. Because of all these reasons, and due to the risk of haemorrhage during treatment with low-dose ASA, the benefit of administering low-dose ASA to all obstetric APS patients without a history of thrombosis is not clear. The conclusion is that it should be administered to selected high-risk patients, as is the case for healthy carriers of APA and, during follow-up, to individualise the thrombotic risk and detect and treat associated cardiovascular risk factors in these patients and inform them about their risk of thrombosis, as well as using prophylactic LMWH in situations at high risk of thrombosis75–78 (LoE 4).

The results of the different studies which were identified are consistent, as all of them describe an increased thrombotic risk in this population subgroup and emphasise the need to grade thrombotic risk (according to their antibody profile, associated cardiovascular risk factors or the presence of other autoimmune diseases) while detecting and controlling cardiovascular risk factors. All of these studies indicate the need to administer low-dose ASA in selected patients with greater thrombotic risk, while they do not make a clear case for the benefit of administering the said treatment to all patients without individualising their risk.

Given that there are a noteworthy number of patients with isolated obstetric APS, and because the different studies, in spite of their limitations, show an increased risk of thrombosis in this population subgroup, the preparatory group considers that these patients should be monitored and assessed. Monitoring, controlling cardiovascular risk factors and the primary prevention of thrombosis using low-dose ASA, at least in the patient subgroup with high thrombotic risk, have a clear benefit in comparison with not applying any of these interventions.

In patients with antiphospholipid syndrome who require a solid organ transplant, what should the therapeutic attitude be?

Recommendation: rigorous anticoagulation control is recommended before and after a solid organ transplant, especially a kidney transplant (Grade √ recommendation).

Recommendation: routine screening for antiphospholipid antibodies before a solid organ transplant in all patients with a history of thromboembolic events (Grade √ recommendation).

The origin of thrombosis in patients who require a solid organ transplant is multifactorial regardless of the location of the transplant. The surgery itself, the disease which gave rise to the need for transplant and the prolonged immobilisation which both situations involve are risk factors for thrombosis. Most especially, terminal kidney failure, dialysis and permanent vascular access are risk factors for thrombosis. This is always so for kidney transplant, but it is also the case in the transplant of other solid organs. Moreover, patients with APS or APA who require transplant have the additional risk of losing the graft due to systemic thrombosis, graft thrombosis or thrombosis of the vascular anastomosis.79–84 The risk is higher in patients with APS and kidney transplant,85–95 although there are no meta-analyses or studies with controls. Four retrospective studies of a total of 2918 kidney transplants agree that the detection of APA at the moment of transplant is associated with a greater number of complications and more losses of the graft in patients with SLE as well as in patients with other diseases.86,87,90,92 In a retrospective study of 178 kidney transplants without SLE, Ducloux et al.87 found post-transplant venous thrombosis in 18% of the patients with APA and in 6.2% of the patients without the said antibodies, respectively (P<.001). Post-transplant arterial thrombosis is also more common in patients with APA (8 vs. 2.3%, respectively; P<.001). In 85 patients with SLE, Stone et al.92 found manifestations of APS in 15 of 25 kidney transplant patients with APA and in 5 of 60 kidney transplants without these antibodies (P<.0001).

Four prospective studies of a total of 2215 kidney transplants found more complications in patients with APS or APA.88,89,94,95 The data are contradictory respecting the evolution of transplanted kidneys. Wagenknecht et al.95 find more APA in the group with loss of graft than they do in the group with a functioning transplant (57% vs. 35%; P=.02). Forman et al.89 do no link anticardiolipin antibodies with graft loss. Fernandez-Fresnedo et al.,88 in a prospective study of 197 kidney transplants, do not associate the detection of APA prior to transplant (27%) with a higher risk of post-transplant complications. Nevertheless, 15.7% of the patients with APA de novo after transplant did show a significant rise in graft rejection.

Nor are there any meta-analyses or studies with controls in the case of liver and heart transplants which evaluate the risk of complications in patients with APS or APA. A retrospective study of 35 liver transplant patients83 finds anticardiolipin antibodies in all 7 patients with hepatic artery thrombosis and in 15 of the 28 transplants without thrombosis (53.5%), although other studies do not confirm these findings. Two prospective studies that include 45 pacientes96,97 and 2 retrospective studies with 299 patients98,99 did not find increased risk of thrombosis after liver transplant.

In spite of the risk of bleeding,100,101 the experts agree in recommending rigorous control of anticoagulation before and after transplant.94,100 Although it is true that the preference is to use LMWH or unfractionated heparin due to its shorter half life,102 the results are similar with oral anticoagulants.93

Lastly, given the increased risk of thrombosis and that sudden thrombosis intra- or post-transplant may be the first sign of catastrophic or undiagnosed APS,81,103 some experts recommend the routine screening of all patients prior to kidney transplant.91 Others only recommend this in patients with a history of arterial or venous thrombosis.86,101

In patients with antiphospholipid antibodies and neoplasias, what should the therapeutic attitude be?

Recommendation: thromboprophylaxis with low molecular weight heparin is recommended in patients with a high risk serological profile and neoplasias, especially in situations that increase thromboembolic risk (surgery, catheter implant, the start of chemotherapy) (Grade √ recommendation).

Patients with solid or haematological tumours have a higher prevalence of APA than the controls.104,105 Evaluation of whether there is a higher incidence of thromboembolic manifestations in these patients gives contradictory results. Some studies find an increase of thrombosis in patients with APA106 while others do not find this association.107,108

The highest incidence of thrombosis has been described in solid tumours and in association with APA isotypes IgG or IgA109,110 and antibodies against domain I of aβ2GPI.111 Although the presence of APA may contribute to increased risk of thrombosis in patients with malignity,112 it does not seem clear that APA levels contribute to the mechanism causing thrombosis in these patients. On the contrary, although certain neoplasias such as haematological or lymphoproliferative ones may affect the production of APA, as IgM isotypes predominate there is no greater risk of thrombosis.108 Levels of APA are also known to possibly fall and even to disappear after the commencement of chemotherapy.113 Thus the experts agree that thromboprophylaxis with LMWH is important for these patients, above all in situations of thromboembolic risk (prolonged immobilisation, surgery or catheter implant). Some studies conclude that commencing certain chemotherapy treatments increases the risk of causing thrombosis.114,115 Based on this, the experts understand that it would be recommendable to use primary thromboprophylaxis, and that in the patients where APA levels have fallen or disappeared anticoagulation could be replaced by antiaggregation.

Following up healthy individuals with APA showed an increase in the incidence of lymphoproliferative tumours, and more specifically non-Hodgkin's lymphoma, in comparison with the general population. The authors concluded that the presence of APA may be a risk factor for haematological neoplasias, and that this should be taken into account in the initial evaluation of older patients, those with high titres of APA and the presence of thrombosis with no known cause.116 Other studies find haematological neoplasias in 26% of patients with APA,113 with a risk 2.6 times higher of suffering this type of neoplasia.117 Neoplasia is also one of the main causes of death in these patients.43 A retrospective study compared patients with a solid neoplasia and APA with or without thromboembolic manifestations with a control group. They found 8% of APA in the patients with thrombosis vs. 1.4% in those without thrombosis; only 4 patients remained APA positive; in the patients with thrombosis and APA there were no differences in their demographic characteristics, clinical pattern or the prognosis when they were compared with the patients with thrombosis and without APA. Given these results and together with the low titre and transitory nature of the APA, the authors concluded that APA plays no pathogenic role in thrombosis in patients with solid cancer and thrombosis.118

If it is necessary to temporarily suspend anticoagulation in patients with the antiphospholipid syndrome, what should be the therapeutic attitude?

Recommendation: the recommendation is to suspend anticoagulation in the case of invasive procedures with moderate or high risk of haemorrhage, and to perform bridging therapy (Grade D recommendation).

Recommendation: for bridging therapy the recommendation is to use individualised doses of low molecular weight heparin adjusted for weight and kidney function, suspending it at least 24h prior to the invasive procedure (Grade D recommendation).

Recommendation: In pregnant patients with APS who use low molecular weight heparin at therapeutic or intermediate doses, the recommendation is to suspend this at least 24h before birth or other procedures. During birth it is not necessary to suspend treatment in patients who use acetylsalicylic acid at a dose of 100mg (Grade D recommendation).

There is little evidence regarding how to suspend anticoagulation in patients with APS or the presence of APA. Taking into account that 10% of anticoagulated patients (with or without APS) will receive surgery in one year, the perioperative management of these patients, who may be at high risk of thrombosis, is vitally important.119

The BRIDGE study, which only included anticoagulated patients with arrhythmia, found no significant differences in thrombotic risk between patients who had received bridging therapy and those who had not. Nevertheless, an increase in the risk of haemorrhage was detected compared with the patients who had not received bridging therapy in terms of total bleeding (13.1% vs. 3.4%), as well as major bleeding (4.2% vs. 0.9%).119 Different meta-analyses have shown similar findings.120,121

Other clinical trials included highly heterogeneous patients or insufficient sample sizes of patients with APS,120–122 hindering the establishment of recommendations. Thus the recommendations found in the literature are chiefly based on ACCP guides (2012), which distinguish depending on the thrombotic risk of the patient and the risk of haemorrhage during surgery or the procedure.119,123

Subsequently, extrapolating from BRIDGE study data, groups of experts have drawn up new recommendations for patients at low or intermediate risk of thrombosis, such as the presence of acquired thrombophilia.124 These recommendations conclude: (1) in patients with APS (high thrombotic risk or recent venous thrombosis <3 months) 2 situations may arise: (a) if the risk of haemorrhage is moderate or high, VKA must be suspended at least 3 or 4 days beforehand, starting with heparin at intermediate doses and recommencing anticoagulation as soon as possible with intermediate or therapeutic doses of LMWH if the patient is not at risk of bleeding; (b) if there is a low risk of haemorrhage, VKA should not be suspended. (2) If the patient has an intermediate risk of thrombosis (such as the presence of APA or venous thrombosis in the previous 3 months), if the risk of haemorrhage is moderate or high, VKA should be suspended at least 3 or 4 days beforehand, starting with LMWH at a prophylactic dose and maintaining this until it is possible to restart VKA, overlapping both treatments during at least 4 days; if the risk of haemorrhage is low, the recommendation is not to suspend VKA.

Respecting direct action oral anticoagulants (DOAC), the recommendations are based on international records or pivotal studies. In general the experts do not recommend using LMWH after suspending direct action oral anticoagulation for at least 72h, 48h or 24h before the procedure (basing the decision to suspend it earlier on the renal function of the patient). If the duration of the postoperative state or the situation of the patient makes it impossible to recommence treatment with the said anticoagulant, the recommendation is to commence with LMWH at a prophylactic dose and maintain this, depending on patient evolution.124,125

For pregnant women with obstetric APS international groups of experts recommend using LMWH at therapeutic or intermediate doses, suspending the treatment at least 24h prior to the procedure. If they are taking ASA, the therapy may be maintained and LMWH will recommence at a suitable dose in less than 24–48h.123

The group of panellists considers that the results of the BRIDGE trial and the meta-analyses are consistent respecting the high risk of haemorrhage in bridging therapy in general, and that in low-risk cases the recommendation is not to use LMWH; however, there is little evidence for patients at high risk of thrombosis, such as patients with APS. Due to this, the group of panellists has taken into account the recommendations of other groups of experts and has decided to recommend, in patients with APS, a bridging therapy that balances the benefit/risk of thrombosis, while minimising the risk of bleeding due to surgery.

Moreover, as there is a high risk of recurrence while anticoagulation is suspended in many patients with APS, the group of panellists considers that in these patients the risk of haemorrhage due to surgery should be evaluated, establishing bridging therapies which are adapted to the risk in a personalised way.

In a patient with catastrophic antiphospholipid syndrome, what should the therapeutic attitude be?

Recommendation: in a patient with catastrophic APS the initial treatment should include what is known as triple therapy, which consists of anticoagulation, preferably with intravenous unfractionated heparin, associated with high doses of glucocorticoid, plasmapheresis or intravenous immunoglobulin (Grade D recommendation).

Recommendation: in cases that are refractory to triple therapy associating rituximab or eculizumab may be considered (Grade D recommendation).

As the prevalence of catastrophic APS is very low (<1% of all APS cases), all of the most relevant available information about this rare but severe situation originates in the data of the international registry of catastrophic APS which, according to updated figures, contains the information corresponding to approximately 500 patients.126

Although the mortality of catastrophic APS has fallen in recent years, it is still very high (it currently stands at 63%).127 The improvement in the prognosis for catastrophic APS may be due to factors such as earlier identification, the correction and treatment of causal factors (such as infection) and, as a result of all of these factors, earlier commencement of the treatment.128

Diagnosis of catastrophic APS is based on classification criteria that were updated in 2005129 (see Table 2 in part I). As it is a rare entity the experts agree in suspecting catastrophic APS above all in patients where thrombosis rapidly appears in several organs, together with the presence of APA. Studies emphasise that ruling out other diseases is of key importance in differential diagnosis. These fundamentally affect microcirculation, and they include microangiopathic haemolytic anaemia or thrombotic thrombopenic purpura130 as well as eclampsia, preeclampsia or the HELLP syndrome (hemolysis, elevated liver enzymes and low platelet count) in pregnant patients.131 Lastly, and due to the fact that in 2/3 of patients with catastrophic APS there is a precipitating factor, the importance of identifying these factors is emphasised, as if they are treated or corrected this may improve the evolution of catastrophic APS.127 These factors most especially include infections (47%), cancer (18%), surgery (17%), subtherapeutic anticoagulation (11%), oral contraceptives (7%) and pregnancy.129,131

The evidence found on the treatment of catastrophic APS is restricted to studies of series of cases and expert consensus.

Anticoagulation is considered to be the fundamental treatment for catastrophic APS. The evidence for this originates in the analysis of 280 patients with catastrophic APS, of which 244 received some type of anticoagulation vs. 36 patients who did not. Survival was significantly better in the anticoagulated patients (63% vs. 22%; P<.0001).129 Although there are no studies which determine the specific type of anticoagulation, the authors conclude that unfractionated heparin should be used, above all because its effect is reversible and the preference for intravenous administration in the most critical patients.128

There are no prospective studies or any clearly significant data on the use of glucocorticoids in catastrophic APS. The majority of experts recommend using them to reduce the extremely intense inflammatory response which occurs in catastrophic APS.128 In the majority of the cases described in the literature a combination of anticoagulation and glucocorticoids was used.126,128 No significant differences were found when the impact of glucocorticoids on the prognosis for catastrophic APS was analysed specifically.132 Nevertheless, a large number of the patients included in the international register of catastrophic APS and in the published isolated cases were treated using this combination. The groups of experts therefore recommend always using high intravenous bolus doses of glucocorticoids (500–1000mg/iv/3 days)together with anticoagulation, followed by oral glucocorticoids (1mg/kg).128 In the case of associated severe infection the use of more moderate doses of glucocorticoids should be considered.

Due to the beneficial role of plasmapheresis in patients with different types of thrombotic microangiopathy, as well as the accepted pathogenic mechanism of the APA,133 it has also been proposed as a potential treatment in combination with anticoagulation and glucocorticoids in patients with catastrophic APS.134 A study in which 18 patients were treated using triple therapy and 19 patients were only treated with anticoagulation and glucocorticoids, showed a higher survival rate (77.8% vs. 55.4%; P=.083) in those who received triple therapy.135

In connection with IVIG associated with anticoagulation and glucocorticoids, the studies show that the patients who received this combination had a higher survival rate than those who did not.128 However, in the majority of patients IVIG was used together with plasmapheresis, and this combination too showed a higher survival rate. Although there is no definitive standardised dose,131 0.4g/kg is used during 5 days.128 Some authors recommend administering IVIG after plasmapheresis; nevertheless, other experts administer it simultaneously with plasmapheresis, supplementing it the next day with 200mg/kg to compensate for the immunoglobulin that may have been withdrawn during plasmapheresis.

The last analysis of the international catastrophic APS registry (the CAPS registry)136 evaluated the relationship between triple therapy and mortality in these patients. The triple therapy was associated with greater survival in comparison with the group that had not received the same treatment (adjusted OR 7.7; CI 95%: 2.0–29.7) or other combinations of treatments included in triple therapy (adjusted OR 6.8; CI 95%: 1.7–26.9). Triple therapy gave rise to a reduction of 47.1% in mortality compared with the group that did not receive it, and a reduction of 34.4% in comparison with any other combination of treatments. The authors concluded that triple therapy is independently associated with a higher rate of survival in patients with catastrophic APS.136 The expert therapeutic attitude to catastrophic APS is therefore to use triple therapy: anticoagulation, glucocorticoids and plasma replacement or IVIG.

The review of the international catastrophic APS registry137 analysed patients who been treated using rituximab. 20 patients in treatment with rituximab were identified, and in 8 of them it was the first line of treatment, while in the others rituximab was administered as rescue therapy. 15 of the 20 patients were said to have a suitable response to rituximab.

Eculizumab is a humanised monoclonal antibody which inhibits the activation of fraction 5 of the complement. It is indicated in atypical uraemic-haemolytic syndrome and in the nocturnal paroxistic haemoglobinuria.138 As activation of the complement has been considered to be a key factor in animals models of APS,139 eculizumab has been used in severe isolated cases of catastrophic APS.140 Taking into account the fact that eculizumab has only been used in a very small number of patients with catastrophic APS, and until well-designed clinical trials appear, the authors conclude that eculizumab may be used in case of catastrophic APS that is refractory to triple therapy.139,140

Some authors recommend using cyclophosphamide in cases of catastrophic APS associated with SLE. A study compared the demographic and clinical characteristics and analytical results of 103 patients with SLE and catastrophic APS with those of 127 patients who only had primary catastrophic APS.141 In 47% of the SLE-APS patients who were given cyclophosphamide mortality fell significantly (odds ratio=0.20; 0.006–0.71; P=.013). The patients with catastrophic APS without associated SLE showed an increase in mortality (odds ratio=8.5; 1.91–37.83), although these patients were more severe and had a larger number of affected organs.

After the systematic review of existing scientific evidence for treating primary APS which was undertaken to prepare these recommendations, the panel of experts considers that many aspects should be included in the future research agenda. The following may be mentioned, among others:

Obstetric APS:

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  More randomised clinical trials are required, with good methodological quality, to study the efficacy of LMWH and ASA at low doses in the treatment of obstetric APS in its different variants, as well as the use of other treatments in isolation or combined.

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  There is a need to carry out well-designed long-term studies on the monitoring and individualised treatment of patients with obstetric APS after pregnancy.

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  Good quality studies are necessary on the need to administer antithrombotic prophylaxis to patients with APS who are going to be subjected to assisted reproduction techniques.

Refractory obstetric APS:

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  New tools or scores must be developed which make it possible to identify the patients with obstetric APS who are at high risk of recurrence.

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  It is necessary to design multicentre prospective studies that make it possible to determine the role of HCQ or prednisone in the treatment of refractory obstetric APS.

Recurrent APS:

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  Prospective multicentre studies are needed to make it possible to determine the role of HCQ in the prevention of thrombotic recurrence in high risk patients.

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  It is necessary to design prospective multicentre studies that make it possible to determine the role of rituximab in the prevention of thrombotic recurrence in high risk patients.

Catastrophic APS:

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  New tools or scores have to be developed to enable identification of those individuals with APS who are at high risk of developing catastrophic APS.

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  More prospective multicentre studies are needed which make it possible to determine the role of biological therapy in patients with catastrophic APS that is refractory to triple therapy.