Validation of the preliminary criteria for the classification of catastrophic antiphospholipid syndrome

OBJECTIVE: To describe the characteristics of patients with catastrophic antiphospholipid syndrome (APS) included in the International Registry of patients with this condition (CAPS registry) and to analyse the value of the recently proposed preliminary criteria for the classification of catastrophic APS. METHODS: A review of the first 220 patients included in the website based CAPS registry was undertaken and the preliminary criteria for their classification were tested; 175 unselected patients with systemic lupus erythematosus or APS, or both, acted as controls. RESULTS: The mean age of the patients was 38 (14) years (range 7 to 74), with a female preponderance (F/M, 153/67). The main clinical manifestations included renal involvement in 154 (70%), pulmonary in 146 (66%), cerebral in 133 (60%), cardiac in 115 (52%), and cutaneous in 104 (47%); 114 patients (52%) recovered after the catastrophic APS event (mortality 48%). Patients who received the combination of anticoagulation plus steroids plus plasma exchange or intravenous immunoglobulins had the best survival rate (63%, p = 0.09). Sufficient data could be analysed for application of the classification criteria in 176 patients. According to the preliminary criteria, 89 patients (51%) could be classified as having "definite" and 70 (40%) as having "probable" catastrophic APS, thus given a sensitivity of 90.3% with a specificity of 99.4%. Positive and negative predictive values were 99.4% and 91.1%, respectively. CONCLUSIONS: The preliminary criteria for the classification of catastrophic APS and the CAPS registry are useful tools for epidemiological studies.     

Validation of the Sapporo criteria for antiphospholipid syndrome

OBJECTIVE: To test the Sapporo criteria for the classification of the antiphospholipid syndrome (APS). METHODS: We classified 243 consecutive patients who had clinical diagnoses of primary APS (n = 49), secondary APS (n = 26), systemic lupus erythematosus (SLE) without clinical APS (n = 131), and lupus-like disease without clinical APS (n = 37). RESULTS: Sensitivity, specificity, positive predictive value, and negative predictive value were 0.71, 0.98, 0.95, and 0.88, respectively. False-negative findings were the result of patients being classified on the basis of minor criteria that were not included in the Sapporo criteria, such as livedo reticularis, thrombocytopenia, low-titer IgG or IgM anticardiolipin antibody, IgA anticardiolipin antibody, and anti-beta2-glycoprotein I antibody. Some patients with false-negative results were true seronegative cases. CONCLUSION: The Sapporo criteria for APS compare favorably with the American College of Rheumatology criteria for SLE and are usable for clinical studies.     

Thrombosis and Anti-phospholipid Syndrome: a 5-Year Update on Treatment

Purpose of Review

The aim of this review is to provide an update of the therapeutic tools for thrombotic anti-phospholipid syndrome (APS), focusing on the last 5 years.

Recent Findings

Early studies appointed anticoagulation at moderate intensity as the mainstay of treatment of thrombotic APS; in the last 5 years, the strategy has not much mutated. Some uncertainties regarding the role of direct oral anticoagulants and the optimal regimen for arterial thrombotic APS still persist: high-intensity anticoagulation, anticoagulation plus anti-platelet agent, and double anti-platelet agents being the possible alternatives. Several drugs have been proposed as effective additional tools for the management of thrombotic APS: hydroxychloroquine, statins, vitamin D, and sirolimus might be beneficial when added on the top of anticoagulation. Pregnant women with thrombotic APS should be switched to low-dose aspirin plus low molecular weight heparin at therapeutic dose. Despite adequate treatment, APS patients display a significant rate of recurrences; rituximab, eculizumab, and intravenous immunoglobulins are among the options to be considered for these patients.

Summary

From 2013 to date, the kaleidoscope of therapeutic options in thrombotic APS has been enriched, but tangible improvements in the management of patients are still awaited.

     

The Management of Stroke in Antiphospholipid Syndrome

Ischemic stroke is one of the most common complications of the antiphospholipid syndrome (APS). Because of the relative lack of definitive prospective studies, there is still some debate as to whether the persistent presence of antiphospholipid antibodies (aPLs) increases the risk of recurrent stroke. There is more evidence for aPLs as a risk factor for first stroke. The mechanisms of ischemic stroke are considered to be thrombotic and embolic. APS patients with thrombotic stroke frequently have other, often conventional vascular risk factors. Transesophageal echocardiogram is strongly recommended in APS patients with ischemic stroke because of the high yield of valvular abnormalities. The appropriate management of thrombosis in patients with APS is still controversial because of limited randomized clinical trial data. This review discusses the current evidence for antithrombotic therapy in patients who are aPL positive but do not fulfill criteria for APS, and in APS patients. Alternative and emerging therapies including low molecular weight heparin, new oral anticoagulants (including direct thrombin inhibitors), hydroxychloroquine, statins, and rituximab, are also addressed.     

Antiphospholipid syndrome associated with infections: clinical and microbiological characteristics of 100 patients

OBJECTIVE: To describe and analyse the clinical characteristics of 100 patients with antiphospholipid syndrome (APS) associated with infections. METHODS: Patients were identified by a computer assisted search (Medline) of published reports to locate all cases of APS published in English, Spanish, and French from 1983 to 2003. The bilateral Fisher exact test was used for statistics. RESULTS: 59 female and 41 male patients were identified (mean (SD) age, 32 (18) years (range 1 to 78)): 68 had primary APS, 27 had systemic lupus erythematosus, two had "lupus-like" syndrome, two had inflammatory bowel disease, and one had rheumatoid arthritis. APS presented as a catastrophic syndrome in 40% of cases. The main clinical manifestations of APS included: pulmonary involvement (39%), skin involvement (36%), and renal involvement (35%; nine with renal thrombotic microangiopathy, RTMA). The main associated infections and agents included skin infection (18%), HIV (17%), pneumonia (14%), hepatitis C (13%), and urinary tract infection (10%). Anticoagulation was used in 74%, steroids in 53%, intravenous immunoglobulins in 20%, cyclophosphamide in 12%, plasma exchange in 12%, and dialysis in 9.6%. Twenty three patients died following infections and thrombotic episodes (16 with catastrophic APS). Patients given steroids had a better prognosis (p = 0.024). The presence of RTMA and requirement for dialysis carried a worse prognosis (p = 0.001 and p = 0.035, respectively). CONCLUSIONS: Various different infections can be associated with thrombotic events in patients with APS, including the potentially lethal subset termed catastrophic APS. Aggressive treatment with anticoagulation, steroids, and appropriate antibiotic cover is necessary to improve the prognosis.     

Emerging Therapies in Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a hypercoagulable state characterized by arterial and venous thromboses and pregnancy morbidity in the presence of antiphospholipid antibodies. Although warfarin remains the main therapeutic choice in APS, there is still concern about its efficacy, safety, and patient compliance. Patients with refractory APS to conventional therapy as well as patients with non-classical manifestations of APS may have alternative treatment approaches. APS pathogenesis has been further elucidated over the past years identifying new molecules as potential new treatment targets. This review summarizes available data from in vitro and animal models and clinical studies on the role of new potential treatment approaches including new oral anticoagulants and immunoregulatory agents: direct thrombin or factor Xa inhibitors, hydroxychloroquine, statins, B cell inhibition, complement inhibition, peptide therapy, nuclear factor κB and p38 mitogen-activated kinase inhibitors, defibrotide, abciximab, mTOR inhibitor, and other potential targets. Large multicenter prospective studies of well-characterized APS patients are needed to assess the efficacy and safety profile of these potential treatment alternatives.     

Syndrome des antiphospholipides « séronégatif » : mythe ou réalité ?

The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and/or obstetrical manifestations and the persistent presence, at least 12 weeks apart, of antiphospholipid antibodies (aPL) such as lupus anticoagulant (LA) and/or anticardiolipin antibodies (ACL) and/or anti-β2 glycoprotein I antibodies (aβ2GPI). The finding of patients with clinical profile highly suggestive of APS but who are negative for conventional biological criteria has led to the concept of seronegative APS. In the last few years, new antigen targets and methodological approaches have been employed to more clearly identify this syndrome in patients with thrombosis or obstetrical complications without conventional aPL. Although seronegative APS is still controversial, there is increasing recognition of the existence of this subgroup. However, clinical relevance of non conventional aPL need to be confirmed by efforts toward standardizing new biological tools and longitudinal studies involving large cohort of patients.     

Insights into the diagnosis and pathogenesis of the antiphospholipid syndrome

The Antiphospholipid syndrome (APS), formerly known as Anticardiolipin or Hughes syndrome, is a systemic autoimmune disorder characterized by obstetrical complications and thrombotic events affecting almost every organ-system in patients persistently testing positive for antiphospholipid antibodies (aPL). The contribution of the extra-criteria aPL to the pathogenesis of APS have exceeded the expectations of a simple, direct pathologic ‘hit’ leading to thrombogenesis or obstetrical complications, and more pathologic pathways are being linked directly or indirectly to aPL. The value of extra-criteria aPL is on the rise, and these antibodies are nowadays evaluated as markers for risk assessment in the diagnostic approach to APS. A diagnosis of APS should be considered in pediatric patients with suggestive clinical and laboratory picture. Management of APS remains mostly based on anticoagulation, while other drugs are being tested for efficacy and side effects. Low-dose aspirin may have a role in the management of thrombotic and obstetric APS. Due to the high variability in disease severity and complication recurrence outcomes, new tools are being developed and validated to assess the damage index and quality of life of APS patients.     

Rarer clinical associations of antiphospholipid antibodies

Detection of antiphospholipid antibodies (aPL) are central to the definition of the antiphospholipid (antibody) syndrome (APS). Thrombosis in certain vascular beds, such as the cerebral circulation, the veins of the lower legs and cutaneous vessels, and/or fetal loss, are common manifestations of APS. However, aPL have been found in association with a large range of other clinical conditions-these conditions constitute a rather heterogeneous group and are the subject of this review. Thus, aPL may rarely be found in association with thromboses of vascular beds other than those commonly associated with APS. The combination of thrombosis and aPL still satisfies the criteria for APS, and management of this group of patients is the same as that of APS associated with the more common manifestations of the disease. Alternatively, aPL may be detected in a range of conditions where thrombosis cannot be clearly demonstrated, such as duodenal ulcer or transverse myelopathy. The approach to management of patients who have aPL in association with these conditions is less clear, although in some cases interventions to remove the associated antibody have been associated with amelioration of the condition. Finally, in several studies, aPL have been detected in a proportion of patients with conditions occurring commonly in the normal population-these findings have to be treated with caution in view of inconsistent findings between the reported results and methodological limitation of studies purporting to show positive results.     

Asymptomatic myocardial ischemic disease in antiphospholipid syndrome: A controlled cardiac magnetic resonance imaging study

Objective

Antiphospholipid syndrome (APS) may cause coronary thrombosis. This study was undertaken to determine the prevalence of silent myocardial disease in patients with APS, using late gadolinium enhancement (LGE) of cardiac magnetic resonance imaging (CMRI).

Methods

Twenty‐seven consecutive patients with APS and 81 control subjects without known cardiovascular disease underwent CMRI. The prevalence of occult myocardial ischemic disease, as revealed by LGE, was compared between patients with APS and controls, and factors associated with myocardial disease were identified in patients with APS.

Results

Myocardial ischemic disease, as characterized by LGE on CMRI, was present in 8 (29.6%) of 27 patients with APS, and imaging with LGE showed a typical pattern of myocardial infarction (MI) in 3 patients (11.1%). The myocardial scarring revealed on CMRI was not detected by electrocardiography or echocardiography. Although both patients with APS and control subjects shared a low risk of cardiovascular events, as calculated with the Framingham risk equation (mean ± SD 5.1 ± 8.2% and 6.5 ± 7.6%, respectively, for the absolute risk within the next 10 years; P = 0.932), the prevalence of myocardial ischemia was more than 7 times higher in patients with APS (P = 0.0006 versus controls). No association was found between myocardial disease in patients with APS and classic coronary risk factors. The presence of myocardial scarring tended to be more closely associated with specific features of APS, such as duration of the disease, presence of livedo, and positivity for anti–β₂‐glycoprotein I antibodies.

Conclusion

The finding of a significant and unexpectedly high prevalence of occult myocardial scarring in patients with APS indicates the usefulness of CMRI with LGE for the identification of silent myocardial disease in such patients.

     

Long term outcome of catastrophic antiphospholipid syndrome survivors

BACKGROUND: Catastrophic antiphospholipid syndrome (APS) is defined as life threatening multiple organ thromboses developing simultaneously or over a short period. The survival rate of catastrophic APS is about 50%, but the long term outcome of patients who survive is unknown. OBJECTIVE: To determine the long term outcome of patients with catastrophic APS and provide further information on patients who survived. PATIENTS AND METHODS: The clinical characteristics and outcomes of 130 patients with catastrophic APS have been reported previously. Six new cases were recently added to this series. Based on these publications, the authors who reported patients who had survived were contacted. Each author was asked (a) what treatment they gave their patients after the catastrophic APS; (b) if their patients had any further thrombosis. RESULTS: 63/136 (46%) patients died at the initial event. Of the remaining 73 patients, information was available for 58 (79%). Thirty eight (66%) patients did not develop further APS related events during an average follow up of 67.2 months. Eleven (19%) patients developed further APS related events but were still alive. No patients developed further catastrophic APS. Nine (16%) patients died: due to multiple organ failure (three patients); myelofibrosis (one); pneumonia (one); and APS related events (four). CONCLUSION: Sixty six per cent of patients who survive an initial catastrophic APS event remained symptom free with anticoagulation during an average follow up of 67.2 months. Twenty six per cent of the survivors developed further APS related events and the mortality rate of these patients was about 25%.     

The molecular basis of antiphospholipid syndrome

We herein review evidence that the phospholipid-binding protein beta2 glycoprotein-1 (beta2GPI) is a causative autoantigen in APS. Recent work suggests that the molecular regions in beta2GPI that facilitate autoimmunization are those that promote binding to negatively charged phospholipids by means of strong positive (anionic) charge and hydrophobicity. Although many common infections can cause antiphospholipid antibodies to be produced in humans, such postinfectious aPL are rarely associated with thromboses or pregnancy morbidity, the central features of antiphospholipid syndrome (APS). We propose that the causes of APS include those infectious agents that mimic the above molecular domains in beta2GPI. In people who are susceptible to APS, tolerance to self-beta2GPI and phospholipids is likely to be broken by foreign bacterial or viral proteins that contain such beta2GPI-like epitopes.     

Diffuse alveolar hemorrhage in the antiphospholipid syndrome: spectrum of disease and treatment

OBJECTIVE: To describe clinical manifestations, laboratory findings, and treatment of patients with the antiphospholipid syndrome (APS) who develop diffuse alveolar hemorrhage. METHODS: Diffuse alveolar hemorrhage is an occasionally reported manifestation of the APS. The diagnosis, however, may be overlooked or manifestations attributed to another disease process. Seven episodes in 5 patients with primary APS were identified and retrospectively reviewed for presenting symptoms and signs, laboratory findings, and response to treatment. RESULTS: The severity of the condition varies, and diffuse alveolar hemorrhage may be the initial manifestation of APS. Patients may present with symptoms ranging from cough, dyspnea, and fever with or without hemoptysis, to symptoms of acute respiratory failure. Hypoxemia and anemia are usually present. Other causes need to be excluded. Bronchoscopy and bronchoalveolar lavage with or without biopsy often aid in confirming the diagnosis. The pathologic abnormality appears to be microvascular thrombosis with or without capillaritis. Treatment with corticosteroids usually leads to marked improvement. CONCLUSION: Patients with APS may present with diffuse alveolar hemorrhage resulting in mild to life threatening symptoms. Prompt and thorough evaluation to confirm the diagnosis and treatment with corticosteroids usually leads to rapid improvement. The clinical setting will dictate whether other therapies such as immunosuppressive agents or intravenous immunoglobulin are required.     

The antiphospholipid syndrome

Antiphospholipid antibody syndrome (APS) is characterised by the presence of frequently recurring venous and/or arterial thrombosis, abortions and repeated evidence of lupus anticoagulants and/or anticardiolipin (aCL)-antibodies. The presence of lupus anticoagulants and/or high levels of aCL-antibodies in particular increases the risk of thrombosis. At present there are several models for the systemic and cell-damaging pathogenesis of phospholipid-antibodies. Where there are repeated occurrences of thrombo-embolic complications long-term anticoagulant treatment is indicated. For patients who have APS in pregnancy, the use of low-molecular heparin and acetylsalicylic acid (ASS) is recommended. According to recent research, a large number of antibodies can be found in APS patients, which are directed against phospholipids and plasmaproteins, but partly also against individual genetic polymorphism, which suggests focussing in future on the genetic basis of APS as well as on influencing "auto-immune thrombosis" by modulating the immune system.     

Management of Obstetric Antiphospholipid Syndrome

Recurrent early miscarriages (excluding chromosomal anomalies), late fetal loss, and maternal thrombosis are characteristic of obstetric antiphospholipid syndrome (APS). Obstetric complications such as preeclampsia, fetal growth restriction, premature delivery, and fetal death also occur in higher frequency in APS patients than in the general population. A high-risk obstetric center is needed for proper evaluation of and intervention with pregnant women with APS. Association with lupus carries additional risk of thrombosis when antiphospholipid antibodies (aPLs) are present. Gestational results with live births are improved to about 80% when antithrombotic therapy is used, but failure in 20% to 30% of the cases despite correct treatment with low-dose aspirin with or without heparin reveals new pathways for pregnancy loss in APS and unmet needs. At the moment, there is no recommendation to investigate patients with infertility for the presence of aPLs.     

Catastrophic antiphospholipid syndrome during pregnancy and puerperium: maternal and fetal characteristics of 15 cases

BACKGROUND: The catastrophic variant of the antiphospholipid syndrome (APS) is a life-threatening form of presentation of this syndrome that can be triggered by several factors. AIM: To describe the characteristics of patients who developed catastrophic APS triggered during pregnancy and puerperium. METHODS: A review of the first 255 cases collected in the website-based "CAPS Registry" was undertaken. Three new and unpublished cases of catastrophic APS developed during pregnancy and puerperium were added. RESULTS: Fifteen cases were identified. The mean (range) age was 27 (17-38) years. Most patients had a previous unsuccessful obstetric history. In 7 of 14 (50%) cases with available medical history, the catastrophic APS appeared during pregnancy, in 6 (43%) during the puerperium and in 1 (7%) after curettage for a fetal death. The main clinical and serological characteristics were similar to those patients with catastrophic APS triggered by other factors, except for a history of a higher prevalence of previous abortions (p<0.01). Several specific features were found, including the HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome in 8 (53%) patients, placental infarctions in 4 (27%) patients, and pelvic vein thrombosis and myometrium thrombotic microangiopathy in 1 (7%) patient each. Mortality rate was high for the mothers (46%), and for the babies (54%). CONCLUSIONS: It is important to consider the possibility of the development of catastrophic APS in those patients with signs of HELLP syndrome and multiorgan failure during pregnancy or puerperium, especially in those patients with previous history of abortions and/or thrombosis.     

Long-term outcome of patients with antiphospholipid syndrome who undergo percutaneous coronary intervention

Objectives: Patients with antiphospholipid antibody syndrome (APS) have an increased risk of atherothrombotic complications. There are limited data regarding the outcome of patients with APS who undergo percutaneous coronary intervention (PCI). Accordingly, we aimed to assess the long-term outcomes of these patients. Methods: Nineteen APS patients who underwent PCI between the years 2003 and 2008 were compared to 380 patients who had undergone PCI during the same period (PCI group) and were matched by age (±5 years), gender, diabetes and hypertension. In addition, APS patients were compared to 1,458 patients with ST segment elevation myocardial infarction (MI) who were treated with PCI during the same period. Six-month to 4-year clinical outcomes were evaluated. Results: The indication for PCI in the APS group was acute coronary syndrome in 52.6% of patients. After 1 year of follow-up, patients with APS had higher rates of target vessel revascularization than the other two groups, which translated to higher rates of major adverse cardiac events. There were no differences in MI or mortality rates between the groups. Conclusions: Patients with APS who undergo PCI have worse long-term clinical outcomes, driven by higher rates of revascularization, than other patients undergoing PCI. Further study is warranted to examine the mechanisms underlying these findings.     

Catastrophic manifestation of the antiphospholipid syndrome.

We describe a young woman who displayed the "malignant" variant of the antiphospholipid syndrome (APS), also known as the "catastrophic APS." Renal insufficiency, retinopathy, cerebral infarcts, bone marrow necrosis, skin ulcers, and nasal septum perforation were the result of widespread thrombotic microangiopathy. She recovered during high intensity anticoagulation.