Pediatric antiphospholipid syndrome: clinical features and therapeutic interventions in a single center retrospective case series.

BACKGROUND/PURPOSE: Pediatric antiphospholipid syndrome (APS) is a thromboinflammatory disease characterized by the presence of circulating antiphospholipid antibodies and either thrombotic events or pregnancy morbidity. The objective of this study was to review a large institution's experience to better understand the characteristics of children with APS. METHODS: We conducted a retrospective review of pediatric APS at a tertiary referral center. The electronic medical record system was queried from 2000 through 2019, and 21 cases were included based on meeting the revised Sapporo Classification criteria by age 18 or younger. Comparisons between primary and secondary APS patients were made with two-tailed t-tests. RESULTS: Twenty-one patients were included with a median age at diagnosis of 16 years and median follow-up of 5.8 years. Secondary APS was slightly more common than primary APS (11 vs. 10 cases) and was primarily diagnosed in the context of systemic lupus erythematosus. Two thirds of patients (67%) also had "non-criteria" manifestations of APS including thrombocytopenia, autoimmune hemolytic anemia, and livedo reticularis/racemosa. Almost half of patients (43%) had recurrent thrombosis, typically when patients were subtherapeutic or non-adherent with anticoagulation. Damage Index in Patients with Thrombotic APS (DIAPS) scores indicated a chronic burden of disease in both primary and secondary APS patients. CONCLUSION: This case series of pediatric APS provides important context regarding disease phenotypes displayed by children with APS. High prevalence of non-criteria clinical manifestations highlights the need to consider these characteristics when developing pediatric-specific classification criteria and when considering this relatively rare diagnosis in pediatric practice.

The digestive system involvement of antiphospholipid syndrome: pathophysiology, clinical characteristics, and treatment strategies.

Antiphospholipid syndrome (APS) is an autoimmune disease mainly characterised by vascular thrombosis and pregnancy morbidity. APS has broad spectrum of clinical manifestations. The digestive system involvement of antiphospholipid syndrome is a critical but under-recognised condition. Digestive system involvement may be the result of direct (autoimmune-mediated) or indirect (thrombotic) mechanisms. Liver is the most commonly involved organ, followed by intestines, oesophagus, stomach, pancreas and spleen. This review describes possible digestive system manifestations in APS patients, and illustrates the epidemiology and possible pathophysiology of APS. The role of different treatment strategies in the management of digestive system manifestations of APS were also discussed.Key messagesAntiphospholipid syndrome is a multi-organ, multi-system disease and its clinical manifestation spectrum is gradually expanding. Since the first diagnosis of APS, the clinical manifestations of digestive system have been reported successively. This narrative review describes the major digestive system manifestations of APS and illustrates the epidemiology, pathophysiology and the role of therapeutic strategies of these patients.

Extracellular Vesicles and Antiphospholipid Syndrome: State-of-the-Art and Future Challenges.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thromboembolism, obstetric complications, and the presence of antiphospholipid antibodies (aPL). Extracellular vesicles (EVs) play a key role in intercellular communication and connectivity and are known to be involved in endothelial and vascular pathologies. Despite well-characterized in vitro and in vivo models of APS pathology, the field of EVs remains largely unexplored. This review recapitulates recent findings on the role of EVs in APS, focusing on their contribution to endothelial dysfunction. Several studies have found that APS patients with a history of thrombotic events have increased levels of EVs, particularly of endothelial origin. In obstetric APS, research on plasma levels of EVs is limited, but it appears that levels of EVs are increased. In general, there is evidence that EVs activate endothelial cells, exhibit proinflammatory and procoagulant effects, interact directly with cell receptors, and transfer biological material. Future studies on EVs in APS may provide new insights into APS pathology and reveal their potential as biomarkers to identify patients at increased risk.

Clinical manifestations in patients with antiphospholipid antibodies: Beyond thrombosis and pregnancy loss.

The clinical spectrum of the antiphospholipid syndrome (APS) encompasses additional manifestations other than thrombosis and pregnancy morbidity, which may potentially affect every organ and system. The pathophysiology of APS indeed cannot be explained exclusively by a prothrombotic state and the "extra-criteria" manifestations of the syndrome should be attributed to other mechanisms, such as inflammation, complement and platelet activation. In this case-series, we report patients with uncommon clinical APS presentations, to highlight relevant peculiarities of the syndrome, potentially paving the way for a further update of clinical as well as laboratory manifestations of this complex immunological condition.

Missed hypereosinophilic syndrome in a critically ill patient with systemic lupus erythematosus.

A high functioning 74-year-old man with systemic lupus erythematosus presented to the emergency department with acute anxiety. He was found to have elevated cardiac enzymes and admitted to the cardiology service for investigation. In hospital, he developed an erythematous papular rash, and deteriorated to being somnolent and bedridden. He was found to have new multiterritory ischaemic strokes. It was eventually noted that he had persistent eosinophilia, present even on admission, which had been overlooked as the total leucocyte count was normal. Serology for antiphospholipid antibody syndrome (APS) was positive. He was diagnosed with hypereosinophilic syndrome (HES) secondary to new APS, and responded to high-dose steroids. This case highlights the importance of fully evaluating a leucocyte differential to make a diagnosis of HES. We discuss the definition, clinical manifestations, diagnostic approach and management of this important condition.

Damage index for antiphospholipid syndrome during long term follow-up: Correlation between organ damage accrual and quality of life.

BACKGROUND: Consequences of organ damage in primary antiphospholipid syndrome (PAPS) are diverse, our aim was to determine organ damage over time and the correlation of organ damage accrual with health-related quality of life (HRQoL) in PAPS. METHODS: First phase: retrospective cohort applying Damage Index for Antiphospholipid Syndrome (DIAPS) at 1, 5, 10, 20 years, or longer since diagnosis. Second phase: cross-sectional study, assessing HRQoL by the Medical Outcomes Study Short Form 36 (SF-36), and organ damage accrual. Descriptive statistics and Spearman correlation coefficient were used. RESULTS: Sixty-seven patients were included, mean follow-up:15 years. Deep vein thrombosis prevailed (71.6%), pulmonary embolism (35.8%) and stroke (32.8%). Organ damage was found in 98.5%, with a cumulative DIAPS value of 3, with greater involvement in the neuropsychiatric and peripheral vascular domains. Regarding HRQoL, deterioration in the physical component summary (PCS) was found in 89.6%. Organ damage accrual correlated inversely and significantly with all the SF-36 domains, mainly with the total score and PCS. Body pain and PCS correlated the most (rho = -0.503, rho = -0.475). CONCLUSIONS: Organ damage accrual impaired HRQoL in PAPS. Secondary thromboprophylxis through adequate systemic management and control of cardiovascular risk factors are necessary to prevent further impairment.

How I treat anticoagulant-refractory thrombotic antiphospholipid syndrome.

The standard treatment of thrombotic antiphospholipid syndrome (APS) is lifelong oral anticoagulation with a vitamin K antagonist (VKA), generally warfarin. A minority of patients with APS rethrombose despite seemingly adequate anticoagulation. These patients are deemed anticoagulant refractory. The management of anticoagulant-refractory APS is largely empirical and extrapolated from other clinically similar situations. Further options include increased VKA anticoagulation intensity or alternative antithrombotic strategies, including low-molecular-weight heparin, fondaparinux, the addition of antiplatelet therapy, and consideration of vascular options. Patients with anticoagulant-refractory thrombotic APS may have APS-associated thrombocytopenia, which necessitates balancing the risk of recurrent thrombosis vs bleeding to achieve adequate anticoagulation. The multiple mechanisms involved in the generation of the thrombotic phenotype in APS suggest that anticoagulation alone may not control thrombosis. Thus, other modalities, including adjunctive treatment (hydroxychloroquine, statins, and vitamin D) for APS-related thrombosis, merit consideration, as do immunomodulatory therapy and complement inhibition. Patients with APS may have coexistent systemic lupus erythematosus, which adds to the complexity of managing their thromboembolic disease. However, with attention to detail and judicious application of the limited data, it is possible to minimize the morbidity resulting from anticoagulant-refractory thrombotic APS. Multicenter studies are required to guide the sequence of interventions and their comparative efficacy in patients with anticoagulant-refractory thrombotic APS.

Molecular Biomarkers in Multiple Sclerosis and Its Related Disorders: A Critical Review.

Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS) which can lead to severe disability. Several diseases can mimic the clinical manifestations of MS. This can often lead to a prolonged period that involves numerous tests and investigations before a definitive diagnosis is reached. As well as the possibility of misdiagnosis. Molecular biomarkers can play a unique role in this regard. Molecular biomarkers offer a unique view into the CNS disorders. They help us understand the pathophysiology of disease as well as guiding our diagnostic, therapeutic, and prognostic approaches in CNS disorders. This review highlights the most prominent molecular biomarkers found in the literature with respect to MS and its related disorders. Based on numerous recent clinical and experimental studies, we demonstrate that several molecular biomarkers could very well aid us in differentiating MS from its related disorders. The implications of this work will hopefully serve clinicians and researchers alike, who regularly deal with MS and its related disorders.

Antiphospholipid syndrome with chronic thromboembolic pulmonary hypertension and coronary artery disease: a case report.

BACKGROUND: Antiphospholipid syndrome (APS) is characterized by the production of antiphospholipid antibodies associated with recurrent vascular thrombosis. There have been few reports of combination of chronic thromboembolic pulmonary hypertension (CTEPH) and coronary artery disease in APS, therefore, it is unclear about appropriate treatment strategy. CASE PRESENTATION: The patient was a 39 year-old-lady who had been suffering from hypoxia without chest pain. Transthoracic echocardiography showed severe pulmonary hypertension and mild hypokinesis of left ventricular anteroseptal wall. Simultaneously with the diagnosis of CTEPH, coronary angiography revealed severe stenosis of the left anterior descending artery. She underwent pulmonary endarterectomy (PEA) concomitant with coronary artery bypass grafting (CABG) successfully. CABG could be performed concomitantly during rewarming. During perioperative period, she was free from any thromboembolic and bleeding events despite receiving anticoagulant and antiplatelet therapies. CONCLUSIONS: PEA concomitant with coronary artery bypass grafting was feasible for APS patients complicated with CTEPH and coronary artery disease. APS patients with the presence of left ventricular dysfunction should be evaluated for coronary artery disease.

Fatigue in adults with primary antiphospholipid syndrome: findings from a mixed-methods study.

OBJECTIVE: This study aimed to explore the experience and impact of fatigue in adults with primary antiphospholipid syndrome (pAPS). METHODS: This sequential, explanatory mixed-methods study enrolled adults with a six-month or more history of pAPS. Consenting participants completed the Functional Assessment of Chronic Illness Therapy-Fatigue subscale (FS), Multi-Dimensional Perceived Social Support Scale, Patient Health Questionnaire (PHQ9), Pittsburgh Sleep Quality Index (PSQI), International Physical Activity Questionnaire (IPAQMETS). Relationships between FS and other variables were explored with multiple linear regression. Interviews were conducted with a subgroup of participants, and the data were analysed thematically. RESULTS: A total of 103 participants were recruited (Mage = 50.3 years; standard deviation = 10.1 years; 18 males). Of these, 62% reported severe fatigue. Greater fatigue was associated with lower mood, physical inactivity, poorer sleep quality and lower perceived social support. The best-fit model explained 56% of the variance in FS (adjusted R2 = 0.560, F(3, 74) = 33.65, p > 0.001) and included PHQ9 and IPAQMETS as significant predictors, and PSQI as a non-significant predictor. Twenty participants completed interviews. Three key themes were identified: characteristics of fatigue, impact on life and coping strategies. CONCLUSION: Fatigue was a common symptom of pAPS and challenging to manage. Other factors, particularly mood and physical activity, influenced fatigue. Evidence-based self-management interventions are needed.

Prevention of Pregnancy Complications in Antiphospholipid Syndrome.

Despite a lot of research on antiphospholipid antibodies (aPL), standardization of test systems, and better definition of its clinical symptoms, the pathomechanism of this acquired autoimmune disease is not yet fully explained. Progress in treatment increased the live birth rate in 70 to 80% of women suffering from obstetric antiphospholipid syndrome (OAPS). However, still 20 to 30% will develop adverse pregnancy outcome. Lack of awareness of this disorder as the cause for pregnancy complications is very harmful to mothers and to their newborns. Complications can be avoided or minimized by proper treatment. The aim of this article is to increase the awareness of gynecologists and medical personal for OAPS.

The assessment of patients with the antiphospholipid antibody syndrome: where are we now?

The antiphospholipid antibody syndrome (APS), a chronic autoimmune thrombophilia with an increased mortality and morbidity, has been recognized for more than three decades. Unlike other autoimmune rheumatic conditions such as systemic lupus erythematosus, myositis and Sjögren's syndrome, relatively few attempts have been made to develop activity, damage or disease-specific quality of life indices for APS. In this review of the literature, we consider those attempts that have been made to develop assessment tools for patients with APS, but also reflect upon the nature of the condition, to discuss, in particular, whether an activity index is appropriate for this disease.

A 36-Year-Old Woman Presenting With Left Upper Quadrant Discomfort, Encephalopathy, and Respiratory Failure.

CASE PRESENTATION: A 36-year-old woman with a history of hypertension and alcoholism reported 2 days of left upper quadrant pain and jaundice. Within hours of admission, she became somnolent and hypoxic. The patient was then intubated. She had no history of drug abuse, cigarette smoking, liver disease, autoimmune disease, or pancreatitis. She had no home medications.

Catastrophic antiphospholipid syndrome following the introduction of rivaroxaban.

Catastrophic antiphospholipid syndrome is the most severe complication of antiphospholipid syndrome. Vitamin K antagonists are the reference treatment for preventing relapsing thrombotic complications in patients with antiphospholipid syndrome. Direct oral anticoagulants are nonetheless sometimes used in this setting. We report two cases of women who were triple-positive for antiphospholipid antibodies and developed catastrophic antiphospholipid syndrome in the week after the introduction of rivaroxaban. The first patient, who had had a previous thrombotic event, had multiorgan failure 3 days after vitamin K antagonists was replaced by rivaroxaban, and the second developed a similar clinical presentation 7 days after introduction of the same treatment. Both catastrophic antiphospholipid syndrome episodes were successfully treated with heparin followed by vitamin K antagonists, corticosteroids, and plasmapheresis. These two cases highlight for the inefficacy of rivaroxaban preventing severe thrombotic events such as catastrophic antiphospholipid syndrome and thus provide further support for recommendations that vitamin K antagonists must remain the reference anticoagulant in patients with triple-positive antiphospholipid antibodies.

Stroke in systemic lupus erythematosus: epidemiology, mechanism, and long-term outcome.

OBJECTIVE: To determine stroke prevalence, mechanisms, and long-term outcome in a cohort of Hispanic patients with systemic lupus erythematosus (SLE). METHODS: We analyzed demographical data, the timing between SLE diagnosis and stroke onset, stroke type, recurrence, and outcomes from an institutional database of 4451 patients with SLE followed from 1993 to 2018. RESULTS: We observed 139 strokes (3.1%), for an incidence rate of 1.25 per 1000 person-years: 81 (58.3%) acute ischemic stroke (AIS), 19 (13.7%) subarachnoid hemorrhage (SAH), 17 (12.2%) cerebral venous thrombosis, 13 (9.4%) intracerebral hemorrhage (ICH), and 9 (6.5%) transient ischemic attack. Median time from SLE diagnosis to acute stroke was 60 months (interquartile range 12-132 months). AIS had a bimodal presentation with 26% occurring within the first year and 30% >10 years after SLE diagnosis. In contrast, 75% of ICH cases occurred >3 years (and 34% >10 years) after SLE diagnosis. The most important cause of AIS was secondary antiphospholipid syndrome (48%). Hypertension was associated with 69% of ICH cases, while aneurysmal rupture was observed in 78% of SAH cases. Excellent recovery at hospital discharge was observed in 65%. Stroke recurrence was observed in 7%. The long-term all-cause fatality rate was 8%. CONCLUSIONS: The prevalence of stroke in this cohort was 3.1%. Ischemic strokes had a bimodal presentation, occurring either early after SLE diagnosis or after a several-year delay. Half of the hemorrhagic strokes occurred >10 years after the diagnosis of SLE. Clinical outcome was usually good with a relatively low recurrence rate.

Sudden Cardiac Arrest as the First Manifestation in a Patient with Catastrophic Antiphospholipid Syndrome.

We herein report a 26-year-old woman with sudden cardiac arrest who had no remarkable medical history. While resuscitation was successfully performed with adrenalin administration and extracorporeal membrane oxygenation, the cause of cardiac arrest could not be determined for over two weeks. Given the presence of autoimmune disease along with the findings of refractory renal insufficiency and thrombocytopenia, a kidney biopsy and blood examinations, including lupus anticoagulant testing, were performed, which proved the presence of antiphospholipid syndrome. The patient was successfully treated with steroid pulse therapy. This drastic case scenario highlighted the fact that autoimmune disease can be the cause of sudden cardiac arrest.

New insights into antiphospholipid-related endothelial dysfunction by assessment of vascular glycocalyx layer: results from a preliminary cross-sectional study.

INTRODUCTION: Antiphospholipid syndrome (APS) is associated with greater atherothrombotic risk and endothelial dysfunction, suggesting that endothelial glycocalyx is impaired in this disease. OBJECTIVES: The aim was to investigate the endothelial glycocalyx and the relationship between glycocalyx markers, endothelial dysfunction parameters and atherosclerotic markers in APS. METHODS: A total of 15 primary arterial APS patients and healthy controls were included in the study. Glycocalyx was assessed in both groups by sublingual sidestream dark field imaging and syndecan-1 plasma level. Endothelial function was evaluated by brachial artery flow-mediated dilatation (FMD) and early atherosclerosis by carotid intima media thickness (IMT). Thrombotic profile was also performed by measuring the plasma level of the tissue factor (TF). RESULTS: APS patients had significantly increased syndecan-1 plasma level 38.6 ± 5.0 pg/ml vs. 19.1 ± 3.5 pg/ml; p < 0.01 and a reduced glycocalyx thickness 0.26 ± 0.03 µm vs. 0.75 ± 0.07 µm; p < 0.01 compared with control. FMD was impaired in APS patients compared with control, 5.68% ± 0.42 vs. 8.29 ± 0.30, p < 0.01, respectively. IMT was significantly increased in APS patients compared with control, 0.52 ± 0.13 mm vs. 0.40 ± 0.06 mm, p < 0.01, respectively. Soluble TF, thiobarbituric acid-reactive substances levels were increased in the sera from APS patients compared with control. CONCLUSIONS: This preliminary study supports, for the first time, that in APS patients endothelial glycocalyx is impaired, which could lead to thrombosis, endothelial dysfunction and early atherosclerosis.

Cardiovascular Disease in Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by venous, arterial or microvascular thrombosis or obstetric events in the presence of persistently positive antiphospholipid antibodies and constitutes a major cause of cardiovascular events in young people. Τhis review highlights the pathophysiology of cardiovascular complications in patients with APS and possible treatment options. Patients with APS have endothelial dysfunction, accelerated endothelial proliferation and intimal hyperplasia, atherogenesis, platelet activation, inflammatory products secretion and coagulation-fibrinolytic dysregulation. Cardiovascular complications include accelerated atherosclerosis, acute coronary syndrome, Libman-Sacks endocarditis, cardiomyopathy and venous, arterial or intracardiac thrombi. Moreover, pulmonary hypertension and peripheral microvascular dysfunction are common findings. Management of these patients is not well documented. The role of primary thrombosis prevention remains controversial in individuals with positive antiphospholipid antibodies. Treatment of traditional cardiovascular risk factors according to current guidelines for the prevention of cardiovascular disease in the general population is recommended for primary prevention of APS. Anticoagulation therapy with unfractionated or low-molecular-weight heparin overlapped with a vitamin K antagonist remains the mainstay of the treatment for APS patients with venous thrombosis, whereas direct oral anticoagulants are not yet recommended. Data are scarce regarding the secondary arterial thrombosis prevention and it is not clear whether dual or triple antithrombotic therapy is necessary. To date, it is recommended to follow current guidelines for the management of acute coronary syndrome in the general population. New treatment targets are promising options for patients with catastrophic APS.