Course Of Antiphospholipid Syndrome Research Articles

Insight into antiphospholipid syndrome: the role and clinical utility of neutrophils extracellular traps formation

Antiphospholipid syndrome (APLS) is a systemic immune dysregulation distinguished by repetitive complications and pregnancy loss in the absence of definite etiology. Most research focuses on the laboratory detection and clinical features of APLS, but its precise etiology remains to be deeply explored. NETosis is a newly developed theory in the pathophysiology of APLS which may serve as the missing bridge between coagulation and inflammation reaching the disease progression and severity. We aimed in this study to navigate the prognostic role of NETosis in thrombotic APLS. Our study included 49 newly diagnosed APLS patients (both 1ry and 2ry) who met clinical and laboratory criteria as per the international consensus statement on the update of the classification criteria for definite APLS and were sub-classified according to the occurrence of thrombotic events in thrombotic and non-thrombotic types. In addition, 20 sex and age-matched reactive subjects and 20 sex and age-matched healthy volunteer controls were enrolled. NETosis formation was assessed by measuring serum Myeloperoxidase (MPO) and Histones level using the enzyme-linked immunosorbent assay (ELISA) technique. Both MPO and Histones levels were able to discriminate among APLS cases from normal controls, showing significant cutoffs of > 2.09 ng/ml for MPO and > 1.45 ng/ml for Histones (AUC values were 0.987and 1.000, respectively). These values can be used as predictors for NETosis pathophysiology in APLS patients. Additionally, these markers demonstrated a significant association with several prognostic indicators, including thrombosis, higher PT and INR, and lower hemoglobin (Hb) levels which are supposed to be ameliorated by using NETs inhibitors. In conclusion, we suggest that measuring NETosis markers, MPO, and Histones, in the early course of APLS using proposed cutoff values will facilitate the timely initiation of anti-NETosis therapy and improve the overall prognosis, particularly for patients with thrombotic APLS.

Heart valve disease in primary antiphospholipid syndrome.

APS-associated heart valve disease (HVD) is well described. Nonetheless, limited data exist on clinical parameters associated with the course of primary APS (pAPS) patients with HVD. The goal of this study was to assess clinical features and related outcomes in patients with APS-associated HVD. In this multicentre retrospective study, we identified 33 pAPS patients with HVD (pAPS-HVD group) and compared their clinical course with 128 pAPS patients with normal heart valves on echocardiography (pAPS-control group). pAPS-HVD patients had more cerebrovascular events (56.3% vs 25%, P = 0.005) and livedo reticularis (24.2% vs 7.8%, P = 0.013) than pAPS-controls. Furthermore, catastrophic-APS (CAPS) (12.1% vs 2.4%, P = 0.034), recurrent thrombosis (33.3% vs 4.7%, P < 0.001) and need for advanced therapy (i.e. IVIG, plasmapheresis or rituximab) were more frequent in pAPS-HVD patients. Anti-β2-glycoprotein 1 IgG (84.8% vs 63.2%, P = 0.034), anti-cardiolipin IgG (90.9% vs 64.8%, P = 0.005) and triple positive aPL (75.8% vs 56.5%, P = 0.047) were commoner in pAPS-HVD patients vs pAPS-controls. Ten of the 33 patients with pAPS-HVD underwent valve surgery, which was associated with male gender, smoking, arterial limb ischaemia and livedo reticularis. pAPS-HVD patients had a more severe APS clinical course including CAPS and thrombotic events as well as a specific serology, namely IgG isotype aPL antibodies and triple positivity. Our data suggest that pAPS-HVD represents a high-risk subgroup of APS patients.

Ethnicity and Antiphospholipid Syndrome in Israel.

Antiphospholipid syndrome (APS) is an acquired coagulopathy associated with the presence of antiphospholipid antibodies. Whether ethnicity modulates APS clinical course is not known. The aim of our study was to assess the interplay of ethnicity and APS in Israel. We retrospectively evaluated the ethnic distribution of APS patients from 3 medical centers in Israel compared to the general population. Ethnic groups were defined according to the Israeli Bureau of Statistics as Ashkenazi (European), former Union of Soviet Socialist Republics (USSR), North African, Asian (West Asia, Greece, and Turkey), Israeli Arab individuals, and others. Our cohort included 382 patients. The prevalence of Ashkenazi and Asian ethnicities was more pronounced (33% versus 12.8% and 15.4% versus 7.7%, respectively; P < 0.001), while Israeli Arabs were less represented (5.2% versus 31.1%; P < 0.001) relative to their part in the general population. Arab patients were younger at presentation (mean ± SD 28 ± 10 years versus 34 ± 13 years; P < 0.001) and were more likely to present with venous thrombosis (50% versus 35%; P = 0.037) and to suffer from venous thrombotic recurrence (45% versus 16%; P < 0.001) compared to other ethnicities. Mortality was higher among patients of Asian ethnic origin (8.8% versus 1.1%; P = 0.005); intriguingly, this group experienced cardiovascular risk factors more often (i.e., dyslipidemia and hypertension). Ethnicity may affect the prevalence and/or natural course of APS, which is less prevalent and differs clinically in Israeli Arab patients, while mortality was linked with Asian ethnicity.

Arterial and Venous Thrombosis as a Symptom of Antiphospholipid Syndrome – A Noticeable Analysis from the Past.

Antiphospholipid syndrome (APS), defined as combination of venous and/or arterial thrombosis as well as obstetric complications with antiphospholipid antibodies presence in blood, is an example of acquired thrombophilia. The thrombotic episodes in the APS course are highly recurrent, with an increasing incidence with years after secondary anticoagulant prophylaxis cessation. In between 2005-2011 a study was conducted in Poznań, Poland, with the aim to find a correlation between actual APS diagnostic guidelines (criteria from Sydney’2006) and the clinical feature of thrombosis in this syndrome with coexistence of inherited thrombophilia and risk factors for cardio-vascular disease included. Additionally, a selection of the highest thromboembolic risk group was made among asymptomatic patients with antiphospholipid antibodies (APA) detected to compare with APS patients. An association between a type of laboratory test confirming the longtime APA presence and thrombotic risk was analyzed as well. The follow up had lasted for meanly 47 months and included 75 patients (50 females and 25 males) at the mean age of 43, divided into three groups (25 persons each): I – with asymptomatic APA, IIA – with arterial episodes in the history and IIB – with past venous complications in the course of APS. The majority of them comprised persons with primary APS or with asymptomatic APA (aAPA) - without any other autoimmune diseases. The laboratory tests included: lupus anticoagulant (LA) according to the 3-step procedure recommended by ISTH (International Society on Thrombosis and Hemostasis), anticardiolipin (ACA) – of IgG and IgM class and anti-β2-glycoprotein I (aβ 2 GPI) – of IgG class, both with the cut-off value of 99 percentile. D-dimer and fibrinogen concentration, protein C and antithrombin activity, activated protein C resistance, free protein S concentration, factor VIII were further analyzed. Among comorbidities and risk factors for venous and arterial thrombosis, there was significantly more frequent incidence of autoimmune diseases in the asymptomatic group of people compared to patients after thromboembolic episodes. Most often the aAPA presence was confirmed in the LA tests – the majority of positive results appeared among patients with asymptomatic course and with past venous thrombosis as well and less frequently - in the group of arterial episodes in the history. Any significant differences were found in the reference to the incidence of thrombotic episodes in the retrospective assessment of symptomatic patients and prospective – in the whole investigated group, although the time of their occurrence after beginning of observation period almost doubled in people with past thromboembolic episodes, comparing to the earlier asymptomatic persons.

Adrenal failure and antiphospholipid syndrome.

We herein report two cases of primary adrenal insufficiency (AI) associated with antiphospholipid syndrome (APS). In both patients, the main finding that led to the diagnosis was hyponatraemia. The major difference between the two cases was the time at which AI evolved during the course of APS. In the first patient, AI developed acutely along with other presenting features of APS. In the second patient, the AI was unmasked during a stressful situation induced by severe inflammation that occurred 7 years after the first APS manifestation and had probably evolved slowly during the previous few years. These cases emphasise the importance of considering AI in patients with either suspected or newly diagnosed APS as well as in patients who have long been known to have APS. The symptoms and signs alerting the clinician to possible AI are general abdominal complaints, fever, hypotension, and hyponatraemia. Conversely, patients with primary AI should be questioned about the signs and symptoms of APS.

Diagnosis and therapy of antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a clinical condition that has not been well defined yet. Although the clinical component is well established, the laboratory part is a mood issue. According to current guidelines, 3 tests (lupus anticoagulant, anticardiolipin, and anti β2-glycoprotein I antibodies) are officially recommended to assess the presence of antiphospholipid antibodies. According to test positivity, patients are classified into categories in clinical studies. However, it is now clear that classification categories have a different impact on the clinical course of APS. Indeed, patients and healthy carriers with a full positive antibody profile (triple positivity) are those at the highest risk of events. Patients with a single test positivity are those at a lower risk. In this review, on the basis of a laboratory profile, we grade the diagnosis of APS into definite, probable/possible, and uncertain. We also discuss secondary prevention of thrombotic APS, prevention of pregnancy morbidity, and treatment of catastrophic APS. Finally, new tools in laboratory diagnosis and treatment are highlighted.

Éruption cutanée atypique au cours d’un syndrome des antiphospholipides

Antiphospholipid syndrome (APS) is characterised by arterial or venous thrombosis combined with the presence of specific antibodies known as antiphospholipids. It is commonly associated with cutaneous signs. Herein we report a case of atypical cutaneous eruption occurring during the course of APS and we discuss the possible mechanism. A 45-year-old woman consulted twice within six months for an erythematosus papular eruption around the neckline. She was being followed-up for antiphospholipid syndrome treated with fluindione (Préviscan®), and her International Normalized Ratio (INR) was consistent with the prescribed anticoagulation target. Blood tests confirmed the presence of anticardiolipin and antiphospholipid antibodies, but no laboratory evidence of lupus was seen. Histopathological examination of a skin biopsy demonstrated the presence within the vascular lumen of a weakly eosinophilic anhistic substance positive for PAS stain. The patient was given acetone salicylic acid (Kardégic®) combined with fluindione, and four years later, she had presented no relapses. Despite a clinically evocative appearance, the diagnosis of lupus tumidus was ruled out in our patient by histopathological features, and associated systemic lupus erythematosus was repeatedly refuted on the basis of clinical and laboratory data. We suggest that the specific histological images of intraluminal deposits within the dermal vessels seen in this patient, although not typical of thrombosis, are associated with APS. The clinical remission seen from the start of antiplatelet treatment could be due to the action of these drugs against the obstruction of small-calibre dermal vessels.

Pulmonary embolism in the course of antiphospholipid syndrome

A short overview of the literature on pulmonary thromboembolism in the course of antiphospholipid syndrome (APS) is presented. The mechanism of pulmonary thrombosis and related arterial emboli as well as non-thrombotic changes in pulmonary vessels are discussed. The antithrombotic prophylaxis, conservative and surgical treatment of pulmonary thrombosis associated with APS are reviewed.

Antiphospholipid Antibodies in Malignancy

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by arterial and venous thrombotic events associated with antiphospholipid antibodies. Antiphospholipid syndrome is commonly seen with collagen vascular diseases; however, other entities that can cause APS include chronic viral infections, certain medications, and malignancies. We present an interesting patient with an atypical presentation and course of presumed APS, which lead us to perform an exhaustive search for a secondary cause. The patient was ultimately found to have splenic marginal zone lymphoma. Analysis of the current data in the literature is presented for APS, antiphospholipid antibodies, and malignancy. Based on the literature findings and our experience, we recommend a thorough and repeated evaluation for an underlying malignancy in patients who have an atypical presentation and features of APS.

Clinico-genealogical investigation of antiphospholipid syndrome

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Clinical course of high-risk patients diagnosed with antiphospholipid syndrome.

The characteristics and the clinical course of antiphospholipid syndrome (APS) in high-risk patients that are positive for all three recommended tests that detect the presence of antiphospholipid (aPL) antibodies have not been described. This retrospective analysis of prospectively collected data examined patients referred to Italian Thrombosis Centers that were diagnosed with definite APS and tested positive for aPL [lupus anticoagulant (LA), anti-cardiolipin (aCL), and anti-beta2-glycoprotein I (beta2GPI) antibodies]. Laboratory data were confirmed in a central reference laboratory. One hundred and sixty patients were enrolled in this cohort study. The qualifying events at diagnosis were venous thromboembolism (76 cases; 47.5%), arterial thromboembolism (69 cases; 43.1%) and pregnancy morbidity (11 cases; 9.7%). The remaining four patients (2.5%) suffered from catastrophic APS. The cumulative incidence of thromboembolic events in the follow-up period was 12.2% (95% CI, 9.6-14.8) after 1 year, 26.1% (95% CI, 22.3-29.9) after 5 years and 44.2% (95% CI, 38.6-49.8) after 10 years. This was significantly higher in those patients not taking oral anticoagulants as compared with those on treatment (HR=2.4 95% CI 1.3-4.1; P<0.003). Major bleeding associated with oral anticoagulant therapy was low (0.8% patient/years). Ten patients died (seven were cardiovascular deaths). Patients with APS and triple positivity for aPL are at high risk of developing future thromboembolic events. Recurrence remains frequent despite the use of oral anticoagulants, which significantly reduces the risk of thromboembolism.

Retirada de la anticoagulación en el síndrome antifosfolípido primario cuando se negativizan los anticuerpos anticardiolipina

The recommended treatment in patients with primary antiphospholipid syndrome (APS) after a thrombotic event is long-term anticoagulation. However, it is still not exactly known how to manage patients who remain stable for years and whose antiphospholipid antibodies (APA) decrease until becoming negative. This study aims to assess the course of the primary APS in a group of patients after anticoagulation therapy is discontinued. Ten patients with primary APS who had developed deep venous thrombosis in the limbs (9) or in the aorta (1) were included. After a minimum period of 12 months of anticoagulation therapy, this was discontinued if the patients were negative APA during the follow-up in two consecutive measurements. Six patients (60%) developed persistent negative APA. Four had transient risk factors (2 pregnant, 1 immobilization, 2 oral contraceptives). No new thrombosis episode was observed after a follow-up period of 21 +/- 4.9 months. Our data suggest that anticoagulation can be discontinued in those patients with primary APS and persistent negative APA, especially if the thrombotic event was venous and occurred in association with a transient risk factor, such as immobilization or pregnancy. Extensive studies are required to confirm these results.

Amputation of Digits or Limbs in Patients with Antiphospholipid Syndrome

To describe the characteristics of patients with peripheral vascular disease leading to amputation of digits or limbs encountered in patients with the antiphospholipid syndrome (APS). Twenty-one cases derived from several geographical centers (Brazil, Serbia, Italy, Israel, United Kingdom, and South Africa) are presented. The major clinical, serological, and histopathological data (where available) of this cohort are described, documented, and analyzed. Patients were suffering mainly from systemic lupus erythematosus (9 patients) or primary APS (8 patients). Peripheral vascular occlusions occurred during the course of the catastrophic APS in 5 patients. The vascular occlusions occurred both early and very late in the course of the disease (time after APS diagnosis, 0-38 years). Vasculitis was present in 7 patients and 5 demonstrated the typical antiphospholipid antibody (aPL)--vasculopathy with complicating bland thrombosis. Myocardial infarctions had occurred in 4 patients but it was not possible to determine whether they suffered from premature atherosclerotic disease or whether the infarctions were aPL-related. The appearance of livedo reticularis preceding the arterial thrombosis was noted in 9 patients. Cryoglobulinemia was detected in only 1 patient. Peripheral vascular disease leading to amputation of digits or limbs is a severe complication encountered in patients with APS. In the absence of histopathology, it may be difficult to distinguish whether concomitant atherosclerotic occlusions, vasculitis, or aPL-related thrombosis of peripheral vessels is the main cause of the vascular ischemia. Treatment should, therefore, include full anticoagulation as well as corticosteroids and immunosuppression in these patients.

The Role of Zinc in Thrombosis and Pulmonary Embolism in the Course of Antiphospholipid Syndrome (APS)—Short Review

Antiphospholipid antibodies may occur in the course of various diseases, but its presence is not necessarily associated with clinical symptoms. Zinc has multiple biological roles. For example, it stabilizes the cell's membrane and regulates its functions by influencing the synthesis of phospholipids and its distribution. The present review focuses on the possible associations between zinc and antiphospholipid antibodies and with the symptoms of antiphospholipid syndrome.

Catastrophic Antiphospholipid Syndrome

Catastrophic Antiphospholipid Syndrome

The infectious origin of the antiphospholipid syndrome: induction by passive transfer of anti- β2GPI Abs induced by common bacteria

The antiphospholipid syndrome is characterized by a wide variety of vaso-occlusive manifestations associated with autoantibodies directed against β2-glycoprotein-I. The pathogenicity of anti-β2GPI antibodies has been demonstrated in animal models. The factor(s) causing production of anti-β2GPI remain unidentified, but several indirect arguments support the idea that microbial agents might influence the course of antiphospholipid syndrome and an association with microbial pathogens has recently been documented. Microbes can contain chemical structures that mimic normal host self-proteins, a phenomenon termed molecular mimicry. Employing a peptide phage display library, we identified hexapeptides that react specifically with anti-β2GPI monoclonal antibodies. These peptides were found to modulate the experimental model for antiphospholipid syndrome. In the current study we found high homology between one of the hexapeptides- TLRVYK, and various bacteria and viruses. We therefore immunized naive mice with a panel of TLRVYK-corresponding microbial particles to find whether they posses a pathogenic potential for autoimmunity. We show that mice which were infused with antibodies derived from mice immunized with tetanus toxoid, haemophilus influenzae or with neisseria gonorrhoeae developed clinical manifestations of experimental antiphospholipid syndrome (e.g. mice infused with anti-β2GPI derived from tetanus immunized developed thrombocytopenia 497 ± 98 × 10-3 cells/dl compared to 1012 ± 214 × 10-3 cells/dl in control mice, high percentage of fetal resorption 48 ± 3% in comparison to 4 ± 2% and prolonged aPTT 69 ± 4 sec in comparison to 23 ± 3 sec in mice infused with IgG from Shigella disenteriae immunized mice). The pathogenetic mechanism for anti-β2GI generation seems to be an epitope mimicry with common bacterial molecules.

The Intrarenal Vascular Lesions Associated with Primary Antiphospholipid Syndrome

Even 10 yr after the identification of the antiphospholipid syndrome (APS), renal involvement in the course of APS is still relatively unrecognized, and is probably underestimated. The association of anticardiolipin antibodies and/or lupus anticoagulant with the development of a vaso-occlusive process involving numerous organs is now confirmed. In a multicenter study, 16 cases of "primary" APS (PAPS) were found and followed for 5 yr or more, all with renal biopsy. In all 16 cases of PAPS, there was a vascular nephropathy characterized by small vessel vaso-occlusive lesions associated with fibrous intimal hyperplasia of interlobular arteries (12 patients), recanalizing thrombi in arteries and arterioles (six patients), and focal cortical atrophy (10 patients). In combination, these led to progressive destruction of the kidney, accelerated by acute glomerular and arteriolar microangiopathy in five patients. Focal cortical atrophy is a distinctive lesion, present in 10 biopsies, and likely represents the histologic and functional renal analogue to the multiple cerebral infarcts detected on imaging studies. The clinical hallmark of this vascular nephropathy in PAPS is systemic hypertension, only variably associated with renal insufficiency, proteinuria, or hematuria. The ensemble of histologic renal lesions defined in this study should aid in the separation of the lesions found in cases of secondary APS, especially systemic lupus erythematosus, into those lesions related to APS and those related to the underlying disease.

Le syndrome des antiphospholipides (SAPL) : une nouvelle cause d'hémorragie bilatérale des surrénales

We report 3 cases of bilateral adrenal hemorrhage associated with the antiphospholipid syndrome (APS). In one of primary APS adrenal insufficiency was the presenting feature. The antiphospholipid antibodies must be searched in « auto-immuneAddison's disease, and adrenal hemorrhage must be searched with CT-scan or MRI if hyponatremia and hyperkaliema occur durint the course of APS.