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Background: Lupus anticoagulant hypoprothrombinemia syndrome (LAHPS) is a rare autoimmune condition characterized by acquired prothrombin (FII) deficiency associated with antiphospholipid syndrome (APS) and life-threatening bleeding. We present the case of a 34-year-old woman with heavy menstrual bleeding (HMB), positive Lupus anticoagulant (LA) test, and high titer anticardiolipin antibodies Immunoglobulin G (ACA IgG) and anti-β2 glycoprotein I antibodies IgG (antiB2GPI IgG). Severe iron deficiency anemia necessitated recurrent blood transfusions and intravenous iron infusions from 2018 to 2021., Results: In January 2022, she was admitted to our clinic. Von Willebrand disease screening and platelet function analysis (PFA100) were normal. FII and FIX deficiencies were detected, without factor IX inhibitors. Anti-phosphatidylserine/prothrombin antibodies were confirmed by Padua University lab. To reduce antibody titers and menstrual bleeding, immunosuppressive therapy (Rituximab 375 mg/m2 weekly ×4 weeks) and hormonal therapy (desogestrel 75 mcg/day) were initiated., Conclusion: After 1-year, complete remission of clinical symptoms was achieved, with normalization of FII and FIX values and moderate reduction of aPS/PT titers, especially IgM isotype., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Several scores can predict clinical outcomes of patients with Acute Coronary Syndromes (ACS). The validated PARIS (Patterns of Non-Adherence to Anti-Platelet Regimen in Stented Patients) score is poorly used in clinical practice because it needs items that are not always easily available. The ACEF (Age, Creatinine, and Ejection Fraction) score is more attractive because it only includes three items. We compared these scores to risk-stratify ACS patients enrolled into the START (Survey on anticoagulated pAtients RegisTer)-ANTIPLATELET registry. ACS patients who completed 1-year follow-up ( n = 1171) were grouped in tertiles (low, medium, and high-risk) according to their ACEF/PARIS scores. Primary endpoints were: one-year MACCE (major adverse cardiac and cerebrovascular events: death, non-fatal myocardial infarction, stroke or target vessel revascularization) and NACE (net adverse cardiac and cerebrovascular events): MACCE plus major bleeding). MACCE incidence was higher in the high-risk tertile (15%) VS low/medium (3/7 %) risk tertiles ( P < .001). NACE incidence in the high-risk tertile was 24% VS low/medium (9/15 %) risk tertiles ( P < .001), independently of the risk score used . The ACEF score has similar accuracy as the validated PARIS score for the estimation of ischemic/bleeding risk. Thereby, we strongly suggest its use in clinical practice to risk-stratify ACS patients and select optimal therapeutic strategies., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background/purpose: APS ACTION Registry was created to study the outcomes of patients with persistently positive antiphospholipid antibodies (aPL) with or without other systemic autoimmune disease (SAIDx). Given that immunosuppression (IS) is used for certain aPL manifestations, for example, thrombocytopenia (TP), our primary objective was to describe the indications for IS in aPL-positive patients without other SAIDx. Secondly, we report the type of IS used in patients with selected microvascular or non-thrombotic aPL manifestations., Methods: An online database is used to collect clinical data. The inclusion criteria are positive aPL based on the laboratory section of the APS Classification Criteria, tested at least twice within one year prior to enrollment. Patients are followed every 12 ± 3 months. For this descriptive retrospective and prospective analysis, we included aPL-positive patients without other SAIDx and excluded those with new SAIDx classification during follow-up. For each patient, we retrieved clinical data at baseline and follow-up including selected aPL manifestations (diffuse alveolar hemorrhage [DAH], antiphospholipid-nephropathy [aPL-N], livedoid vasculopathy [LV]-related skin ulcers, TP, autoimmune hemolytic anemia [AIHA], cardiac valve disease [VD]), and IS medications., Results: Of 899 patients enrolled, 537 were included in this analysis (mean age 45 ± 13 years, female 377 [70%], APS Classification in 438 [82%], and at least one selected microvascular or non-thrombotic aPL manifestation in 141 (26%)). Of 537 patients, 76 (14%) were reported to use IS (ever), and 41/76 (54%) received IS primarily for selected aPL manifestation. In six of 8 (75%) DAH patients, 6/19 (32%) aPL-N, 4/28 (14%) LV, 25/88 (28%) TP, 6/11 (55%) AIHA, and 1/43 (2%) VD, the IS (excluding corticosteroids/hydroxychloroquine) indication was specific for selected aPL manifestation., Conclusion: In our international cohort, 14% of aPL-positive patients without other SAIDx were reported to receive IS; the indication was at least one of the selected microvascular and/or non-thrombotic aPL-related manifestations in half. Thrombocytopenia was the most frequent among those selected aPL-related manifestations; however, approximately one-third received IS specifically for that indication. Diffuse alveolar hemorrhage was frequently treated with IS followed by AIHA and aPL-N. Systematic controlled studies are urgently needed to better define the role of IS in APS.

Objectives: Studies on microparticles (MPs) in patients with antiphospholipid antibodies (aPL) are sparse and inconclusive. The relation between MPs and different aPL antibody profiles has never been tested. We evaluated the presence of platelet and endothelial microparticles in patients positive for IgG anti-β2-glycoprotein I (aβ2GPI) antibodies according to triple, double and single positive aPL profiles., Methods: Megamix (Biocytex) was used to set up the MPs gating according to the datasheet. Markers of Platelet Microparticles (PMPs) were CD41a-PE and annexin-V-FITC that was used to determine phosphatidylserine (PS) exposure. CD144-FITC was used as a marker of Endothelial Microparticles (EMPs)., Results: The number of total MPs and EMPs was significantly higher in triple positive groups with respect to single positive group and showed a significant correlation with IgG aβ2GPI titers. The number PMPs was the lowest in triple positive group and inversely correlated with IgG aβ2GPI titers., Conclusions: Elevated levels of total MPs and EMPs suggest a state of vascular activation in IgG aβ2GPI positive individuals according to the number of positive tests. PMPs may be fast cleared from circulation in high risk triple positive patients.

Background: DOACs are characterized by a higher incidence of gastrointestinal bleeding and this may be different among males and females. Female patients were underrepresented in the DOAC pivotal trials. We aimed to assess real-world differences in gastrointestinal bleeding with oral anticoagulants (DOACs and VKAs) among males and females with atrial fibrillation. Methods: We performed a population-based retrospective analysis on linked administrative claims. Atrial fibrillation patients of 65 years and above were considered. Bleeding risk factors were assessed through HASBED and previous history of gastrointestinal disease. A time-to-event analysis compared gastrointestinal bleeding between males and females. Results: The overall cohort consisted of 15338 (55% female) DOAC and 44542 (50% female) VKA users. Most of the patients showed HASBED ≥2. Incidence rate of GI bleeding was higher in females as compared to males among DOAC users (0.90% vs 0.59%), and significant gender difference in GI bleeding was found, after adjustment, in the Cox regression analysis (HR 1.48, 95%CI 1.02-2.16). In the VKA group, no significant difference among genders was found in the time-to-event analysis. Conclusions: Our data suggest that female patients treated with DOACs have a higher risk of GI bleeding versus male patients; this difference is not observed in VKA patients.

Background: Venous thromboembolism (VTE) is a frequent and serious disease that requires immediate and long-term anticoagulant treatment, which is inevitably associated with a risk of bleeding complications. Some studies, though not all, reported a higher risk of bleeding in female patients treated with either old anticoagulants [vitamin k antagonists (VKAs)] or recent anticoagulants [direct oral anticoagulants (DOACs)]. Furthermore, analyses of clinical trials reported an abnormal vaginal bleeding in women of reproductive age treated with DOACs. This study aimed at comparing the risk of bleeding in an inception cohort of VTE women and men included in a prospective observational registry., Methods: Baseline characteristics and bleeding events occurring during anticoagulation in patients of both sexes, included in the START-Register after a first VTE, were analyzed., Results: In all, 1298 women were compared with 1290 men. Women were older and more often had renal diseases; their index events were often provoked (often by hormonal contraception and pregnancy), and more frequently presented as isolated pulmonary embolism (PE). The rate of bleeding was similar in women (2.9% patient-years) and men (2.1% patient-years), though it was higher when uterine bleeds were included (3.5% patient-years, p = 0.0141). More bleeds occurred in VKA- than DOAC-treated patients (6.4% versus 2.6%, respectively; p = 0.0013). At multivariate analysis, age ⩾ 75 years was associated with higher prevalence of bleeds., Conclusion: The occurrence of bleeding was not different between women and men during anticoagulation after VTE. Only after inclusion of vaginal/uterine bleeds, the rate of bleeding was higher in women. The incidence of bleeding was higher in women treated with VKAs., Plain Language Summary: The risk of bleeding in women anticoagulated for deep vein thrombosis or pulmonary embolism is not higher than that in men, except for vaginal bleeding: Background:: The occurrence of a venous thromboembolic event (VTE, including deep vein thrombosis and pulmonary embolism) necessarily requires a period of at least 3-6 months of treatment with anticoagulant drugs [either vitamin k antagonists (VKA) or, more recently, direct oral anticoagulants (DOACs)]. Anticoagulation therapy, however, is associated with a risk of bleeding that is influenced by several factors. Sex is one of these factors as some authors have hypothesized that women are at higher risk than men. Furthermore, some studies have recently found more vaginal bleeding in VTE women treated with a DOAC compared with those who received VKAs. Methods:: The present study aimed to compare the frequency of bleeds occurring in women and in men who were treated with DOACs or VKAs for a first VTE event and followed in real-life conditions. Since the beginning of their anticoagulant treatment, the patients were included in a prospective, multicenter, observational registry (the START-Register), and bleeding events were recorded. Results:: A total of 1298 women were compared with 1290 men. Women were older and more often were affected by renal diseases; their VTE events were often associated with risk factors (especially hormonal contraception and pregnancy) and presented as isolated pulmonary embolism. The rate of all bleeding events (including major, non-major but clinically relevant, and minor bleeds) was higher in women (3.5% patient-years) than in men (2.1% patient-years, p = 0.0141); however, the difference was no longer statistically significant after exclusion of uterine bleeds (2.9% patient years). More bleeding occurred in women receiving VKA as anticoagulant drug compared with those treated with a DOAC (6.4% versus 2.6%, respectively; p = 0.0013). At multivariate analysis, age ⩾ 75 years was associated with higher prevalence of bleeds. Conclusion:: In conclusion, we found that in real-life conditions, the rate of bleeding events occurring during anticoagulation after a VTE episode is not higher in women than in men. Only after inclusion of vaginal bleeds, the rate of bleeding was higher in women. More bleeds (including vaginal bleeding) occurred in women treated with VKA than DOACs., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2021.)

Objective: This study aimed to use cluster analysis (CA) to identify different clinical phenotypes among antiphospholipid antibodies (aPL)-positive patients., Methods: The Alliance for Clinical Trials and International Networking (APS ACTION) Registry includes persistently positive aPL of any isotype based on the Sydney antiphospholipid syndrome (APS) classification criteria. We performed CA on the baseline characteristics collected retrospectively at the time of the registry entry of the first 500 patients included in the registry. A total of 30 clinical data points were included in the primary CA to cover the broad spectrum of aPL-positive patients., Results: A total of 497 patients from international centres were analysed, resulting in three main exclusive clusters: (a) female patients with no other autoimmune diseases but with venous thromboembolism (VTE) and triple-aPL positivity; (b) female patients with systemic lupus erythematosus, VTE, aPL nephropathy, thrombocytopaenia, haemolytic anaemia and a positive lupus anticoagulant test; and (c) older men with arterial thrombosis, heart valve disease, livedo, skin ulcers, neurological manifestations and cardiovascular disease (CVD) risk factors., Conclusions: Based on our hierarchical cluster analysis, we identified different clinical phenotypes of aPL-positive patients discriminated by aPL profile, lupus or CVD risk factors. Our results, while supporting the heterogeneity of aPL-positive patients, also provide a foundation to understand disease mechanisms, create new approaches for APS classification and ultimately develop new management approaches.

Optimal medical therapy (OMT) at discharge is recommended after acute coronary syndrome (ACS). Few studies report the impact of OMT on long-term clinical outcome in a real-world scenario. We evaluated the impact of discharge OMT on top of dual-antiplatelet therapy (DAPT) on clinical outcome in the real-world ACS population of the Survey on anTicoagulated pAtients RegisTer ANTIPLATELET registry. The primary end point was major adverse cardiac and cerebrovascular event (MACCE), a composite of death, myocardial infarction, stroke, or target vessel revascularization. The co-primary end point was net adverse cardiac and cerebrovascular event (NACE), based on MACCE plus major bleeding. Consecutive patients with ACS with 1-year follow-up were enrolled. They were evaluated at discharge for the use of a β-blocker, angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers and statins. Optimal medical therapy was defined as the use of ≥2 of 3 medications. At multivariate analysis, both MACCE and NACE were significantly higher in non-OMT patients than in OMT patients (MACCE 18 [19] vs 59 [9], hazard ratio [HR] = 0.44 [0.26-0.75], P = .002, NACE 19 [20] vs 67 [10], HR = 0.47 [0.28-0.79], P = .004). In this real-world scenario, OMT at discharge on top of DAPT seems associated with a better clinical outcome compared with patients discharged on non-OMT.

Platelet activation and decrease in platelet count characterize the development of the most feared form of antiphospholipid syndrome (APS), i.e. catastrophic APS (CAPS). We aimed to assess if immuno-affinity purified anti-β2-glycoprotein I (aβ2GPI) antibodies enhance platelet activation inducing a significant flow obstruction in a platelet function analyzer (PFA). Affinity purified aβ2GPI antibodies were obtained from 13 triple positive patients with a strong lupus anticoagulant (LA) and high titers of IgG anticardiolipin antibodies (aCL) and IgG aβ2GPI. Platelet activation stimulated by adenosine diphosphate (ADP) in the presence or absence of aβ2GPI was measured by the expression of P-selectin on platelet surface using flow cytometry. P-selectin expression remained close to baseline when normal whole blood was incubated with aβ2GPI alone. When stimulated using aβ2GPI combined with ADP, P-selectin expression (28.42 ± 5.15% vs. 20.98 ± 3.94%, p  = 0.0076) was significantly higher than ADP alone. Closure time of normal whole blood passed through the PFA was significantly shorter using affinity purified aβ2GPI than control IgG both in Col/ADP (160.1 ± 62.1 s vs. 218.6 ± 43.8 s; p  = 0.021) and Col/EPI cartridges (149.5 ± 26.7 s vs. 186.9 ± 45.5 s; p  = 0.030). Thus, platelet activation is enhanced by aβ2GPI antibodies with a consequent premature closure in a PFA, possibly resembling that in microcirculation in patients with CAPS.

We investigated whether gender influences antiplatelet treatment in patients with acute coronary syndrome (ACS). The primary end point was major adverse cardiac and cerebrovascular events (MACCEs), a composite of death, myocardial infarction (MI), stroke, or target vessel revascularization. The coprimary end point was net adverse cardiac and cerebrovascular events (NACEs), based on MACCE plus major bleeding. From January 2014 to December 2016, 840 consecutive patients with ACS who completed 1-year follow-up were enrolled, 625 (74%) males and 215 (26%) females. Percutaneous coronary interventions (PCI) and drug-eluting stents (DES) were more often used in males (PCI: 532 [87%] vs 168 [80%], P = .02 and DES 474 [76%] vs 143 [66%], P = .01). Males were more often treated with dual antiplatelet therapy (DAPT; 94% vs 88%, P = .01). In DAPT, ticagrelor was the most prevalent strategy, regardless of gender (47% vs 49%, P = .68); clopidogrel was preferred in women (42% vs 33%, P = .04); and prasugrel was preferred in men (11% vs 17%, P = .04). At multivariate analysis, MACCE and NACE were similar between genders. Therefore, although P 2 Y 12 inhibitor choice in DAPT might be influenced by gender, a DAPT choice, tailored by balancing the ischemic/bleeding risk, has a similar clinical outcome irrespective of gender.

The epidemiology and management of patients with acute coronary syndromes (ACSs) have evolved. We aimed to describe recent demographics and therapeutic changes in the Italian ACS population. We analyzed data from 2 multicenter consecutive Italian registries (the EYESHOT [EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalised in iTalian cardiac care units] and START-ANTIPLATELET registries) enrolling patients with ACS between December 2013 and June 2016. An overall population of 3756 patients with ACS was enrolled: 2585 in the EYESHOT and 1171 in the START-ANTIPLATELET. Compared with the EYESHOT, patients in the START-ANTIPLATELET registry presented more frequently with ST-segment elevation myocardial infarction and were more often smokers and dyslipidemic (all P < .001) and had atrial fibrillation ( P = .018) but were less frequently aged ≥75 years and with a history of major bleeding (all P < .001). Analysis of treatment strategy showed a significant increase in the use of percutaneous coronary intervention, drug-eluting stents, dual antiplatelet therapy, and ticagrelor in the START-ANTIPLATELET (all P < .001), with a substantial decline in the proportion of patients conservatively managed and on clopidogrel at discharge ( P < .001). A lower rate of in-hospital events was recorded in the START-ANTIPLATELET compared with the EYESHOT. The START-ANTIPLATELET and EYESHOT registries provide consecutive snapshots in the contemporary management of patients with ACS in Italy, showing important changes in both demographic characteristics and treatment strategies.

Background: New oral anticoagulants may simplify long-term therapy in conditions requiring anticoagulation. Rivaroxaban is a direct factor Xa inhibitor that has been extensively studied and is now approved for the prevention and therapy of a number of thromboembolic conditions., Objective and Methods: This is a multicentre, randomized, open-label, study that will evaluate if Rivaroxaban 20 mg od (or 15 mg od in patients with moderate renal insufficiency) is non-inferior to warfarin (INR target 2.5), for the prevention of thromboembolic events, major bleeding and death in high risk (triple positive) patients with antiphospholipid syndrome. Secondary endpoints will assess the incidence of any individual component of the composite end point. An external adjudication committee will evaluate all suspected outcome events. This will be a unique trial, as it will enrol the biggest homogenous cohort of high risk APS individuals., Conclusion: The methods and the study design should be appropriate to achieve study results that are both scientifically valid and relevant to clinical practice., (© The Author(s) 2015.)

Background: Ferritin is an iron storage protein considered also as an acute phase reactant with high levels in various inflammatory conditions. Recently, a plausible role for ferritin in the pathogenesis of immune-mediated and especially autoimmune diseases has been suggested. However, the link between ferritin and the antiphospholipid syndrome (APS) has been rarely explored. Therefore, in the current study we evaluated ferritin levels and their correlation to clinical and serological manifestations in patients with APS. We further analyzed ferritin levels among patients with the catastrophic variant of APS (cAPS)., Methods: Ferritin levels were determined in serum samples of 176 APS patients and 98 matched healthy controls according to age and sex (LIAISON, DiaSorin, Italy). APS samples were further analyzed for antiphospholipid (anti-cardiolipin, anti- beta-2-glycoprotein, lupus anticoagulant) and anti-infectious antibodies (CMV, EBV, rubella, toxoplasma, HBV) (LIAISON, DiaSorin, Italy). Clinical, serological and demographic manifestations were recorded. An additional analysis of ferritin levels among 14 patients with cAPS was performed., Results: Hyperferritinemia was present in 9% vs. 0% of APS patients and controls, respectively (p < 0.001). Among patients with APS, ferritin levels correlated with venous thrombosis, cardiac, neurological, and hematological manifestations and the presence of anti-CMV-IgM antibodies. Hyperferritinemia was present in 71% of cAPS patients, and ferritin levels among this subgroup were significantly higher compared with APS-non-cAPS patients (816 ± 847 ng/ml vs. 120 ± 230 ng/ml, p < 0.001)., Conclusions: Herein, we found that hyperferritinemia correlates with the presence of APS, its clinical manifestations and specifically with the catastrophic variant of this disease. Hyperferritinemia was also linked with anti-CMV antibodies among patients with APS. These associations allude to a pathogenic role of ferritin in the pathogenesis of APS, and the plausible role of ferritin as a marker of ensuing cAPS, although further studies are needed to elucidate these associations.

Beta2-glycoprotein I (β(2)GPI), a relevant antigen in Antiphospholipid Syndrome (APS), binds anionic macromolecules including heparin (Hep). A possible formation of ternary complexes between β(2)GPI, antibodies and Hep in APS is thus possible. The aim of this study was to evaluate Hep-β(2)GPI interaction in patients with APS. The affinity of Heps of different length, including unfractionated Hep (UFH), low-molecular weight Hep (enoxaparin) and pentasaccharide (fondaparinux), to human β(2)GPI was estimated by fluorescence spectroscopy, yielding dissociation constant (K(d)) values of 1.1, 24.0 and 89.4 µM, demonstrating that the longer UFH binds to β(2)GPI far more tightly than the shorter ones. Plasma and protein G-purified IgGs from eight patients with APS (i.e. five with thromboembolic disease and three with catastrophic APS), were fractionated by affinity chromatography using a Hep (UFH)-bound column, eluted with a linear NaCl gradient. For each chromatographic analysis, fractions were collected in the whole NaCl gradient and tested by ELISA for the presence of β(2)GPI and anti-β(2)GPI IgG. The results of Hep-affinity chromatography and ELISAs concurrently indicate that either β(2)GPI and anti-β(2)GPI IgG elute from the Hep column in the same chromatographic peak, at a retention time identical to that of the purified, isolated β(2)GPI, thus suggesting that circulating immunocomplexes containing β(2)GPI are present in patients with APS.

Results for lupus anticoagulant (LA) are expressed as ratio of patient-to-normal clotting times (LA-ratio) according to the equation LA-ratio = (Patient(Clotting time)/Normal(Clotting time)). However, numerical results vary according to the method used for testing, thus making difficult the between-method and between-laboratory comparison of results. The hypothesis that the standardization model currently employed for the international normalized ratio for patients on warfarin is valid also for LA standardization has been taken into consideration. The model calls for the determination of a LA-sensitivity index (LASI) for each commercial method for LA detection against a common standard method. The LASI is then used to convert the LA-ratio into a scale called standardized LA-ratio (SLA-ratio) according to the equation SLA-ratio = (LA-ratio)(LASI). The model proved effective in minimizing the between-method variability of results for LA detection. If implemented it could be a valuable tool to improve the comparability of results obtained in different laboratories, to quantify the LA potency and thus pave the way to the organization of collaborative clinical trials aimed at assessing whether the potency of LA is a risk factor for clinical events.

Antiprothrombin (aPT) antibodies may be detected by an enzyme-linked immunosorbent assay (ELISA) using a purified antigen or a phosphatidylserine/prothrombin complex (aPS/PT). IgG/IgM antibodies directed against aPS/PT were assessed in 158 patients with primary antiphospholipid syndrome (PAPS). They were detected in 80/158 (50.6%) PAPS patients; IgG alone was positive in 12 (7.6%), IgM alone in 36 (22.8%), and both IgG and IgM isotypes in 32 (20.2%) PAPS patients. IgG and IgM aPS/PT were significantly associated with both vascular thrombosis and pregnancy morbidity. IgG aPS/PT was significantly associated with venous thrombosis (p = 0.023), whilst IgG and IgM aPS/PT were associated with arterial thrombosis (p < 0.001 and p < 0.001, respectively). Logistic regression analysis showed that IgM and IgG aPS/PT were independent risk factors for thrombosis (odds ratio (OR) 3.5 [95% confidence interval (CI) 1.6-7.9] and OR 4.1 [95% CI 1.4-11.7], respectively) and IgM aPS/PT was an independent risk factor for arterial thrombosis (OR 2.7 [95% CI 1.1-6.7]). In conclusion, these findings indicate that aPS/PT are clinically relevant in PAPS.

Secondary prevention of venous thromboembolism in antiphospholipid syndrome (APS) is usually made using vitamin K antagonists (VKAs) to maintain an international normalized ratio (INR) between 2.0 and 3.0. The optimal intensity of anticoagulation was determined in two prospective randomized controlled trials, both excluding the benefit of more intense anticoagulation. The same regimen is also recommended in patients with APS and arterial thromboembolism as aspirin does not appear to protect against recurrences. The duration of treatment is usually indefinite because of a substantial risk of recurrence.

Treatment of pregnant women with antiphospholipid syndrome (APS) should be set apart from that from thrombotic APS patients. Patients with a history of pregnancy morbidity but no vascular thrombosis are usually treated with a prophylactic dose of heparin plus low-dose aspirin; whereas, those with previous vascular thrombosis alone or associated with previous pregnancy morbidity, are commonly treated with a therapeutic dose of heparin generally combined with low-dose aspirin. However, in about 20% of pregnant APS women these regimens fail. In this context, we conducted a case-control study on a large multicentre cohort of conventionally treated pregnancies to verify whether specific laboratory profiles and/or clinical characteristics are predictive of unsuccessful pregnancy outcome during conventional treatments. Multivariate analysis showed that pregnancy failure during conventional therapies was independently associated with a history of both thrombosis and pregnancy morbidity, the presence of systemic lupus erythematosus (SLE) or other systemic autoimmune diseases and triple antiphospholipid antibody positivity. With the aim to discover the most effective and safe treatments in high-risk pregnant APS women a large-scale multicentre study focusing on the effect of treatments on pregnancy outcome in women with APS and further risk factors for pregnancy failure has been designed.

A single positive laboratory test among those exploring the presence of antiphospholipid antibodies is not associated with thromboembolic events and does not identify patients with antiphospholipid syndrome. On the other hand, more than one laboratory test positive, and in particular all three tests positive, is strongly associated to thromboembolic events and identifies high risk patients. Triple positivity is in fact related to the presence of a specific anti-β2-glycoprotein I (anti-Domain I) antibody, also able to prolong coagulation tests. Monoclonal antibodies against Domain I with Lupus Anticoagulant activity might be candidate material for standardization of antiphospholipid assays. Much work remains to be done in this field.

While mainly based on the use of fluorinated steroids, there is no standard management of anti-Ro/La-related congenital heart block (CHB). This is a report concerning two consecutive cases of anti-Ro/La-related second-degree block treated with betamethasone (4 mg/day), weekly plasmapheresis, and intravenous immunoglobulins (IVIGs; 1 g/kg) administered every 15 days, a therapy that was begun shortly after CHB was detected and continued until delivery. The newborns were also treated with IVIG (1 g/kg) soon after birth and continued fortnightly until the anti-Ro/La antibody levels became undetectable. In both cases second-degree AV block reverted to a stable sinus rhythm with a first-degree atrioventricular (AV) block. Moreover, there was no recurrence of CHB when therapy was suspended, as confirmed by a 29 month and an eight month follow-up, respectively.

The antiphospholipid syndrome (APS) is defined by the presence of thrombosis and/or pregnancy morbidity in combination with the persistent presence of circulating antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies and/or anti-β2-glycoprotein I antibodies in medium to high titers. The management of thrombosis in patients with APS is a subject of controversy. This set of recommendations is the result of an effort to produce guidelines for therapy within a group of specialist physicians in Cardiology, Neurology, Hematology, Rheumatology and Internal Medicine, with a clinical and research focus on APS.

Current classification criteria for definite antiphospholipid syndrome (APS) mandate the use of one or more of three positive 'standardized' laboratory assays to detect antiphospholipid antibodies (aPL) (viz: anticardiolipin [aCL] IgG and IgM; anti-β(2)glycoprotein I [anti-β(2)GPI] antibodies IgG and IgM; and/or a lupus anticoagulant [LAC]), when at least one of the two major clinical manifestations (thrombosis or pregnancy losses) are present. Although, efforts of standardization for these 'criteria' aPL tests have been conducted over the last 27 years, reports of inconsistencies, inter-assay and inter-laboratory variation in the results of aCL, LAC, and anti-β(2)GPI, and problems with the interpretation and the clinical value of the tests still exist, which affect the consistency of the diagnosis of APS. A Task Force of scientists and pioneers in the field from different countries, subdivided in three working groups, discussed and analyzed critical questions related to 'criteria' aPL tests in an evidence-based manner, during the 13(th) International Congress on Antiphospholipid Antibodies (APLA 2010, April 13-16, 2010, Galveston, TX). These included: review of the standardization and the need for international consensus protocol for aCL and anti-β(2)GPI tests; the use of monoclonal and/or polyclonal standards in the calibration curve of those tests; and the need for establishment of international units of measurement for anti-β(2)GPI tests. The group also reviewed the recently updated guidelines for LAC testing, and analyzed and discussed the possibility of stratification of 'criteria' aPL tests as risk factors for APS, as well as the clinical value of single positive vs. multiple aPL positivity. The group members presented, discussed, analyzed data, updated and re-defined those critical questions at a preconference workshop that was open to congress attendees. This report summarizes the findings, conclusions, and recommendations of this Task Force.

Antiphospholipid syndrome (APS) is diagnosed in the presence of vascular thrombosis or pregnancy morbidity occurring in patients with circulating antiphospholipid antibodies (lupus anticoagulant [LA] and/or IgG/IgM anticardiolipin [aCL] and/or IgG/IgM anti-beta2glycoprotein I [abeta2GPI] antibodies). Each test may identify different autoantibodies; a single test makes the diagnosis possible when positive on two or more occasions at least 12 weeks apart. However, single test positivity may be unrelated to pathogenic antibodies, which are now considered to be a subclass of abeta2GPI antibodies directed against the domain I of this protein. Conversely, all three positive tests identify a single class of abeta2GPI antibodies, thus identifying high-risk patients with APS.

The objective of this study was to evaluate the safety and efficacy of low-intensity warfarin treatment plus aspirin during the first 6 months after surgery in patients undergoing heart valve substitution with mechanical prostheses. Vitamin K antagonists (VKA) are able to reduce but not eliminate thrombosis and systemic embolism in patients with mechanical heart valves. The intensity of treatment and additional use of aspirin in these patients is still controversial. Consecutive patients undergoing aortic or mitral valve replacement (or a combination of the two) with mechanical prostheses were invited to participate in the study. After stratifying for site of prosthesis, patients were randomized to receive low intensity VKA treatment (target INR 2.5) plus aspirin (100 mg/day) for the first six months (Group A) or standard-intensity (INR target 3.7) VKA treatment (Group B). Mean follow-up was 1.5 years. Principal outcome events were systemic embolism, major bleeding, and vascular death. A total of 94 patients in Group A and 104 in Group B were randomized and followed up for 144 and 163 patient years, respectively. There were 5 (5%) events in Group A (4 major bleeding events and 1 vascular death) and 4 (4%) in group B (2 major bleeding events and 2 ischemic stroke). All the events except 1 occurred within the first 6 months after surgery. Cumulative incidence of primary outcome events was 5.8% (95% CI 0.9 to 10.7) in Group A and 4.3% (95% CI 0.2 to 8.4) in Group B (p=0.6). Low-intensity treatment plus aspirin during the first six months after surgery appears to be as effective and safe as moderate-high-intensity anticoagulation.

The optimal therapeutic management of patients with antiphospholipid syndrome (APS) during pregnancy is debatable. In the present prospective cohort study the use of a low molecular weight heparin (LMWH) (nadroparin), administered alone twice daily in 30 pregnant women who were diagnosed with APS on the basis of the current classification criteria, is evaluated. Dosage was adjusted according to anti-Xa levels in the patients as the pregnancies progressed. Three women, in whom an important gradual fall in platelet count in the first trimester did not respond to increased nadroparin doses, were shifted to a second-line treatment protocol. Fetal loss occurred in two of the 27 remaining women (7.40%), while 25 (92.59%) delivered 25 live infants, between the 32nd and 40th weeks of gestation. No fetal problems were registered during pregnancies, while maternal complications occurred in two of the 25 patients (8%). Moreover, there were no thrombotic events in any of the women during the study. Patient compliance was good and only minor side-effects were reported. The results of this study indicate that nadroparin alone is useful and safe in the management of pregnant patients with APS. However, in consideration of the good pregnancy outcome obtained in patients with only pregnancy morbidity when heparin and aspirin were used together, other studies comparing nadroparin twice daily with once daily plus Aspirin would be useful to ascertain which is more effective in these patients.

Classic anticoagulant drugs are very effective, save lives and have been used for more than 50 years. Nevertheless, some drawbacks are encountered in their routine clinical use. Recently, pharmaceutical research has developed new drugs, some of which are already on the market. This is the case of fondaparinux, a pentasaccharide which can interact with antithrombin, thus inhibiting factor Xa. Modification of its structure (idraparinux) has led to more stable binding with antithrombin and to an increase in its half-life allowing for once-a-week administration. Another important oral compound is ximelagatran which directly binds thrombin and blocks its catalytic site. There is no need for laboratory control, and phase II and phase III studies are encouraging. Thus, in the next few years, we may witness great changes in the treatment of patients with thromboembolic disorders.

Failure of anticoagulant therapy in a patient with a St. Jude heart valve in the mitral position is reported. After 8 years of optimal anticoagulation at an International Normalized Ratio between 2.5 and 3.5, a floating thrombus was discovered by chance during transthoracic echocardiography and then surgically removed. A study for congenital or acquired thrombophilia disclosed a positivity for activated protein C resistance, due to the presence of factor V Leiden. The intensity of warfarin anticoagulation was increased to provide more protection for the patient.

This study was undertaken to determine whether a prolongation of pharmaceutical antithrombotic prophylaxis beyond hospitalization for hip fracture is associated with a reduced mortality rate. One hundred seventy-nine cases with hip fracture (patients older than 50 years of age) admitted to local general hospitals in 1999 who received postdischarge prescription of any antithrombotic agent (heparin, oral anticoagulants, antiplatelet drugs) and 179 age- and sex-matched patients with hip fracture who did not were included. Postdischarge mortality was assessed at 90 days. Compared with patients who did not receive postdischarge prescription of antithrombotic agents, those who did had an odds ratio of 0.22 (95% confidence interval 0.08-0.59) for all causes of mortality. This result did not change after excluding nonvascular mortality (odds ratio, 0.17; confidence interval, 0.03-0.73; p=0.011). Patients admitted to the hospital for hip fracture are at high risk of death after discharge if they are not given antithrombotic treatment. To substantiate these data, ad hoc prospective randomized trials are needed.

Temporary discontinuation of high-intensity oral anticoagulant treatment is not recommended in patients undergoing dental surgery. This policy is not based on solid data from randomized clinical trials but on expert consensus. The alternative, i.e., to continue treatment and treat patients with tranexamic acid mouthwash, often is not applicable. A prospective cohort study was carried out to evaluate bleeding and thromboembolic complications in patients bearing prosthetic heart valves and registering International Normalized Ratio (INR) values between 2.0 and 4.5, who underwent dental procedures after a 2-day suspension of warfarin treatment. One hundred four consecutive patients receiving high-intensity anticoagulation underwent 123 dental procedures after 2 days' warfarin withdrawal. No major bleeding complications occurred in the week after the procedure; minor bleeding requiring local measures occurred in two patients. No thromboembolic events and no cases of bacterial endocarditis were recorded in the 3 months after the procedure. A mean decrease in INR by approximately 1.0 U (from 2.95+/-0,59 to 1.87+/-0,46) occurred after 2 days' warfarin suspension. Seven days after reinitiation of warfarin, INR values returned to the therapeutic range in 90% of cases. The calculated average time spent at INR less than 2.0 (critical value) was 28 hours. Two days' warfarin suspension is a simple and safe policy for patients with prosthetic heart valves undergoing dental surgery.

Antiphospholipid syndrome (APS) is defined by the presence of aPL antibodies in patients with thromboembolic phenomena. Some antiphospholipid (aPL) antibodies, such as those directed against beta2-glycoprotein I (beta2GPI), are associated with thromboembolism, possess Lupus Anticoagulant (LA) activity and recognize their target antigen only when bound to specific surfaces or to phospholipids (PL). To ascertain whether both free and antibody-bound beta2GPI circulate in APS, we set up an ELISA to detect [IgG anti-beta2GPI-beta2GPI] immune complexes. In this system, rabbit anti-human beta2GPI antibodies were adsorbed onto plastic plates, incubated with patient plasma, and bound complexes were detected by means of alkaline phosphatase-labeled goat anti-human IgG; each assay was stopped when positive controls consisting of in vitro generated immune complexes reached an Optical Density (OD) of 0.5 at 405 nm. Plasma from 16 patients with APS showed a mean OD405 of 0.291 (range 0.115-0.558), not statistically different from the mean obtained for 15 age- and sex-matched healthy volunteers (mean OD405 = 0.169, range 0.066-0.264). Surprisingly, levels of immune complexes in 14 patients with other autoimmune diseases and no circulating anti-beta2GPI antibodies were statistically higher (mean OD405 = 0.552, range 0.204-0.991) than those of healthy subjects and patients with APS. These data indicate that while autoantibodies to beta2GPI are mainly unbound in plasma of patients with APS, they are complexed with their antigen in patients with other autoimmune diseases, possibly reflecting a higher binding affinity.

Antithrombin III (AT III), the primary inhibitor of plasma protease coagulation proteins, was evaluated in groups of patients with different neoplastic disease. When compared with that of 25 health subjects, the mean value of AT III biologic activity was elevated in all groups, significantly in gastrointestinal (p less than 0.02) and lung (p less than 0.001) tumors, lymphoma (p less than 0.02) and in the group with various primary cancers (p less than 0.05). No difference was found between 46 patients tested under chemoradiotherapy and 216 patients who had not undergone therapy for at least 1 month. Four patients with clinical thrombosis had normal ATIII biologic activity. Of the 262 patients studied, 14 had low AT III biologic activity without clinical thrombosis and normal protein concentration. In 71 patients (27%) an excess of immunoassayable protein of 20% or more over biologic activity was found. Double immunoelectrophoresis performed in 5 of these showed for 3 patients an enlarged second are of precipitation. Moreover, no correlation was observed between the activity and protein AT III concentration (r = 0.05). The likelihood of the presence of circulating AT III-protease complexes is discussed.

Forty-four patients (9 stage II, 15 sage III, 7 stage IV, and 13 in complete remission) with Hodgkin's disease without any clinical coagulation disorder were studied. Fibrinogen behavior was evaluated by measuring fibrinogen level and using 1251-fibrinogen, the half-life, survival and fibrinogen turnover. Platelet count and fibrinogen/fibrin degradation products (FDP) were also assayed. The fibrinogen half-life, survival and turnover were significantly longer and faster, than those found in 10 healthy subjects, in stage II, III and IV subjects (p less than 0.001, p less than 0.001, p less than 0.05 for stage II; p less than 0.001, p less than 0.001, p less than 0.001 for stage III; p less than 0.005, p less than 0.005, p less than 0.001 for stage IV, respectively). In most cases, FDP values were within the normal range, although they were significantly higher than those of control group in stages III and IV. Intravascular coagulation and fibrinolysis were not found in the 13 patients with complete remission. In these patients, the behavior of fibrinogen was normal, suggesting that the parameters studied are related to the presence of the tumor, and can be useful in monitoring the state of remission.