Thrombin Generation Assay in Antiphospholipid Antibodies Positive Subjects as a Personalized Thrombotic Risk Assessment: State of the Art and Perspectives.

PURPOSE OF THE REVIEW: Thrombotic risk assessment in antiphospholipid positive (aPL +) subjects is a major challenge, and the study of in vitro thrombin generation (thrombin generation assays (TGA)) could provide useful information. Activated protein C (APC) sensitivity is involved in thrombotic events in antiphospholipid syndrome patients. We summarized methods used to assess APC sensitivity with TGA and evaluated the prognostic role of APC resistance through literature search. RECENT FINDINGS: APC resistance induced by aPL is a complex pathway. Several cross-sectional studies assessed APC sensitivity to understand thrombotic event mechanisms in aPL + subjects. Only one prospective cohort had investigated the prognostic impact of APC resistance in aPL + subjects, with a positive and significant correlation between APC sensitivity and the risk of thrombosis during the follow up (hazard ratio, 6.07 [95% CI, 1.69-21.87]). APC resistance assessed with TGA could be associated with thrombotic events in aPL + subjects.

Thrombocytopenia in antiphospholipid syndrome: Is anticoagulation and/or antiaggregation always required?

The antiphospholipid syndrome (APS) is an autoimmune and prothrombotic condition defined by the association of thrombotic events and/or obstetrical complications and the persistence of antiphospholipid antibodies (aPL) over time. Among the new criteria recently included in the 2023 ACR/EULAR classification criteria for APS, thrombocytopenia is one of the most frequent. The occurrence of thrombocytopenia in aPL/APS patients is important to consider because it could predict APS-related clinical events with a 3-fold increased risk for thrombotic events or obstetrical morbidity or all-cause deaths. A debate on the need or not of anticoagulation and/or antiaggregation in APS patients and aPL carriers with thrombocytopenia took place on the 7th edition of the International Congress on Controversies in Rheumatology and Autoimmunity (CORA), that was organized in Turin, Italy, on March 18th, 2023, and this review summarizes the main arguments that were discussed in this session.

Obturator Bypass Remains a Useful Option.

BACKGROUND: The femoral tripod remains technically crucial in vascular surgery, as well for an elective revascularization as for an extensive approach to the arterial tree. The management of septic complications and healing disorders in this area is really challenging. Obturator bypass (OB) represents an alternative sometimes employed in this context, but few recent series were recently published. The objectives of this work were thus to evaluate the results of OB in terms of patency, morbi-mortality, healing evolution and absence of reinfection. METHODS: This was a monocentric retrospective study including all the patients treated by OB, whatever the cause, between January 2010 and December 2020. Primary outcomes were the primary and the secondary patencies. The secondary outcomes were the morbi-mortality, freedom from infection and healing. RESULTS: During this period, 23 OBs were carried out in 22 patients, with a majority of men (77%) whose median age was 70 years [34-87]. The indications were infection in 19 patients (86%), and iterative thrombosis in 3 patients (14%). The substitute was an arterial allograft in 82% of the cases, and the outflow was the deep femoral artery only in 14% of the cases. The median operative time was 224 min [111-391] and median blood losses were 900 mL [300-3,900]. We observed 7 systemic (32%), and 8 local complications (36%). Healing was obtained in 90% of the cases, and freedom from infection was obtained in 100% of the cases. The median duration of follow-up was 594 days [5-2,517]. One-year, 2-year and 3-year primary patency rates were 84%, 78%, and 63%, respectively. One-year, 2-year and 3-year secondary patencies were 94%, 94%, and 80%, respectively. One-month, 1-year, 2-year and 3-year survival rates were 86%, 73%, 67%, and 53%, respectively. CONCLUSIONS: Our study showed that the OB represents a relevant alternative in the event of complex lesions of the femoral tripod, with good patency and healing rates and good infection control. On the other hand, its consequences in terms of morbi-mortality confirm that OB is a major surgery that should be used when a traditional approach is not possible.

Circulating Endothelial Cells are Associated with Thromboembolic Events in Patients with Antiphospholipid Antibodies.

BACKGROUND: Endothelial damage has been described in antiphospholipid antibody (aPL)-positive patients. However, it is uncertain whether circulating endothelial cells (CECs)-which are released when endothelial injury occurs-can be a marker of patients at high risk for thrombosis. METHODS: Ninety-seven patients with aPL and/or systemic lupus erythematosus (SLE) were included. CECs were determined by an automated CellSearch system. We also assayed plasma levels of tissue factor-bearing extracellular vesicles (TF+/EVs) and soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) as markers of endothelial dysfunction/damage. RESULTS: Patients' mean age was 46.1 ± 13.9 years, 77 were women. Thirty-seven had SLE and 75 patients were suffering from antiphospholipid syndrome. Thirty-seven percent of patients presented a medical history of arterial thrombosis and 46% a history of venous thromboembolism (VTE). Thirteen patients had increased levels of CECs (>20/mL), with a mean CEC level of 48.3 ± 21.3 per mL. In univariate analysis, patients with obesity or medical history of myocardial infarction (MI), VTE, or nephropathy had a significant increased CEC level. In multivariate analysis, obesity (odds ratio [OR] = 6.07, 95% confidence interval [CI]: 1.42-25.94), VTE (OR = 7.59 [95% CI: 1.38-41.66]), and MI (OR = 5.5 [95% CI: 1.1-26.6)] were independently and significantly associated with elevated CECs. We also identified significant correlations between CECs and other markers of endothelial dysfunction: sTREM-1 and TF+/EVs. CONCLUSION: This study demonstrated that endothelial injury assessed by the levels of CECs was associated with thromboembolic events in patients with aPL and/or autoimmune diseases.

Risk of livedo with antiphospholipid antibodies in patients with systemic lupus erythematosus: A systematic review and meta-analysis.

BACKGROUND: Livedo is a well-known skin condition in patients with systemic lupus erythematosus (SLE) which correspond to small vessels involvement. The influence of antiphospholipid antibodies (aPL) on the occurrence of livedo is controversial. The aim of our study was to estimate the risk of livedo associated with aPL in patients with SLE. METHODS: We conducted a systematic review and meta-analysis of the literature from 1977 to 2021 to estimate the risk of livedo in SLE patients according to different aPL profiles. Data sources were PubMed, Embase, Cochrane Library, hand search, and reference lists of studies. Studies were selected if they included SLE patients with descriptions of the exposure to aPL and the outcome (livedo). Two independent investigators assessed study eligibility, quality, and extracted patient characteristics from each study as well as exposure (aPL) and outcome (livedo). Risk estimates were pooled using random effects models and sensitivity analyses. For all stages of the meta-analysis, we followed the PRISMA guidelines. PROSPERO registration number: CRD42015027377. RESULTS: Of the 2,355 articles identified, 27 were included with a total of 4,810 SLE patients. The frequency of livedo was 25.5% in aPL-positive patients and 13.3% in aPL-negative patients. The overall Odds Ratio (OR) for livedo in aPL-positive patients compared to aPL-negative patients was 2.91 (95% CI; 2.17-3.90). The risk of livedo was significantly increased for most of aPL subtypes, including lupus anticoagulant (LA) (OR = 4.45 [95% CI; 2.21-8.94]), IgG anticardiolipin (OR = 3.95 [95% CI; 2.34-6.65]), and IgG anti-ß2-glycoprotein 1 (OR = 3.49 [95% CI; 1.68-7.27]). CONCLUSIONS: We demonstrated in this meta-analysis an excess risk of livedo in aPL-positive SLE patients compared to aPL-negative patients. For daily practice, in patients with SLE, livedo associated with aPL could correspond to a peculiar group of patients with small vessel disease. Livedo could be a good candidate for inclusion in future classification criteria for antiphospholipid syndrome.

Association between carotid revascularization for asymptomatic stenosis and cognitive functions.

Asymptomatic carotid stenosis (ACS) can cause cognitive dysfunction, related to cerebral hypoperfusion and microemboli. These mechanisms could be treated by carotid revascularization, but the impact of carotid angioplasty stenting (CAS) or carotid endarterectomy (CEA) on cognitive functions remains unclear. The aim of this systematic review was to realize a report on the actual state of results about asymptomatic carotid stenosis revascularization and cognitive function. We performed a systematic literature review to analyze all studies assessing the impact of asymptomatic carotid stenosis revascularizations on cognitive functions. We reviewed all publications published in Medline database and Cochrane between January 2010 and January 2020 including subjects with a cognitive evaluation and receiving carotid revascularization for asymptomatic stenosis. We identified 567 records for review, and finally we included in the systematic review 20 studies about ACS revascularization and cognitive functions. Only observational studies analyzed the impact of CEA and CAS on cognitive functions. Thus, too heterogeneous data associated to the lack of randomized controlled trials with an evaluation of optimal medical treatment did not enable to affirm the interest of the revascularization management of ACS in cognitive domain. There was a lack of standardization and finally studies were too heterogeneous to conclude on the impact of carotid revascularization on cognitive functions. There is an urgent need to harmonize research in this domain in order to prevent and treat cognitive dysfunction related to ACS, especially in our society with an aging population.

Antiphospholipid antibodies and the risk of autoimmune hemolytic anemia in patients with systemic lupus erythematosus: A systematic review and meta-analysis.

BACKGROUND: According to criteria for the classification of Systemic Lupus Erythematosus (SLE), autoimmune hemolytic anemia is one of the disease-defining hematologic disorders together with thrombocytopenia. Since the recognition of Antiphospholipid Syndrome (APS), hemolytic anemia was frequently reported but several studies yielded contradictory results on the association between antiphospholipid antibodies (aPL) and hemolytic anemia. Therefore, we evaluated the association of aPL and autoimmune hemolytic anemia in SLE patients by conducting a systematic review and meta-analysis of available literature. METHODS: MEDLINE, EMBASE, Cochrane Library, congress abstracts, and reference lists of eligible studies were searched from 1987 to 2020. Studies were selected if they included SLE patients with descriptions of exposure to aPL and occurrence of hemolytic anemia. Three reviewers extracted study characteristics and association data from published reports. Risk estimates were pooled using random effects models and sensitivity analyses. We followed the PRISMA guidelines for all stages of the meta-analysis (Supplemental Table). PROSPERO registration number: CRD42015027376. RESULTS: From 3555 articles identified, 38 studies met inclusion criteria and included 8286 SLE patients. 20.5% of aPL-positive SLE patients had hemolytic anemia compared to 8.7% in aPL-negative SLE patients. The overall pooled Odds Ratio (OR) for hemolytic anemia in aPL positive patients was 2.83 (95% CI; 2.12-3.79). Among aPL subtypes, the risk of hemolytic anemia was highest for lupus anticoagulant (OR = 3.37 [95% CI; 2.26-5.04]) and, antiß2Glycoprotein I antibodies (OR = 3.21 [95% CI; 1.54-6.72]), especially IgM antiß2Glycoprotein I (OR = 3.01 [95% CI; 1.26, 7.24]). CONCLUSIONS: The occurrence of hemolytic anemia was strongly associated with presence of aPL in SLE patients. Interestingly, IgM isotypes indicate an increased risk of hemolytic anemia in SLE.

A new pro-thrombotic mechanism of neutrophil extracellular traps in antiphospholipid syndrome: impact on activated protein C resistance.

OBJECTIVES: In APS, precise evaluation of thrombotic risk is a major challenge. Different players, such as activated protein C (APC) resistance or neutrophil extracellular traps (NETs) contribute to the risk of thrombosis. Nevertheless, no study has investigated the interaction between these actors. The main objective of this study was to investigate the relation between NETs and APC resistance. METHODS: We designed a cross-sectional study including APS/antiphospholipid antibodies (aPL) patients and patients with autoimmune diseases (AID). We performed thrombin generation tests without and with APC to determine APC resistance. To evaluate circulating NETs, we measured plasma levels of MPO-DNA complexes and cell-free DNA with ELISA. RESULTS: We recruited 117 patients with definite APS/aPL or AID. We found a positive correlation between NETs and APC resistance, in APS patients and specifically in patients with high thrombotic risk, displaying LA or positivity of all three aPL tests (triple+), or anti-domain I IgG (aDI+). All these patient subgroups had increased NETs concentrations and APC resistance. As the risk profile for thrombosis increased, the relationship between NETs and APC resistance was stronger. CONCLUSION: We have shown that NETs participate in the hypercoagulable state of APS patients by contributing to APC resistance, in particular in high-risk patients. In these most at-risk patients, a targeted action on NETs could reduce APC resistance and constitute a new therapeutic approach in the treatment of APS patients in addition to antithrombotic therapy.

Systematic Review of Antiphospholipid Antibodies in COVID-19 Patients: Culprits or Bystanders?

PURPOSE OF REVIEW: COVID-19 patients have a procoagulant state with a high prevalence of thrombotic events. The hypothesis of an involvement of antiphospholipid antibodies (aPL) has been suggested by several reports. Here, we reviewed 48 studies investigating aPL in COVID-19 patients. RECENT FINDINGS: Prevalence of Lupus Anticoagulant (LA) ranged from 35% to 92% in ICU patients. Anti-cardiolipin (aCL) IgG and IgM were found in up to 52% and up to 40% of patients respectively. Anti-ß2-glycoprotein I (aß2-GPI) IgG and IgM were found in up to 39% and up to 34% of patients respectively. Between 1% and 12% of patients had a triple positive aPL profile. There was a high prevalence of aß2-GPI and aCL IgA isotype. Two cohort studies found few persistent LA but more persistent solid phase assay aPL over time. aPL determination and their potential role is a real challenge for the treatment of this disease.

Atypical paronychia: don't forget herpesvirus.

Paronychia is usually caused by bacterial infections. Herpetic whitlow is an acute infection of the fingers or toes caused by herpes simplex viruses and it typically presents with vesicles. We report the case of a 78-year-old woman with gingivostomatitis and atypical paronychia in several fingers without blisters.