This invited review follows the oral presentation “To Sequence or Not to Sequence, That Is Not the Question; But ‘When, Who, Which and What For?’ Is” given during the State of the Art session ...“Translational Genomics in Thrombosis: From OMICs to Clinics” of the International Society on Thrombosis and Haemostasis 2023 Congress. Emphasizing the power of next-generation sequencing technologies and the diverse strategies associated with DNA variant analysis, this review highlights the unresolved questions and challenges in their implementation both for the clinical diagnosis of venous thromboembolism and in translational research.
Newer P2Y12 blockers (prasugrel and ticagrelor) demonstrated significant ischaemic benefit over clopidogrel after acute coronary syndrome (ACS). However, both drugs are associated with an increase in ...bleeding complications. The objective of the present study was to evaluate the benefit of switching dual antiplatelet therapy (DAPT) from aspirin plus a newer P2Y12 blocker to aspirin plus clopidogrel 1 month after ACS.
We performed an open-label, monocentric, and randomized trial. From March 2014 to April 2016, patients admitted with ACS requiring coronary intervention, on aspirin and a newer P2Y12 blocker and without adverse event at 1 month, were assigned to switch to aspirin and clopidogrel (switched DAPT) or continuation of their drug regimen (unchanged DAPT). The primary outcome was a composite of cardiovascular death, urgent revascularization, stroke and bleeding as defined by the Bleeding Academic Research Consortium (BARC) classification ≥2 at 1 year post ACS. Six hundred and forty six patients were randomized and 645 analysed, corresponding to 322 patients in the switched DAPT and 323 in the unchanged DAPT group. The primary endpoint occurred in 43 (13.4%) patients in the switched DAPT group and in 85 (26.3%) patients in the unchanged DAPT (HR 95%CI 0.48 (0.34-0.68), P < 0.01). No significant differences were reported on ischaemic endpoints, while BARC ≥ 2 bleeding occurred in 13 (4.0%) patients in the switched DAPT and in 48 (14.9%) in the unchanged DAPT group (HR 95%CI 0.30 (0.18-0.50), P < 0.01).
A switched DAPT is superior to an unchanged DAPT strategy to prevent bleeding complications without increase in ischaemic events following ACS.
An unbiased approach to SARS-CoV-2-induced immune dysregulation has not been undertaken so far. We aimed to identify previously unreported immune markers able to discriminate COVID-19 patients from ...healthy controls and to predict mild and severe disease.
An observational, prospective, multicentric study was conducted in patients with confirmed mild/moderate (n = 7) and severe (n = 19) COVID-19. Immunophenotyping of whole-blood leukocytes was performed in patients upon hospital ward or intensive care unit admission and in healthy controls (n = 25). Clinically relevant associations were identified through unsupervised analysis.
Granulocytic (neutrophil, eosinophil, and basophil) markers were enriched during COVID-19 and discriminated between patients with mild and severe disease. Increased counts of CD15+CD16+ neutrophils, decreased granulocytic expression of integrin CD11b, and Th2-related CRTH2 downregulation in eosinophils and basophils established a COVID-19 signature. Severity was associated with emergence of PD-L1 checkpoint expression in basophils and eosinophils. This granulocytic signature was accompanied by monocyte and lymphocyte immunoparalysis. Correlation with validated clinical scores supported pathophysiological relevance.
Phenotypic markers of circulating granulocytes are strong discriminators between infected and uninfected individuals as well as between severity stages. COVID-19 alters the frequency and functional phenotypes of granulocyte subsets with emergence of CRTH2 as a disease biomarker.
Background
Although the triple positivity of antiphospholipid antibodies (aPL) is important for classifying high‐risk patients, interpretation of aPL positivity, namely the lupus anticoagulant (LA), ...anti‐cardiolipin (aCL), and anti‐beta2‐glycoprotein I autoantibodies (aB2GPI) remains challenging for thrombotic risk stratification.
Objective
To compare biological and clinical data between triple aPL– and single aCL–positive patients.
Methods
Of the 6500 patients assayed for aPL in daily practice within 3 years, we retrospectively analyzed data from 161 patients that were either triple aPL–positive or single aCL–positive with 5 years’ follow‐up for 121 of them.
Results
Whatever triple or single aPL positivity, we found a high prevalence of “carrier” patients (43%), which led us to question the clinical relevance of the triple aPL positivity. This result also justified the need to identify high‐risk profiles. In asymptomatic patients, high risk of thrombotic events is associated with (1) two positive tests for LA or a Rosner Index >27 combined with both aCL‐IgG and aB2GPI‐IgG positivity, (2) persistent single aCL positivity without an associated autoimmune disease. In symptomatic patients, we demonstrated differences in the phenotype of patients and their therapeutic anticoagulation according to the number of positive aPL but we did not find differences in the number of clinical events, recurrence, or relapse, even in the absence of treatment.
Conclusion
This study shows that the thrombotic risk does not necessarily increase with the number of positive tests and raises the question of the therapeutic management of single aCL–positive patients.
The identification of a bacterial, viral, or even noninfectious cause is essential in the management of febrile syndrome in the emergency department (ED), especially in epidemic contexts such as flu ...or CoVID‐19. The aim was to assess discriminative performances of two biomarkers, CD64 on neutrophils (nCD64) and CD169 on monocytes (mCD169), using a new flow cytometry procedure, in patients presenting with fever to the ED during epidemics. Eighty five adult patients presenting with potential infection were included during the 2019 flu season in the ED of La Timone Hospital. They were divided into four diagnostic outcomes according to their clinical records: no‐infection, bacterial infection, viral infection and co‐infection. Seventy six patients with confirmed SARS‐CoV‐2 infection were also compared to 48 healthy volunteers. For the first cohort, 38 (45%) patients were diagnosed with bacterial infections, 11 (13%) with viral infections and 29 (34%) with co‐infections. mCD169 was elevated in patients with viral infections, with a majority of Flu A virus or Respiratory Syncytial Virus, while nCD64 was elevated in subjects with bacterial infections, with a majority of Streptococcus pneumoniae and Escherichia coli. nCD64 and mCD169 showed 90% and 80% sensitivity, and 78% and 91% specificity, respectively, for identifying patients with bacterial or viral infections. When studied in a second cohort, mCD169 was elevated in 95% of patients with SARS‐CoV‐2 infections and remained at normal level in 100% of healthy volunteers. nCD64 and mCD169 have potential for accurately distinguishing bacterial and acute viral infections. Combined in an easy and rapid flow cytometry procedure, they constitute a potential improvement for infection management in the ED, and could even help for triage of patients during emerging epidemics.
Ethnicity and Haemostasis: Challenge in the genomics era Morange, Pierre‐Emmanuel; Ibrahim‐Kosta, Manal
Journal of thrombosis and haemostasis,
June 2020, 2020-06-00, 20200601, 2020-06, Letnik:
18, Številka:
6
Journal Article
Patients with acute venous thromboembolism (VTE) require anticoagulant therapy to prevent recurrent VTE and death, which exposes them to an inherent increased risk of bleeding. Identification of ...patients at high risk of bleeding, and mitigating this risk, is an essential component of the immediate and long‐term therapeutic management of VTE. The bleeding risk can be estimated by either implicit judgment, weighing individual predictors (clinical variables or biomarkers), or by risk prediction tools developed for this purpose. Management of bleeding risk in clinical practice is, however, far from standardized. International guidelines are contradictory and lack clear and consistent guidance on the optimal management of bleeding risk. This report of the ISTH subcommittee on Predictive and Diagnostic Variables in Thrombotic Disease summarizes the evidence on the prediction of bleeding in VTE patients. We systematically searched the literature and identified 34 original studies evaluating either predictors or risk prediction models for prediction of bleeding risk on anticoagulation in VTE patients. Based on this evidence, we provide recommendations for the standardized management of bleeding risk in VTE patients.
Summary
Venous thromboembolism (VTE) has a strong genetic component. This review summarizes what is known at the seventeen genes that are now well established to harbour VTE‐associated genetic ...variants. In addition, it discusses additional candidate genes that deserve further validation before being claimed as VTE associated genes. Finally, several research strategies are briefly described to identify other molecular determinants of the disease.
Bleeding severity in severe haemophilic patients, with low thrombin generation (TG) capacity, can vary widely between patients, possibly reflecting differences in tissue factor pathway inhibitor ...(TFPI) level.
To compare free TFPI (fTFPI) levels in patients with severe haemophilia A (sHA) and severe haemophilia B (sHB) and to investigate in these patients as a whole the relationships between bleeding and TG potential, between TG potential and fTFPI level and between fTFPI level and bleeding tendency.
Data on bleeding episodes retrospectively recorded during follow-up visits over 5-10 years were collected and used to calculate the annualised joint bleeding rate (AJBR). fTFPI levels and basal TG parameters were determined in platelet-poor plasma (PPP) and platelet-rich plasma (PRP) using calibrated automated tomography (CAT).
Mean fTFPI levels did not differ significantly between sHA (n = 34) and sHB (n = 19) patients. Mean values of endogenous thrombin potential (ETP) and thrombin peak (peak) in PPP and PRP were two-fold higher when fTFPI levels < 9.4 versus > 14.3 ng/mL. In patients treated on demand, ETP and peak in PRP were doubled when AJBR was
, AJBR being halved in patients with a low fTFPI level (9.4 ng/mL). In patients on factor prophylaxis, no association was found between TG parameters and either fTFPI level or AJBR.
In patients treated on demand, bleeding tendency was influenced by fTFPI levels, which in turn affected basal TG potential. In patients on prophylaxis, bleeding tendency is probably determined primarily by the intensity of this treatment.
Background
Coagulation factor V (FV), present in plasma and platelets, has both pro‐ and anticoagulant functions.
Objective
We investigated an FV‐deficient patient (FV:C 3%, FV:Ag 4%) paradoxically ...presenting with recurrent venous thrombosis (11 events) instead of bleeding.
Methods/Results
Thrombophilia screening revealed only heterozygosity for the F2 20210G>A mutation. Although thrombin generation in the patient's platelet‐poor plasma was suggestive of a hypocoagulable state, thrombin generation in the patient's platelet‐rich plasma (PRP) was higher than in control PRP and extremely resistant to activated protein C (APC). This was partially attributable to the complete abolition of the APC‐cofactor activity of FV and a marked reduction of plasma tissue factor pathway inhibitor antigen and activity. The patient was homozygous for a novel missense mutation (Ala2086Asp, FVBesançon) that favors a “closed conformation” of the C2 domain, predicting impaired binding of FV(a) to phospholipids. Recombinant FVBesançon was hardly secreted, indicating that this mutation is responsible for the patient's FV deficiency. Model system experiments performed using highly diluted plasma as a source of FV showed that, compared with normal FVa, FVaBesançon has slightly (≤1.5‐fold) unfavorable kinetic parameters (Km, Vmax) of prothrombin activation, but also a lower rate of APC‐catalyzed inactivation in the presence of protein S.
Conclusions
FVBesançon induces a hypercoagulable state via quantitative (markedly decreased FV level) and qualitative (phospholipid‐binding defect) effects that affect anticoagulant pathways (anticoagulant activities of FV, FVa inactivation, tissue factor pathway inhibitor α level) more strongly than the prothrombinase activity of FVa. A possible specific role of platelet FV cannot be excluded.
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