Relationship between plasma tissue Factor Pathway Inhibitor (TFPI) levels, thrombin generation and clinical risk of bleeding in patients with severe haemophilia A or B.

INTRODUCTION: 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. AIM: 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. METHODS: 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). RESULTS: 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 ≤ 4.9 $ \le 4.9$ , 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. CONCLUSION: 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.

[Point-of-care testing for D-dimer in the exclusion of venous thromboembolism: a critical analysis]. / Les dispositifs délocalisés de dosage des D-dimères dans l'exclusion de la maladie thromboembolique veineuse : une analyse critique.

Point-of-care testing (POCT) for D-dimer is an alternative to -laboratory testing for the exclusion of venous thromboembolism (VTE). This critical review by the "CEC et biologie délocalisée" working group of the "Société Française de Thrombose et d'Hémostase" (French Society of -Thrombosis and Haemostasis) aims to present the characteristics of six POCT D-dimer assays available in France in 2023. The article highlights the need to define VTE -exclusion thresholds specific to each technique and validated by clinical studies. There is insufficient data to validate the use of cut off suggested by manufacturers, and age-adjusted thresholds. The article discusses the role of laboratories in justifying and prescribing POCT D-dimer, according to objective criteria, such as the availability and turnaround time of classical laboratory tests. They should also encourage rational prescribing, limited to patients with low risk of venous thromboembolism, following an assessment of clinical probability according to national and international guidelines.

Factors Influencing Anti-Xa Assays: A Multicenter Prospective Study in Critically Ill and Noncritically Ill Patients Receiving Unfractionated Heparin.

BACKGROUND: The presence of dextran sulfate (DS) in reagents and the type of blood collection tube (citrate/citrated-theophylline-adenosine-dipyridamole [CTAD]) can lead to discrepancies between unfractionated heparin (UFH) anti-Xa levels. OBJECTIVES: To evaluate the extent of the effect (1) of different reagents containing or not containing DS and (2) of the blood collection tubes, on UFH anti-Xa levels, in various clinical situations (NCT04700670). METHODS: We prospectively included patients from eight centers: group (G)1, cardiopulmonary bypass (CPB) after heparin neutralization (n = 39); G2, cardiothoracic intensive care unit (ICU) after CPB (n = 35); G3, medical ICU (n = 53); G4, other medical inpatients (n = 38). Blood was collected into citrated and CTAD tubes. Chromogenic anti-Xa assays were centrally performed, using seven reagent/analyzer combinations including two without DS. The association between anti-Xa levels and covariates was tested using a linear mixed-effects model. RESULTS: We analyzed 4,546 anti-Xa values from 165 patients. Median anti-Xa levels were systematically higher with reagents containing DS, whatever the patient group, with the greatest effect observed in G1 (0.32 vs. 0.05 IU/mL). Anti-Xa levels were slightly higher in CTAD than in citrate samples, irrespective of the assay. The model showed: (1) a significant dextran-patient group interaction (p < 0.0001), the effect of DS on anti-Xa levels varying from 30.9% in G4 to 296% in G1, and (2) a significant effect of CTAD, varying between patient groups (p = 0.0302). CONCLUSION: The variability of anti-Xa levels with a great overestimation of the values, using a reagent containing DS, can lead to different treatment decisions, especially after heparin neutralization by protamine. Clinical consequences of these differences remain to be demonstrated.

Smoking and Activated Clotting Time during coronary angiography and angioplasty: protocol for the ACT-Tobacco trial.

Background: During percutaneous transluminal coronary angioplasty (PTCA), activated clotting time (ACT) measurements are recommended to attest a correct anticoagulation level and, if needed, to administer further unfractionated heparin (UFH) to obtain a therapeutic ACT value. Our clinical routine led us to observe that smokers had lower ACT values after standardized UFH administration during PTCA. Procoagulant status in smokers is well documented. Objectives: To determine whether tobacco negatively affects UFH anticoagulation during PTCA when evaluated by ACT. Methods: The ACT-TOBACCO trial is a single-center, noninterventional, prospective study. The primary end point is the comparison of ACT values after standardized UFH administration between active smokers and nonsmokers (active smoker group vs nonsmoker group) requiring coronary angiography followed by PTCA. The main secondary end points include ACT comparison after the first and second standardized UFH administration according to the patient's smoking status (active, ex-, or nonsmoker) and the clinical presentation of ischemic cardiomyopathy: stable (silent ischemia or stable angina) or unstable (unstable angina or acute coronary syndrome without or with ST-segment elevation). Conclusions: To the best of our knowledge, ACT values during PTCA between smokers and nonsmokers have not previously been compared. As current PTCA procedures increase in complexity and duration, the understanding of procoagulant risk factors such as smoking and the need for reliable anticoagulation monitoring becomes essential to balance hemorrhagic risk against thrombotic risk.

[POCT-management during the first wave of Covid-19 in France. Results of a national survey leaded by the SFBC-POCT Working Group]. / Gestion de la biologie délocalisée lors de la première vague de Covid-19 en France. Résultats de l'enquête nationale menée par le groupe de travail des EBMD de la SFBC.

During the first wave of Covid-19 in France, in spring 2020, healthcare institution's laboratory had to adapt itself quickly to the growing demand for emergency biology, in particular by reorganizing their POCT analyzers: redeployment of analyzers and/or new installations. In order to analyze this management, a subgroup of 15 hospital biologists from the SFBC Working Group "Biochemical markers of Covid-19" sent, in fall 2020, an on-line survey to French hospital laboratories using POCT. Answers analysis (n = 86) shows a territorial disparity related to the severity of the first wave: increased activity essentially in red zones, management of unexpected situations, training of additional nursing staff for 40 % of the laboratories... The survey also showed simplification of aspects related to accreditation those periods of health crisis. An additional survey, carried out in the spring of 2021, showed good overall satisfaction of the healthcare services (n = 139) concerning the services provided by biology in the POCT sector. Because of their great adaptation capacity, the laboratories and their POCT-teams have played a key role in the management of the first wave of Covid-19 in France. However, the success of these organizations requires an essential collaboration between laboratories and healthcare services. The results of this survey are fundamental in the context of the prolongation of the pandemia throughout the world with a POCT sector appearing to be growing.

Running after Activated Clotting Time Values in Patients Receiving Direct Oral Anticoagulants: A Potentially Dangerous Race. Results from a Prospective Study in Atrial Fibrillation Catheter Ablation Procedures.

BACKGROUND: Activated Clotting Time (ACT) guided heparinization is the gold standard for titrating unfractionated heparin (UFH) administration during atrial fibrillation (AF) ablation procedures. The current ACT target (300 s) is based on studies in patients receiving a vitamin K antagonist (VKA). Several studies have shown that in patients receiving Direct Oral Anticoagulants (DOACs), the correlation between ACT values and UFH delivered dose is weak. OBJECTIVE: To assess the relationship between ACT and real heparin anticoagulant effect measured by anti-Xa activity in patients receiving different anticoagulant treatments. METHODS: Patients referred for AF catheter ablation in our centre were prospectively included depending on their anticoagulant type. RESULTS: 113 patients were included, receiving rivaroxaban (n = 30), apixaban (n = 30), dabigatran (n = 30), and VKA (n = 23). To meet target ACT, a higher UFH dose was required in DOAC than VKA patients (14,077.8 IU vs. 9565.2 IU, p < 0.001), leading to a longer time to achieve target ACT (46.5 min vs. 27.3 min, p = 0.001). The correlation of ACT and anti-Xa activity was tighter in the VKA group (Spearman correlation ρ = 0.53), compared to the DOAC group (ρ = 0.19). Despite lower ACT values in the DOAC group, this group demonstrated a higher mean anti-Xa activity compared to the VKA group (1.56 ± 0.39 vs. 1.14 ± 0.36; p = 0.002). CONCLUSION: Use of a conventional ACT threshold at 300 s during AF ablation procedures leads to a significant increase in UFH administration in patients treated with DOACs. This increase corresponds more likely to an overdosing than a real increase in UFH requirement.

Impact of Geographic Region on the COMMANDER-HF Trial.

OBJECTIVES: This study sought to compare patient characteristics, outcomes, and treatment effects among regions in the COMMANDER-HF trial. BACKGROUND: Globalization of cardiovascular trials increases generalizability. However, regional differences may also introduce heterogeneity in results. METHODS: Incidence rates and interactions with treatment were recorded in pre-specified regions: Eastern Europe, Western Europe and South Africa, North America, Asia-Pacific, and Latin America. RESULTS: Most patients (n = 3,224; 64.2%) were from Eastern Europe; 458 (9.1%) were from Western Europe and South Africa; 149 (3.0%) were from North America; 733 (14.6%) were from Asia-Pacific; and 458 (9.1%) were from Latin America. Compared with patients from Eastern Europe, patients from Western Europe and South Africa, North America, and Asia-Pacific were older and more likely to have coronary interventions and cardiac devices. Patients from Eastern Europe had the lowest event rates. For the primary outcome of myocardial infarction (MI), stroke, or all-cause death, event rates (100/year) were 11.6 in Eastern Europe (10.8 to 12.5); 19.5 (16.5 to 23.0) in Western Europe and South Africa; 14.2 (10.5 to 19.2) in North America; 17.7 (15.4 to 20.3) in Asia-Pacific; and 18.6 (15.6 to 22.1) in Latin America. There was a lower incidence of bleeding in Eastern Europe. Blood concentrations of rivaroxaban (Xarelto, Titusville, New Jersey) at 4 weeks were undetectable in 21% patients from Eastern Europe (n = 128) compared to 5% in other regions (n = 42). There was no evidence of treatment-by-region heterogeneity for the primary outcome (interactionp = 0.14), but a favorable effect on the secondary outcome of MI, stroke, or cardiovascular death was observed in Western Europe and South Africa, North America, and Latin America but not in Eastern Europe and Asia-Pacific (interactionp = 0.017). CONCLUSIONS: In the COMMANDER-HF study, patients from Eastern Europe had a lower risk profile and fewer cardiovascular and bleeding events, possibly related to lower treatment adherence. Those differences might have influenced the effect of rivaroxaban therapy. (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure [COMMANDER HF]; NCT01877915).

Platelet Counting: Ugly Traps and Good Advice. Proposals from the French-Speaking Cellular Hematology Group (GFHC).

Despite the ongoing development of automated hematology analyzers to optimize complete blood count results, platelet count still suffers from pre-analytical or analytical pitfalls, including EDTA-induced pseudothrombocytopenia. Although most of these interferences are widely known, laboratory practices remain highly heterogeneous. In order to harmonize and standardize cellular hematology practices, the French-speaking Cellular Hematology Group (GFHC) wants to focus on interferences that could affect the platelet count and to detail the verification steps with minimal recommendations, taking into account the different technologies employed nowadays. The conclusions of the GFHC presented here met with a "strong professional agreement" and are explained with their rationale to define the course of actions, in case thrombocytopenia or thrombocytosis is detected. They are proposed as minimum recommendations to be used by each specialist in laboratory medicine who remains free to use more restrictive guidelines based on the patient's condition.

Type of plasma preparation used for plasma exchange and clinical outcome of adult patients with acquired idiopathic thrombotic thrombocytopenic purpura: a French retrospective multicenter cohort study.

BACKGROUND: Plasma exchange (PE) is the first-line therapy of acquired thrombotic thrombocytopenic purpura (TTP). Several plasma preparations have been available; their equivalence in terms of outcome remains uncertain. STUDY DESIGN AND METHODS: We performed a retrospective analysis of the cases prospectively reported from 2005 to 2010 to the national registry established by the thrombotic microangiopathies French reference center. We analyzed 108 initial episodes of acquired idiopathic TTP in adults treated with PE, 81 with solvent/detergent (S/D) plasma, and 27 with quarantine fresh-frozen plasma (qFFP). The primary endpoint was the time to platelet (PLT) count recovery. RESULTS: Time to PLT count recovery was not significantly different with S/D plasma versus qFFP (median, 15 days vs. 19 days, respectively; p = 0.126). Complete remission rates, exacerbations, and survival were comparable. By multivariate competitive risk (Fine-Gray) analysis, the only significant association with a shorter time to PLT count recovery was the absence of additional treatment (hazard ratio, 2.06; 95% confidence interval [CI], 1.39-3.05; p < 0.001). There was a significant interaction between type of plasma and age, and for patients less than 40 years old, the use of S/D plasma was associated with a shorter time to PLT count recovery versus qFFP (median, 13 [95% CI, 9-16] days vs. 20 [95% CI, 16-64] days, respectively; p = 0.004). CONCLUSION: The outcomes of acquired TTP treated with S/D plasma or qFFP seem similar and therefore both preparations can be used safely for PE in this indication. The faster response of S/D plasma observed in younger patients warrants confirmation in prospective studies.

[A case of dysfibrinogenemia without hemorrhagic diathesis or thromboembolism linked to a new mutation p.H103N in fibrinogen γ chain]. / Un cas de dysfibrinogénémie sans complication hémorragique ni thrombotique lié à une nouvelle mutation p.H103N de la chaîne γ du fibrinogène.

This work describes a dysfibrinogenemia linked to a new mutation in the gene coding for fibrinogen γ chain. Dysfibrinogenemia was fortuitously discovered in a 9-year old boy consulting for symptoms suggesting meningitis. DNA was extracted from blood, the fibrinogen genes coding for Aα, Bß and γ chains were sequenced, and compared with consensus sequences. Apart from the patient, dysfibrinogenemia and the mutation p.H103N in the γ chain of fibrinogen with heterozygous status were found in his mother, without any symptom. This mutation is unknown in fibrinogen variant databases and seems to affect mostly fibrin polymerisation. The reporting of this new p.H103N mutation in the γ chain has a great interest for improving the knowledge of the fibrinogen gene and its expression. Even if no haemorrhage was observed in this case, the expression of this mutation impaired the function of the molecule, particularly polymerisation, and could induce bleeding during an important surgery.

Internal carotid thrombus in patients with inflammatory bowel disease: two cases.

Increased ischemic stroke risk is observed in patients with inflammatory bowel disease (IBD). Causes and physiopathological aspects of cerebral infarct, in this specific population, are less often described. There is little information to provide guidelines for the best curative and preventive treatment. We report 2 cases of ischemic strokes due to internal carotid thrombus in patients during active phase of IBD. Ulceration of early atherosclerotic plaques activated by a hypercoagulation state may cause a thrombus. A combined therapy with heparin and corticosteroids was used for both our patients. Lysis of the thrombus was obtained after several days without surgical treatment and shown by ultrasonography. These cases highlight an aetiology of stroke in patients with IBD and use of a synergic treatment to respond to hypercoagulability in link with IBD. Benefits and safety of this therapy should be confirmed with clinical studies.

Hemodilution with stroma-free [correction of stoma-free] hemoglobin at physiologically maintained viscosity delays the onset of vasoconstriction.

Solutions of modified cell-free hemoglobin, prepared from outdated red blood cells, have been developed during the past decade to circumvent the increasing need for allogeneic blood. Despite improvements in the safety and efficacy of these solutions, undesirable effects such as an increase in vascular tone leading to hypertension have not been fully resolved, which might hinder their clinical usefulness. To discriminate between the pharmacological and rheological effects of cell-free hemoglobin, we compared the effects of blood/cell-free hemoglobin mixtures of high versus low viscosity on hemodynamics and vascular hindrance, an index of vascular tone, which was normalized for blood viscosity. Anesthetized rats were subjected to 50% exchange transfusion with (1) high-viscosity solutions: whole blood (n=5) or red blood cells mixed with cell-free hemoglobin (Hb-Hv group, n=5); (2) low-viscosity solutions: cell-free hemoglobin (Hb-Lv group, n=5) or human albumin (n=5). Two hours after hemodilution, vascular hindrance remained unchanged in animals transfused with whole blood and albumin. Hb-Lv induced an immediate and sustained increase in vascular hindrance (208%). Conversely, in Hb-Hv animals, the vascular hindrance increase was delayed and smaller (27% to 147%), whereas peripheral resistance increased gradually (94% after 2 hours). Our results demonstrate the beneficial effects of cell-free hemoglobin in the presence of the animals' own red blood cells in maintaining physiological viscosity and limiting vasoconstriction because of the pharmacological properties of cell-free hemoglobin.