Abstract Introduction Pregnancy is a well-established risk factor for venous thromboembolism, and is associated with a state of hypercoagulability or parameters of thrombin generation. Currently, ...there is a lack of consensual data on thrombin generation during pregnancy. This study aimed to find a sensitive and specific biological marker of coagulation activation and to identify parameters of thrombin generation. Patients and methods The population included 101 women with uncomplicated pregnancies. The objective of this study was to correlate thrombin generation test (measured at 5pM tissue factor, 4 μM lipids and without thrombomodulin), with fibrinogen and markers of blood coagulation activation: D-dimer, prothrombin fragments 1+2 (F1+2), thrombin-antithrombin complexes (TAT) and fibrin monomer complexes (FMC) in these women. Internal quality control was performed in each set of experiments. Results Fibrinogen, D-dimer, F1+2, and TAT concentrations increased significantly throughout pregnancy, and were correlated with term of pregnancy. In our study, thrombin generation seemed to increase early on, and then remained stable throughout normal pregnancy, in contrast with other markers of blood coagulation activation, excepting FMC. The latter are subject to large inter-individual variations, especially during second trimester. No correlation was demonstrated between thrombin generation parameters and other activation markers. Conclusion While markers of coagulation activation significantly increased during pregnancy, thrombin generation increased only early on and remains stable during pregnancy. Finding a sensitive and specific biological marker for vascular pregnancy complications, such as FMC and thrombin generation levels, requires further investigation.
Therapeutic angiogenesis has yet to fulfill its promise for the clinical treatment of ischemic diseases. Given the impact of macrophages during pathophysiological angiogenesis, we asked whether ...macrophages may similarly modulate vascular responses to targeted angiogenic therapies. Mouse matrigel plug assay and rat myocardial infarction (MI) model were used to assess angiogenic therapy with either VEGF-A or FGF-2 with HGF (F+H) delivered locally via albumin–alginate microcapsules. The infiltration of classical M1-type and alternative M2-like macrophages was assessed. Clodronate was used to prevent macrophage recruitment, and the VEGFR2 blocking antibody, DC101, to prevent VEGF-A signaling. At 3 weeks after matrigel implantation, the combination therapy (F+H) led to increased total, and specifically M2-like, macrophage infiltration versus control and VEGF-A plugs, correlating with the angiogenic response. In contrast, VEGF-A preferential recruited M1-type macrophages. In agreement with a direct role of M2-like macrophages in F+H-induced vessel growth, clodronate radically decreased angiogenesis. Further, DC101 reduced F+H-induced angiogenesis, without altering macrophage infiltration, revealing macrophage-derived VEGF-A as a crucial determinant of tissue responsiveness. Similarly, increased cardiac M2-like macrophage infiltration was found following F+H therapy post-MI, with strong correlation between macrophage levels and angiogenic and arteriogenic responses. In conclusion, M2-like macrophages play a decisive role, linked to VEGF-A production, in regulation of tissue responsiveness to angiogenic therapies including the combination of F+H. Our data suggest that future attempts at therapeutic revascularization in ischemic patients might benefit from coupling targeted growth factor delivery with either direct or indirect approaches to recruit pro-angiogenic macrophages in order to maximize therapeutic angiogenic/arteriogenic responses.
Viscoelastic tests allow a reduction in blood product transfusion. Three modern devices are currently available (rotational thromboelastometry ROTEM sigma, thromboelastography TEG 6S, and Quantra). ...No study has compared the performances of these 3 devices simultaneously.
An observational, nonrandomized cohort study.
A single-center of cardiac surgery in a university hospital.
A total of 30 consecutive measurements from at least 10 adult patients presenting significant bleeding in the intensive care unit after cardiac surgery
Viscoelastic tests using ROTEM sigma, TEG 6S, and Quantra were performed concomitantly with conventional coagulation measurements
The authors included 16 patients with 31 blood samples. After the exclusion of missing values, 27 samples were analyzed. Correlation with platelet count was as follows: ROTEM, r = 0.84 0.66-0.93, p < 0.0001; Quantra, r = 0.83 0.64-0.92, p < 0.0001; TEG 6S, r = 0.64 0.29-0.83, p = 0.001. Correlation with fibrinogen (Clauss assay) was as follows: ROTEM, r = 0.85 0.68-0.93, p < 0.0001; Quantra, r = 0.88 0.74-0.95, p < 0.0001; TEG 6S, r = 0.79 0.55-0.91, p < 0.0001. No difference was observed for the detection of residual circulating heparin (anti-Xa activity >0.1), with 87% of correct identification for Quantra and 80% for both ROTEM and TEG 6S (p = 0.3). Time to first results after the beginning of the test was shorter for Quantra than ROTEM and TEG 6S (136 126-152 seconds v 205 176-221 seconds, p = 0.003 and v 450 372-516 seconds, p < 0.0001 respectively).
ROTEM sigma, TEG 6S, and Quantra performed similarly for exploring platelet count or residual circulating heparin. Thromboelastography 6S presented a weaker correlation with fibrinogen Clauss.
Background: Oral anti-Xa inhibitors have demonstrated noninferiority to vitamin K antagonists (VKAs) for the prevention of stroke in patients with atrial fibrillation and recurrent venous ...thromboembolism. They are associated with a decrease in major bleeding. In contrast with VKA, no coagulation monitoring is required. However, in clinical practice, determination of drug concentration is sometimes necessary. Objective: The objective of this study was to evaluate a low-molecular-weight heparin (LMWH) calibrated anti-Xa assay for the quantification of rivaroxaban and apixaban plasma concentration in emergency. Methods: The anti-Xa plasma concentration of rivaroxaban and apixaban were measured in emergency in 210 patients using STA anti-Xa liquid assay. For each plasma concentration <150 ng/mL of rivaroxaban or apixaban, an anti-Xa assay calibrated with LMWH was performed. Results: We demonstrated a significant correlation between LMWH anti-Xa activity and rivaroxaban (R2 = 0.947) or apixaban (R2 = 0.959) concentration and a significant correlation between rivaroxaban and apixaban plasma concentration (R2 = 0.972). A LMWH anti-Xa activity <0.50 IU/mL could exclude a plasma concentration of rivaroxaban and apixaban >30 ng/mL and indicate the feasibility of invasive procedure. Conclusion and Relevance: In the absence of a specific test, LMWH-calibrated anti-Xa assay could be used to determine the presence and evaluate the plasma concentration of oral anti-Xa inhibitors. However, these initial findings require confirmation using other chromogenic calibrated oral anti-Xa assays.
•Factor XI deficiency in plasma was not correlated with clinical bleeding phenotype.•With 1 pM of tissue factor, a non-significant decrease of TGA was observed in FXI deficiency bleeders.•During ...pregnancy, a normalization of thrombin generation was observed in FXI deficiency.
Factor XI (FXI) deficiency is characterized by a lack of correlation between FXI plasma levels and the occurrence of hemorrhagic events. The main objective of our study was to determine whether thrombin generation assay (TGA) could be used to assess the hemorrhagic phenotype of patients with FXI deficiency.
All patients had confirmed laboratory measurement of FXI < 50% in two plasma samples. Relevant bleeding history was evaluated by a senior physician. TGA was performed with Calibrated Automated Thrombography, in platelet poor plasma, from patients and healthy controls. The assay was performed with PPP low reagent (1 pM of human tissue factor).
Seventy-six patients with FXI deficiency were included between 2011 and 2020. Among them, eight patients had severe deficiency (FXI < 15%). Mean age was 34 years range: 9–77. Endogenous thrombin potential (ETP) was significantly lower in patients with FXI deficiency and bleeding (573 nM·min 225–1214) or no bleeding (732 nM·min 222–1435), compared to healthy controls (1184 nM·min 933–1518). No difference was observed for ETP and peak between patients with FXI deficiency and bleeding and patients with FXI deficiency and no bleeding. No difference was observed for ETP (923 nM·min 377–1497 vs 1063 nM·min 252–2529), peak (82 nM 28–154 vs 131 nM 20–330) or velocity (13.7 nM/min 3.6–29.6 vs 26.5 nM/min 2.5–90) in women with (n = 4) and without history (n = 17) of post-partum bleeding. No difference of thrombin generation was observed in pregnant women with FXI deficiency (ETP: 1395 nM·min 351–2529; peak: 154 nM 26–330; velocity: 29.6 nM/min 4.1–90.0), compared to healthy controls and a control group of healthy pregnant women.
In conclusion, under our experimental condition, a non-significant decrease of thrombin generation was observed in plasma samples of patients with FXI deficiency and bleeding. Our results suggest an increase of coagulation parameters during pregnancy in women with FXI deficiency. A larger sample size or other experimental conditions are required to evaluate the use of TGA in FXI deficiency.
Heparin-induced thrombocytopenia (HIT) is a rare, iatrogenic condition, characterized by its potential severity and diagnostic difficulties. The diagnosis is based on a set of arguments allowing the ...calculation of a pre-test score pointing to HIT. There are rapid diagnostic tests for suspected HIT. Among these, the STic Expert® HIT has a good sensitivity to detect HIT. However, it must be performed within 2 hours after sampling. The aim of this study was to evaluate a delayed STic Expert® HIT test at 8 hours and in frozen plasma. Thirty-six patients were prospectively included for HIT testing between April 01, 2018, and July 1, 2022, at the University Rouen Hospital. For any request for HIT testing, an analysis by STic Expert® HIT was performed within 2 hours and 8 hours post-sampling. Any positive result was confirmed by a functional test, platelet aggregation with heparin, release of 14C-serotonin assay (SRA), and immunological assay by a research for anti-platelet factor 4 IgG antibodies. Twenty-three patients had a STic Expert® HIT. Sixteen presented platelet aggregations in the presence of heparin and had a positive anti-PF4 test, 17 had a positive SRA. Six patients had no HIT. For the test performed within 2 hours of collection, the Se = 100%, Sp = 68.42%, PPV = 73.91%, and NPV = 100%. The X2 = 18.21 with p < 0.001. For the test performed at 8 hours post sampling, the Se = 100%, Sp = 68.42%, PPV = 73.91% and NPV = 100%. The X2 = 18.21 with p < 0.001. In conclusion, we have demonstrated that the STic Expert® can be used to perform an HIT diagnostic test 8 hours after sampling and on thawed plasma. However, this study needs to be confirmed on a larger number of samples.
The management of patients with inherited bleeding disorders in oral surgery requires the systematic evaluation of bleeding risk and the setting up of an adequate treatment protocol by the referring ...haematologist, defining a replacement therapy and a recommended length of hospital stay. The purpose of this study was to determine the bleeding risk associated with oral surgery for each type of inherited bleeding disorder and to evaluate the efficacy of the treatment protocols set up in our tertiary care center.
We included all patients with an inherited bleeding disorder, managed in our oral and maxillofacial surgery department with a treatment protocol set up by our local Haemophilia Treatment Centre for an oral surgical procedure.
Between January 2006 and December 2018, 295 treatment protocols were set up for the management of patients with haemorrhagic risk in oral surgical procedures. Of these, 203 were scheduled to take place in our department. A total of 180 oral surgical procedures for 147 patients were included. The incidence of bleeding complications in our study was 4.44% (8 out of 180) with a significantly higher risk in patients with haemophilia, the mean time to onset of bleeding was 11 days.
The use of a treatment protocol for the management of patients with inherited bleeding disorders in oral surgery seems effective. Our rate of bleeding complications was comparable to data in the literature, and often lower.
Coagulation factor XII (FXII) plays a role in thrombin generation, fibrinolysis, inflammation, angiogenesis, chemotaxis and diapedesis. FXII deficiency is not associated with bleeding risk unlike ...other coagulation factors.
We investigated thrombin generation assay (TGA) profile modification in FXII deficiency and the correlation with TGA and deficiency severity. TGA was performed in platelet poor plasma (PPP) with tissue factor (1 pmol/L) and phospholipid (4 µmol/L) standardized concentration. Thrombin generation profiles were compared in 54 patients with FXII deficiency, 25 healthy controls and 23 patients with hemophilia A (factor VIII (FVIII) deficiency. Patients with FXII deficiency were classified in three groups based on FXII activity (30–50%, 10–29%, <10%). FVIII deficiency was included as a bleeding control group.
As expected, we found a correlation between FXII deficiency and activated partial thromboplastin time (aPTT). A decrease of thrombin generation was observed in healthy controls and all FXII deficiency groups. A decrease of endogenous thrombin potential (ETP), peak and velocity was observed in patients with FVIII deficiency compared to FXII deficiency. A decrease of thrombin generation was noted in patients with FXII deficiency and bleeding history compared to patients with FXII deficiency and thrombosis history.
In this study, thrombin generation profiles were not sensitive to FXII deficiency. TGA could distinguish bleeding and thrombotic tendency in FXII deficiency. Our results should therefore be considered as exploratory and deserve confirmation.
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