Hemophilia is a rare bleeding disorder due to factor VIII (FVIII) or FIX deficiency involved in hemophilia A (HA) or HB, respectively. Treatment has long relied on invasive IV infusions of the missing factor for prophylaxis or bleeding treatments. Despite significant progress in patient care, there is still no oral procoagulant drug available for people with hemophilia. Such an oral procoagulant could provide benefits to other inherited and acquired bleeding disorders, as well as anticoagulant-induced bleeding. To find chemical compounds that could become potential future orally administered procoagulants, we designed a hierarchical high-throughput screening protocol combining 2 successive screening filters: a miniaturized fibrin formation assay, followed by a thrombin generation assay, both on severe HA plasma. We screened 3 chemical collections totaling > 2300 chemical compounds; we identified adapalene, a commercialized antiacneic compound (Differin), which is strongly hydrophobic. To design a drug that could be orally administered, we developed a series of chemical analogs of adapalene, and 3 of them, with similar procoagulant activities in FVIII-deficient plasma, showed improved solubilities. The mechanism of action was thoroughly investigated by a series of thrombin generation and enzymatic assays. These studies conclude that the procoagulant activity of the chemical compounds in FVIII-deficient plasma is due to the activation of FXII.

BACKGROUND:Fibrinogen is the first coagulation factor to drop during severe hemorrhage, making it an early biomarker for assessing bleeding severity. OBJECTIVES:To evaluate the analytical and clinical performance of the Tsmart FIB Batrox©, a novel point-of-care test using batroxobin, a snake venom-derived enzyme insensitive to heparins and direct thrombin inhibitors, performed on the LabPad Evolution analyzer. The assay delivers results in less than 4 min from citrated whole blood, addressing unmet needs in emergency settings. PATIENTS AND METHODS:This study included 121 residual citrated (0.109 mol/L) samples collected for routine coagulation testing. Fibrinogen levels measured by the Tsmart FIB Batrox© assay were compared against the Clauss method (gold standard), performed in the central laboratory using the same samples. RESULTS:The Tsmart FIB Batrox© demonstrated excellent correlation with the Clauss assay (r = 0.94), particularly in the clinically critical range for severe bleeding. Bland-Altman analysis revealed negligible bias. No interference from hematocrit variations or anticoagulants was observed. At fibrinogen cut-offs of 1.0 g/L and 2.0 g/L, it exhibited high diagnostic accuracy (area under the ROC curve values of 0.99 and 0.98, respectively). Precision testing confirmed excellent repeatability and reproducibility, with coefficients of variation <10% across all ranges. CONCLUSION:The Tsmart FIB Batrox© system enables rapid and accurate fibrinogen measurement from a single drop of citrated whole blood, even at the lowest detectable concentrations. Its strong correlation with the Clauss method, high diagnostic accuracy, and POC feasibility make it a valuable tool for real-time decision-making in hemorrhage management.

AbstractChronic mountain sickness is a maladaptive syndrome that affects individuals living permanently at high altitude and is characterized primarily by excessive erythrocytosis (EE). Recent results concerning the impact of EE in Andean highlanders on clotting and the possible promotion of hypercoagulability, which can lead to thrombosis, were contradictory. We assessed the coagulation profiles of Andeans highlanders with and without excessive erythrocytosis (EE+ and EE−). Blood samples were collected from 30 EE+ and 15 EE− in La Rinconada (Peru, 5100–5300 m a.s.l.), with special attention given to the sampling pre‐analytical variables. Rotational thromboelastometry tests were performed at both native and normalized (40%) haematocrit using autologous platelet‐poor plasma. Thrombin generation, dosages of clotting factors and inhibitors were measured in plasma samples. Data were compared between groups and with measurements performed at native haematocrit in 10 lowlanders (LL) at sea level. At native haematocrit, in all rotational thromboelastometry assays, EE+ exhibited hypocoagulable profiles (prolonged clotting time and weaker clot strength) compared with EE− and LL (all P < 0.01). At normalized haematocrit, clotting times were normalized in most individuals. Conversely, maximal clot firmness was normalized only in FIBTEM and not in EXTEM/INTEM assays, suggesting abnormal platelet activity. Thrombin generation, levels of plasma clotting factors and inhibitors, and standard coagulation assays were mostly normal in all groups. No highlanders reported a history of venous thromboembolism based on the dedicated survey. Collectively, these results indicate that EE+ do not present a hypercoagulable profile potentially favouring thrombosis.

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder resulting from the development of inhibitory autoantibodies against the circulating factor VIII (FVIII:C). It occurs in patients without a family or personal history of bleeding.1 AHA incidence is approximately 1.5 cases/million/year2 and is idiopathic in about 50% of cases AHA.3 AHA is biologically characterized by an isolated deficiency of coagulation factor VIII (FVIII:C) secondary to autoantibodies targeting specific epitopes that cause neutralization and/or accelerated clearance of FVIII from the plasma (auto-FVIII Abs).4 More often, diagnosis is triggered by a bleeding event3 and confirmed by laboratory data: a decreased level of FVIII:C, usually lower than 30% and the presence of anti-FVIII antibodies with a titer >0.6 Bethesda Unit/mL.5 In case of severe bleeding event, an hemostatic treatment with bypassing agents, including recombinant Factor VIIa (rFVIIa) or activated prothrombin complex concentrates (aPCCs), is recommended.6, 7 More recently, the recommendations for hemostatic treatment in AHA included a "new" treatment, susoctocog alfa (Obizur®): a recombinant porcine FVIII (rpFVIII).5 This recombinant and highly purified protein has comparable biochemical and hemostatic properties to plasma-derived porcine factor VIII, but much lower risks of infection and toxicity. This recombinant anti-hemophilic factor porcine sequence (rpFVIII) is a B-domain deleted FVIII produced in baby hamster kidney (BHK) cells. Susoctocog alfa was approved for treatment of bleeding episodes in AHA in October 2014 in the United States and in November 2015 in Europe. Nevertheless, as recommended in the summary of product characteristics (SmPC), prior to any treatment with rpFVIII, it is necessary to test the cross-reactivity of auto-FVIII Abs with rpFVIII. A close monitoring of rpFVIII activity during treatment is also recommended.5 However, some questions remain concerning this laboratory assessment. The method used for the titration of anti-porcine FVIII inhibitors is comparable to that conventionally used in our laboratories. However, SmPC notifies that the patient's plasma must be incubated with plasma titrated for porcine factor-VIII instead of the normal human plasma usually used. In addition, the reference/control should be obtained by diluting rpFVIII in plasma deficient in factor VIII and not in imidazole buffer, as usually carried out.8 The aim objective of this study is first to validate in a field study the modified Nijmegen method used in our laboratories for the anti-rpFVIII titration. Ten French laboratories participated to this study and each used its local own automated, aPTT reagent and FVIII deficient plasma to perform the FVIII one-stage assay (OSA). We first compared the stability of rpFVIII after 2 h-incubation at 37°C in buffered FVIII-deficient plasma (FVIII-DP) or in imidazole buffer (IB). Recombinant pFVIII was supplied by Takeda and was first reconstituted with 1 mL of distilled water, then diluted (1/11) in buffered factor VIII-DP containing von Willebrand factor (Siemens) to obtain a concentration close to 100 IU/dL. Two different volume-to-volume mixtures were then prepared: Mixture 1: rpFVIII at 100 IU/dL + FVIII-DP and Mixture 2: rpFVIII at 100 IU/dL + IB. Factor VIII activity was measured, with a FVIII assay calibrated with NIBSC calibrator, immediately and after 2 h incubation at 37°C. Procedure was repeated in each participant laboratory three times (i.e., on three different days) resulting in three assay runs. After 2 h incubation, a decrease in rpFVIII activity was observed in each mixture and the mean differences ± standard deviation (SD) were minus 1.9 ± 3.4 IU/dL and minus 1.8 ± 2.9 IU/dL when standard rpFVIII was diluted in FVIII-deficient plasma or Imidazole buffer, respectively (Figure 1) without statistical difference between these variations (t-test: p = 0.938). We then applied the modified Nijmegen method to assess the cross-reactivity of plasma from patients with congenital hemophilia A with inhibitors (PWA) or AHA. In this step, each sample was systematically tested in two different centers (paired-centers described in Table 1). Thirty eight samples from 26 patients with AHA and 12 samples from 7 patients with hemophilia A (PWA) with circulating anti-FVIII antibodies were tested. In each laboratory, plasma samples dilutions were performed with IB instead of FVIII-DP. To evaluate the inter-laboratory variations, a set of 10 samples were systematically sent to two different laboratories. In addition, a control sample (weak human FVIII inhibitor plasma control, Cryopep, Montpellier, France) was tested in each run. Anti-rpFVIII titration was performed in each center using the following method: prior to testing, plasma samples were incubated for 30 min at 58°C as recommended by Verbruggen et al.9 and centrifuged for 10–15 min at 2500 g. Recombinant pFVIII (substrate) was reconstituted with 1 mL of distilled water and diluted 1:11 in FVIII-deficient plasma containing VWF to obtain an activity close to 100 IU/dL. For anti-rpFVIII titration, each laboratory used its own aPTT reagent and calibration curves. Several dilutions of the samples with IB were systematically performed (1:1, 1:2, 1:5, 1:10, 1:20, and 1:30). Results of rpFVIII antibodies titration of the 50 plasmas selected are shown in Table 1, and the median results obtained in the two different laboratories are shown in Figure 2 according to the population studied. We did not observed cross-reactivity to rpFVIII with the FVIII inhibitor control plasma (data none show). In 25/50 plasma samples tested, no cross-reactivity against rpFVIII was detected in either laboratory. The mean anti-hFVIII titer of these 25 samples was 14.9 BU/mL [range: 0.7–112 BU/mL]. In contrast, cross-reactivity with rpFVIII was detected by both laboratories in 19/50 samples with a mean titer of 8.5 BU/mL [range: 1.0–93.3 BU/mL]. The mean anti-hFVIII titer of these 19 samples was 37.6 BU/mL [range: 1–320 BU/mL]. Among these 19 samples, 10 came from AHA patients and 9 came from PWA with inhibitors. Cross-reactivity was clearly detected in 26% (10/38) of samples from AHA patients versus 75% (9/12) of samples from PWA with inhibitors. However, several samples from one patient were tested, and if we analyze the frequency of cross-reactivity according to patients, it was detected in 7/26 (27%) patients with AHA versus 4/7 (57%) PWA with inhibitors. Discrepancies between laboratories were reported in six samples (CO04, TOP1, NA12, RO08, LI01, and LI03) with a mean anti-rpFVIII titer equal to 0.9 BU/mL [range 0.6–1.36 BU/mL]. Among these, five were from AHA patients with probably a type 2 kinetic, which is more frequent in AHA.6 In addition, due to the multiplicity of reagents/methods used to measure residual FVIII, the concordance of results between laboratories can be relatively poor. Cross-reactivity was therefore considered positive in 16 of the 38 AHA samples (42%) but a cross-reactivity against rpFVIII above 20 BU/mL was detected in only one sample from a PWA with a titer of anti-hFVIII inhibitor at 57 BU/mL. In conclusion, our field study demonstrated the feasibility of using imidazole buffer to detect anti-rpFVIII antibodies, and confirmed the absence of impact of aPTT reagent and calibration curves on the method.10 The United Kingdom Haemophilia Centre Doctor's organisation guidelines11 recommended to use "a locally verified one-stage APTT-based assays calibrated against plasma standards to monitor rpFVIII" and a modified Bethesda assay using rpFVIII as the substrate without precision about the use of FVIII deficient plasma or imidazole buffer. A specific calibration curve using rpFVIII has been recommended by Novembrino to determine recovery as well as FVIII-DP containing VWF both for diluting standard rpFVIII and for performing OSA.12 Our study confirmed a frequency of cross-reactivity with rpFVIII close to 40% in AHAs. However, high cross-reactivity, above 20 BU/mL, contraindicating treatment, is rare and has not been observed in our AHA population. All authors contributed to perform analysis of this study. V. Le Cam Duchez, C. Ternisien, and C. Pouplard contributed to the design of study and wrote the manuscript. All authors read and approved the final manuscript. This work was supported by Takeda. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Stauffer, Emeric, François Caton, Raphael Marlu, Aurélien Pichon, Landry Seyve, Michael Furian, Aymeric Paillisser, Florence Berquet, Jeremy De Abreu, Blandine Deschamps, Benoit Polack, Philippe Connes, Paul Robach, Stéphane Doutreleau, Julien V. Brugniaux, Samuel Verges, and Benoit Champigneulle. Acclimatized lowlanders exhibit a hypocoagulable profile after a passive ascent at high altitude. High Alt Med Biol. 26:209-214, 2025. Background: Discordant results have been previously reported regarding the impact of high-altitude (HA) exposure on coagulation. We aimed to investigate changes in coagulation parameters in lowlanders exposed to HA for 14 days using a combination of dynamic coagulation assays and conventional in vitro tests. Material and Methods: We assessed coagulation in 10 lowlanders using whole-blood rotational thromboelastometry (ROTEM), thrombin generation assay (TGA) on poor-platelet plasma, and conventional coagulation tests. Tests were performed at low altitude (LA, 210 m) and at the end of a 14-day sojourn at HA, including passive ascents to 3,800 m for 6 days and then to 5,100 m for 8 days. Results: Conventional tests revealed significant changes in coagulation factors and inhibitors after HA exposure, although these changes remained within normal ranges. ROTEM assays demonstrated a delayed clot initiation in EXTEM/FIBTEM, without any alteration in clot firmness, in HA versus LA (p < 0.01). TGA changes showed an increase in time to peak (p < 0.01), a decrease in endogenous thrombin potential (p < 0.05), and a decrease in thrombin peak (p < 0.001). Conclusions: We found no evidence of hypercoagulability in lowlanders after a 14-day sojourn at HA. In contrast, dynamic coagulation assays (ROTEM and TGA) revealed a hypocoagulable pattern.

Background:Anticoagulation for cardiopulmonary bypass (CPB) in cases of heparin-induced thrombocytopenia (HIT) is challenging as no convenient and proven alternative, such as heparin alone, exists. A "platelet anesthesia" concept using antiplatelet agent cangrelor with heparin has been successfully reported in this setting.Key Clinical Question:In cases of acute HIT, is CPB with cangrelor plus heparin effective and safe?.Clinical Approach:We report the case of a patient who developed, 2 weeks after patent foramen ovale (PFO) closure, a delayed-onset HIT complicated with carotid, popliteal, and PFO device thromboses that could not be controlled by argatroban anticoagulation and required urgent cardiac surgery. CPB for PFO occluder removal and popliteal thrombectomy were performed using cangrelor with heparin without complication. Neither a new thromboembolic event nor abnormal bleeding was noticed in the postoperative period.Conclusion:CPB using cangrelor with heparin seems to be an effective alternative for acute HIT.

Introduction: Cerebral venous sinus thrombosis (CVST) is a rare disease with highly variable clinical presentation and outcomes. Clinical studies suggest a role of inflammation and coagulation in CVST outcomes. The aim of this study was to investigate the association of inflammation and hypercoagulability biomarkers with CVST clinical manifestations and prognosis. Methods: This prospective multicenter study was conducted from July 2011 to September 2016. Consecutive patients referred to 21 French stroke units and who had a diagnosis of symptomatic CVST were included. High-sensitivity C-reactive protein (hs-CRP), neutrophil-to-lymphocyte ratio (NLR), D-dimer, and thrombin generation using calibrated automated thrombogram system were measured at different time points until 1 month after anticoagulant therapy discontinuation. Results: Two hundred thirty-one patients were included. Eight patients died, of whom 5 during hospitalization. The day 0 hs-CRP levels, NLR, and D-dimer were higher in patients with initial consciousness disturbance than in those without (hs-CRP: 10.2 mg/L [3.6-25.5] vs 23.7 mg/L [4.8-60.0], respectively; NLR: 3.51 [2.15-5.88] vs 4.78 [3.109.59], respectively; D-dimer: 950 mu g/L [520-2075] vs 1220 mu g/L [950-2445], respectively). Patients with ischemic parenchymal lesions (n = 31) had a higher endogenous thrombin potential(5pM) than those with hemorrhagic parenchymal lesions (n = 31): 2025 nM min (1646-2441) vs 1629 nM min (1371-2090), respectively (P =.0082). Using unadjusted logistic regression with values >75th percentile, day 0 hs-CRP levels of >29.7 mg/L (odds ratio, 10.76 [1.55-140.4]; P =.037) and day 5 D-dimer levels of >1060 mg/L (odds ratio, 14.63 [2.28-179.9]; P =.010) were associated with death occurrence. Conclusion: Two widely available biomarkers measured upon admission, especially hsCRP, could help predict bad prognosis in CVST in addition to patient characteristics. These results need to be validated in other cohorts.

Background: Gla-domainless factor (F) Xa (GD-FXa) was proposed as a trap to endogenous anticoagulant tissue factor pathway inhibitor (TFPI) to restore thrombin generation in hemophilia. Using computational chemistry and experimental approaches, we previously showed that S195A GD-FXa also binds TFPI and restores ex vivo coagulation in plasma obtained from person(s) with hemophilia. Methods: To design a GD-FXa variant with improved anti-TFPI affinity, we performed molecular dynamics simulations and identified suitable sites for mutagenesis. The calculations identified residues R150FXa and K96Fxa as cold-spots of interaction between GD-FXa and the K2 domain of TFPI. In the three-dimensional model, both residues face toward TFPI hydrophobic residues and are thus potential candidates for mutagenesis into hydrophobic residues to favor an improved protein-protein interaction. Results: Catalytically inactive GD-FXa variants containing the S195A mutation and the additional mutations K96Y, R150I, R150G, R150F, and K96YR150F, were produced to experimentally confirm these computational hypotheses. Among these mutants, the R150FFXa and the K96YR150FFXa were slightly more effective than S195A GD-FXa in restoring coagulation in FVIII deficient plasmas. However, in surface plasmon resonance experiments, they showed TFPI binding affinities in the same range and acted similarly as S195A GD-FXa in FXa/TFPI competition assays. In contrast, the R150 mutants completely lost their interactions with antithrombin as observed in the surface plasmon resonance experiments. Conclusions: We therefore conclude that their antithrombin resistance is responsible for their improved thrombin generation, through an extension of their half-lives.

Background:Despite the wide use of bleeding scores and the reliability of clotting factor level measurement, bleeding risk stratification before surgery remains challenging in patients with rare inherited bleeding disorders.Objectives:This multicenter observational prospective study assessed in patients with rare coagulation factor deficiency, the perioperative hemostatic management choices by hemostasis experts and the bleeding outcomes after surgery.Methods:One hundred seventy-eight patients with low coagulation activity level (factor [F] II, FV, combined FV-FVIII, FVII, FX, or FXI <50%) underwent 207 surgical procedures. The bleeding outcome, Tosetto's bleeding score, and perioperative hemostatic protocols were collected.Results:Among the 81 procedures performed in patients with severe factor deficiency (level ≤10%), 27 were done without factor replacement (including 6 in patients at high bleeding risk), without any bleeding event. Factor replacement therapy was used mainly for orthopedic procedures. In patients with mild deficiency, 100/126 surgical procedures were carried out without perioperative hemostatic treatment. In patients with FVII or FXI deficiency, factor replacement therapy was in function of the procedure, bleeding risk, and to a lesser extent previous bleeding history. Tranexamic acid was used in almost half of the procedures, particularly in case of surgery in tissues with high fibrinolytic activity (76.8%).Conclusions:The current perioperative hemostatic management of patients with rare bleeding disorders appears to be adapted. Among the 207 procedures, only 6 were associated with excessive bleeding. Our findings suggest that rather than the bleeding score, factor level and surgery type are the most relevant criteria for perioperative factor replacement therapy.

Blood phenotypes are defined by the presence or absence of specific blood group antigens at the red blood cell (RBC) surface, due to genetic polymorphisms among individuals. The recent development of genomic and proteomic approaches enabled the characterization of several enigmatic antigens. The choline transporter‐like protein CTL2 encoded by the SLC44A2 gene plays an important role in platelet aggregation and neutrophil activation. By investigating alloantibodies to a high‐prevalence antigen of unknown specificity, found in patients with a rare blood type, we showed that SLC44A2 is also expressed in RBCs and carries a new blood group system. Furthermore, we identified three siblings homozygous for a large deletion in SLC44A2 , resulting in complete SLC44A2 deficiency. Interestingly, the first‐ever reported SLC44A2‐deficient individuals suffer from progressive hearing impairment, recurrent arterial aneurysms, and epilepsy. Furthermore, SLC44A2 null individuals showed no significant platelet aggregation changes and do not suffer from any apparent hematological disorders. Overall, our findings confirm the function of SLC44A2 in hearing preservation and provide new insights into the possible role of this protein in maintaining cerebrovascular homeostasis.

Gla-domainless factor Xa (GD-FXa) was proposed as a trap to the endogenous anticoagulant Tissue Factor Pathway Inhibitor (TFPI) to restore thrombin generation in hemophilia. Using computational chemistry and experimental approaches, we previously showed that S195A GD-FXa also binds TFPI and restores ex vivo coagulation in hemophilia plasmas. To design a GD-FXa variant with improved anti-TFPI activity and identify suitable sites for mutagenesis, we performed molecular dynamics simulations. The calculations identified residues R150 FXa and K96 FXa as cold-spots of interaction between GD-FXa and the K2 domain of TFPI. In the three-dimensional model, both residues are facing TFPI hydrophobic residues and are thus potential candidates for mutagenesis into hydrophobic residues to favor an improved protein-protein interaction. Catalytically inactive GD-FXa variants containing the S195A mutation and additional mutations as K96Y, R150I, R150G and R150F were produced to experimentally confirm these computational hypotheses. Among these mutants, the R150F FXA showed increased affinity for TFPI as theoretically predicted, and was also more effective than S195A GD-FXa in restoring coagulation in FVIII deficient plasmas. Moreover, the R150 mutants lost interaction with antithrombin, which is favorable to extend their half-life.

Laboratory Method to Detect VITT The rare vaccine-induced immune thrombotic thrombocytopenia that may follow adenovirus-based Covid-19 vaccination resembles heparin-induced thrombocytopenia, but rapid assays for anti-PF4 antibodies used to diagnose HIT may be negative in patients with VITT. The PF4-serotonin release assay appears to detect the IgG antibodies to PF4-PVS that mediate this condition.

BACKGROUND:Plasmapheresis can deplete pathogenic antibodies and allow ABO- and/or HLA-incompatible transplantation.AIM:To determine the impacts of three modalities of plasmapheresis (centrifugal plasmapheresis [cTPE], single-filtration plasmapheresis [mTPE], double-filtration plasmapheresis [DFPP]) on hemostasis parameters and thrombin generation.MATERIALS/METHODS:Prospective, comparative study on 21 patients that received three modalities of plasmapheresis (7 patients/group). Hemostasis (prothrombin time [PT], activated partial thromboplastin time [aPTT], procoagulant factors and natural anticoagulants) were measured before and after the first plasmapheresis session. Thrombin generation was also assessed in platelet-poor plasma using an STA-Genesia (Stago) analyzer and Thromboscreen reagents (Stago) in 4-5 patients from each group.RESULTS:Both cTPE and mTPE resulted in high decreases in proteins, whatever their molecular weights. Median post/pre ratios were 0.27 to 0.55 for cTPE for most proteins (except FVIII [0.64] and VWF [0.57]). Median post/pre-ratios of mTPE were 0.28 to 0.56 for all proteins. DFPP decreased high-molecular-weight proteins (fibrinogen, FV, FVIII, FXI, VWF) and proteins strongly bound to large molecules (protein SandTFPI). Median post/pre ratios with cTPE and mTPE were similar to DFPP for fibrinogen and FXIII. Regarding thrombin generation, cTPE and mTPE did not significantly modify endogenous thrombin potential (ETP) and DFPP induced a slight decrease in ETP (median post/pre ratio at 0.73) in the absence of thrombomodulin. ETP inhibition by thrombomodulin was decreased for all procedures.CONCLUSIONS:DFPP depleted high molecular-weight proteins in contrast to cTPE and mTPE, which significantly decreased all proteins. Regarding thrombin generation, depletion of procoagulant factors was counterbalanced by a decrease in some natural anticoagulants whatever plasmapheresis method used; with all methods, fibrinogen and FXIII were highly depleted.

Nearly 18% of patients on a waiting list for kidney transplantation (KT) are highly sensitized, which make access to KT more difficult. We assessed the efficacy and tolerance of different techniques (plasma exchanges [PE], double-filtration plasmapheresis [DFPP], and immunoadsorption [IA]) to remove donor specific antibodies (DSA) in the setting of HLA-incompatible (HLAi) KT. All patients that underwent apheresis for HLAi KT within a single center were included. Intra-session and inter-session Mean Fluorescence Intensity (MFI) decrease in DSA, clinical and biological tolerances were assessed. A total of 881 sessions were performed for 45 patients: 107 DFPP, 54 PE, 720 IA. The procedures led to HLAi KT in 39 patients (87%) after 29 (15–51) days. A higher volume of treated plasma was associated with a greater decrease of inter-session class I and II DSA (p = 0.04, p = 0.02). IA, PE, and a lower maximal DSA MFI were associated with a greater decrease in intra-session class II DSA (p < 0.01). Safety was good: severe adverse events occurred in 17 sessions (1.9%), more frequently with DFPP (6.5%) p < 0.01. Hypotension occurred in 154 sessions (17.5%), more frequently with DFPP (p < 0.01). Apheresis is well tolerated (IA and PE > DFPP) and effective at removing HLA antibodies and allows HLAi KT for sensitized patients.

L’impact d’un traitement Intercept sur la capacité hémostatique plaquettaire reste débattu. L’étude par viscoélastométrie (VE) quantifie les propriétés mécaniques plaquettaires dans un caillot de sang total.

Background Fibrinogen reconstitution after therapeutic apheresis has been poorly studied. Apheresis modalities, for example, plasma exchange (PE), double-filtration plasmapheresis (DFPP), or selective immunoadsorption (IA), may have different impacts. Methods We retrospectively investigated therapeutic apheresis sessions performed at our center across four modalities (PE, DFPP, and IA with or without plasma filtration). Fibrinogen levels were assessed at the beginning and end of each apheresis session, and immediately before the subsequent session. We adjusted measurements on hematocrit values to account for hemoconcentration. Results Between January 10, 2016 and March 2, 2020, we included 90 patients for a total of 754 apheresis sessions (PE: 35; DFPP: 351; IA only: 109; IA + plasma filtration: 259). Each patient received a median of five sessions (1Q 3; 3Q 9); median plasma volume treated was 5.5 L (1Q 4.3 L; 3Q 7.0 L). Within a session, DFPP and PE induced a significantly greater depletion of fibrinogen than both IA modalities, even after adjustment for the treated plasma volume. Median fibrinogen reconstitution was 0.8 (0.4-1.2) g/L (median time between sessions: 38 hours). In multivariate analysis, fibrinogen reconstitution was significantly associated with intersession time (+0.66 g/L/log-hour P < .001), apheresis modality (ANOVA; P < .001), initial fibrinogen concentration (+0.15 g/L per gram of fibrinogen; P < .001), and the last fibrinogen concentration from the previous apheresis session (-0.14 g/L per gram of fibrinogen; P < .001). In a model that considered hemoconcentration, the results were unchanged. Conclusions We demonstrate that fibrinogen reconstitution was highly variable between patients and apheresis sessions. Apheresis modalities had a significant impact on fibrinogen reconstitution, regardless of hemoconcentration.

OBJECTIVES: To describe the successful recovery from multiple and life-threatening venous thrombosis after ChAdOx1 nCoV-19 vaccination. DESIGN: Case report. SETTING: University Hospital. Patient: Few days after the first dose of the ChAdOx1 nCoV-19 vaccine, a 21-year-old woman experienced massive thrombosis in the deep and superficial cerebral veins together with seizures, neurologic focal deficit, and thrombocytopenia. In the neurointensive care unit, her condition worsened despite early decompressive craniectomy. She developed bilateral segmental pulmonary embolism, left hepatic, and left external iliac venous thrombosis. INTERVENTION: Argatroban (0.5–2.2 µg/kg/min) and high-dose IV immunoglobulin (1 g/kg/d for 2 consecutive days) were initiated on day 6 after admission. With these therapies, there was a gradual resolution of multiple sites of venous thrombosis, and platelet count returned to normal. The patient left the ICU with full consciousness, expressive aphasia, and right hemiparesis. CONCLUSIONS: This case of vaccine-induced immune thrombotic thrombocytopenia shows that a good outcome can be obtained even with multiple and life-threatening venous thrombotic lesions. Argatroban and high-dose IV immunoglobulin along with management of severe cerebral venous thrombosis played a major role in this epilogue.

Coronavirus disease 2019 (COVID-19) is associated with a high risk of thrombotic events, particularly in critically ill patients. Anticoagulants at higher than standard thromboprophylaxis doses have been advocated by our group [1]. Although higher doses may help reduce thrombotic complications, the risk of hemorrhage could limit the benefit of such a strategy unless individualized to high thrombotic risk patients. D-dimers have been extensively studied in COVID-19, and elevated levels are associated with increased mortality, but whether it predicts thrombotic events is unclear.