Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a curative treatment for chemo-resistant hematological malignancies. Because of transport restriction imposed by the coronavirus ...disease 2019 pandemic, regulatory bodies and societies recommended graft cryopreservation before recipient conditioning. However, the freezing and thawing processes, including washing steps, might impair CD34+ cell recovery and viability, thereby impacting the recipient engraftment. Over 1 year (between March 2020 and May 2021), we aimed to analyze the results of frozen/thawed peripheral blood stem cell allografts in terms of stem cell quality and clinical outcomes.
Transplant quality was evaluated by comparing total nucleated cells (TNCs), CD34+ cells and colony-forming unit–granulocyte/macrophage (CFU-GM)/kg numbers as well as TNC and CD34+ cell viabilities before and after thawing. Intrinsic biological parameters such as granulocyte, platelet and CD34+ cell concentrations were analyzed, as they might be responsible for a quality loss. The impact of the CD34+ cell richness of the graft on TNC and CD34 yields was evaluated by designing three groups of transplants based on their CD34 /kg value at collection: >8 × 10 6/kg, between 6 and 8 × 106/kg and <6 × 106/kg. The consequences of cryopreservation were compared in the fresh and thawed group by evaluating the main transplant outcomes.
Over 1 year, 76 recipients were included in the study; 57 patients received a thawed and 19 patients a fresh allo-SCT. None received allo-SCT from a severe acute respiratory syndrome coronavirus 2–positive donor. The freezing of 57 transplants led to the storage of 309 bags, for a mean storage time (between freezing and thawing) of 14 days. For the fresh transplant group, only 41 bags were stored for potential future donor lymphocyte infusions. Regarding the graft characteristics at collection, median number of cryopreserved TNC and CD34+ cells/kg were greater than those for fresh infusions. After thawing, median yields were 74.0%, 69.0% and 48.0% for TNC, CD34+ cells and CFU-GM, respectively. The median TNC dose/kg obtained after thawing was 5.8 × 108, with a median viability of 76%. The median CD34+ cells/kg was 5 × 106, with a median viability of 87%. In the fresh transplant group, the median TNC/kg was 5.9 × 108/kg, and the median CD34+ cells/kg and CFU-GM/kg were 6 × 106/kg and 276.5 × 104/kg, respectively. Sixty-one percent of the thawed transplants were out of specifications regarding the CD34+ cells/ kg requested cell dose (6 × 106/kg) and 85% of them would have had this dose if their hematopoietic stem cell transplant had been infused fresh. Regarding fresh grafts, 15.8% contained less than 6 × 106 CD34+ cells /kg and came from peripheral blood stem cells that did not reach 6 × 106 CD34+ cells /kg at collection. Regarding the factor that impaired CD34 and TNC yield after thawing, no significant impact of the granulocyte count, the platelet count or the CD34+ cells concentration/µL was observed. However, grafts containing more than 8 × 10 6/kg at collection showed a significantly lower TNC and CD34 yield.
Transplant outcomes (engraftment, graft-versus-host disease, infections, relapse or death) were not significantly different between the two groups.
The use of enhanced half‐life (EHL) FVIII has improved the quality of prophylaxis in haemophilia A, but with a benefit that may vary from one patient to another. We analysed the pharmacokinetic data ...obtained with efmoroctocog alfa (rFVIII‐Fc) in 114 patients and, in 47 cases, compared them to those previously measured with non‐EHL FVIII. The in vivo recovery (IVR) of rFVIII‐Fc measured with one stage clotting assay (OSA) and chromogenic assay (CSA) was 2.2 and 2.8 IU/mL per IU/kg, respectively. The median half‐life (T1/2) of rFVIII‐Fc was 14.5 hours whatever the FVIII:C assay used, but variable and correlated with preinfusion VWF:Ag levels (r = .76). Both IVR and T1/2 were lower in patients under 12 years old (2.4 IU/mL per IU/kg and 11.1 hours, respectively; CSA). PK study of rFVIII‐Fc vs non‐EHL FVIII showed a T1/2 ratio of 1.4 in favour of rFVIII‐Fc, regardless of the patient's age. However the relative increase in T1/2 with rFVIII‐Fc was lower than 30% in one‐third of patients evaluated, particularly when the previous FVIII administered was a BHK‐derived product. This study therefore suggests that analysis of individual PK profile in response to a specific FVIII concentrate is potentially useful before a switch in haemophilia A patients.
International Normalized Ratio (INR), which standardizes prothrombin time (PT) during oral anticoagulation, has been extended to standardize PT in liver diseases and is included in prognostic models ...such as the Model for End stage Liver Disease (MELD). However, mechanisms of PT prolongation in liver diseases differ from those involved in oral anticoagulation, and the thromboplastin reagents differ in their sensitivities to these 2 mechanisms. Our aim was to determine whether, in the calibration model for thromboplastins proposed by the World Health Organization, the use of plasmas from patients with liver diseases instead of plasmas from patients on oral anticoagulation could lead to a new INR specific for liver diseases (INR “LD”), achieving a real standardization of PT. First, 5 thromboplastins were calibrated against an international reference using 60 plasmas of patients with liver failure and, in a second step, the variation of PT reported as seconds, the ratio of patient PT to normal PT, INR, and INR“LD” was assessed in 34 other patients. MELD scores were calculated with the INR values obtained with the 5 thromboplastins. Only INR“LD” eliminated variability in PT results observed with the different thromboplastins. The discrepancy between MELD scores were up to 4 and 7 points in 52% and 17% of the patients, respectively. Conclusion: INR “LD” may provide a common international scale of PT reporting in hepatology. Its adoption would be an important step because of the significant impact on MELD score induced by interlaboratory variability in INR determination. (HEPATOLOGY 2007.)
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.
Abstract Background Pulmonary hypertension (PH) is a life-threatening condition that may affect outcomes in patients with systemic lupus erythematosus (SLE). The role of antiphospholipid antibodies ...(aPL) on the risk of PH is controversial. Therefore our objective was to estimate the risk of PH (WHO groups 1-5) including associated pulmonary arterial hypertension (APAH, WHO group 1 only) related to aPL in patients with SLE. Methods Systematic review and meta-analysis were performed: MEDLINE, EMBASE, Cochrane Library, congress abstracts, and reference lists of eligible studies were searched through 2015. Studies were selected if they included SLE patients with descriptions of the exposure to aPL and the outcomes (PH including APAH). Two reviewers extracted study characteristics and outcome data from published reports. Estimates were pooled using random effects models and sensitivity analyses. PROSPERO registration number: CRD42015016872. Results Of 984 identified abstracts, 31 primary studies (five cohorts, 13 case-control, 13 cross-sectional) met inclusion criteria, including 4480 SLE patients. Prevalence of PH in aPL-positive vs. aPL-negative SLE patients was 12.3% vs. 7.3%, respectively. The overall pooled odds ratio (OR) for PH was 2.28 (95% CI, 1.65 to 3.15) ( I 2 = 39%). The risk of APAH was also significantly increased (OR = 2.62 95% CI, 1.11-6.15). The risk of PH was the highest for lupus anticoagulant (OR = 1.96 95% CI, 1.31-2.92) and IgG anticardiolipin antibodies (OR = 2.64 95% CI, 1.30-5.36) while other antibodies were not significantly associated with PH. Conclusions Among SLE patients, aPL can identify patients at risk for PH and APAH. These findings warrant implementation of effective screening and early treatment strategies.
Le syndrome des antiphospholipides est une thrombophilie caractérisée par l’association d’un événement clinique thrombotique (artériel et/ou veineux) ou obstétrical, associé à la présence durable ...d’anticorps antiphospholipides. L’atteinte pouvant toucher l’ensemble de l’arbre vasculaire, une atteinte rénale est fréquemment associée avec la description maintenant bien codifiée de la néphropathie associée au syndrome des antiphospholipides. Nous proposons dans cette revue des recommandations actualisées sur la prise en charge du syndrome des antiphospholipides en néphrologie. La thérapeutique se base sur une anticoagulation plus ou moins une antiagrégation à long terme en fonction des événements cliniques sans oublier le recours à une néphroprotection classique (contrôle strict de la pression artérielle avec notamment des thérapeutiques bloquant le système rénine–angiotensine–aldostérone). Le syndrome catastrophique des antiphospholipides est une complication extrêmement grave pouvant mettre en jeu le pronostic vital du patient. Celui-ci justifie une attention toute particulière, ainsi qu’une prévention dans les situations à risque. Nous illustrons également les difficultés de prise en charge au long cours de ces patients, tant en dialyse qu’en transplantation rénale.
The antiphospholipid syndrome is a thrombophilia characterized by the combination of arterial and/or venous thrombotic events or obstetric clinical events, associated with persistent presence of antiphospholipid antibodies. In this syndrome, thromboses may affect all of the vascular tree, renal damage is frequently associated with a specific antiphospholipid syndrome nephropathy. We propose in this review to provide updated recommendations on the management of antiphospholipid syndrome in nephrology. Treatment is based on long-term anticoagulant therapy with or without antiplatelet agents according to clinical events. The use of a conventional nephroprotection must not be forgotten (strict control of blood pressure with drugs blocking the renin–angiotensin–aldosterone system). Catastrophic antiphospholipid syndrome is an extremely severe complication which can threaten the vital prognosis of the patient. This justifies particular surveillance, as well as prevention in high-risk situations. We also illustrate the difficulties of long-term management in these patients, both in dialysis or kidney transplantation.
Replacement therapy with plasma‐derived or recombinant FVIII and FIX (pdFVIII/pdFIX or rFVIII/rFIX) concentrates is the standard of treatment in patients with haemophilia A and B, respectively. ...Measurement of factor VIII (FVIII:C) or factor IX (FIX:C) levels can be done by one‐stage clotting assay (OSA) or chromogenic substrate assay (CSA). The French study group on the Biology of Hemorrhagic Diseases (a collaborative group of the GFHT and MHEMO network) presents a literature review and proposals for the monitoring of FVIII:C and FIX:C levels in treated haemophilia A and B patients, respectively. The use of CSA is recommended for the monitoring of patients treated with pdFVIII or rFVIII including extended half‐life (EHL) rFVIII. Except for rFVIII‐Fc, great caution is required when measuring FVIII:C levels by OSA in patients substituted by EHL‐rFVIII. The OSA is recommended for the monitoring of patients treated with pdFIX or rFIX. Large discordances in the FIX:C levels measured for extended half‐life rFIX (EHL‐rFIX), depending on the method and reagents used, must lead to great attention when OSA is used for measuring FIX:C levels in patients substituted by EHL‐rFIX. Data of most of recent studies, obtained with spiked plasmas, deserve to be confirmed in plasma samples of treated patients.
Dabigatran etexilate, rivaroxaban and apixaban (DOACs) are widely used and measurement of their concentration is desirable in certain clinical situations. Target-specific assays are available but ...limited information exists on their performance especially in their ability to accurately measure low and high concentrations.
To define, in a multicenter study, the precision and accuracy of DOAC measurements in daily practice.
15 plasma samples (kindly provided by Hyphen-Biomed) spiked with 5 blinded concentrations of dabigatran, rivaroxaban or apixaban (targeted 0–40–100–250–500ng/mL, actual concentrations measured by HPLC-MS/MS), were sent to 30 haemostasis laboratories. DOAC concentration, PT and aPTT were measured once in each sample using local reagents. Interlaboratory precision was determined by its coefficient of variation (CV) and accuracy by its bias.
464 DOAC measurements were performed in the 30 laboratories using 4 dabigatran and 5 rivaroxaban/apixaban calibrated assays on 3 analysers. Inter-laboratory CVs were below 18% for concentrations ≥100ng/mL, and higher for concentrations ~40ng/mL; biases were below 8% for all drugs and concentrations. In DOAC-free samples, concentrations were all below the lower limit of quantification except for one value (dabigatran: 35ng/mL). Depending on the concentrations, significant differences were found between reagents in rivaroxaban and apixaban concentration values. PT and aPTT ratios displayed a low sensitivity to apixaban.
Our results suggest that calibrated DOAC assays allow the reliable measurement of a wide range of drug concentrations, even though improvement of their performances is necessary, especially for measuring low concentrations.
•Information on the performances of direct oral anticoagulants (DOAC) assays are required.•A wide range of DOAC concentrations were tested in a multicenter study (30 laboratories).•Good accuracy and acceptable precision of DOAC commercial assays were found.•Improvements are necessary for measuring low DOAC concentrations.•PT or aPTT are unable to detect low concentrations of rivaroxaban and dabigatran and “on-therapy” concentrations of apixaban.
Abstract The “so-called” pediatric tubes are often used when collecting smaller blood volume is necessary, particularly in pediatric patients or in case of difficult/recurrent sampling. The aim of ...this multicenter study was to compare coagulation test results evaluated in evacuated polymer tubes containing 0.109 M citrate (1 vol./9 vol.) specifically designed to allow either a partial (2.0 mL,“pediatric”) or a total (3.5 mL) filling. No significantly relevant discrepancy was found between routine coagulation test results in both tubes collected from untreated patients and from patients on vitamin K antagonist or low molecular weight heparin. In contrast, aPTT was significantly shorter and anti-FXa activity was significantly lower in partial-draw than in full-draw tubes collected from 46 patients receiving unfractionated heparin (UFH). This discrepancy was likely related to increased platelet activation in partial-draw tubes, as suggested by higher platelet factor 4 plasma concentrations and platelet P-Selectin expression in partial-draw than in full-draw citrate tubes. To confirm this hypothesis, we then evaluated partial-draw tubes containing CTAD, a mixture of anticoagulant and antiplatelet agents. In 25 patients on UFH, aPTT and anti-FXa activity were not significantly different in partial-draw CTAD tubes and in full-draw citrate tubes. In conclusion, despite increased platelet activation, samples collected into partial-draw citrate tubes allow accurate routine coagulation testing in all patients but those requiring UFH assessment, in which their use could lead to significant underestimation of anticoagulation. In such cases, partial-draw tubes containing CTAD could be validly used to monitor heparin therapy as well as to perform routine coagulation testing.
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