ABSTRACT
BACKGROUND: Efmoroctocog alfa (rFVIIIFc) is an extended half-life FVIII used notably in surgery for patients with haemophilia A. More information is needed of its usage in real-life. METHODS: Adult patients with HA followed at the Lyon Comprehensive Hemophilia Care Center who underwent a surgery with rFVIIIFc were included in this retrospective analysis. The pharmacokinetics of rFVIIIFc was assessed by plasma factor VIII clotting activity (FVIII:C) using both one-stage (OSA) and chromogenic substrate (CSA) assays. RESULTS: A total of 39 major and 31 minor surgeries were performed in 49 patients treated with rFVIIIFc. The median dose of rFVIIIFc infused before major and minor surgeries respectively was 67.5 ((interquartile range [IQR] 52.6-76.9) and 48.0 (38.5-51.8) IU/kg. For major surgeries, during the first postoperative week, the median residual FVIII:C was 78 (64.5-101.5) IU/dL with OSA and 99 (71-118) IU/dL with CSA (p < .0001). After surgery, rFVIIIFc doses were adjusted according to CSA results. This led to a significant decrease of rFVIIIFc consumption compared to what would have been proposed according to the OSA assay, without unusual bleeding or appearance of inhibitor. Considering the high price of the molecule, this was also associated with a significant cost reduction. CONCLUSION: Dose adjustment of rFVIIIFc according to FVIII: C measured by CSA is effective, safe and well tolerated in patients with haemophilia A undergoing invasive surgery.
Subject(s)
Factor VIII , Hemophilia A , Immunoglobulin Fc Fragments , Adult , Humans , Factor VIII/therapeutic use , Hemophilia A/drug therapy , Retrospective Studies , Recombinant Fusion Proteins/therapeutic use , Recombinant Proteins/therapeutic use , Half-LifeABSTRACT
INTRODUCTION AND AIM: Severe haemophilia B (HB) is characterized by spontaneous bleeding episodes, mostly into joints. Recurrent bleeds lead to progressive joint destruction called haemophilic arthropathy. The current concept of prophylaxis aims at maintaining the FIX level >3-5 IU/dL, which is effective at reducing the incidence of haemophilic arthropathy. Extended half-life FIX molecules make it easier to achieve these target trough levels compared to standard FIX concentrates. We previously reported that the fusion of a recombinant FIX (rFIX) to factor XIII-B (FXIIIB) subunit prolonged the half-life of the rFIX-LXa-FXIIIB fusion molecule in mice and rats 3.9- and 2.2-fold, respectively, compared with rFIX-WT. However, the mechanism behind the extended half-life was not known. MATERIALS AND METHODS: Mass spectrometry and ITC were used to study interactions of rFIX-LXa-FXIIIB with albumin. Pharmacokinetic analyses in fibrinogen-KO and FcRn-KO mice were performed to evaluate the effect of albumin and fibrinogen on in-vivo half-life of rFIX-LXa-FXIIIB. Finally saphenous vein bleeding model was used to assess in-vivo haemostatic activity of rFIX-LXa-FXIIIB. RESULTS AND CONCLUSION: We report here the key interactions that rFIX-LXa-FXIIIB may have in plasma are with fibrinogen and albumin which may mediate its prolonged half-life. In addition, using the saphenous vein bleeding model, we demonstrate that rFIX-FXIIIB elicits functional clot formation that is indistinguishable from that of rFIX-WT.
Subject(s)
Hemophilia B , Hemostatics , Joint Diseases , Vascular Diseases , Mice , Rats , Animals , Factor IX/genetics , Factor IX/pharmacology , Factor IX/therapeutic use , Factor XIII/pharmacology , Factor XIII/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Recombinant Fusion Proteins/pharmacokinetics , Hemophilia B/drug therapy , Hemorrhage/prevention & control , Hemostatics/therapeutic use , Albumins , Fibrinogen/therapeutic use , Half-Life , Joint Diseases/drug therapy , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use , Recombinant Proteins/chemistryABSTRACT
BACKGROUND: In patients with FXI deficiency, the risk of surgery-related bleeding is poorly correlated with plasma FXI activity (FXI:C); the latter can therefore not be used as a reliable predictor of bleeding in surgeries. OBJECTIVES: The aim of this retrospective study was to determine whether thrombin generation assay (TGA) could be used to evaluate the risk of surgery-related bleeding in FXI-deficient patients. TGA parameters were compared to FXI:C values, haemostatic treatments and surgical outcomes. PATIENTS: All patients followed at the haemophilia treatment care centre (Lyon, France) with a FXI:C < 50IU/dL, and for whom a baseline TGA was performed between January 2014 and December 2019, were included. RESULTS: Among the 175 surgeries reported herein in 49 patients, FXI concentrates were used for 11 (6%) surgeries and fresh frozen plasma was used for five (3%) surgeries; these surgeries were performed in patients with two or three impaired TGA parameters. No haemostatic treatment was prescribed for 119 (68%) surgeries. A surgery-related bleeding occurred in 12 patients during 21 (12%) surgeries. Thrombin generation was significantly reduced or delayed in patients who reported surgery related-bleeding. Among the 34 (68%) surgeries performed without haemostatic treatment in patients with three impaired TGA parameters, a surgery-related bleeding was reported in 44% of cases (15 surgeries out of 34). CONCLUSION: The present study confirmed that TGA is an interesting laboratory test in FXI deficiency, for determining the bleeding risk and guiding the haemostatic management of surgeries, while taking into account the surgical bleeding risk and the history of bleeding.
Subject(s)
Factor XI Deficiency , Thrombin , Blood Loss, Surgical , Factor XI , Factor XI Deficiency/complications , Factor XI Deficiency/surgery , Humans , Retrospective Studies , Thrombin/therapeutic useABSTRACT
Hemophilia A is an inherited bleeding disorder characterized by a lack of plasma clotting factor VIII (FVIII). In prophylaxis or during surgery, FVIII infusions are necessary to prevent bleeding. The authors describe the perioperative challenges and application of a multidisciplinary hemostatic management approach to a Caucasian male newborn, with antenatal diagnoses of moderate hemophilia A (2 IU/dL) and dextro-transposition of the great arteries requiring arterial switch surgery within the first month of life. Because both conditions are rare, only few reports in the literature are available describing perioperative management of hemophilia in neonates and children undergoing cardiac surgery. After baseline FVIII determination and normal standard coagulation studies, iterative intravenous pharmacist-prepared plasma-derived FVIII boluses were calculated (35 IU/kg) and administered intravenously every 6 hours for 24 hours, then switched to a continuous infusion and guided by daily chromogenic clotting FVIII activity assay for targeted values between 80 and 100 IU/dL. Successful cardiac surgery, using cardiopulmonary bypass, was performed with continuous infusion of FVIII at 5 IU/kg/h. Thirteen days after surgery, the FVIII antibody screening remained negative and continuous infusion was switched in favor of a daily intravenous bolus treatment to facilitate reconciliation to the center of origin. The authors' multidisciplinary strategy, established antenatally, allowed for successful care in this highly complex and rare situation.
Subject(s)
Hemophilia A , Hemostatics , Transposition of Great Vessels , Arteries , Child , Factor VIII , Female , Hemophilia A/complications , Hemostatics/therapeutic use , Humans , Infant, Newborn , Male , Pregnancy , Transposition of Great Vessels/surgery , Treatment OutcomeABSTRACT
INTRODUCTION: Lightening the injection burden is commonly believed to improve prophylaxis adherence. Efmoroctocog alfa (rFVIIIFc) is the first recombinant FVIII-Fc fusion protein available in France. This clotting factor with an extended half-life could thus improve medication adherence. AIM: The study primarily aimed to assess the real-life impact on prophylaxis adherence of haemophilia A patients, when switching from a standard to an extended half-life FVIII. METHODS: This study was an observational, monocentre, non-interventional study aiming at assessing haemophilia A patients' real-life adherence during the first-year post-rFVIIIFc prophylaxis initiation. Medication adherence was assessed using two methods: the medication possession ratio (MPR), which is based on the hospital pharmacy dispensing data, and self-reported VERITAS-Pro® questionnaire. Patients on rFVIIIFc prophylaxis for at least 12 months, following a 12-month standard FVIII prophylaxis, were eligible for inclusion. RESULTS: In 2019, 47 male patients were undergoing rFVIIIFc prophylaxis in our Hemophilia Center, among which 36 meeting the inclusion criteria. Switching from standard to extended half-life FVIII prophylaxis resulted in increased mean dosing, while the mean number of weekly prophylactic injections (2.6 ± 0.5 vs 1.8 ± 0.3) decreased. Following rFVIIIFc initiation, a non-significant increase in median MPR occurred and the self-reported VERITAS-Pro® questionnaire demonstrated improved adherence to rFVIIIFc prophylaxis. Comparing adherent and non-adherent patients revealed age as the only factor likely to impact adherence (p = .07). CONCLUSION: Our patient cohort exhibited high adherence levels before and after FVIII switching, based on MPR and VERITAS-Pro® questionnaire. The latter is likely a useful tool to quantity prophylaxis adherence from a patient's perspective in daily use.
Subject(s)
Hemophilia A , Factor VIII/therapeutic use , Half-Life , Hemophilia A/drug therapy , Hemorrhage , Humans , Male , Medication Adherence , Recombinant Fusion ProteinsABSTRACT
BACKGROUND: Haemophilic arthropathy (HArt) is a serious complication in patients with hemophilia. Early diagnosis and treatment are essential to minimise the development of HArt. The use of biomarkers may improve early diagnosis of HArt. Circulating microRNAs (miRNAs) are small, non-coding RNAsthat regulate gene expression, and are being investigated as promising biomarkers due to their role in joint and bone metabolism. AIMS: To investigate differential expression of miRNAs and their relationship to arthropathy in patients with hemophilia A. METHODS: miRNA expression was examined in a pilot study followed by a validation study (100 hemophilia A patients with [n = 83] and without HArt [n = 17], 14 controls). Differential miRNA expression was investigated using real-time quantitative PCR. RESULTS: The pilot study identified 2 miRNAs differentially expressed in patients with Hart (Pettersson score ≥ 1), after adjusting for the false discovery rate (FDR). The validation study evaluated these 2 miRNAs. The results demonstrated that two miRNAs (miR- 208a-3p and 524-3p) were significantly underexpressed in plasma of patients with HArt compared to patients without arthropathy, with FDR <0.05 (Fig. 1). In addition, 3 miRNAs (130a-3p, miR- and 506-3p) were significantly underexpressed in patients with moderate HArt (Pettersson score 4 to 7). CONCLUSIONS: In this proof of concept study we identified a signature of 5 circulating miRNAs associated with Hart with potential as diagnosis tools for HArt. These miRNAs are potential negative regulators of gene expression, suggesting their activity in HArt by interfering with osteoblastic (miR- 208a-3p) and osteoclastic (miR-506-3p) differentiation to impair bone mineralization and remodeling processes, or regulating chondrogenesis (miR-335-5p). miRNAs associated with earlier stages of HArt will be further investigated in a sub-study of the prospective clinical trial PROVE, which will investigate the effects of long-term prophylaxis with simoctocog alfa versus emicizumab in adults with hemophilia A.
ABSTRACT
BACKGROUND: Emicizumab has been approved for the prophylaxis of patients with hemophilia A with or without inhibitors. However, spontaneous and trauma-induced breakthrough bleeds have been reported in patients on emicizumab prophylaxis, and no laboratory assay has been validated to evaluate the hemostatic activity of emicizumab. OBJECTIVES: The thrombin generation assay (TGA) could be a surrogate marker of the hemostatic efficacy of emicizumab. The correlation between TGA and the methods used to measure emicizumab blood concentration was evaluated in this study. METHODS: TGA was modified by the use of a trigger reagent combining a very low concentration of tissue factor and activated factor (F)XI. Emicizumab quantification was performed by 3 methods: the modified 1-step FVIII assay and 2 methods based on liquid chromatography and mass spectrometry (LC-MS). RESULTS: Using tissue factor/activated FXI-triggered TGA and platelet-poor plasma, a relationship was observed between the area under the thrombin generation curve (endogenous thrombin potential [ETP]) and the clinical response of patients to emicizumab. The ultrastructure of fibrin clots was consistent with ETP results and showed that emicizumab had a hemostatic activity equivalent to 20 to 30 IU/dL of FVIII. Finally, pharmacokinetic/pharmacodynamic analyses showed no correlation between ETP and LC-MS nor with modified 1-stage FVIII assay, but a statistically significant correlation between the LC-MS methods and the time-to-peak results of the TGA. CONCLUSION: Using a modified TGA, this study showed that patients who experienced breakthrough bleeds while on emicizumab had a lower thrombin-generating capacity compared with others with good clinical response to emicizumab.
Subject(s)
Antibodies, Bispecific , Antibodies, Monoclonal, Humanized , Hemophilia A , Hemostasis , Thrombin , Humans , Hemophilia A/drug therapy , Hemophilia A/blood , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Bispecific/pharmacology , Antibodies, Bispecific/pharmacokinetics , Antibodies, Bispecific/therapeutic use , Antibodies, Bispecific/blood , Thrombin/metabolism , Adult , Hemostasis/drug effects , Male , Young Adult , Adolescent , Hemorrhage/blood , Middle Aged , Treatment Outcome , Chromatography, Liquid , Blood Coagulation Tests , Hemostatics/therapeutic use , Hemostatics/pharmacology , Hemostatics/pharmacokinetics , Mass Spectrometry , Blood Coagulation/drug effects , Child , Severity of Illness IndexABSTRACT
INTRODUCTION: Hemophilia is a rare constitutional bleeding disorder due to a deficiency in Factor VIII or Factor IX. Recurrent hemarthroses, one of the major complications of the disease, lead to hemophilic arthropathy, a disabling condition that requires early diagnosis. Traditionally, clinical examination and plain film radiography have been used to diagnose hemophilic arthropathy. Magnetic resonance imaging (MRI) and ultrasound can be more useful for diagnosing soft-tissue changes. However, but each of these methods has limitations and diagnosis of arthropathy can be delayed. AIM: The aim of this project was to assess plasmatic biomolecules indicative of osteo-cartilaginous damage in patients with hemophilia with or without known arthropathy, in order to improve the diagnosis of this major complication of the disease. METHODS: In this monocentric retrospective study, 40 patients with hemophilia A or B, for whom a plasma sample was available, provided informed consent for further analyses (multiplex immunoassays and ELISA) and collection of relevant clinical information in their medical files. Correlations were sought for between biomarkers of interest and the severity of joint lesions assessed according to Pettersson's radiologic score. RESULTS: Two biomarkers were identified, respectively SDF-1α and COMP. Their plasmatic levels were significantly increased in patients with arthropathy compared to controls and patients without arthropathy. These values correlated significantly with the Pettersson score in patients under regular prophylaxis. CONCLUSION: Two plasma biomarkers have been identified that could help assess the presence and severity of hemophilic arthropathy.
Subject(s)
Arthritis , Hemophilia A , Humans , Hemophilia A/complications , Hemophilia A/diagnosis , Hemophilia A/pathology , Chemokine CXCL12 , Cartilage Oligomeric Matrix Protein , Retrospective Studies , Hemarthrosis/diagnostic imaging , Hemarthrosis/etiology , Arthritis/complications , Radiography , BiomarkersABSTRACT
: The risk of pregnancy-related venous thromboembolism is high in patients with inherited thrombophilia. The aim of this study was to compare the risk of pregnancy related-venous thromboembolism of women with protein C (PC) deficiency to patients with heterozygous factor V Leiden mutation. 145 consecutive pregnant women with confirmed PC deficiency or heterozygous factor V Leiden mutation were prospectively enrolled in the study. Lyon venous thromboembolism-risk score was used to individually tailor antithrombotic prophylaxis. The use of a validated clinical score presents the advantage to have a homogenous management of the venous thromboembolism risk in patients having similar risk factors. 53 pregnancies with PC deficiency were compared with 190 pregnancies in heterozygous factor V Leiden mutation carriers. 50% of the patients with PC deficiency and 64% of the heterozygous factor V Leiden mutation carriers were asymptomatic. According to the Lyon-venous thromboembolism risk score, 50% of patients with PC deficiency and 51% of heterozygous factor V Leiden carriers did not received any antepartum heparin prophylaxis. 34 and 37% of patients respectively received heparin prophylaxis during the third trimester only. No venous thromboembolism was observed in patients with PC deficiency and one postpartum venous thromboembolism occurred in a patient with heterozygous factor V Leiden. In the absence of randomized controlled clinical studies, we report here a large prospective series of pregnant women with PC deficiency. In our cohort, no difference of outcome, in terms of venous thromboembolism, was observed between pregnant women with PC deficiency and those with heterozygous factor V Leiden. Based on our results, low-molecular-weight heparin prophylaxis should not be mandatory in all pregnant women with PC deficiency. Similar prophylaxis strategies may be applied to women with factor V Leiden mutation or PC deficiency.
Subject(s)
Factor V/metabolism , Protein C Deficiency/genetics , Thrombophilia/genetics , Venous Thrombosis/etiology , Adult , Female , Humans , Mutation , Pregnancy , Risk FactorsABSTRACT
Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder. We report herein a case of AVWS due to a monoclonal gammopathy of undetermined significance, in which a transient but prolonged response to a treatment by intravenous immunoglobulin (IVIG) was observed. The diagnosis was fortuitously made in a preoperative setting for neurosurgery, after biological exploration of an isolated prolonged activated partial thromboplastin time. AVWS was confirmed by an accelerated clearance of an infused plasma-derived von Willebrand factor (VWF) concentrate. High doses of IVIG were used to perform the neurosurgery. Fifty-four days after IVIG, the patient was still responding to treatment with normal levels of factor VIII and VWF.