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.

A French Real-World Evidence Study Evaluating the Efficacy, Safety, and Pharmacokinetic Parameters of rVIII-SingleChain in Patients with Hemophilia A Receiving Prophylaxis.

BACKGROUND: rVIII-SingleChain is a recombinant factor VIII (FVIII) with increased binding affinity to von Willebrand factor compared with other FVIII products. rVIII-SingleChain is indicated for the treatment and prevention of bleeding episodes in patients with hemophilia A. OBJECTIVES: To collect real-world evidence data from patients treated with rVIII-SingleChain to confirm the efficacy and safety established in the clinical trial program and carry out a population pharmacokinetic (PK) analysis. METHODS: This interim analysis includes data, collected between January 2018 - September 2021, from patients treated with rVIII-SingleChain prophylaxis at French Hemophilia Treatment centers. Data on annualized bleeding rates, dosing frequency, and consumption before and after switching to rVIII-SingleChain were recorded. A population PK analysis was also conducted to estimate PK parameters. RESULTS: Overall, 43 patients switched to prophylaxis with rVIII-SingleChain either from a previous prophylaxis regimen or from on-demand treatment. Following the switch to rVIII-SingleChain, patients maintained excellent bleed control. After switching to rVIII-SingleChain, most patients maintained or reduced their regimen. Interestingly, a majority of patients treated >2 ×/weekly with a standard half-life FVIII reduced both injection frequency and FVIII consumption with rVIII-SingleChain. A PK analysis revealed a lower clearance of rVIII-SingleChain (1.9 vs. 2.1 dL/h) and a longer half-life both in adolescents/adults (n = 28) and pediatric (n = 6) patients (15.5 and 11.9 hours, respectively vs. 14.5 and 10.3 hours) than previously reported. CONCLUSIONS: Patients who switched to rVIII-SingleChain prophylaxis demonstrated excellent bleed control and a reduction in infusion frequency. A population PK analysis revealed improved PK parameters compared with those reported in the clinical trial.

Prostate biopsy and prostate cancer management in patients with haemophilia: The experience of French Haemophilia Treatment Centres.

BACKGROUND: Data are limited on prostate cancer (PC) management in patients with haemophilia (PWH). AIM: To describe PC screening and diagnosis, treatment modalities and bleeding complications in a group of unselected PWH followed at French Haemophilia Treatment Centres (HTCs) PATIENTS AND METHODS: PC screening, management and bleeding complications were retrospectively investigated at 14 French HTCs between 2003 and 2018. RESULTS: Among> 1549 > 50-year-old PWHs, 73 (4.7%) underwent PC screening (median age 71.1 years; 67/6 HA/HB, 17/56 severe-moderate/mild). At diagnosis, haematuria was infrequent. Prophylaxis was administered during 76/86 (88%) prostate biopsies (PB) (n = 67 clotting factor concentrates, CFC; n = 9 desmopressin; n = 17 associated with tranexamic acid, TA). Bleeding (11/86, 12.8%) occurred mainly post-prophylaxis (median delay: 7 days): haematuria (9/11, 81.8%), and rectal bleeding (2/11, 18.2%) including one major (1.2%). PC was confirmed in 50/86 PB and in two prostatectomy specimens (total n = 50 patients, n = 6 with only active surveillance). Surgery (n = 28/44 patients) was managed with CFC. Fifteen patients had radiotherapy/brachytherapy, 10 had hormone therapy; CFC-based prophylaxis was only prescribed for brachytherapy (n = 2). Major bleedings occurred in 3/28 (10.7%) and 2/15 (13.3%) patients who underwent surgery and radio/brachytherapy, respectively. No bleeding risk factor was found. CONCLUSION: Our data indicate that PB requires prophylaxis for atleast 7 days, using CFC, desmopressin or TA in function of haemophilia severity. PC surgery should be considered at high bleeding risk. Long-term post-procedural CFC or oral TA could be discussed. Radiotherapy/brachytherapy also should be managed with prophylaxis (CFC or TA).

Compliance with Early Long-Term Prophylaxis Guidelines for Severe Hemophilia A.

OBJECTIVES: To evaluate the applicability and compliance with guidelines for early initiation of long-term prophylaxis in infants with severe hemophilia A and to identify factors associated with guideline compliance. STUDY DESIGN: This real-world, prospective, multicenter, population-based FranceCoag study included almost all French boys with severe hemophilia A, born between 2000 and 2009 (ie, after guideline implementation). RESULTS: We included 333 boys in the study cohort. The cumulative incidence of long-term prophylaxis use was 61.2% at 3 years of age vs 9.5% in a historical cohort of 39 boys born in 1996 (ie, before guideline implementation). The guidelines were not applicable in 23.1% of patients due to an early intracranial bleeding or inhibitor development. Long-term prophylaxis was delayed in 10.8% of patients. In the multivariate analysis, 2 variables were significantly associated with "timely long-term prophylaxis" as compared with "delayed long-term prophylaxis": hemophilia treating center location in the southern regions of France (OR 23.6, 95% CI 1.9-286.7, P = .013 vs Paris area) and older age at long-term prophylaxis indication (OR 7.2 for each additional year, 95% CI 1.2-43.2, P = .031). Long-term prophylaxis anticipation was observed in 39.0% of patients. Earlier birth year (OR 0.5, 95% CI 0.3-0.8, P = .010 for birth years 2005-2009 vs 2000-2004) and age at first factor replacement (OR 1.9 for each additional year, 95% CI 1.2-3.0, P = .005) were significantly associated with "long-term prophylaxis guideline compliance" vs "long-term prophylaxis anticipation." CONCLUSIONS: This study suggests that long-term prophylaxis guidelines are associated with increased long-term prophylaxis use. However, early initiation of long-term prophylaxis remains a challenge.

Long-Term Antithrombotic Treatments Prescribed for Cardiovascular Diseases in Patients with Hemophilia: Results from the French Registry.

Cardiovascular diseases (CVDs) are a major issue in aging patients with hemophilia (PWHs). Antithrombotic agents are widely used in the general population for CVD treatment, but this recommendation is not fully applicable to PWHs. To improve treatment strategies, a prospective case-control study (COCHE) that analyzed CVD management and follow-up (2 years/patient) in PWHs was performed in France from 2011 to 2018. In total, 68 PWHs (median age: 65 years [39-89]; 48 mild, 10 moderate, and 10 severe hemophilia) were included (n = 50 with acute coronary syndrome, n = 17 with atrial fibrillation, n = 1 with both). They were matched with 68 control PWHs without antithrombotic treatment. In our series, bleeding was significantly influenced by (1) hemophilia severity, with a mean annualized bleeding ratio significantly higher in COCHE patients than in controls with basal clotting factor level up to 20%, (2) antihemorrhagic regimen (on-demand vs. prophylaxis) in severe (hazard ratio [HR] = 16.69 [95% confidence interval, CI: 8.2-47.26]; p < 0.0001) and moderate hemophilia (HR = 42.43 [95% CI: 1.86-966.1]; p = 0.0028), (3) type of antithrombotic treatment in mild hemophilia, with a significantly higher risk of bleeding in COCHE patients than in controls for dual-pathway therapy (HR = 15.64 [95% CI: 1.57-115.8]; p = 0.019), anticoagulant drugs alone (HR = 9.91 [95% CI: 1.34-73.47]; p = 0.0248), dual antiplatelet therapy (HR = 5.31 [95% CI: 1.23-22.92]; p = 0.0252), and single antiplatelet therapy (HR = 3.76 [95% CI: 1.13-12.55]; p = 0.0313); and (4) HAS-BLED score ≥3 (odds ratio [OR] = 33 [95% CI: 1.43-761.2]; p = 0.0065). Gastrointestinal bleeding was also significantly higher in COCHE patients than in controls (OR = 15 [95% CI: 1.84-268]; p = 0.0141). The COCHE study confirmed that antithrombotic treatments in PWHs are associated with increased bleeding rates in function of hemophilia-specific factors and also of known factors in the general population.

Postauthorization safety surveillance study of antihaemophilic factor (recombinant) reconstituted in 2 mL sterile water for injection in children with haemophilia A.

INTRODUCTION: Antihaemophilic factor (recombinant) (rAHF; ADVATE® ) is approved for prophylaxis and treatment of bleeding in children and adults with haemophilia A. Reconstitution in 2 mL sterile water for injection instead of 5 mL allows for a 60% reduction in infusion volume and administration time, but could increase the likelihood of hypersensitivity and infusion-related reactions, especially in children. AIM: To assess local tolerability, safety and effectiveness of rAHF 2 mL during routine clinical practice factor VIII (FVIII) replacement (on-demand and prophylaxis) in children with severe (FVIII < 1%) or moderately severe (FVIII 1%-2%) haemophilia A. METHODS: This was a prospective, non-interventional, postauthorization safety surveillance study (NCT02093741). Eligible patients were previously treated with rAHF and had a negative inhibitor test result during ≤10 exposure days prior to study entry. RESULTS: Of 65 patients enrolled (0-11 years of age), 54 and 11 had severe and moderately severe haemophilia A, respectively; 56 patients received prophylaxis, and 11 had ≤50 exposure days, of which 4 had ≤4 exposure days. No patients reported local hypersensitivity reactions, treatment-related adverse events or developed inhibitors. Investigators rated overall effectiveness of rAHF 2 mL prophylaxis as excellent or good. Ninety-four bleeding events in 34 patients were treated. Haemostatic effectiveness was rated as excellent or good for 75.8% of bleeds; 86.2% of bleeds required 1 or 2 infusions. CONCLUSION: In children with severe/moderately severe haemophilia A, no hypersensitivity reactions were reported with rAHF 2 mL treatment, and the safety and effectiveness are consistent with data previously reported for rAHF 5 mL.

Congenital factor XIII deficiency: comprehensive overview of the FranceCoag cohort.

This FranceCoag network study assessed 33 patients with congenital factor XIII (FXIII) deficiency presenting FXIII levels <10 iu/dl. Diagnosis was based on abnormal bleeding in 29 patients, a positive family history in 2, recurrent miscarriages in 1 and was fortuitous in 1. Eighteen patients (62·1%) presented life-threatening umbilical or intracranial haemorrhages (ICH). Seven of the 15 patients who experienced ICH were diagnosed but untreated, including 3 with secondary neurological sequelae. All pregnancies without prophylaxis (26/26) led to miscarriages versus 3/16 with prophylaxis. In patients exhibiting FXIII levels <10 iu/dl, prophylaxis could be discussed at diagnosis and at pregnancy. Further controlled prospective studies are needed.

Hemostatic profile of infants with spontaneous prematurity: can we predict intraventricular hemorrhage development?

BACKGROUND: Defining hemostatic profile for preterm infants is a challenge when severe bleedings are frequent. METHODS: The aim was to define the hemostatic profile at birth of infants with spontaneous prematurity and to evaluate whether characteristic profiles can predict the development of intraventricular hemorrhage (IVH) in prematures. RESULTS: We included 122 newborns with a median age of 315/7 gestational age (GA) [292/7;340/7] and median weight of 1145 g [785;1490]. Levels of fibrinogen, factor II (FII) and factor V (FV) rose with GA (p = 0.017,p = 0.009, p = 0.001). In the group of 230/7 - 286/7 GA, the 5th percentile was defined as 0.6 g/L for fibrinogen, 15 IU/dL for FII and 16 IU/dL for factor V (n = 30). In the group of 290/7-326/7 GA, the 5th percentile was defined as 1.0 g/L for fibrinogen, 24 IU/dL for FII and 41 IU/dL for factor V (n = 46). In the group of 330/7-366/7 GA, the 5th percentile was defined as 1.0 g/L for fibrinogen, 24 IU/dL for FII and 30 IU/dL for factor V (n = 46). Level of fibrinogen was higher in case of vaginal delivery and lower in case of IUGR. Only lower level of FV at birth was significantly associated with IVH (63.5 [46.0; 76.5] vs 74.0 [58.0; 89.0], p = 0.026) with an unadjusted OR per SD increase in FV of 0.57 (95%CI, 0.34 to 0.96). After adjustment for age, the association between FV level and IVH was slightly attenuated (adjusted OR, 0.70; 95%CI, 0.40 to 1.23) but remained not significant (p = 0.22).There was no correlation with FII and fibrinogen. CONCLUSIONS: We can define hemostastic profile of prematures and corroborate references ranges for studied parameters. Further large studies are still called for, to correlate the grade of hemorrhage and the factor V level at birth.

Management of bleeding and invasive procedures in haemophilia A patients with inhibitor treated with emicizumab (Hemlibra® ): Proposals from the French network on inherited bleeding disorders (MHEMO), the French Reference Centre on Haemophilia, in collaboration with the French Working Group on Perioperative Haemostasis (GIHP).

INTRODUCTION: Emicizumab (Hemlibra® ) recently became available and requires an adaptation for managing bleeding, suspected bleeding and emergency or scheduled invasive procedures in haemophilia A patients with inhibitor. This implicates a multidisciplinary approach and redaction of recommendations for care that must be regularly adapted to the available data. AIM: The following text aims to provide a guide for the management of people with haemophilia A with inhibitor treated with emicizumab in case of bleeding or invasives procedures. METHODS: The French network on inherited bleeding disorders (MHEMO), the French Reference Centre on Haemophilia (CRH), in collaboration with the French Working Group on Perioperative Haemostasis (GIHP) have been working together to make proposals for the management of these situations. RESULTS: Haemostatic treatment and other medications should be given stepwise, according to the severity and location of the bleeding or the risk of bleeding of the procedure as well as the haemostatic response obtained at each step in order to ensure an optimal benefit/risk ratio. CONCLUSION: The lack of data means that it is only possible to issue proposals rather than recommendations.

Benefits of Delayed Cord Clamping in Red Blood Cell Alloimmunization.

BACKGROUND AND OBJECTIVE: Several studies have shown the benefits of delayed cord clamping (DCC) in preterm and in healthy newborns at short and long term. Our objective was to evaluate the potentials benefits and risks of DCC in red cell alloimmunization. METHODS: This was a comparative before/after study of all living born neonates followed after fetal anemia requiring in utero transfusion. DCC was defined as cord clamping 30 seconds after birth. RESULTS: We included a continuous series of 72 neonates: 36 without DDC (group 1) and 36 with DDC (group 2). Hemoglobin at birth was lower in group 1 (10.2 vs 13.4 g/dL, P = .0003); 7 (25%) neonates in group 1 vs 24 (70.6%) in group 2 had no anemia at birth (P = .004). The rate of transfusion was similar between the 2 groups. Postnatal exchange transfusions were more likely performed in the group without DCC than in the group with DCC (47.2% vs 19.4%, P = .0124). Delay between birth and first transfusion was higher in group 2 (0 [0-13] vs 1 [0-21], P = .0274). The maximum level of bilirubin, the rate of intensive phototherapy, and the total duration of phototherapy were similar in the 2 groups. CONCLUSIONS: This study highlights a significant benefit of DCC in anemia secondary to red blood cell alloimmunization with a resulting decreased postnatal exchange transfusion needs, an improvement in the hemoglobin level at birth and longer delay between birth and first transfusion with no severe hyperbilirubinemia.

Molecular background of novel silent RHCE alleles.

BACKGROUND: The absence of expression of C/c and E/e antigens has been associated with rare variant RHCE alleles, referred to as silent RHCE alleles, classically identified among individuals with a rare D- - or Rhnull phenotype. This work reports on different molecular mechanisms identified in three novel silent RHCE alleles. STUDY DESIGN AND METHODS: Samples from D- - or Rhnull individuals and their family members, from families for whom Rh phenotype and/or serologic data were unexplained by inheritance of conventional RH alleles, were analyzed. Genomic DNA and transcripts were tested by sequencing analysis. RESULTS: The first silent allele was a RHCE*cE allele carrying an intronic IVS3+5G>A mutation. The second was a RHCE*ce allele carrying an intronic IVS7-2A>G mutation, whereas the third was a silent RHCE*ce allele carrying a 5-bp deletion (Nucleotides 679-683) in Exon 5. CONCLUSION: In addition to hybrid alleles and nucleotide deletion, intronic mutations may be associated with the nonexpression of RhCE antigens. Regarding the RH system, silent alleles may not be investigated among D- - or Rhnull individuals only. Rh phenotype and/or serologic data unexplained by inheritance of conventional RH alleles should lead to molecular investigations.

[Indications and monitoring of antithrombotic prophylaxis for venous thromboembolism during pregnancy and post-partum]. / Indications et surveillance du traitement prophylactique de la maladie thrombo-embolique veineuse au cours de la grossesse et du post-partum.

Pregnancy and puerperium are well-known risk factors for venous thromboembolism, but the actual incidence of the disease is low (about 1/1,500 pregnancies). Pregnancy-associated venous thromboembolism is rare, though it is still the second cause of maternal death in France. Several types of prophylaxis are available, mainly clinical vigilance and aggressive investigation of women with symptoms of venous thromboembolism, or antithrombotic prophylaxis. Given the low incidence of the pathology, it seems desirable to select high-risk groups of women for such strategies. The most studied and identified risk factors are prior episodes of venous thromboembolism and biological thrombophilias. Prophylaxis through low molecular weight heparin during pregnancy and the puerperium should be considered mainly in these two groups. Noteworthy, no prospective and randomized study is available, and treatment recommendations are grade C.