Jerzy Windyga

Institute of Hematology and Blood Transfusion, Warsaw, Warszawa, Masovian Voivodeship, Poland

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Publications (98)233.92 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Inhibitor development represents the most serious side effect of haemophilia treatment. Any difference in risk of inhibitor formation depending on the product used might be of clinical relevance. It was this study's objective to assess inhibitor development according to clotting factor concentrate in severe haemophilia A and B. The European Haemophilia Safety Surveillance (EUHASS) was set up as a study monitoring adverse events overall and according to concentrate. Since October 2008, inhibitors were reported at least quarterly. Number of treated patients was reported annually, specifying the number of patients completing 50 exposure days (Previously Untreated Patients, PUPs) without inhibitor development. Cumulative incidence, incidence rates and 95 % confidence intervals (CI) were calculated. Data from October 1, 2008 to December 31, 2012 were analysed for 68 centres that validated their data. Inhibitors developed in 108/417 (26 %; CI 22-30 %) PUPs with severe haemophilia A and 5/72 (7 %; CI 2-16) PUPs with severe haemophilia B. For Previously Treated Patients (PTPs), 26 inhibitors developed in 17,667 treatment years [0.15/100 treatment years (CI 0.10-0.22)] for severe haemophilia A and 1/2836 (0.04/100;(CI 0.00-0.20) for severe haemophilia B. Differences between plasma-derived and recombinant concentrates, or among the different recombinant FVIII concentrates were investigated. In conclusion, while confirming the expected rates of inhibitors in PUPs and PTPs, no class or brand related differences were observed.
    Thrombosis and Haemostasis 01/2015; 113(4). DOI:10.1160/TH14-10-0826 · 5.76 Impact Factor
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    ABSTRACT: Recently, we reported that distinct isotypes and IgG subclasses of FVIII-specific antibodies are found in different cohorts of patients with hemophilia A and in healthy individuals. Led by these findings, we further investigated the distinguishing properties among the different populations of FVIII-specific antibodies. We hypothesized that the affinity of antibodies would discriminate between the neutralizing and non-neutralizing antibodies found in different study cohorts. To test this idea, we established a competition-based ELISA technology to assess the apparent affinities for each isotype and IgG subclass of FVIII-specific antibodies without the need for antibody purification. We present a unique data set of apparent affinities of FVIII-specific antibodies found in healthy individuals, patients with congenital hemophilia A with and without FVIII inhibitors and patients with acquired hemophilia A. Our data indicate FVIII-specific antibodies found in patients with FVIII inhibitors have an up to 100-fold higher apparent affinity than that of antibodies found in patients without inhibitors and in healthy individuals. High-affinity FVIII-specific antibodies could be retrospectively detected in longitudinal samples of an individual patient with FVIII inhibitors as long as 543 days before the first positive Bethesda assay. This suggests that these antibodies might serve as potential biomarkers for evolving FVIII inhibitor responses. Copyright © 2014 American Society of Hematology.
    Blood 12/2014; DOI:10.1182/blood-2014-09-598268 · 9.78 Impact Factor
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    ABSTRACT: Hemophilia B management has improved considerably since the introduction of high-purity plasma-derived factor IX (pdFIX) products in the early 1990s. Recombinant FIX (rFIX) was introduced more recently and has potential safety advantages over the older blood-based products. Until recently, only one such product, nonacog alfa (BeneFIX(®), Pfizer, Inc.), has been available. However, a new rFIX product, BAX326 (RIXUBIS, Baxter Healthcare Corp.), has now been approved by the US Food and Drug Administration. BAX326 undergoes rigorous virus elimination and purification steps during manufacture, and has low activated FIX activity, which confers low thrombogenic potential in humans. Preclinical studies showed promising pharmacokinetic and safety profiles, and these early findings have since been expanded in a series of prospective, multicenter, clinical studies. Foremost among these is a pivotal phase I/III study of BAX326 and its use in routine prophylaxis or on-demand treatment in patients aged 12-65 years with severe (FIX level <1%) or moderately severe (FIX level ≤2%) hemophilia B. This study confirmed the pharmacokinetic equivalence of BAX326 and nonacog alfa, and showed a significant reduction in annualized bleeding rate with BAX326 prophylaxis compared with on-demand treatment (79% versus historic controls; p < 0.001). The hemostatic efficacy of BAX326 was rated as 'excellent' or 'good' in 96% of bleeds. BAX326 was also associated with statistically significant and clinically meaningful improvements in physical health-related quality of life. Results are similarly encouraging in a pediatric study in children aged up to 12 years and in a study in hemophilia B patients undergoing surgery. A further study showed safe transition, with no inhibitor formation in any patient, from treatment with a pdFIX product to BAX326. Overall, the safety profile of BAX326 in clinical trials has been strong, with no inhibitor or specific antibody formation, thrombosis, or treatment-related serious adverse events or anaphylaxis.
    10/2014; 5(5):168-80. DOI:10.1177/2040620714550573
  • Haemophilia 09/2014; 20(6). DOI:10.1111/hae.12555 · 2.47 Impact Factor
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    ABSTRACT: In the phase 3 B-LONG [Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Subjects with Haemophilia B] study, rFIXFc dosed every 1–2 weeks was safe and efficacious in previously treated subjects with haemophilia B. To date, there are no evaluations of transitioning from conventional to long-acting factor IX (FIX) prophylaxis. This post-hoc analysis of B-LONG subjects compared prophylaxis with other FIX products and rFIXFc. Pre- and on-study data were analysed to assess dosing regimen, weekly FIX consumption and annualized bleeding rates (ABRs). Population pharmacokinetics models were used to generate FIX activity profiles with rFIXFc and recombinant FIX prophylaxis. Thirty-nine subjects, previously treated prophylactically, were evaluated. Prior to study, most subjects (69·2%) received twice-weekly FIX infusions; on study, subjects infused rFIXFc once every 1–2 weeks with c. 30–50% reductions in weekly consumption. On-study estimated mean ABRs were lower than pre-study estimated mean ABRs. Models predicted that rFIXFc administered 50 iu/kg weekly and 100 iu/kg every 10 d would maintain steady-state FIX trough levels ≥1 iu/dl in 95·4% and 89·2% of subjects, respectively. These results indicate that patients receiving rFIXFc prophylaxis can markedly reduce infusion frequency and FIX consumption, have a greater likelihood of maintaining FIX activity >1 iu/dl and experience fewer bleeding episodes compared with prior FIX prophylaxis.
    British Journal of Haematology 09/2014; DOI:10.1111/bjh.13109 · 4.96 Impact Factor
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    ABSTRACT: Background: Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. Objectives: To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. Patients and methods: In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept (TM) 2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 : 2 to treatment with vatreptacog alfa (one to three doses at 80 mu g kg(-1)) or rFVIIa (one to three doses at 90 mu g kg(-1)). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. Results: In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24-48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. Conclusions: This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit-risk profile is unlikely to be achieved with vatreptacog alfa.
    Journal of Thrombosis and Haemostasis 06/2014; 12(8). DOI:10.1111/jth.12634 · 5.55 Impact Factor
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    ABSTRACT: Individuals with hemophilia B experience frequent and spontaneous bleeding episodes into joints and muscles that can lead to severe arthropathy, chronic pain, disability, and diminished quality of life (QoL). Prophylaxis with factor nine (FIX) concentrates may reduce the frequency of bleeding events and improve QoL. Recombinant FIX (rFIX) concentrates are a potentially safer treatment option than plasma-derived FIX products with respect to pathogen transmission risk, but until recently, only one licensed rFIX product was available. We describe a newly approved rFIX concentrate, BAX326 (RIXUBIS; Baxter Healthcare Corporation). Phase III studies of BAX326 demonstrated its efficacy and safety in prophylactic, on-demand, and surgical settings and showed that its pharmacokinetic properties were comparable to those of the licensed comparator. Importantly, prophylaxis with BAX326 significantly improved physical health-related QoL, demonstrating that this new rFIX treatment that has the potential to improve outcomes in hemophilia B patients.
    Expert Review of Hematology 06/2014; 7(3):333-42. DOI:10.1586/17474086.2014.903153 · 2.14 Impact Factor
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    ABSTRACT: Post-transplant lymphoproliferative disorders (PTLD) is a serious complication following solid organ transplantation or allogeneic hematopoietic stem cell transplantation (allo-HSCT). Pathogenesis of PTLD indicates a strong association with Epstein-Barr virus (EBV) infection. Clinical improvement is observed with reduction in immunosuppression intensity alone or administration of immuno-, chemo- and radiotherapy. We present a case of a 32-year-old man with EBV-associated PTLD as mononucleosis-like syndrome according to the 2008 World Health Organization classification with central nervous system involvement and presence of lupus anticoagulant (LA) following allo-HSCT, where decreasing the immunosuppression was not possible because of concurrent graft versus host disease (GvHD). In this situation rituximab and foscarnet in combination with immunosuppressive therapy improved PTLD and GvHD; at the same time disappearance of lupus anticoagulant was observed.
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    Blood transfusion = Trasfusione del sangue 05/2014; 12(Suppl 3):s515-s518. DOI:10.2450/2014.0008-14s · 1.90 Impact Factor
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    ABSTRACT: Haemostatic management of haemophilia B patients undergoing surgery is critical to patient safety. The aim of this ongoing prospective trial was to investigate the haemostatic efficacy and safety of a recombinant factor IX (rFIX) (Bax326)† in previously treated subjects (12–65 years, without history of FIX inhibitors) with severe or moderately severe haemophilia B, undergoing surgical, dental or other invasive procedures. Haemostatic efficacy was assessed according to a predefined scale. Blood loss was compared to the average and maximum blood loss predicted preoperatively. Haemostatic FIX levels were achieved peri- and postoperatively in 100% of subjects (n = 14). Haemostasis was ‘excellent’ intraoperatively in all patients and postoperatively in those without a drain, and ‘excellent’ or ‘good’ at the time of drain removal and day of discharge in those with a drain employed. Following the initial dose, the mean FIX activity level rose from 6.55% to 107.58% for major surgeries and from 3.60% to 81.4% for minor surgeries. Actual vs. predicted blood loss matched predicted intraoperative blood loss but was equal to or higher than (but less than 150%) the maximum predicted postoperative blood loss reflecting the severity of procedure and FIX requirements. There were no related adverse events, severe allergic reactions or thrombotic events. There was no evidence that BAX326 increased the risk of inhibitor or binding antibody development to FIX. BAX326 was safe and effective for peri-operative management of 14 subjects with severe and moderately severe haemophilia B.
    Haemophilia 04/2014; 20(5). DOI:10.1111/hae.12419 · 2.47 Impact Factor
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    ABSTRACT: Total knee replacement in patients with haemophilia A is achallenging procedure with high risk of complications. Due to the massive destruction of the joint and significantly reduced range of motion, total knee replacement should be performed only by asurgeon with high degree of expertise and experience. During the perioperative period, patients require factor VIII (FVIII) replacement therapy supervised by ahaematologist, under control of plasma activity levels. Possible early complica-tions include delayed wound healing, soft tissue and joint bleeding, development of pseudoaneurysm and early infection. Once complications occur, prompt detection and introduction of proper treatment is fundamental.
    01/2014; 30(1):39-42. DOI:10.5114/ms.2014.41997
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    ABSTRACT: Little is known about the health-related quality of life (HRQoL) burden of haemophilia B. The aim of this study was to assess HRQoL burden of haemophilia B, the benefit of recombinant factor IX (rFIX) prophylaxis and the HRQoL benefit of achieving a zero annual bleed rate. Subjects receiving rFIX (BAX326) prophylaxis or on-demand completed the SF-36 survey. Baseline SF-36 scores were compared to the general US population scores to understand the HRQoL burden. Changes in SF-36 scores between baseline and follow-up were tested using t-tests. Subgroup analysis was conducted to examine SF-36 change among subjects who switched to BAX326 prophylaxis. SF-36 scores were also compared between those with zero bleeds and those who bled during the study. Compared to the US norms, subjects reported lower average scores in all physical and several mental HRQoL domains. At follow-up, prophylaxis subjects reported statistically significant and clinically meaningful improvements in overall physical HRQoL, as measured by the Physical Component Score (PCS) (mean change 2.60, P = 0.019), Bodily Pain (BP) (3.45, P = 0.015) and Role Physical (RP) domains (3.47, P = 0.016). Subjects who switched to prophylaxis from intermittent prophylaxis or on-demand experienced more pronounced improvements not only in the PCS (3.21, P = 0.014), BP (3.71, P = 0.026), RP (4.43, P = 0.008) but also in Vitality (3.71, P = 0.04), Social Functioning (5.06, P = 0.002) and General Health domains (3.40, P = 0.009). Subjects achieving zero bleeds reported lower BP (P = 0.038). Prophylaxis with BAX326 significantly improved HRQoL in patients with moderately severe or severe haemophilia B by reducing bleeds.
    Haemophilia 11/2013; 20(3). DOI:10.1111/hae.12315 · 2.47 Impact Factor
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    ABSTRACT: Patients with severe haemophilia A experience frequent and spontaneous bleeding, causing debilitating damage to joints and decreasing quality of life. Prophylaxis with factor VIII (FVIII) reduces joint damage if initiated early. Circulating FVIII levels may be influenced by endogenous von Willebrand factor (VWF), a chaperone protein that binds and stabilizes FVIII. The aim of this study was to determine whether endogenous VWF antigen (VWF:Ag) levels are correlated with FVIII pharmacokinetic (PK) parameters and clinical outcomes in patients with severe haemophilia A. Previously treated, non-inhibitor patients in a multinational, randomized, double-blind, Ph II study received prophylaxis with once-weekly BAY 79-4980 (35 IU kg(-1) ) or thrice-weekly recombinant sucrose-formulated FVIII (rFVIII-FS; 25 IU kg(-1) ). PK parameters were evaluated at weeks 1 and 26. The number of bleeds per patient during the study was captured as part of the core efficacy endpoint. Spearman rank correlations assessed relationships of VWF:Ag levels with patient age, PK and annualized bleeding rate. Of 131 study patients (aged 13-64 years; BAY 79-4980, n = 63; rFVIII-FS, n = 68), 27 (21%; n = 15 and 12 respectively) were evaluable for PK assessment. Baseline VWF:Ag levels correlated with patient age (P < 0.0001). There was no significant difference in PK results between treatments; thus, PK parameters and VWF levels of all patients were analysed together. AUCnorm and T1/2 significantly increased with increased VWF:Ag (P < 0.001); clearance significantly decreased with increased VWF:Ag (P = 0.002). Annualized bleeding rate in patients treated with 3× per week rFVIII-FS significantly correlated with VWF:Ag and age (P = 0.038 and 0.021 respectively). PK parameters as well as the clinical outcome significantly correlated with endogenous VWF:Ag. The improved clinical outcome in subjects with high VWF:Ag levels may be explained by VWF:Ag influence on FVIII PK.
    Haemophilia 11/2013; 20(1). DOI:10.1111/hae.12294 · 2.47 Impact Factor
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    ABSTRACT: Background. Spontaneous intraarticular bleeds in congenital coagulation disorders result in early and extensive damage to the joints and periarticular structures. Total arthroplasty is the only effective method of treating these defects. Interim surgical procedures (arthroscopy, osteotomy, etc.) exist that can postpone arthroplasty, especially considering the fact that the condition affects young people. The aim of this paper is to discuss the range of trauma care and orthopedic procedures performed in patients with congenital coagulation disorders. Also presented are early results of joint arthroplasty in these patients. Material and methods. A total of 168 trauma care and orthopedic procedures were performed in patients with congenital coagulation disorders at the Clinical Department of Orthopedics and Traumatology of the Central Clinical Hospital of the Ministry of Interior in Warsaw in the years 2010-2013. Among them were total arthroplasties (79 arthroplasties of the knee, 30 of the hip, 3 of the ankle and 1 of the elbow), arthroscopies, filling bone cysts with grafts and trauma procedures. The HHS, KSS, AOFAS and MEPS scales were used to evaluate the respective clinical results of hip, knee, ankle and elbow arthroplasty procedures. A VAS was used to evaluate pain intensity. In knee arthroplasty patients, quality of life parameters were evaluated with the WOMAC index. Results. In patients post hip arthroplasty, HHS scores increased by 50.22 points and VAS scores increased by 6.34 points. An increase of 116.41 points in KSS scores and 6.67 points in VAS scores was recorded in patients after knee arthroplasty. Also, WOMAC scores improved by 53.8 points after surgery. Evaluation of early results of ankle arthroplasty in the AOFAS scale showed a mean improvement of 35.5 points and a 5-point improvement in VAS scores. MEPS scores, used for evaluation of elbow arthroplasty results, improved from 15 to 70 points, with an improvement from 6 to 2 points in VAS scores. Conclusions. 1. Orthopedic procedures in patients with congenital coagulation disorders require thorough preparation of the patient and close cooperation between the orthopedic and hematological teams. 2. Early clinical outcomes are promising. 3. Decreased pain intensity, increased joint range of motion and improved quality of life post-surgery are observed.
    10/2013; 15(6):601-16. DOI:10.5604/15093492.1091516
  • Acta haematologica Polonica 09/2013; 44. DOI:10.1016/j.achaem.2013.07.131
  • Acta haematologica Polonica 09/2013; 44. DOI:10.1016/j.achaem.2013.07.128
  • Acta haematologica Polonica 09/2013; 44. DOI:10.1016/j.achaem.2013.07.140
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    ABSTRACT: BAX326 is a recombinant factor IX (rFIX; nonacog gamma) manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps (solvent/detergent treatment and 15 nm nanofiltration). The aim of this prospective trial was to investigate the pharmacokinetics, haemostatic efficacy and safety of BAX326 in previously treated patients aged 12-65 years with severe or moderately severe haemophilia B. BAX326 was safe and well tolerated in all 73 treated subjects; adverse events considered related to treatment (2.7% incidence, all non-serious) were transient and mild, and no hypersensitivity reactions, inhibitor formation or thrombotic events were observed. Pharmacokinetic (PK) equivalence (n = 28) between BAX326 and a licensed rFIX was confirmed in terms of the ratio of geometric mean AUC0-72 h per dose. Twice-weekly prophylaxis [mean duration 6.2 (±0.7) months; 1.8 (±0.1) infusions per week, 49.5 (±4.8) IU kg(-1) per infusion] was effective in preventing bleeding episodes, with a significantly lower (79%, P < 0.001) annualized bleed rate (4.2) compared to an on-demand treatment in a historical control group (20.0); 24 of 56 subjects on prophylaxis (43%) did not bleed throughout the study observation period. Of 249 total acute bleeds, 211 (84.7%) were controlled with one to two infusions of BAX326. Haemostatic efficacy at resolution of bleed was rated excellent or good in 96.0% of all treated bleeding episodes. The results of this study indicate that BAX326 is safe and efficacious in treating bleeds and routine prophylaxis in patients aged 12 years and older with haemophilia B.
    Haemophilia 07/2013; 20(1). DOI:10.1111/hae.12228 · 2.47 Impact Factor
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    ABSTRACT: In this study we assessed homocysteine level in 106 patients with ET – 80 females and 26 males, mean age 54 (23–82) and in 20 healthy persons – 6 males and 14 females, mean age 41 (31–54). We also searched for a relation between homocysteine level and MTHFR gene mutation as well as vitamin B12 and folic acid concentration. Median homocysteine serum level was higher in ET patients than in control group. Elevated homocysteine level primarily stems from folic acid deficiency rather than from the presence of MTHFR gene mutation. Median folic acid level was lower in ET patients presenting thrombotic and bleeding complications than in ET patient without vascular episodes. We concluded that folic acid substitution may not only prevent hyperhomocysteinemia but also the development of vascular complications in ET patients.
    Acta haematologica Polonica 07/2013; 44(3):333–339. DOI:10.1016/j.achaem.2013.07.025
  • Acta haematologica Polonica 07/2013; 44:143. DOI:10.1016/j.achaem.2013.07.146

Publication Stats

467 Citations
233.92 Total Impact Points

Institutions

  • 2005–2014
    • Institute of Hematology and Blood Transfusion, Warsaw
      Warszawa, Masovian Voivodeship, Poland
  • 2002–2014
    • Instytut Hematologii i Transfuzjologii
      Warszawa, Masovian Voivodeship, Poland
  • 2013
    • Ludwig-Maximilians-University of Munich
      München, Bavaria, Germany
  • 2006
    • American Thrombosis and Hemostasis Network
      Chicago, Illinois, United States