The anticoagulant effect of a Low Molecular Weight Heparin from Alfa Farmaceutici, Bologna, Italy, was studied in human volunteers of either sex. Assays of plasma anti Xa (S-2222) and anti IIa (cromozym TH) activities, and of PTT, were performed following single or repeated administration by intravenous (i.v.), subcutaneous (s.c.) or intramuscular (i.m.) route. Each set of experiments was carried out in groups of subjects ranging from 6 to 12. After i.v. adm. of 8000 and 16000 I.U. AXa peak level and half life in plasma of the anti Xa activity were about double than the corresponding values of anti IIa activity and the effect on PTT, when compared with the same reference material (heparin, Third Internat. Standard). Similar differences between these pharmacological effects were found in the response curves obtained after s.c. or i.m. adm. of 16000 and 8000 I.U. Appreciable anti Xa activity was found in plasma 16-20 hours after adm. of 16000 I.U., and 10 hours after 8000 I.U. After repeated i.m. or s.c. adm. for 7 days, no cumulative effect was observed with 16000 I.U. once daily. By giving 8000 b.i.d., mean peak levels of .35-.40 U/ml of anti Xa activity were reached in the first day and of .45-.55 U/ml in the following days, a residual activity in the order of .1-.2 U/ml being always detected in the samples drawn immediately before the following injection.
Background Development of inhibitors is the most serious complication in haemophilia A treatment. The assessment of risk for inhibitor formation in new or modified factor concentrates is traditionally performed in previously treated patients ( PTP s). However, evidence on risk factors for and natural history of inhibitors has been generated mostly in previously untreated patients ( PUP s). The purpose of this study was to examine cases of de novo inhibitors in PTP s reported in the scientific literature and to the EU ropean HA emophilia Safety Surveillance ( EUHASS ) programme, and explore determinants and course of inhibitor development. Methods We used a case series study design and developed a case report form to collect patient level data; including detection, inhibitor course, treatment, factor VIII products used and events that may trigger inhibitor development (surgery, vaccination, immune disorders, malignancy, product switch). Results We identified 19 publications that reported 38 inhibitor cases and 45 cases from 31 EUHASS centres. Individual patient data were collected for 55/83 (66%) inhibitor cases out of 12 330 patients. The median (range) peak inhibitor titre was 4.4 (0.5–135.0), the proportion of transient inhibitors was 33% and only two cases of 12 undergoing immune tolerance induction failed this treatment. In the two months before inhibitor development, surgery was reported in nine (22%) cases, and high intensity treatment periods reported in seven (17%) cases. Conclusions By studying the largest cohort of inhibitor development in PTP s assembled to date, we showed that inhibitor development in PTP s, is on average, a milder event than in PUP s.
Introduction and Objectives: Non-severe hemophilia A (baseline FVIII:C, 2-40 IU/dL) is caused by a mutation in the F8 gene. There is limited knowledge on the factors determining the variation in baseline FVIII:C. The aim is to identify the determinants of baseline FVIII:C in non-severe hemophilia A patients. Materials and Methods: We analyzed clinical data for non-severe hemophilia A patients, treated between 1980-2013, in European Haemophilia Treatment Centers (HTCs) participating in the INSIGHT/RISE project. We performed analyses on mutations that were present in ≥10 patients. Age (at FVIII:C measurement), F8 gene mutation, VWF:Ag, VWF:Act and HTC were analyzed as potential determinants by multivariate regression analyses. Results: We identified nine missense mutations present in ≥10 patients in 321 individuals, median age 23 years (IQR 7-47). From these individuals we had data on 667 FVIII:C measurements in 5 HTCs. Median baseline FVIII:C, VWF:Ag and VWF: Act were 17 IU/dL (IQR 11-22), 98 IU/dL (IQR 78-128) and 91 IU/dL (70-115) respectively. Baseline FVIII:C, VWF:Ag and VWF:Act all increased with age, both in the total population and within the two largest mutation groups (Asn618Ser, 113 patients; Arg593Cys, 107 patients). VWF:Ag, age and F8 mutation were significant predictors of baseline FVIII:C (p <0.0001-0.024). In mutations that were present in ≥10 patients the determinants age, F8 mutation, VWF:Ag and HTC together explained 61% of the variation in baseline FVIII:C. Within the specific mutation group Asn618Ser only 21% of the variance in baseline FVIII:C was explained by the combined potential determinants, with VWF:Ag and HTC as significant predictors (p = 0.008 and 0.013 respectively). Among individuals with the Arg593Cys F8 genotype the determinants age, VWF:Ag and HTC were significant predictors (p <0.0001 for age and VWF:Ag and p = 0.04 for HTC), together explaining 34% of the variance in baseline FVIII:C. Conclusion: In non-severe hemophilia A patients carrying the same F8 mutation the determinants age, VWF:Ag and HTC contribute to baseline FVIII:C to variable extends. With the studied determinants we can only explain 61% of the variance in baseline FVIII:C. This suggests that yet unknown factors influence FVIII:C in nonsevere hemophilia A.
To evaluate the efficacy and safety of the factor VIII/von Willebrand factor concentrate Haemate-P as replacement therapy in patients with von Willebrand's disease (VWD) undergoing surgical or invasive procedures.Between January 1996 and October 2002, 26 patients (12 males and 14 females, median age 41.5 years, range 9-80 years), followed at three Italian Hemophilia Centers (Trento, Verona and Parma), with VWD type 1 (19 cases) and VWD type 2B (7 cases), underwent 43 surgical or invasive procedures: major surgery (14 cases), minor surgery (11 cases), dental extractions (11 cases), invasive diagnostic procedures (7 cases). Replacement therapy with factor VIII/von Willebrand factor concentrate (Haemate-P) was administered in the surgical setting as perioperative prophylaxis against excessive bleeding.The mean total dose (range) of Haemate-P used for major surgery was 284.1 IU VWF:RCo/kg (range 125.0-976.4), for minor surgery it was 120.8 IU VWF:RCo/kg (range 42.9-173.3), for dental extractions it was 38.4 IU VWF:RCo/kg (range 23.5-100.0) and for invasive procedures it was 87.3 VWF:RCo/kg (range 27.3-160.0). We recorded one bleeding episode 3 days after multiple dental extractions in a patient with severe periodontal disease; this bleeding was controlled with 2 further administrations of concentrate. We did not observe thrombotic episodes or other side effects following infusion of the concentrate.In conclusion, Haemate-P was effective and safe in preventing excessive bleeding after major and minor surgery or invasive procedures in VWD patients.
Although desmopressin (DDAVP) is considered as the treatment of choice for many patients with mild hemophilia A, several aspects of DDAVP therapy remain unclear, including the rate and type of response and the molecular determinants of its clinical efficacy. To investigate these issues, we retrospectively studied all patients with mild hemophilia A followed up at the Parma Hemophilia Center. A total of 75 patients were enrolled who underwent a DDAVP test, and out of whom, 76% (57/75) had a complete or partial response. Response to DDAVP was significantly correlated to the patients' age (median age of responders and nonresponders: 24 and 18 y, respectively; p = 0.04) and type of mutation (all the 10 patients with mutations in the promoter region were nonresponders). The median basal factor VIII (FVIII):C level was significantly lower in responders than in nonresponders (0.14 vs. 0.19 IU/mL, respectively; p = 0.01); this was mainly due to nonresponders with promoter region mutations who had higher basal FVIII:C levels. During the 12-year follow-up, 82 of 237 (35%) bleeding episodes occurring in 27 responder patients were treated with 246 DDAVP infusions with complete or partial efficacy in 92% (75/82). Overall, 142 events were managed with 253 prophylactic DDAVP infusions, which were hemostatically effective in 96% of cases. No severe adverse reactions to DDAVP administration were recorded during the study period. These results document the safety and efficacy of DDAVP as a treatment or prevention of bleeding in patients with mild hemophilia A, also in the context of home treatment, and encourage the more widespread use of this product.
Haemophilias are X-linked inherited bleeding disorders, due to de novo F8/F9 gene variants in 30-50% of cases. The identification of causative variant in index cases (IC) is crucial for genetic counselling in related women. Over the last 20 years the Emilia-Romagna Regional Haemophilia Registry documented high proportions of sporadic severe haemophilia.To clarify if carriers' reproductive choices influence the sporadic/familial ratio of severe haemophilia.Genetic counselling and genotyping in 221 relatives of severe IC were retrospectively reviewed, retrieving reproductive choices and pregnancy history of childbearing-age carriers from familial and sporadic pedigrees and according to the IC degree of relationship (mothers, daughters, II/other).Carriers' identification rates were lower in sporadic women and in other-degree relatives. Among childbearing age women (n = 140), carriers were 37/48 (77%) and 57/92 (62%) of familial and sporadic relatives, respectively. Forty-five/57 sporadic carriers experienced 67 pregnancies, while 21/37 familial carriers had 39 pregnancies (four voluntary terminations), with a significantly higher number of affected sons in the former (40/67 vs. 12/35, P = .025). Prenatal diagnosis was chosen by 40% and 47% of sporadic and familial aware carriers, respectively. Sporadic mothers often avoided further pregnancies (17/38, 45%) after a firstborn affected child, while familial mothers tended to face pregnancies without prenatal approaches (6/10, 60%).In this cohort sporadic offspring account for more than 70% of severe haemophilia cases. This increasing proportion is likely to reflect the influence in reproductive choices of awareness of carriers' status, particularly in sporadic mothers, and of prenatal diagnosis options.
Review Articles| January 14 2005 Computer Assisted Anticoagulant Therapy Subject Area: Cardiovascular System , Hematology , Pathology and Cell Biology C. Manotti; C. Manotti Centro per le Malattie dell'Emostasi, Azienda Ospedaliera di Parma, Italy Search for other works by this author on: This Site PubMed Google Scholar C. Pattacini; C. Pattacini Centro per le Malattie dell'Emostasi, Azienda Ospedaliera di Parma, Italy Search for other works by this author on: This Site PubMed Google Scholar R. Quintavalla; R. Quintavalla Centro per le Malattie dell'Emostasi, Azienda Ospedaliera di Parma, Italy Search for other works by this author on: This Site PubMed Google Scholar A. Tagliaferri; A. Tagliaferri Centro per le Malattie dell'Emostasi, Azienda Ospedaliera di Parma, Italy Search for other works by this author on: This Site PubMed Google Scholar M. Lombardi; M. Lombardi Centro per le Malattie dell'Emostasi, Azienda Ospedaliera di Parma, Italy Search for other works by this author on: This Site PubMed Google Scholar M. Tassoni M. Tassoni Centro per le Malattie dell'Emostasi, Azienda Ospedaliera di Parma, Italy Search for other works by this author on: This Site PubMed Google Scholar Pathophysiology of Haemostasis and Thrombosis (2003) 33 (5-6): 366–372. https://doi.org/10.1159/000083831 Article history Published Online: January 14 2005 Content Tools Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation C. Manotti, C. Pattacini, R. Quintavalla, A. Tagliaferri, M. Lombardi, M. Tassoni; Computer Assisted Anticoagulant Therapy. Pathophysiology of Haemostasis and Thrombosis 1 December 2003; 33 (5-6): 366–372. https://doi.org/10.1159/000083831 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsPathophysiology of Haemostasis and Thrombosis Search Advanced Search This content is only available via PDF. 2003Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Article PDF first page preview Close Modal You do not currently have access to this content.
The hemophilia community is living in exciting times, thanks to recent and relevant developments in this field and great expectations for new treatment approaches that are able to significantly and positively affect patients' outcomes and quality of life.[1] [2] [3] [4] [5] Interestingly, one most important innovation, a hemostatic agent enabling a very effective prophylaxis of bleeding given subcutaneously (the bispecific antibody against factor [F] X and activated FIX emicizumab),[2] [3] is being introduced for patients who developed alloantibodies against FVIII, the so-called inhibitors. The management of these patients has always been considered challenging because inhibitors make the standard effective and safe replacement with FVIII concentrates unfeasible and, therefore, make difficult the treatment of bleeding, leaving patients at a high risk of complications, both in the acute phase and in regard to long-term morbidity.[6] Due to the epidemiological impact of inhibitors (present in ∼30% of previously FVIII-unexposed patients and persistent/high titer in two-thirds of cases),[6] [7] searching for pathophysiological mechanisms and strategies for management is particularly important in hemophilia A (HA). Indeed, a relevant body of literature addressing such issues has been generated over the last decades. However, significant challenges are also raised by the inhibitors encountered, albeit less frequently, in clinical practice in other congenital bleeding disorders (CBDs): (1) in hemophilia B (HB) and von Willebrand's disease (VWD), additional morbidity due to allergic reactions can occur;[6] [8] (2) in rare CBDs, little information concerning management is available;[9] and (3) in deficiencies of platelet membrane glycoproteins, the clinical impact of alloantibodies and alternative treatment approaches are poorly understood.[10] With this background, the 11 chapters presented in this latest issue of Seminars in Thrombosis and Hemostasis deal with the current state of the art of pathophysiology and management of alloantibodies in CBDs. It is easy to understand why seven of them focus on hemophilia, particularly on HA, discussing, at this current time of possible evolving scenarios, the most recent literature data. Alloantibodies in HB, VWD, rare CBDs, and congenital deficiencies of platelet surface glycoproteins are reviewed in the remaining four chapters.
