the Journal of Coagulation Disorders Vol 2 Issue 1

First Attempt at Immune Tolerance Induction with Factor VIII/von Willebrand Factor Concentrates in Hemophilia A Children with High‐Titer Inhibitors

Platokouki H, Pergantou H, Komitopoulou A, Xafaki P, First Attempt at Immune Tolerance Induction with Factor VIII/von Willebrand Factor Concentrates in Hemophilia A Children with High‐Titer Inhibitors. Journal of Coagulation Disorders., February 2010; 2(1) 35-40


Helen Platokouki, Helen Pergantou, Anna Komitopoulou and Panagiota Xafaki

Affiliations: Haemophilia/Haemostasis Unit, “Aghia Sophia” Children’s Hospital


ABSTRACT

Immune tolerance induction (ITI) has been used for years to eradicate factor VIII (FVIII) inhibitors, a serious complication of treatment for children with hemophilia A. The optimal product to be used and dosing regimens are still under investigation. The possibility that the use of FVIII/von Willebrand factor (FVIII/vWF) concentrate might improve the success rate and shorten the duration of ITI has been suggested. The charts of seven children (current age 92.3±12.6 months) with severe hemophilia A and high‐titer inhibitors (53.7±44.3 BU) who received FVIII concentrates containing vWF (five children received a concentrate with a vWF:FVIII content ratio of 2.4:1 and two received a concentrate with a ratio of 0.96:1) in a dosing regimen of 100 IU/kg/48 h were reviewed. The results of the treatment were analyzed on tolerance, morbidity, and safety. ITI was completely successful after a mean period of 20.4 months in all seven children who received the product for initial ITI. Three of the seven children only achieved tolerization after an increase in the dose to 150 IU/kg/48 h, at least 17 months after initiation of ITI. Permanent tolerance is maintained for a mean observation period of 28.1 months. A dramatic drop was found in the frequency of hemorrhages per month after ITI in comparison with those before ITI initiation (0.36±0.20 vs 0.84±0.60, P = 0.023). Furthermore, the patients had the same proportionate drop in hemorrhage frequency, falling after ITI to one‐third of the number they had before ITI (correlation coefficient: r = 0.859). No side‐effects were noticed. In conclusion, the use of FVIII/vWF concentrates for ITI seemed to be effective on tolerization of severely affected hemophilia A children with high‐titer inhibitors, additionally resulting in a decreased number of bleeding episodes.

Keywords: hemophilia A, factor VIII (FVIII) inhibitor, immune tolerance, factor VIII (FVIII)/von Willebrand factor concentrate

Correspondence: Helen Platokouki, Haemophilia/Haemostasis Unit, “Aghia Sophia” Children’s Hospital, Thivon/M. Asias, 115 27 Athens, Greece

Clinical Utility of the Less Commonly Employed Assays for Lupus Anticoagulant Detection: the Evidence

Chronobiology of Vascular Disorders: a “Seasonal” Link between Arterial and Venous Thrombotic Diseases?

Manfredini R, Manfredini F, Malagoni AM, Boari B, Salmi R, Dentali F, Ageno W, Chronobiology of Vascular Disorders: a “Seasonal” Link between Arterial and Venous Thrombotic Diseases? Journal of Coagulation Disorders., February 2010; 2(1) 61-68

Roberto Manfredini ^1, Fabio Manfredini ^2, Anna Maria Malagoni ^2, Benedetta Boari ^3, Raffaella Salmi ^3, Francesco Dentali ⁴ and Walter Ageno ⁴

Affiliations: ¹Department of Clinical and Experimental Medicine, Section Clinica Medica, University of Ferrara, Ferrara, Italy; ²Vascular Diseases Center, University of Ferrara, Ferrara, Italy; ³Department of Internal Medicine, S Anna General Hospital of Ferrara, Ferrara, Italy and ⁴Department of Clinical Medicine, University of Insubria, Varese, Italy


ABSTRACT

Rhythmic patterns have been observed in most biological functions, and oscillations with a peak and trough have been demonstrated for many bodily functions, including arterial blood pressure, heart rate, vascular tone, coagulation, and fibrinolysis. Depending on cycle length, these oscillations can be circadian, ultradian, circannual, or seasonal. In recent decades, many studies have investigated the possibility of seasonal variations in several diseases, especially in the cardiovascular system and specifically in some arterial and venous diseases. Traditionally, the two vascular beds have been considered as separate entities, each characterized by its own risk factors and diseases. Recently, however, a series of findings has revealed analogs between these two entities that are also supported by chronobiological findings. The latest findings about seasonal variations in major arterial and venous diseases and possible common underlying risk factors are presented and discussed here.

Keywords: Chronobiology, seasons, acute myocardial infarction, stroke, aortic diseases, venous thromboembolism, pulmonary embolism

Correspondence: Roberto Manfredini, Department of Clinical and Experimental Medicine, Section Clinica Medica, University of Ferrara, Via Savonarola 9, 44100 Ferrara, Italy. Tel: (39)‐0532‐236817; Fax: (39)‐0532‐236816; e‐mail: mfr@unife.it

Prophylaxis with Recombinant Activated Factor VII in Hemophilia Patients with Inhibitors

Auerswald G, Morfini M, Prophylaxis with Recombinant Activated Factor VII in Hemophilia Patients with Inhibitors. Journal of Coagulation Disorders., February 2010; 2(1) 1-8


Günter Auerswald ¹ and Massimo Morfini ²

Affiliations: ¹Prof.-Hess-Kinderklinik, Bremen, Germany and ²Agency for Hemophilia, Azienda Ospedaliero Universitaria Careggi, Florence, Italy


ABSTRACT

Treatment of bleeding episodes or during surgery in people with hemophilia A (FVIII deficiency) or hemophilia B (FIX deficiency) who have developed antibodies (inhibitors) to FVIII or FIX (especially high titer inhibitors) is difficult as a normal replacement with factor VIII or IX is not effective. rFVIIa is used to treat bleeds in patients with hemophilia who have developed such antibodies to FVIII or FIX (inhibitors, especially high titer inhibitors). Its effects on the coagulation system, however, may last for longer than pharmacokinetic data suggest. Furthermore, data supporting the concept of rFVIIa‐mediated prophylaxis in hemophilia patients with inhibitors are now being published. A recently described clinical trial of prophylaxis with rFVIIa in 22 frequently bleeding hemophilia patients with inhibitors was the first to report the results of a prospective randomized study evaluating the potential benefits of a bypassing agent in such a prophylactic setting. Here we review data from this study together with other information currently available relating to the prophylactic use of rFVIIa in patients with hemophilia and inhibitors outside the surgical arena. Overall, data from more than 70 patients described in a range of publications suggest that prophylaxis with rFVIIa can decrease bleeding frequency, increase mobility, reduce pain and have other quality of life benefits in hemophilia patients with inhibitors. There are no reports of any adverse event profiles attributable to the use of rFVIIa in these patients. The prolonged prophylactic effect of rFVIIa may be explained, at least in part, by its diffusion into the extravascular space and the formation of complexes with tissue factor to facilitate thrombin generation on platelets. In addition, rFVIIa could be internalized into platelets, which subsequently increases the duration of its availability. Further research into rFVIIa prophylaxis and its mechanism of action in hemophilia patients with inhibitors is warranted.

Keywords: Hemophilia, inhibitors, prophylaxis, recombinant activated factor VII

Correspondence: Günter Auerswald , MD, Prof.‐Hess‐Kinderklinik, Klinikum Bremen‐Mitte, St.‐Jürgen‐Straße 1, D28177 Bremen, Germany, Tel: (+49‐421)4975410, Fax: (+49‐421)4973311, e‐mail: guenterauerswald@aol.com

Anticoagulation of Pregnant Women with Mechanical Heart Valve Prosthesis: A Systematic Review of the Literature (2000–2009)

Benefits of Fluid Therapy on the Hemostatic System of Intensive Care Patients

Kozek‐Langenecker SA, Benefits of Fluid Therapy on the Hemostatic System of Intensive Care Patients. Journal of Coagulation Disorders., February 2010; 2(1) 41-48

Sibylle A Kozek‐Langenecker

Affiliations: Department of Anesthesiology, General Intensive Care and Pain Management, Vienna Medical University


ABSTRACT

Intensive care patients may have various coagulopathies depending on the underlying disease. Two diametrical derangements of the hemostatic system may be present and evolve during illness: hypocoagulability and hypercoagulability. These extremes may lead to clinical bleeding, multiple organ failure, or thromboembolism. The present article will focus on critically ill patients with the need for fluid therapy and volume expansion such as in sepsis, trauma, and postoperatively after major surgery. In this group of critically ill patients, fluid therapy is required to restore and maintain intravascular volume, to stabilize hemodynamic conditions, and to improve tissue perfusion. Clinical management always needs to balance benefits against potential risks. Efficacy and safety of various crystalloidal and colloidal fluids has been the subject of controversy for years. Depending on the actual status of the hemostatic system, unspecific hemodilution, specific anticoagulant, and/or antiplatelet side‐effects of fluids may be beneficial by mitigating hypercoagulability or may be harmful by aggravating hypocoagulability. This article reviews the coagulation status of anesthesiological intensive care patients, means of point‐of‐care laboratory monitoring, as well as side‐effects of fluids on coagulation and their potential extrapolated benefits. This article may trigger further clinical outcome studies testing the hypothesis that differential indication of fluids decreases coagulopathy, morbidity, and mortality in the high‐risk group of critically ill patients.

Keywords: hydroxyethyl starch, platelet function, coagulation factors, fibrin polymerization, hypercoagulability, sepsis‐associated coagulopathy

Correspondence: Sibylle A Kozek‐Langenecker, Department of Anesthesiology, General Intensive Care and Pain Management, Vienna Medical University, Währinger Gürtel 18–20, 1090‐Vienna, Austria; Department of Anaesthesia and Intensive Care, Evangelisches Krankenhaus Wien, Hans Sachs‐Gasse 10–12, 1180‐Vienna, Austria. E‐mail: sibylle.kozek@meduniwien.ac.at

Factor VIII Inhibitor Assays: Methodology, Shortcomings, and Challenges

van Geffen M, Dardikh M, Verbruggen B, Factor VIII Inhibitor Assays: Methodology, Shortcomings, and Challenges. Journal of Coagulation Disorders., February 2010; 2(1) 15-22


M van Geffen, M Dardikh  and B Verbruggen

Affiliation: Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands


ABSTRACT

Development of inhibitory antibodies against factor VIII is a serious complication in the treatment of hemophilia patients, as these antibodies inactivate factor VIII, resulting in an increased bleeding tendency and morbidity. The clinical manifestation of inhibitors has to be analyzed by objective laboratory tests to specify the exact nature of the inhibitor. Here, the inhibitor assays, especially the Bethesda assay and the Nijmegen assay, are discussed including their methodological shortcomings. This paper also discusses the epitope specificity of the inhibitor assays and the methods to investigate the specificity of inhibitors against factor VIII concentrates that may contribute to improve the treatment of hemophilia A patients with inhibitors. Finally, the use and limitations of overall clotting assays, such as clot wave form analysis, thromboelastography, and thrombin generation assay, in the management of hemophilia A patients with inhibitors are discussed.

Keywords: hemophilia A, factor VIII inhibitors, Nijmegen assay, Bethesda assay, epitope specificity

Correspondence: B Verbruggen, Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: (31)‐243614796; e‐mail: H.Verbruggen@chl.umcn.nl

Management of Acquired Hemophilia: A Literature Review

Pentasaccharides: a New Class of Anticoagulants in Clinical Practice

Prevalence and Treatment of Von Willebrand Disease‐Related Menorrhagia in Adolescents: A Review

Mikhail S, Kouides P, Prevalence and Treatment of Von Willebrand Disease‐Related Menorrhagia in Adolescents: A Review. Journal of Coagulation Disorders., February 2010; 2(1) 29-34


Sameh Mikhail ¹ and Peter Kouides ²

Affiliations: ¹Lombardi Cancer Center, Georgetown University Hospital, Washington, DC, USA and ²Mary M Gooley Hemophilia Center of Rochester, Rochester General Hospital, Rochester, NY, USA


ABSTRACT

Heavy menstrual bleeding is a fairly common problem among women of reproductive age and a frequent complaint among adolescents. The pathophysiological mechanisms that cause menorrhagia in adolescents are different than those that cause menorrhagia in older women. Compared with the adult menorrhagia population, there have been far fewer studies about the prevalence of bleeding disorders and the efficacy of different treatment strategies in adolescents with menorrhagia. Excessive menstrual bleeding caused by bleeding disorders results in hospitalizations, administration of blood products, time lost from school and other activities, and decreased quality of life. Moreover, managing menorrhagia in patients with undiagnosed disorders of hemostasis may be associated with unwanted risks and complications. The studies evaluating the prevalence of Von Willebrand disease (VWD) in adolescents with menorrhagia identified over 500 patients with a prevalence range from 3% to 36%, depending on the clinical setting studied. The highest prevalence is seen in adolescents referred to an outpatient hemophilia center, whereas the lowest is seen in the acute hospital setting. Treatment of VWD is often complex, requiring a combination of therapies. Furthermore, different subtypes of VWD respond differently to treatment. There are three main hemostatic agents used to stop and/or prevent bleeding at the time of hemostatic challenges, including: (1) the non‐transfusional agent desmopressin; (2) antifibrinolytic therapy; and (3) purified blood products that contain factor VIII and Von Willebrand factor concentrated from plasma. Additional treatment modalities include estrogen–progesterone preparations that are frequently adjunctive and can be an alternative to the main lines of treatment.

Keywords: Adolescents, menorrhagia, von Willebrand disease

Correspondence: Peter Kouides, Mary M Gooley Hemophilia Center, Rochester General Hospital, 1415 Portland Avenue, Suite 425, Rochester, NY 14621, USA. Tel: (1)‐585‐922‐4020; Fax: (1)‐585‐563‐1832; e‐mail: peter.kouides@rochestergeneral.org

Clinical Perspective of Congenital Vitamin K‐Dependent Coagulation Factor Deficiency

Kuperman A, Brenner B, Clinical Perspective of Congenital Vitamin K‐Dependent Coagulation Factor Deficiency. Journal of Coagulation Disorders., February 2010; 2(1) 49-52

Amir A Kuperman ^{1 2} and Benjamin Brenner ¹

Affiliations: ¹Thrombosis and Hemostasis Unit, Institute of Hematology, Rambam Medical Center, and Bruce Rappaport Faculty of Medicine, Technion, Haifa,
Israel and ²Pediatric Hematology, Western Galilee Hospital, Naharriya, Israel


ABSTRACT

The “vitamin K system” requires the normal function of two enzymes: γ‐glutamyl carboxylase and vitamin K epoxide reductase enzyme complex (VKORC1). Heritable enzymatic dysfunction of the γ‐glutamyl carboxylase or the VKOR complex results in the secretion of poorly carboxylated vitamin K‐dependent proteins that play a role in coagulation. The following review focuses on the clinical perspectives of VKCFD (vitamin K‐dependent coagulation factors deficient) I and II, which have received increasing interest lately, and provides a brief explanation about the pathogenesis of the disease. Laboratory assays used for diagnosis are discussed, and management in various clinical settings is reviewed.

Keywords: vitamin K‐dependent coagulation factors deficiency (VKCFD), γ‐glutamyl carboxylase (GGCX), vitamin K epoxide reductase (VKOR)

Correspondence: Benjamin Brenner, Thrombosis and Hemostasis Unit, Institute of Hematology, Rambam Medical Center, and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. Tel: (972)‐4‐8543520; Fax: (972)‐4‐8543886; e‐mail: b_brenner@rambam.health.gov.il

Prophylactic Factor Infusions for Patients with Hemophilia: Challenges with Treatment Adherence