Featured Articles from the Journal of Coagulation Disorders

The Safety and Efficacy History of B-domainless Factor VIII

Mannucci P M.  The Safety and Efficacy History of B-domainless Factor VIII.  Journal of Coagulation Disorders, July 2010; 2(2):  7-9

REVIEW ARTICLE

Pier M. Mannucci

Affiliation: A. Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Medicine and Medical Specialties,
IRCCS Ca` Granda Foundation Maggiore Hospital and University of Milan, Italy


ABSTRACT

Hemophilia A is the predominant cause of an overall burden of hemophilia that affects one in every 5000 males worldwide. Management of hemophilia A revolves around replacement therapy, and introduction of recombinant factor VIII (rFVIII) was a major milestone in this field. First generation rFVIII, which used animal-derived proteins, was followed by second generation products such as B-domain-deleted rFVIII (ReFacto). ReFacto was comparable to full-length rFVIII in its pharmacokinetics, efficacy, safety, hemostatic activity and immunogenicity. The overall hemostatic efficacy of ReFacto was rated good or excellent in 95% of patients without prior treatment history and in more than 99% of patients who were either treated earlier or underwent surgery. Third generation rFVIII such as the plasma/albumin-free Advate were introduced to minimize viral contamination of biological products; however, these were not completely free from biological contamination, as one of the steps in the purification process involved monoclonal antibody derived from mouse hybridoma cell lines. In order to address this issue, a novel product, ReFacto AF has been introduced. ReFacto AF is completely free from biological contamination as it involves no animal- or human-derived raw materials in either the culture or purification process. ReFacto AF is comparable to the original ReFacto in its pharmacokinetic and pharmacodynamic properties as it has similar structural integrity and stability. ReFacto AF also has adverse event profile comparable to ReFacto and other rFVIII products, without any evidence of neoantigenicity. Ongoing long term trials may provide more insight into the efficacy and safety of ReFacto AF in patients with hemophilia A.

Keywords: Coagulation disorder, factor VIII, hemophilia, ReFacto, rFVIII

Correspondence: P. M. Mannucci, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Medicine and Medical Specialties
and Scientific Direction, IRCCS Ca` Granda Foundation Maggiore Hospital and University of Milan, Milan, Italy. Phone :
39-02-55035422;
Fax :
39-02-50320723. Email : pmmannucci@libero.it

Retrospective Evaluation of Secondary Episodic Prophylaxis with rFVIIa in Hemophilia Patients with Inhibitor

Sedano C, Altisent C, Garcia-Candel F, Gimenez F, Mingot ME, Nunez R, Paloma MJ, Soto I, Velasco F, Cid AR, Jimenez V, Fernandez-Lopez MF, Prieto M.  Retrospective Evaluation of Secondary Episodic Prophylaxis with rFVIIa in Hemophilia Patients with Inhibitor.  Journal of Coagulation Disorders, July 2010; 2(2):  1-5

REVIEW ARTICLE

C. Sedano^1, C. Altisent^2, F. García-Candel^3, F. Giménez^4, E. Mingot^5, R. Núñez^6, M. Paloma^7, I. Soto^8, F. Velasco^9, A.R. Cid^10, V. Jiménez^11, M. López-Fernández¹² and M. Prieto¹³

Affiliations: ¹Haematology, Hospital Universitario Marqués de Valdecilla, Santander, ²Haemophilia Unit, Hospital Vall d'Hebron, Barcelona, ³Haematology, Hospital Virgen de la Arrixaca, Murcia, ⁴Haematology, Hospital Torrecárdenas, Almería, ⁵Haematology, Hospital Carlos Haya, Málaga, ⁶Haemophilia Unit, Hospital Virgen del Rocío, Sevilla, ⁷Haematology, Hospital Virgen del Camino, Pamplona, ⁸Haematology, Hospital Central de Asturias, Oviedo, ⁹Haematology, Hospital Reina Sofía, Córdoba, ¹⁰Congenital Coagulophaties Unit, Hospital la Fe, Valencia, ¹¹Haemophilia Unit, Hospital La Paz, Madrid, ¹²Haematology, Complejo Hospitalario A Coruña, A Coruña, ¹³Haematology, Hospital General Yagüe, Burgos, Spain and the Working Group for the Treatment of Haemophilia Patients with Inhibitor from Sociedad Española de Trombosis y Hemostasia (SETH, Spanish Society of Thrombosis and Hemostasis)


ABSTRACT

BACKGROUND
Hemophilic arthropathy is a significant cause of morbidity in hemophilia patients. Prevention of this condition is now a major aim of hemophilia treatment. In patients with high-responding inhibitors, prophylactic administration of bypassing agents may be of benefit, as has been seen in hemophilia without inhibitors.

OBJECTIVES
This retrospective study assesses the reduction in the number of hemarthroses after secondary prophylaxis with rFVIIa is started in hemophilia patients with high-responding inhibitors and initial or advanced arthropathy.

PATIENTS AND METHODS
Nine patients were included: eight with hemophilia A and one with hemophilia B. The number of hemarthrosis episodes occurring in the 3 months following initiation of the prophylaxis program was compared with those in the previous 3 months.

RESULTS
The rFVIIa dose was ≥90 µg/kg, except in two patients who received 60 µg/kg, administered as a single daily dose in six patients, every 2 days in one patient, and three times a week in two patients. Duration of prophylaxis was 1-19 months. In four patients, no hemarthroses occurred during the prophylaxis period. One patient presented only one hemarthrosis, versus eight who had previously . Three patients did not experience any improvement, and one presented a partial response. The overall reduction in the number of joint bleeds in the series was 54% (22 episodes, versus 48 episodes during on-demand treatment).

CONCLUSIONS
These results suggest that secondary rFVIIa prophylaxis reduces the number of hemarthrosis episodes in hemophilia patients with high-responding inhibitors.

Keywords: rFVIIa, hemarthroses, hemophilia, inhibitors, prophylaxis

Correspondence: Carmen Sedano,  Hospital  Marqués de Valdecilla, Servicio de Haematologia-Coagulacion, Av. Valdecilla 25, 39008Santander(Cantabria), Tel: +34 942203816 . Fax: +34 942202559
email: hemsbc@humv.es

Effectiveness of Bosentan in the Treatment of Chronic Thromboembolic Pulmonary Hypertension: A Systematic Review of Randomized and Nonrandomized Trials

Gröne J, Hamulyak K.  Effectiveness of Bosentan in the Treatment of Chronic Thromboembolic Pulmonary Hypertension:  A Systematic Review of Ramdomized and Nonrandomized Trials.  Journal of Coagulation Disorders, July 2010; 2(2):  81-88

REVIEW ARTICLE


Johanna Gröne¹ and Karly Hamulyák²

Affiliations: ¹Faculty of Health, Medicine & Life Sciences, Maastricht University, Maastricht, the Netherlands and ²Department of Haematology, Maastricht University Medical Centre, Maastricht, the Netherlands


ABSTRACT

BACKGROUND
There is a lack of approved medical treatment options in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are not eligible for pulmonary endarterectomy.

OBJECTIVE
To assess the effectiveness of bosentan in improving pulmonary hemodynamics and functional parameters in adults diagnosed with CTEPH.

METHODS
A systematic review of articles identified in PubMed, MEDLINE, Embase, and Cochrane databases with the search terms bosentan and chronic thromboembolic pulmonary hypertension was done. Randomized and nonrandomized trials that compared bosentan to placebo or standard therapy were included. Studies were assessed for methodological quality one period only please.

RESULTS
Only two studies met the predefined inclusion criteria, one randomized controlled trial (RCT, n=157) and one nonrandomized trial (n=34). The RCT found a significant lowering of the pulmonary vascular resistance in the bosentan group after 16 weeks, which did not translate into an improved exercise capacity. The nonrandomized trial showed a significant improvement in 6-minute walking distance when patients receiving bosentan in addition to standard therapy were compared with patients receiving only standard therapy after one year one period only please.

LIMITATIONS
The studies either did not include an adequate number of patients or did not have a sufficiently long follow-up to permit drawing sound conclusions. At review level, there is threat of publication bias, as only published studies were included.

CONCLUSION
The evidence for beneficial effects of bosentan in studies to date is insufficient to clearly establish its role as medical therapy for CTEPH. It is therefore necessary to conduct large randomized clinical trials that follow patients for a minimum of one year to clarify the efficacy of bosentan.

Keywords: chronic thromboembolic pulmonary hypertension, bosentan, systematic review

Correspondence: Johanna Gröne, Onderwijsinstituut FHML (opleiding geneeskunde), Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. Tel: +31 620 418 524; e-mail: j.groene@student.maastrichtuniversity.nl

An Update on HIV-associated Venous Thromboembolism in the Era of Highly Active Antiretroviral Therapy

Aboulafia D M.  An Update on HIV-associated Venous Thromboembolism in the Era of Highly Active Antiretroviral Therapy.  Journal of Coagulation Disorders, July 2010; 2(2):  49-56

REVIEW ARTICLE

David M. Aboulafia

Affiliations: Division of Hematology and Oncology, Virginia Mason Medical Center and Division of Hematology, University of Washington, Seattle, Washington, USA


ABSTRACT

HIV-associated morbidity and mortality have declined dramatically with the advent of highly active antiretroviral therapy (HAART). Prior to HAART, venous thromboembolism events (VTE) were infrequently described in HIV-infected patients. More recent epidemiologic surveys and case series suggest that VTE are 3-10 times more frequent in this group than age-matched controls. Several intersecting mechanisms associated with HIV infection, coupled with traditional risk factors, including advancing age, malignancies, and lifestyle choices, may contribute to their heightened risk of VTE. Optimal evaluation and management of VTE in HIV-infected individuals usually follows recommendations employed for the general population. Yet there are unique aspects to HIV care that suggest that such routine algorithms regarding thrombosis evaluation and treatment may not be universal. Given that HIV-infected patients can now anticipate living a near normal lifespan, VTE will emerge as an increasing problem in the coming decades. Emphasis on the potential benefits of therapeutic lifestyle changes that can minimize VTE risk is an essential component of integrated care of the HIV-infected patient. Additional study of factors that contribute to VTE risk in this population are needed as are long-term results of therapeutic interventions.

Keywords: HIV/AIDS, venous thromboembolism, highly active antiretroviral therapy

Correspondence: David M. Aboulafia, Clinical Professor of Medicine, University of Washington, 1100 Ninth Avenue, P.O. Box 900 (H14-HEM), Seattle, WA 98111-0900, USA. Tel: +1-206-341-1284; Fax: +1-206-223-2382; e-mail: hemdma@vmmc.org

Review of the Literature of FEIBA Administration in Patients with Hemophilia B and Inhibitors

Axel Schoppmann, Karin Jaeger, Roger Berg and Brigitt Abbuehl

Affiliation: Global Clinical and Medical Affairs, TA Hemophilia, Baxter Innovations GmbH, Vienna, Austria

Correspondence: Axel Schoppmann, Ph.D., Director, Global Medical Affairs, TA Hemophilia, Baxter Innovations GmbH, Industriestrasse 67, 1221 Vienna, Austria. Tel: +43 1 20 100 2504; Fax: +43 1 20 100 530. e-mail: axel_schoppmann@baxter.com

ABSTRACT

During the last three decades, the use of FEIBA (Factor Eight Inhibitor Bypassing Activity, Baxter AG, Vienna, Austria) has steadily increased in the management of patients with hemophilia A and inhibitors. This literature review focuses on the reported use of FEIBA in hemophilia B patients with inhibitors, as these rare individuals present with unique management challenges. We have identified and described a total of 37 reports (1979–2010) on the use of FEIBA in 46 hemophilia B patients aged 2–70 years with inhibitors. FEIBA effectively and safely controlled a range of acute soft tissue and joint hemorrhages including several severe and life-threatening bleeding episodes. When used to cover surgery, FEIBA provided appropriate hemostatic control, enabling even major surgeries to be completed successfully. FEIBA also provided effective bleed prevention, allowing several individuals to undergo intensive rehabilitation with good long-term clinical outcomes. FEIBA was well tolerated in the majority of cases reported, although anaphylaxis to factor IX (FIX) was reported in six patients. There were no reports of nephrotic syndrome, but three thrombotic complications were potentially related to FEIBA administration. This review demonstrates that over recent years, anti-inhibitor treatment strategies have been extended to hemophilia B patients with inhibitors including prophylaxis, immune tolerance induction (ITI), and surgery. Although accepting the limitations of using a case series approach to evaluate the efficacy and safety of FEIBA in hemophilia B patients with inhibitors, the findings reported suggest that FEIBA represents an essential treatment option for these rare but clinically challenging individuals.

The Off-Label Use of Recombinant FVIIa in the Treatment of a Patient With T-Cell Non-Hodgkin Lymphoma Who Developed Intra-abdominal and Intra-Pleural Hemorrhages Followed by High-Dose Methotreaxate Therapy

Erol Erduran, Aysenur Bahadir and Mehmet Mutlu

Affiliation: Department of Pediatric Hematology, School of Medicine, Karadeniz Technical University, Trabzon-Turkey

Methotreaxate (MTX) is a folat inhibitor that inhibits DNA, RNA, and protein synthesis. MTX has a lot of side effects especially on the gastrointestinal system such as mucositis, ulcerative stomatit, nausea, vomiting, diarrhea, and hepatic toxicity. Here we reported a 13-year-old girl patient in association with T-cell lymphoblastic non-Hodgkin lymphoma who developed an excessive intra-abdominal and intra-thorasic hemorrhage unresponsive to fresh frozen plasma and thrombocyte transfusions followed by high-dose MTX treatment. Also discussed is the off-label use of rFVIIa in the patients with excessive bleeding unresponsive to conventional treatment. This patient received rFVIIa in a dose of 50 µg/kg every 2 h for three doses (total 300 µg/kg). We suggest that the rFVIIa treatment is effective for excessive bleeding unresponsive to conventional treatment caused by high-dose MTX treatment and the off-label use of rFVIIa may be thought of in the treatment of excessive hemorrhages followed by MTX treatment.

Keywords: methotreaxate, recombinant FVII, non-Hodgkin lymphoma

Correspondence: Erol Erduran, Department of Pediatric Hematology, School of Medicine, Karadenize Technical University, 61080 Trabzon- TURKEY. Tel: +90 462 377 5480; Fax: +90 462 325 05 16; e-mail: erolerduran@yahoo.com

Effect of Adjusted and Non-Adjusted Citrate Concentrations on Coagulation Test Results in Patients With High Hematocrit Values—Breaking the Unproven Leap of Faith

Chidambharam Choccalingam¹, Vijay Amritraj Jeyachandran¹, Sunder Anish Narayanan¹, and Gopi Murali-Mohan Reddy²

Affiliations: ¹Department of Pathology, ²Department of Social and Preventive Medicine, Chettinad Medical College, Kelambakkam, Chennai, Tamil Nadu, India

(Submission Date: 4 April 2012; Acceptance Date: 10 April 2012; Publication Date: 27 April 2012)

ABSTRACT

INTRODUCTION

The routine coagulation tests, prothrombin time (PT) and activated partial thromboplastin time (APTT), give spuriously increased results when performed on blood samples with elevated hematocrit values. To give a fairly accurate coagulation result value in samples with elevated hematocrit, recommendations to adjust citrate concentrations in blood collection tubes were provided based on indirect experiments.

OBJECTIVES

To compare the effect of adjusted and non-adjusted citrate concentrations on coagulation test results (PT and APTT) in samples from patients with high hematocrit values and to evaluate the usefulness of the practice of adjusting citrate volume in patients with hematocrit measurements more than 55%.

METHODS

The PT and APTT results obtained from citrate adjusted and non-citrate adjusted concentrations in 18 patients with high hematocrit (>55%) were compared.

RESULTS

The drop in PT and APTT values from non-adjusted citrate tubes to citrate adjusted tubes were statistically significant. The probability of having a clinically relevant difference in PT and APTT was far greater among patients with extremely high hematocrit (≥60%) when compared to patients with moderately high hematocrit (55%–59.99%).

CONCLUSION

The Clinical and Laboratory Standards Institute recommendation of adjusting the final citrate concentration in the light blue capped tubes for patients with elevated hematocrit (>55%) to estimate the routine coagulation tests PT and APTT is valid; However, we suggest that adjusting the citrate concentration in light blue capped tubes for patients with extremely high hematocrit (≥60%) is mandatory, whereas for patients with moderately high hematocrit (55% to 59.99%), it is optional to give accurate PT and APTT.

Keywords: prothrombin time, activated partial thromboplastin time, elevated hematocrit, adjusted citrate concentrations

Correspondence: Dr C. Chidambharam, 25, 6th Main Road, Raja Annamalai Puram, Chennai, Tamil Nadu 600028, India. Tel: +919600059533; e-mail: chidambharam@gmail.com