Featured Articles from the Journal of Coagulation Disorders

Individually Tailored Prophylaxis in Patients with Severe Hemophilia

Yesim Dargaud^1,2 and Claude Negrier^1,2

Affiliations: ¹Unite d'Hemostase Clinique, Hopital Edouard Herriot, Lyon, France and ²EA 4174, Unite de recherche sur l'hemophilie, Universite Lyon 1, France


ABSTRACT

Since the 1950s, prophylaxis has been used in patients with severe hemophilia in order to prevent joint bleeds and life-threatening bleeding episodes. Several studies have demonstrated the importance of starting prophylactic therapy during the first years of life, before the start of joint damage. However, the regimen can be individualized and adjusted according to the bleeding phenotype of individual patients. In general, the current strategies used for prophylaxis can be divided into those that aim to maintain residual plasma FVIII/FIX activity >1 IU/dL and those that are guided by the clinical bleeding patterns of individual patients. Laboratory markers to predict the phenotype are warranted. Pharmacokinetics have been reported as a useful laboratory tool for factor dosing, but clinical bleeding patterns may be significantly different in patients having similar coagulation factor activity. Therefore, the optimal prophylactic regimen is still under debate and many unanswered questions still exist. Recently, global hemostasis assays, such as the thrombin generation test, have been extensively studied and several groups reported a statistically significant correlation between the thrombin-generating capacity of patients and their bleeding symptoms. Recent data suggest that thrombin generation measurement may be useful for individually tailoring a prophylactic regimen to the needs of each patient with hemophilia. Optimizing prophylactic therapy to patient's phenotype with no loss of clinical effectiveness would be highly relevant and can significantly improve patients' quality of life.

Keywords: hemophilia, prophylaxis, thrombin generation assay, ETP, individualization

Correspondence: Yesim Dargaud, Unite d'Hemostase Clinique, Hopital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France. Tel: +33 4 72117370; Fax: +33 4 72117312; e-mail: ydargaud@univ-lyon1.fr

Can Mutations Identified in Congenital Fibrinogen Disorders Explain the Clinical Manifestations?

Marguerite Neerman-Arbez^1, Yordanka Tirefort^2,3 and Philippe de Moerloose^2,3

Affiliations: ¹Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland, ²Haemostasis Unit, University Hospital of Geneva, Geneva, Switzerland and ³Faculty of Medicine, University of Geneva, Geneva, Switzerland


ABSTRACT

Hereditary fibrinogen abnormalities can be classified in two classes of plasma fibrinogen defects: type I, afibrinogenemia or hypofibrinogenemia, which has absent or low plasma fibrinogen antigen levels (quantitative fibrinogen deficiencies), and type II, dysfibrinogenemia, or hypodysfibrinogenemia, which shows normal or reduced antigen levels associated with disproportionately low functional activity (qualitative fibrinogen deficiencies). Various types of mutations have been described in each type of congenital fibrinogen disorder. The primary aim of this review is to deal with the relationship between the genotype and the clinical phenotype. In afibrinogenemia, most mutations of the FGA, FGB, or FGG fibrinogen encoding genes are null mutations. In some cases, missense or late-truncating nonsense mutations allow synthesis of the corresponding fibrinogen chain but intracellular fibrinogen assembly and/or secretion are impaired. The majority of afibrinogenemia patients have a bleeding diathesis, and no clear relationship exists between the various mutations and the clinical manifestations, especially for the cases with thrombotic complications. In certain hypofibrinogenemic cases, the mutant fibrinogen molecules are produced and retained in the rough endoplasmic reticulum of hepatocytes, causing hepatic disease. Hereditary dysfibrinogemia patients may be asymptomatic, or they may develop bleeding or thrombotic manifestations. In contrast to afibrinogenemia, in many cases the relationship between the genotype and the bleeding or thrombotic phenotype can be explained by the type of mutation. Moreover, some cases of dysfibrinogenemia are caused by mutations involving the C-terminus of the fibrinogen α-chain and are associated with kidney amyloidosis.

Keywords: coagulation, afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, bleeding, thrombosis

Correspondence: Marguerite Neerman-Arbez, Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. Tel: +41 22 379 5655; Fax: +41 22 379 5706; e-mail: Marguerite.Neerman-Arbez@unige.ch

The Safety and Efficacy History of B-domainless Factor VIII

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

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

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