Strategies to Enable a Stable Warfarin Maintenance Dose

Gandara E, Wells P S.  Strategies to Enable a Stable Warfarin Maintenance Dose.  Journal of Coagulation Disorders, July 2010; 2(2):  63-69


REVIEW ARTICLE


Esteban Gandara^1,2 and Philip S Wells^1,2

Affiliations: ¹Thrombosis Program, Department of Medicine, Division of Hematology, University of Ottawa, Ottawa, Ontario, Canada and ²Ottawa Hospital Research Institute, Ottawa, Ottawa, Ontario, Canada


ABSTRACT

    In North America, warfarin is the current standard for oral anticoagulation therapy in the treatment and/or prophylaxis of different thrombotic conditions. In daily clinical practice a significant proportion of patients on long-term warfarin therapy fail to stabilize within their target therapeutic range leading to a resultant increased risk of either thrombotic events or major bleeding. There are many different strategies that have been advocated to improve International Normalized Ratio (INR)[AQ2] control and enable prediction of, or increase probability of, stable maintenance doses of warfarin. These include: knowledge of the genetic polymorphisms that effect warfarin pharmocokinetics, incorporation of these polymorphisms into dosing algorithms, clinically derived dosing algorithms (so-called nomograms), use of computer software as dosing aids, anticoagulation clinics as the model of care, self-monitoring and dosing, supplementation with Vitamin K, better patient education, and increased frequency of monitoring. Some have tested in multiple studies and have proven effective whereas the utility of others is still under investigation. To conclude, there are several strategies proven to increase the time patients spend in therapeutic INR range. In this review we discuss these strategies and their practical applications.

Keywords: warfarin, maintenance dose, randomized trials, evidence-based, venous thromboembolism

Correspondence: Philip S Wells, The Ottawa Hospital, General Campus, LM 12, Box 206, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada. Tel: 613 737 8755; Fax: 613 737 8851.[AQ3]

Use of Human Prothrombin Complex Concentrate in Patients with Acquired Deficiency and Active or in High-Risk Severe Bleeding

REVIEW ARTICLE

Use of Human Prothrombin Complex Concentrate in Patients with Acquired Deficiency and Active or in High-Risk Severe Bleeding

Mendarte L^1, Munne M^1, Rodríguez S^2, Mendarte U³ and Montoro JB¹

Affiliations: ¹Pharmacy Service; ²Haematology Service and ³Digestive Service, Donostia Ospitalea, Donostia, Hospital Universitario Vall d'Hebron, Barcelona, Spain


ABSTRACT

BACKGROUND
Deficiency in prothrombin complex factors is a cause of massive hemorrhage, whose management in emergency situations is subject of debate. Plasma-derived prothrombin complex concentrates (PCC) are indicated for reversing the hemorrhagic diathesis found in acquired deficiencies, together with platelets, fresh frozen plasma (FFP), and cryoprecipitate.

OBJECTIVES
To ascertain how PCC are used in patients with life-threatening hemorrhagic disorders (surgery, trauma, digestive hemorrhage), especially in patients with underlying disease states that limit prothrombin complex factor synthesis (hepatic dysfunction, treatment with oral anticoagulants (OAT)), efficiency is evaluated in terms of concrete clinical situation use and stated as international normalized ratio (INR) change and survival at the end of the episode.

METHODS
In a third-level general hospital, patients with a documented life-threatening hemorrhage who received a PCC prescription were included in the protocol, during a follow-up period of 6 months. Demographic data, treatment indication, INR before and after treatment, hemoglobin (Hgb), hematocrit (Hct), admission diagnosis, PCC dose, current OAT, and treatment with vitamin K, and FFP or other hemoderivative administration were collected.

RESULTS
A total of 124 patients were initially treated with PCC, 102 of whom were finally included. Patients' mean age was 63.73 years (SD 17.82); 67 (66%) were men. Only 39% of patients were treated with OAT prior to the emergency bleeding. Mean PCC dose given was 2720 IU (1551) expressed as factor IX; mean INR before treatment was 2.92 (2.54), and INR after PCC administration was 1.47 (0.44); mean INR variation was – 1.54 (2.89) (P<0.005). Global survival at the end of the episode was 61.2%. No thrombotic events were observed directly.

CONCLUSIONS
PCC seem to be a good alternative to FFP in patients with life-threatening hemorrhagic disorders, especially in OAT patients who need OAT reversion, for severe bleeding or surgery. PCC quickly and significantly reduce INR and bleeding in OAT and non-OAT patients. Moreover, PCC are safer than other blood products and reduce the need for other hemoderivatives.

Keywords: prothrombin complex concentrate, emergency bleeding, oral anticoagulant reversion

Correspondence: Mendarte L, Pharmacy Service, Hospital Universitario Vall d'Hebron, Pø Vall d'Hebron 119-129, Barcelona 08035, Spain. Tel: (34)-932746811; Fax: (34)-932746046; e-mail: iyibcn@vhebron.net

Warfarin Use and Risk of Valvular Calcification

Lerner R G, Sekhri A, Palaniswamy C.  Warfarin Use and Risk of Valvular Calcification.  Journal of Coagulation Disorders, July 2010; 2(2):  57-62

REVIEW ARTICLE

Robert G Lerner, Arunabh Sekhri and Chandrasekar Palaniswamy

Affiliation: Department of Medicine, Division of Hematology & Oncology, New York Medical College, Valhalla, NY, USA


ABSTRACT

Vitamin K is a micronutrient that is required for the activity of various biologically active proteins. Apart from clotting factors, these vitamin K-dependent proteins include regulatory proteins such as protein C, protein S, protein Z, osteocalcin, growth arrest-specific gene 6 protein (Gas6), and matrix Gla protein (MGP). MGP has glutamic acid residues that are gamma-carboxylated by vitamin K-dependent gamma-carboxylase, which enables it to inhibit calcification. Warfarin, being a vitamin K antagonist, inhibits this process and has thus been associated with calcification in various animal and human studies. Although no specific guidelines are presently available to prevent or treat this less recognized side-effect, stopping warfarin and using an alternative anticoagulant seems to be a reasonable therapeutic option. Newer anticoagulants such as dabigatran and rivaroxaban offer promise as future therapeutic options in such a scenario. Agents such as atorvastatin, alendronate, osteoprotegerin, and vitamin K to prevent or treat warfarin-induced calcification are under study.

Keywords: warfarin, valvular calcification, vascular calcification, matrix Gla protein, y-carboxylation, vitamin K

Correspondence: Robert G Lerner, Department of Medicine, Division of Hematology & Oncology, New York Medical College, Valhalla, NY 10595, USA. Tel: M-914-594-4979; Fax: M-914-594-4396; e-mail: ROBERT_LERNER@nymc.edu

Genetic Testing for the Diagnosis of Von Willebrand Disease: Benefits and Limitations

Favaloro E J, Krigstein M, Koutts J, Brighton T, Linderman R.  Genetic Testing for the Diagnosis of Von Willebrand Disease:  Benefits and Limitations.  Journal of Coagulation Disorders, July 2010; 2(2):  37-47

REVIEW ARTICLE

Emmanuel J Favaloro^1, Michael Krigstein^2, Jerry Koutts^1, Timothy Brighton² and Robert Lindeman²

Affiliations: ¹Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, NSW, Australia and ²Department of Haematology, South Eastern Area Laboratory Service (SEALS), Randwick, NSW, Australia


ABSTRACT

von Willebrand disease (VWD) is the most common inherited bleeding disorder and arises from deficiencies and/or defects in the plasma protein von Willebrand factor (VWF). VWD is classified into six different types, with Type 1 identified as a (partial) quantitative deficiency of VWF, Type 3 a (virtually) total deficiency of VWF, and Type 2 identifying four separate types (2A, 2B, 2M, 2N) characterized by qualitative defects. The classification is currently based on phenotypic assays, supplemented by multimeric analysis of the von Willebrand protein. Although genetic analysis is not required in order to diagnose VWD or to define a patient's VWD classification type, genetic analysis may be useful in discrete situations, in order to confirm or assist the diagnosis. In particular, genetic analysis may be useful in: (i) Type 2N VWD (primarily as an aid to discriminate this from hemophilia A/carrier); (ii) Type 2B VWD (primarily as an aid to discriminate this from PT-VWD); (iii) Type 3 VWD (for prenatal assessment/family studies and alloantibody risk assessment); and perhaps also in (iv) other Type 2 VWD investigations; and (v) very select Type 1 VWD investigations (eg, VWF levels are <25 IU/mL, or family studies where causative mutation is already known). However, genetic testing should not be used as a surrogate for a poor phenotypic test approach, and it is important that a thorough phenotypic workup be applied prior to requesting genetic testing in VWD.

Keywords: von Willebrand disease, VWD, diagnosis, genetic testing, molecular analysis

Correspondence: Emmanuel J Favaloro, Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, WSAHS, Westmead, NSW 2145, Australia. Tel: +612 9845 6618; Fax: +612 9689 2331; e-mail: emmanuel.favaloro@swahs.health.nsw.gov.au

The Molecular Basis of Type 3 von Willebrand Disease

Cumming A M, Sutherland M S, Keeney S.  The Molecular Basis of Type 3 von Willebrand Disease.  Journal of Coagulation Disorders, July 2010; 2(2):  29-35

REVIEW ARTICLE

Anthony M Cumming, Megan S Sutherland and Stephen Keeney

Affiliations: Molecular Diagnostics Centre, University Department of Haematology, Manchester Royal Infirmary, Manchester, UK


ABSTRACT

Type 3 von Willebrand disease (VWD), the result of a severe quantitative deficiency of von Willebrand factor (VWF), is associated with moderate to severe bleeding symptoms including epistaxis, menorrhagia, arthropathy, and postoperative bleeding. Inheritance of type 3 VWD is autosomal recessive and the disorder is considered to have a prevalence of 0.5-1 per million individuals in the general population. It was originally assumed that type 3 VWD is caused by large deletions of the gene-encoding VWF (VWF). However, of 109 VWF mutations reported on the International Society on Thrombosis and Hemostasis (ISTH) VWF database (http://www.vwf.group.shef.ac.uk/) to cause type 3 VWD, only 11 are large deletions-ranging from the deletion of a single exon up to the deletion of the entire VWF gene. Approximately 80% of VWF mutations in type 3 VWD give rise to a VWF null allele, ie, nonsense mutations, deletions, splice-site mutations, and small insertions. Missense changes in VWF account for only about 20% of the mutations associated with type 3 VWD. This is unlike type 1 VWD, the result of a partial quantitative deficiency of VWF, where approximately two-thirds of reported mutations are missense in nature. This observation reflects the different genetic basis of type 3 and type 1 VWD in most cases.

Keywords: inherited bleeding disorder, von Willebrand disease, type 3 VWD, VWF mutations, type 3 VWD genetics

Correspondence: Dr. Tony Cumming, Molecular Diagnostics Centre, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. Tel: +44 (0)161 276 4880; e-mail: tony.cumming@cmft.nhs.uk

Blood Coagulation Factors V and VIII: Molecular Mechanisms of Procofactor Activation

Bos M HA, Camire R M.  Blood Coagulation Factors V and VIII:  Molecular Mechanisms of Procofactor Activation:  Journal of Coagulation Disorders, July 2010; 2(2):  19-27

REVIEW ARTICLE

Mettine HA Bos¹ and Rodney M Camire^1,2

Affiliations: ¹Department of Pediatrics, Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA and ²School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA


ABSTRACT

A hallmark of hemostasis is that cells and proteins involved in the formation of a blood clot remain in a quiescent state and are only activated following an appropriate stimulus. The homologous proteins factors V (FV) and VIII (FVIII) cannot participate to any significant degree in their macromolecular enzyme complexes and are thus considered procofactors. Activity is generated following limited proteolysis, indicating that the conversion of the procofactors to factor Va and factor VIIIa must result in structural changes that impart cofactor function. The proteolytic events that lead to the activation of these proteins have been extensively characterized over the past three decades. However, a fundamental understanding of the mechanism(s) by which these proteins are kept as inactive procofactors and how specific bond cleavage facilitates the conversion to the active cofactor state is only starting to become known. These molecular processes undoubtedly play critical regulatory roles, evolved to maintain normal hemostasis since factor Va and factor VIIIa have a tremendous influence on thrombin generation. This review will detail our current understanding of the molecular process of procofactor activation and highlight structural features that play a major role in FV and FVIII activation.

Keywords: factor V, factor VIII, prothrombin activation, FX activation, procofactor, proteolytic activation, hemostasis

Correspondence: Rodney M Camire, Department of Pediatrics, Division of Hematology, The Children's Hospital of Philadelphia, 5018 Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA. Tel: +1 215 590 9968; Fax: +1 215 590 3660; e-mail: rcamire@mail.med.upenn.edu

Individually Tailored Prophylaxis in Patients with Severe Hemophilia

Dargaud Y, Negrier C.  Individually Tailored Prophylaxis in Patients with Severe Hemophilia.  Journal of Coagulation Disorders, July 2010; 2(2):  11-17

REVIEW ARTICLE

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

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

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

Neerman-Arbez M, Tirefort Y, Moerloose P.  Can Mutations Identified in Congenital Fibrinogen Disorders Explain the Clinical Manifestations?  Journal of Coagulation Disorders, July 2010; 2(2):  71-79

REVIEW ARTICLE

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

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

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