Perioperative management of haemophilia B: A critical appraisal of the evidence and current practices.

BACKGROUND: While there is substantial literature addressing the principles of general management of haemophilia, literature on perioperative management of haemostasis is scarce. OBJECTIVE: The aim of this study was to better understand perioperative management among congenital haemophilia B patients (without inhibitors) and to gain insights into real-world surgical practices. METHOD: A systematic literature review, with an emphasis on haemophilia B, was conducted using EMBASE® , Medline® and the Cochrane Library. Studies from 1974 to June 2015 were accessed, and 132 studies were eligible for the full-study review. An international expert panel with five haematologists and one surgeon reviewed the resulting literature and provided further insights. RESULTS: The literature review revealed that documented experience in the perioperative management of bleeding risk in haemophilia B patients is relatively scarce. Therefore, the review was amended to provide a comprehensive overview of the perioperative management for haemophilia A and B patients; the expert panel applied a particular focus to haemophilia B. Several gaps were identified in the literature including the lack of consensus on defining surgery in terms of bleeding risk, optimal factor levels during surgery and lack of robust evidence on surgical outcomes. The ensuing discussions with the expert panel provided validation of some of the results from the systematic literature review and proposed future directions for perioperative management. Suggestions included collaboration with haemophilia treatment centres (HTCs) to collect real-world data on perioperative management, establishing the need for optimal factor level monitoring practice, and the appropriate adoption of extended half-life products in clinical settings.

Results from a large multinational clinical trial (guardian™3) using prophylactic treatment with turoctocog alfa in paediatric patients with severe haemophilia A: safety, efficacy and pharmacokinetics.

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open-label, non-controlled trial investigated the safety, efficacy and pharmacokinetics (PK) of turoctocog alfa, a new rFVIII product, in a paediatric population. The primary objective was to evaluate safety. A total of 31 younger children (0-5 years) and 32 older children (6-11 years), with ≥ 50 exposure days to any factor VIII (FVIII) product and no history of inhibitors, received prophylaxis with turoctocog alfa (25-50 IU kg(-1) every second day or 25-60 IU kg(-1) three times weekly). PK assessments of turoctocog alfa and the patients' previous FVIII product were performed in 28 patients. Mean exposure to turoctocog alfa was 60 exposure days per patient. This corresponds to approximately 4.5 months in the trial. None of the patients developed inhibitors (≥ 0.6 BU) and no safety concerns were raised. A total of 120 bleeding episodes (95%) were controlled with 1-2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as 'excellent' or 'good' haemostatic response) for treatment of bleeding episodes was 92%. Overall, the median annualized bleeding rate was 3.0 (interquartile range: 8.5) bleeds patient(-1) year(-1) . PK parameters were comparable between the two age groups. In conclusion, the present large global clinical trial showed that turoctocog alfa was safe, effective in treatment of bleeding episodes and had a prophylactic effect in paediatric patients.

Results from a large multinational clinical trial (guardian™1) using prophylactic treatment with turoctocog alfa in adolescent and adult patients with severe haemophilia A: safety and efficacy.

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open-label, non-controlled trial investigated the safety and efficacy of turoctocog alfa, a new rFVIII product. The primary objective was to evaluate safety. A total of 150 patients (24 adolescents and 126 adults) with severe haemophilia A (FVIII activity ≤ 1%), with at least 150 exposure days (EDs) to any FVIII product and no history of inhibitors were enrolled, and 146 patients (97%) completed the trial. All patients received prophylaxis with turoctocog alfa for approximately 6 months and had a mean of 85 EDs during the trial. None of the patients developed FVIII inhibitors, there were no indications of early FVIII inhibitor development and no safety concerns were identified. A total of 225 adverse events were reported in 100 (67%) patients, with the most common being events associated with dosing procedures, headaches, and nasopharyngitis. A total of 499 bleeding episodes were reported during the trial, the majority (89%) were controlled with 1-2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as 'excellent' or 'good' haemostatic response) for treatment of bleeding episodes was 81%. The overall median annualized bleeding rate was 3.7 (interquartile range: 8.7) bleeds/patient/year. In conclusion, turoctocog alfa provides a new, safe and effective alternative for prophylaxis and treatment of bleeding episodes in patients with haemophilia A.

Single 270 microg kg(-1)-dose rFVIIa vs. standard 90 microg kg(-1)-dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison.

Evidence suggests greater doses of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) than currently administered may result in enhanced haemostasis and convenience for patients with haemophilia A and B with inhibitors. This study evaluated efficacy and safety of rFVIIa and an activated prothrombin complex concentrate (APCC; Factor Eight Inhibitor Bypassing Activity [FEIBA], Baxter AG, Vienna, Austria) for controlling joint bleeds in a home-treatment setting. Patients received each of three treatments in one of six possible sequences: 270 microg kg(-1) rFVIIa at hour 0 + placebo at hours 3 and 6, 90 microg kg(-1) rFVIIa at hours 0, 3 and 6, and 75 U kg(-1) APCC at hour 0. Efficacy was assessed by the requirement for additional haemostatics within 9 h and by a novel global response algorithm. The percentage of rFVIIa 270 microg kg(-1) group patients requiring additional haemostatics within 9 h (8.3%) was significantly lower than that for the APCC group (36.4%, P = 0.032). The percentage of rFVIIa 90 x 3 microg kg(-1) group patients requiring such rescue medication (9.1%) was also lower compared to the APCC group. This result approached, but did not reach statistical significance (P = 0.069). Both rFVIIa treatment groups showed similar use of rescue medication (8.3% and 9.1% of episodes for rFVIIa 270 microg kg(-1) and rFVIIa 90 x 3 microg kg(-1) groups respectively). No significant differences in treatment response were observed with the global response algorithm (P = 0.173). No safety issues were identified. A single dose of rFVIIa 270 microg kg(-1) is as safe and effective as rFVIIa 90 x 3 microg kg(-1) dosing, and may be considered a potentially more effective alternative to APCCs for the management of joint bleeding in this population.

Treatment of acquired haemophilia with recombinant activated FVII: a critical appraisal.

Acquired haemophilia is a rare bleeding disorder usually caused by the spontaneous formation of inhibitory antibodies to coagulation FVIII. The disease occurs most commonly in the elderly, and although acquired haemophilia may be associated with a variety of underlying conditions, up to 50% of reported cases are idiopathic. Treatment options have traditionally involved human FVIII or FIX replacement therapy (if the inhibitor titre allows), porcine FVIII or the use of activated pro-thrombin complex concentrates. Recombinant activated coagulation FVII (rFVIIa) was available on an emergency and compassionate use basis from 1988 to 1999 at sites in Europe and North America. It has been registered in Europe for use in treating acquired haemophilia since 1996 and has recently been licensed for this indication in the United States. By directly activating FX on the surface of activated platelets at the site of injury (thereby bypassing FVIII and FIX), rFVIIa can circumvent the actions of inhibitory antibodies present in acquired haemophilia patients. This paper provides an overview of experiences with rFVIIa for the treatment of acquired haemophilia from the NovoSeven compassionate and emergency use programmes (1989-1999), the Hemophilia and Thrombosis Research Society Registry, and independent published reports from January 1999 to September 2005. rFVIIa has been reported to provide safe and effective haemostasis as a first line therapy in patients of all ages for a variety of surgical and non-surgical bleeding situations.

Sex-related differences in hemostasis and thrombosis.

Disorders of thrombosis and hemostasis represent both diagnostic and therapeutic challenges for the clinician, in part because of sex-based differences in incidence and presentation. The hemophilias are characterized by specific sex-linked patterns of inheritance, and there are sex differences in the presentation of the autosomally inherited disorders, particularly von Willebrand's disease. The diagnosis of these disorders can be affected by variations in either endogenous or exogenous estrogens, and the hemostatic stresses presented by menstruation and childbirth render any coagulopathy more severe in females than in males. Women are also at increased risk for developing thrombotic and embolic problems while on exogenous estrogens and during pregnancy. This article presents recommendations about the most appropriate and cost-effective ways to screen for the inherited disorders of both thrombosis and hemostasis in men and women. Recommendations are also developed for the treatment of women with these disorders, particularly in the context of pregnancy, contraception, uterine bleeding, and postmenopausal management.

Human recombinant DNA-derived antihaemophilic factor (factor VIII) in the treatment of haemophilia A: conclusions of a 5-year study of home therapy. The KOGENATE Study Group.

Fifty-eight previously treated haemophilic subjects were treated exclusively with the recombinant FVIII (rFVIII-KOGENATE) produced by Bayer Corporation (Berkeley, CA) in an international multicentre prospective study of more than 5 years duration. Fifty-four of the 58 had severe haemophilia (< 2% FVIII) and four had moderate haemophilia (2-5% FVIII); 23/58 (40%) were seropositive for HIV, while 35/58 (60%) were HIV seronegative. Patients were monitored for safety and efficacy over a median period of 4.7 years (range 0.9-5.9 years) and received 17 922 infusions totalling 25.7 million units of rFVIII. Of 7107 bleeding episodes reported in home diaries, 5831 (82%) required only one treatment with rVIII. Twenty-five invasive surgical procedures in 17 patients, including eight joint replacements, were successfully accomplished and 13 serious bleeding episodes in eight patients were successfully treated. FVIII recovery performed on 885 occasions using 39 different lots of rFVIII showed mean incremental recovery of 2.48% IU-1 kg-1 (+/- 0.64). Adverse events were associated with 42 infusions (0.2%); none caused discontinuation of therapy. Immunological parameters remained stable in HIV-seronegative subjects treated with rFVIII; a small decrease in CD4 counts was noted in HIV-seropositive individuals (mean - 37.2 cells mm-3 yr-1). No de novo formation of inhibitors to FVIII was noted; and no clinical allergic reactions occurred to murine or hamster proteins. These conclusions from the longest monitored safety study ever performed for a haemophilia treatment product (with more than 5 years of observation) confirm previous interim study reports that rFVIII is well tolerated over the long-term, has biological activity comparable to that of plasma-derived FVIII, and is safe and efficacious for the treatment of haemophilia A.

Breast health at midlife: guidelines for screening and patient evaluation.

Breast cancer is the leading cause of death of American women aged 40 to 55. The fear that midlife women have of developing breast cancer must be considered as physicians discuss breast health with their patients. Identification of risk factors is important, although 70% of women diagnosed with breast cancer have no known risk factors. Screening mammograms can detect early lesions, but controversy exists over whether they reduce mortality in women younger than ago 50. The American Cancer Society and the National Cancer Institute recently changed their screening mammography recommendations for women aged 40 to 49. A breast self-exam can be performed using the circular or wedge techniques. If a mass is found, physicians can help alleviate a patient's anxiety by providing a diagnosis as quickly as possible.

Liver failure and mortality in HIV-positive haemophiliacs: FOURTEEN-YEAR EXPERIENCE AND LITERATURE REVIEW.

Progression to clinical liver failure has been observed in hepatitis C (HCV)-infected, HIV-seropositive haemophiliacs. We studied the records of 176 haemophiliacs who were infected with HIV and/or HCV seen between 1980 and 1993. Thirty-two of 113 (28%) HIV-seropositive patients died during the study period. Ten of these patients died of liver failure, representing 31% of all mortality. An additional four HIV-seropositive patients who died of other causes had end-stage liver disease. Clinical liver failure occurred in 12% of the HIV-infected cohort. None of the HIV-seronegative, HCV-infected patients suffered from liver failure. Among HIV-infected patients, liver failure was associated with advanced age and decreased CD4 counts. Severe, sporadic ALT elevations were associated with liver failure; persistent transaminase elevations were associated with mortality. We conclude that HIV infection enhances progression of HCV infection to clinical liver failure, and that liver failure is a major cause of mortality in HIV-positive haemophiliacs.

Long term evaluation of septic arthritis in hemophilic patients.

Before 1983, septic arthritis was rare in patients with hemophilia. With the advent of human immunodeficiency virus infection in the hemophilia population, many centers noted an increasing incidence of patients with septic arthritis. Fifteen septic joints in 10 patients with severe hemophilia were documented. Eight patients were human immunodeficiency virus positive, 1 was human immunodeficiency virus negative, and 1 was not tested. The diagnosis was delayed in 5 patients because the symptoms are similar to an acute hemarthrosis. An elevated temperature was common. The white blood cell count was elevated in only 1/3 of the infections, being modified by human immunodeficiency virus infection. Associated risk factors included infected angioaccess catheters (2), pneumonia (2), and generalized sepsis (1). All but 1 joint responded to appropriate antibiotics and either repeated aspiration or arthrotomy. However, 6 patients died of acquired immunodeficiency syndrome from 2 to 109 months after infection. Three patients are alive 29, 86, and 96 months, respectively, after infection.

Spurious fibrinogen levels secondary to pyroglobulinemia in Waldenström's macroglobulinemia.

We report two cases of pyroglobulinemia detected in the course of routine determination of fibrinogen levels measured by the heat-precipitation method and that led to the diagnosis of Waldenström's macroglobulinemia. The incidence of pyroglobulinemia is briefly discussed, and the potential significance of this laboratory artifact is emphasized.

Risks of immunodeficiency, AIDS, and death related to purity of factor VIII concentrate. Multicenter Hemophilia Cohort Study.

In HIV-infected subjects with haemophilia, CD4 counts seem to fall more slowly in those on high-purity factor VIII (FVIII) than on intermediate-purity product. We evaluated whether risks for AIDS or death were associated with either product among 411 HIV-infected individuals. The relative hazard of AIDS was slightly elevated for both current (1.34) [corrected] and cumulative (1.01 per month) use of high-purity products (neither significant). The corresponding hazards for death were 1.49 and 1.03 (neither significant). Thus we found no evidence that high-purity FVIII concentrates retard the development of AIDS.