Peter A. Kouides

Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry

Summary.u2002 Recombinant activated factor VII (rFVIIa), licensed in 1999 for treatment of haemophilia patients with inhibitors (HI), represents an important advance in the therapeutic armamentarium. Standard bolus dosing ranges from 90 to 120u2003mcgu2003kg−1 every 2–3u2003h until arrest of bleeding. As licensure, clinical use of rFVIIa has increased and broadened. Clinicians now use a wide dose range, 90–300u2003mcgu2003kg−1. High‐dose regimens may optimize thrombin generation or burst, and may allow for prolonged dose interval. The Hemophilia and Thrombosis Research Society (HTRS) maintains a registry database to study haemophilia treatment and related disorders, particularly treatment of acute bleeding in HI, acquired haemophilia, FVII deficiency and von Willebrands disease (VWD). To assess the effect of rFVIIa dose on efficacy and safety in the treatment of acute bleeding in HI, data from the HTRS database from January 2000 through June 2002 were analysed. Bleeding episodes were grouped by bolus rFVIIa dose range: <100, 100–150, 150–200 and >200u2003mcgu2003kg−1. Investigator‐reported efficacy for the first 72u2003h of treatment was evaluated. Thirty‐eight congenital HI patients were treated for 555 bleeding episodes. Patient age range was 1–55u2003years (median: 14). Bleeding episodes were spontaneous (45%), caused by trauma (38%), or because of surgery, dental, diagnostic, or medical procedures (17%); bleeding occurred in joint, muscle, and intra/extracranial sites. Treatment location included: 80% at home, 12% at other facilities (treatment centres, ER, inpatient and OR), and 8% at both home/other facilities. Median total dose given over 72u2003h was 360u2003mcgu2003kg−1 (range: 40–4281, mean: 537). Bleeding stopped in 87% of the episodes. Bleeding cessation rate was 84% for the three lower dose groups, and 97% for the highest dose group (Pu2003<u20030.001). Five patients experienced nine adverse events (AEs). AE rates were <1% for <100, 5% for 100–150, 0% for 150–200, <1% for >200u2003mcgu2003kg−1 dose group. Decreased therapeutic response accounted for eight of the nine AEs. These data, which represent the most comprehensive report of rFVIIa use since the USA licensure, demonstrate that bleeding episodes in HI patients can be treated safely and effectively at home and that doses up to 346u2003mcgu2003kg−1 appear to be well‐tolerated. Additionally, rFVIIa doses >200u2003mcgu2003kg−1 appear to significantly increase efficacy (97% in the high‐dose group, compared with 84% in the lower dose groups). Optimal dosing remains to be determined; specifically, what the lowest effective dose is and whether a single high‐dose bolus eliminates the need for repeated dosing. Recombinant FVIIa appears to have a wide safety margin that may allow dose escalation to address these questions.

Emerging clinical concerns in the ageing haemophilia patient.

Summary.u2002 The availability of safe replacement clotting factor concentrates together with effective antiviral drugs to treat human immunodeficiency and hepatitis C viruses and the provision of care at designated haemophilia treatment centres have resulted in a new phenomenon in haemophilia management – the ageing patient. Today, increasing numbers of persons with haemophilia (PWH) are middle‐aged and older, and they face the same age‐related health issues as the general population. The impact of these risks on PWH is unclear, however, and there is a paucity of information about how to manage comorbidities in this patient population. This review focuses on five comorbidities that uniquely affect older PWH: cardiovascular disease, liver disease, cancer, renal disease and joint disease. Available research is summarized and potential management approaches are suggested.

Hemostatic efficacy, safety and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease

This phase 3 trial evaluated the safety and hemostatic efficacy of a recombinant von Willebrand factor (rVWF) for treatment of bleeds in severe von Willebrand disease (VWD). rVWF was initially administered together with recombinant factor VIII (rFVIII) and subsequently alone, as long as hemostatic factor VIII activity (FVIII : C) levels were maintained. Pharmacokinetics (PK) were evaluated in a randomized cross-over design (rVWF vs rVWF:rFVIII at 50 IU VWF:ristocetin cofactor activity [RCo]/kg). Bleed control for all treated bleeds (N = 192 bleeds in 22 subjects) was rated good or excellent (96.9% excellent; 119 of 122 minor, 59 of 61 moderate, and 6 of 7 major bleeds) on a 4-point scale (4 = none to 1 = excellent). A single infusion was effective in 81.8% of bleeds. Treatment success, defined as the number of subjects with a mean efficacy rating of <2.5, was 100%. The PK profile of rVWF was not influenced by rFVIII (mean VWF:RCo terminal half-life: 21.9 hours for rVWF and 19.6 hours for rVWF:rFVIII). FVIII : C levels increased rapidly after rVWF alone, with hemostatic levels achieved within 6 hours and sustained through 72 hours after infusion. Eight adverse events (AEs; 6 nonserious AEs in 4 subjects and 2 serious AEs [chest discomfort and increased heart rate, without cardiac symptomatology] concurrently in 1 subject) were associated with rVWF. There were no thrombotic events or severe allergic reactions. No VWF or FVIII inhibitors, anti-VWF binding antibodies, or antibodies against host cell proteins were detected. These results show that rVWF was safe and effective in treating bleeds in VWD patients and stabilizes endogenous FVIII : C, which may eliminate the need for rFVIII after the first infusion. This trial was registered at www.clinicaltrials.gov as #NCT01410227.

Females with von Willebrand disease: 72 years as the silent majority

Summary. The monthly challenge of menstruation as well as the haemostatic challenge of childbirth post partum renders more females than males symptomatic with von Willebrand disease. Among vWD patients, the obstetrical and gynaecological morbidity is certainly more pronounced in Type 2,3 patients compared to Type 1 patients, but even in the latter group there is a high proportion of menorrhagia with associated anaemia, loss of time from work/school and the use of hysterectomy for ultimate control of bleeding. Despite the well known adage of the “gestational palliation” of vWD, there is a high proportion of postpartum haemorrhage in Type 1 patients also especially after the first 24 h after delivery. This may occur despite normalization of the factor VIIIc level in the third trimester, particularly in Type 2,3 patients. With the increasing availability of intranasal/subcutaneous DDAVP that could be readily administered at home for menorrhagia, there recently has been ongoing efforts internationally to determine the prevalence of vWD in females presenting with menorrhagia with a prevalence of 17% combined from two studies of 180 patients total. Issues remain regarding the optimal dose/schedule of intranasal/subcutaneous DDAVP for menorrhagia and the relative efficacy of antifibrinolytic agents. The proper role of oral contraceptives and danazol also deserves further study in vWd patients with menorrhagia. In sum, a comprehensive care approach in females with vWD is warranted analogous to the successful model of care of male haemophiliacs with the intent to (a) reduce unnecessary surgical interventions for menorrhagia, (b) improve the quality of life during menses and (c) optimize peri‐partum management.

Allergic reactions to cyclophosphamide: Delayed clinical expression associated with positive immediate skin tests to drug metabolites in five patients

BACKGROUNDnCyclophosphamide (CP) is one of the relatively few drugs implicated in systemic allergic reactions for which the metabolites are well known. Formation of CP metabolites is a multistep, time-dependent process (hours) with significant interindividual differences. Although allergic reactions to CP have been recorded in 17 previous reports, skin testing with CP or its metabolites has been included in only five. We now describe five patients receiving monthly cycles of intravenous CP whose allergic reactions included clinical features of type I hypersensitivity but were atypical in their markedly delayed onset (i.e., 8 to 16 hours in patients 1 to 4 and 10 days in patient 5).nnnOBJECTIVEnThe objective was to investigate these late-developing clinical reactions by skin testing with CP and two of its major metabolites.nnnMETHODSnThe five patients and a control group receiving intravenous CP uneventfully were studied by the same skin test protocol.nnnRESULTSnThe four individuals in the control group were unreactive to CP or its metabolites. All five patients with late-onset allergic reactions had positive immediate skin test results to CP metabolites but not to CP itself. We propose that the allergic reactions in patients 1 to 4 were mediated, wholly or in major part, by IgE antibodies reactive with allergens derived from time-dependent drug metabolites. The 10-day lag time in patient 5 is unexplained. Immunomodulation by the underlying malignancies or by the immunosuppressive drugs could have contributed.nnnCONCLUSIONnIgE-mediated allergic drug reactions may have a delayed onset if the allergen is a time-dependent drug metabolite, illustrated in this study by CP.

A Benefit-Risk Review of Systemic Haemostatic Agents Part 2. In Excessive or Heavy Menstrual Bleeding

The first part of this benefit-risk review examined the efficacy and adverse effect profiles of systemic haemostatic agents commonly used in major surgery. The second part of this review examines the efficacy and adverse effect profiles of systemic haemostatic agents commonly used in the treatment of excessive or heavy menstrual bleeding, and provides individual benefit-risk profiles that may assist clinicians in selecting appropriate pharmacological therapy in this setting. Historically, surgery has played a dominant role in treatment; however, pharmacological therapy is increasingly popular, especially in women who wish to retain their fertility. When selecting the appropriate treatment, patient preference should be considered, as well as the benefits and risks associated with each agent. Recommended pharmacological therapies that are effective and generally well tolerated include the levonorgestrel-releasing intrauterine system and the oral agents tranexamic acid, NSAIDs (e.g. mefenamic acid) and combined estrogen/progestogen oral contraceptives. In patients with an underlying bleeding disorder (e.g. von Willebrand disease), an additional option is intranasal desmopressin.

Endometrial ablation for von Willebrand disease-related menorrhagia--experience with seven cases.

Summary.u2002 Background:u2002 Endometrial ablation has recently gained popularity as a treatment of menorrhagia in the general population. In the von Willebrand disease (VWD) patient, intuitively, it would appear that the failure rate would be higher because of the underlying hypocoaguability increasing the likelihood for re‐bleeding. In a consecutive series of seven patients, we assessed the efficacy and safety of endometrial ablation in VWD‐related menorrhagia.

Prophylactic treatment of severe factor X deficiency with prothrombin complex concentrate

Factor X (FX) deficiency is an autosomal recessive trait that occurs in fewer than 1 in 500u2003000 people. Not surprisingly, reports of prophylactic treatment for FX deficiency are exceedingly rare. We now report our experience of the use of prophylactic therapy in a FX‐deficient patient. This 18‐year‐old African‐American male presented at the age of 4½ years with an FX level <u20031%. Treatment was on demand with prothrombin complex concentrates (PCCs) given at two times the dose per kilogram of body weight for factor IX. He experienced frequent epistaxis, soft tissue bleeding and joint bleeding. The development of a target joint (right ankle) prompted the initiation of prophylactic treatment in the beginning of 1998 to the present with 30u2003unitsu2003kg−1 Profilnine twice per week via a home infusion programme. If breakthrough bleeding occurred, he was instructed to infuse another dose. He was instructed that Profilnine should not be infused in more than two doses in 24u2003h or on more than three consecutive days. A trough level drawn 48u2003h post‐infusion showed an FX level of 30%. In the initial 12u2003months with prophylactic treatment, there was no breakthrough bleeding. Subsequently, with an additional 11u2003months of follow‐up, he has reported one bleed. He rates his quality of life improved since starting prophylactic treatment. There have been no thrombotic events. Prophylaxis with PCC for FX deficiency with adequate education and follow‐up can be performed capably in the home setting with a resultant decrease in the frequency of bleeding and attendant complications.

Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres

Summary.u2002 Inherited bleeding disorders are especially problematic for affected girls and women due to the monthly occurrence of menstrual periods and the effects on reproductive health. Although heavy menstrual bleeding (HMB) is the most common manifestation, females with inherited bleeding disorders (FBD) experience other bleeding symptoms throughout the lifespan that can lead to increased morbidity and impairment of daily activities. The purpose of this article is to describe the utility of a female‐focused surveillance effort [female Universal Data Collection (UDC) project] in the United States Haemophilia Treatment Centres (HTCs) and to describe the baseline frequency and spectrum of diagnoses and outcomes. All FBD aged 2u2003years and older receiving care at selected HTCs were eligible for enrolment. Demographic data, diagnoses and historical data regarding bleeding symptoms, treatments, gynaecological abnormalities and obstetrical outcomes were analysed. Analyses represent data collected from 2009 to 2010. The most frequent diagnoses were type 1 von Willebrand’s disease (VWD) (195/319; 61.1%), VWD type unknown (49/319; 15.4%) and factor VIII deficiency (40/319; 12.5%). HMB was the most common bleeding symptom (198/253; 78.3%); however, 157 (49.2%) participants reported greater than four symptoms. Oral contraceptives were used most frequently to treat HMB (90/165; 54.5%), followed by desmopressin [1‐8 deamino‐D‐arginine vasopressin (DDAVP)] (56/165; 33.9%). Various pregnancy and childbirth complications were reported, including bleeding during miscarriage (33/43; 76.7%) and postpartum haemorrhage (PPH) (41/109; 37.6%). FBD experience multiple bleeding symptoms and obstetrical‐gynaecological morbidity. The female UDC is the first prospective, longitudinal surveillance in the US focusing on FBD and has the potential to further identify complications and reduce adverse outcomes in this population.

Menorrhagia from a haematologist's point of view. Part I: initial evaluation

Summary.u2002 The evaluation of menorrhagia should no longer be solely the task of the gynaecologist. In women with ovulatory bleeding (regular cycles), the prevalence of von Willebrand disease (vWD) in about 15% of these, as well as disorders of platelet function and fibrinolysis causing menorrhagia, warrants an active role by the haematologist. Initial intake should include documentation of menorrhagia by the pictorial chart assessment of menstrual flow. Baseline characteristics of menstrual flow should also be documented, including the frequency of changing the sanitary pad on the heaviest day, use of more than one sanitary pad at a time, number of days lost␣from school/work and the impact of menses on␣various quality‐of‐life parameters. Menorrhagia since menarche, a past history of surgical‐ and/or dental‐related bleeding and a past history of postpartum haemorrhage are items of the bleeding symptom audit that appear in part to predict vWD in women with menorrhagia. Epistaxis and easy bruising do not appear to be clearly discriminatory symptoms. Initial testing should include the complete blood cell count, prothrombin time, activated partial thromboplastin time, iron profile, serum creatinine, thyroid stimulating hormone level, factor VIII level, vWF antigen, ristocetin cofactor and platelet aggregation studies. Additional haemostatic studies may also include a factor XI level and euglobulin clot lysis time. This extensive medical evaluation should assure both the patient and the gynaecologist that the possibility of an underlying haemostatic disorder has been thoroughly investigated, to avoid the patient undergoing further costly procedures and surgical interventions if an underlying haemostatic disorder remains unrecognized.