Bruce M. Ewenstein

Factor IX inhibitors and anaphylaxis in hemophilia B

PURPOSEnWe present clinical and laboratory data on 18 children from 12 hemophilia treatment centers in the United States, Canada, and Europe with the purpose of disseminating information regarding a recently recognized, potentially life-threatening complication of treatment in very young children with hemophilia B.nnnPATIENTS AND METHODSnTwelve hemophilia centers from the United States, Canada, and Europe provided clinical information and laboratory data concerning 18 children who had severe allergic reactions to infused factor (F) IX in close association with the development of an inhibitor to FIX. Laboratory testing for establishment of the diagnosis of hemophilia B and inhibitor to FIX was done locally at the centers treating these patients. FIX gene analysis was performed at one of six molecular genetics institutes.nnnRESULTSnAll 18 children had severe hemophilia B, and in each an inhibitor antibody to FIX developed. The median age at the time of anaphylaxis (or anaphylactoid reaction) was 16 months, and the median number of exposure days to FIX was 11. The FIX inhibitor was detected almost simultaneously with the first occurrence of anaphylaxis in 12 of 18 patients. Maximum inhibitor titers were 4.5-600 Bethesda units (BU), with a median titer of 48 BU. FIX gene analysis, performed in 17 of 18 patients, demonstrated complete deletion of the FIX gene in 10 and major derangements in seven. Immune tolerance induction (ITI) regimens have been attempted in 12 patients, with generally poor responses. Two of the 12 experienced nephrotic syndrome while on ITI. Recombinant FVIIa has been successfully used to treat bleeding episodes in 11 of these children.nnnCONCLUSIONnPhysicians treating young children with hemophilia B should be aware of the potentially life-threatening complication of anaphylaxis. Children with complete gene deletions or major derangements of the FIX gene appear to be at greater risk. Those identified by genotype as being at greater risk may need to receive their first 10-20 treatments in a medical facility equipped for handling such emergencies. Recombinant FVIIa, although not licensed for use in the United States, appears to be the most suitable treatment option for bleeding episodes in such patients.

Cancer and venous thromboembolism

The evidence of the important two-way clinical correlation between cancer and venous thromboembolism (VTE) dates back to Trousseaus time. Over time it has been established that cancer patients not only exhibit a higher risk of developing VTE when compared with noncancer patients, but also that VTE, especially in its idiopathic presentation, sometimes acts as an epiphenomenon of a hidden cancer, offering possible chances for anticipated diagnosis of the pathology. Research has contributed greatly to the progression of this field through the identification of VTE risk factors in this setting, and through the assessment of the most adequate thromboprophylaxis and treatment modalities as well as secondary prophylaxis management. Anticoagulant drugs appear to be an attractive strategy in cancer treatment because there is growing evidence for their possible benefits in terms of cancer prognosis and patient survival.

Peptido-leukotrienes are potent agonists of von Willebrand factor secretion and P-selectin surface expression in human umbilical vein endothelial cells

BACKGROUNDnThe peptido-leukotrienes (LTs) and lipoxins (LX) are produced by platelets through the transcellular conversion of leukocyte-derived LTA4 at sites of vascular inflammation and injury, such as during coronary artery balloon angioplasty. We studied the actions of these eicosanoids on vascular endothelium.nnnMETHODS AND RESULTSnWe found that stimulation of cultured human umbilical vein endothelial cells (EC) with LTC4 and LTD4 resulted in the release of high-molecular-weight multimers of von Willebrand factor (vWF) in a concentration- and time-dependent fashion, as measured by ELISA. Neither LXA4 nor LXB4 stimulated vWF release. LTC4 and LTD4 also stimulated a rapid increase in the surface expression of P-selectin indicated by increased binding of anti-P-selectin monoclonal antibody-coated beads. Fluorescence cytometry detected prolonged peaks of [Ca2+]i in EC in response to concentrations of thrombin and LTD4 that induce near-maximal vWF secretion. In contrast, concentrations of LTC4 that induce similar levels of vWF secretion produced only asynchronous oscillations of [Ca2+]i in most EC and rarely induced prolonged peaks of [Ca2+]i. Depletion of external Ca2+ had no apparent impact on LT-stimulated [Ca2+]i transients and vWF secretion, implicating an intracellular pool as the source of this response. Staurosporine, sphingosine, and H-7 each had only modest effects on peptido-LT-induced vWF secretion, suggesting that protein kinase C is not a primary mediator of peptido-LT-induced exocytosis. Inhibitors of cyclooxygenase and platelet-activating factor had no effect on peptido-LT-mediated vWF secretion.nnnCONCLUSIONSnThrough the induction of vWF secretion and P-selectin surface expression, peptido-LTs are likely to play an important role in the interrelated processes of hemostasis and inflammation.

Successful treatment for patients with von Willebrand disease undergoing urgent surgery using factor VIII/VWF concentrate (Humate‐P®)

Summary.u2002 von Willebrand disease (VWD) is characterized by insufficient von Willebrand factor (VWF) activity. It has been proposed that VWF:ristocetin cofactor (VWF:RCo) activity may be useful in evaluating the response to VWD treatment in patients who require replacement therapy. This prospective, open‐label, non‐randomized study evaluated the safety and efficacy of a factor VIII (FVIII)/VWF concentrate (Humate‐P®) used in treatment regimens based on VWF:RCo activity in subjects with VWD in situations requiring urgent and necessary surgery. This article summarizes the results for 39 subjects with 42 evaluable surgical treatment events, 100% of which were rated as excellent/good for overall efficacy (achievement of haemostasis). The median loading dose based upon VWF:RCo activity was 82.3 international units/kilogram (IUu2003kg−1; range 32.5–216.8u2003IUu2003kg−1), and the median maintenance dose per infusion was 52.8u2003IUu2003kg−1 (range 24.2–196.5u2003IUu2003kg−1) for a median of 3u2003days (range 1–50u2003days). The median number of infusions per event was 6 (range 1–67 infusions). Three unanticipated adverse events (peripheral oedema, extremity pain and pseudo‐thrombocytopenia) from two surgical treatment events were reported that were potentially treatment‐related. No serious drug‐related adverse events (AEs) were observed, and no thrombotic events were reported in this study. This study supports the safety and efficacy of the FVIII/VWF concentrate Humate‐P® for the prevention of surgical haemorrhage in patients with VWD when administered in doses calculated in VWF:RCo units.

The economic impact of factor VIII inhibitors in patients with haemophilia.

Summary.u2002 The impact on the cost of care for haemophilia patients with inhibitors is not well defined. To quantify the effect on health care expenditures associated with inhibitors to factor VIII (FVIII) or FIX, we conducted a retrospective cohort study examining product use and outcomes in adult and paediatric haemophilia patients with and without inhibitors. Twelve patients with inhibitors to FVIII or FIX (cases) identified in the haemophilia surveillance system (HSS) at two centres were matched on age, severity of haemophilia, and treatment centre to haemophilia patients without inhibitors. Patients with HIV or significant liver disease were excluded from the study. All eligible non‐inhibitor control patients were selected for inclusion in the study, resulting in a total of 28 controls. We then tracked product usage and hospitalizations from programme entry until 1998 or loss to follow‐up, producing a total database of 184 person‐years of experience. A descriptive matched analysis was conducted to examine annual differences in the cost of product used and hospitalizations. We found that the median cost for factor products among haemophilia patients with inhibitors was

Pulmonary embolism and deep venous thrombosis during pregnancy or oral contraceptive use: Prevalence of factor V Leiden

55u2003853/year,

Successful treatment of urgent bleeding in von Willebrand disease with factor VIII/VWF concentrate (Humate-P®): use of the ristocetin cofactor assay (VWF:RCo) to measure potency and to guide therapy

2760 less than comparable haemophilia patients without inhibitors. The median number of hospitalizations per year was 1.0 for both inhibitor and non‐inhibitor patients and the median number of days hospitalized was virtually the same. Although these findings do not appear to support the belief that there is a substantial increase in the cost of care for haemophilia patients with inhibitors, it does document that a few outlier patients can drive the cost of treatment for this disease. As the largest component of the cost of care is that of factor concentrate, it becomes imperative in the current health care environment to better define the true costs and benefits of treatments designed to eradicate or manage inhibitors. A careful cost accounting of immune tolerance induction (ITI) and other therapeutic strategies, taking into account successes and failures and duration and intensity of therapy, should help to better define the costs and benefits of such approaches. Methods to identify high cost inhibitor patients should be developed so that these strategies may be targeted to appropriate candidates.

Variation in incidence of indinavir-associated nephrolithiasis among HIV-positive patients

Activated protein C resistance caused by factor V Leiden mutation is the most common inherited cause of an underlying predisposition to pulmonary embolism (PE) and deep venous thrombosis (DVT). We studied the frequency of the factor V Leiden mutation in 50 women who had PE and/or DVT during or after pregnancy or during oral contraceptive use. Ten (20%; 95% CI 10% to 34%) of the 50 women were heterozygous for the mutation. First-trimester PE or DVT developed in 6 (60%; 95% CI, 26% to 88%) of the 10 women with the mutation compared with 3 (8%; 95% CI 2% to 20%) of 40 women without the mutation (p = 0.0009). These data indicate that the factor V Leiden mutation is an important risk factor for PE or DVT during pregnancy (especially the first trimester), after pregnancy, or during oral contraceptive use.

A cost minimization model for the treatment of minor bleeding episodes in patients with haemophilia A and high-titre inhibitors

Summary.u2002 This prospective, open‐label, non‐randomized study evaluated the safety and efficacy of factor VIII (FVIII)/von Willebrand Factor (VWF) concentrate (Humate‐P®) using treatment regimens based on VWF:ristocetin cofactor (VWF:RCo) activity in patients with von Willebrand Disease (VWD) in (i) urgent bleeding episodes, or (ii) in patients undergoing urgent and necessary surgery. This article summarizes the results of treatment for the 33u2003patients with 53 urgent bleeding events. The median loading dose of FVIII/VWF concentrate was 67.0 international units per kilogram (IUu2003kg−1) VWF:RCo (range 25.7–143.2u2003IUu2003kg−1), and the median daily maintenance dose per infusion was 74.0u2003IUu2003kg−1 (range 16.4–182.9u2003IUu2003kg−1) for a median duration of 2u2003days (range 1–34u2003days). The overall efficacy (achievement of haemostasis) of FVIII/VWF concentrate was rated as excellent/good for 98% of the urgent bleeding events. No unexpected treatment‐related adverse events or serious drug‐related adverse events (AEs) were observed. This study supports the safety and efficacy of Humate‐P® administered in doses calculated in VWF:RCo units for the treatment of urgent bleeding episodes in patients with VWD.

Severe haemophilia A in a female resulting from two de novo factor VIII mutations

Background:Nephrolithiasis may be an important consequence of indinavir therapy; however little has been published on the variation in incidence between different populations of patients or the possible mechanisms of calculus formation. Objective:To examine variation in the incidence of indinavir-associated nephrolithiasis (IAN) in HIV-positive patients in relation to hemophilia and hepatitis C virus (HCV) infection. Methods:Clinical data were abstracted retrospectively from the medical records of all adult patients treated with indinavir from September 1995 to September 1997. Occurrence of first IAN, defined as flank pain and hematuria after initiation of therapy, was analyzed in relation to hemophilia status and HCV infection. Results:There were 17 episodes of IAN (22%) among 79 patients treated with indinavir. Of 10 patients with hemophilia, 50% developed IAN as compared with 17% of patients without hemophilia (P = 0.03). Median days to first IAN was 22 (range 7–110 days) for hemophiliacs and 156 (range 5–611 days) for those without hemophilia. Data for HCV status were available for 74 out of 79 patients: 10 out of 27 (37%) patients with HCV developed IAN compared with six out of 42 (14%) without HCV (P = 0.02). Conclusion:Overall incidence of IAN was higher than that previously reported and was significantly greater in hemophiliacs than in non-hemophiliacs. HCV may be a contributing factor.