scholarly journals Oral Prophylactic Therapy in Hemophilia A and B (Factor VIII and IX Deficiencies)

1977 ◽  
Author(s):  
W.F. Stapp ◽  
H.B. Boudreaux

The purpose of this ongoing nutritional study with massive doses of choline ultimately is to try and establish an alternative means of prophylactic therapy to recently proposed use of plasma fractions, plasma factor concentrates and earlier so-called “bleeding and clotting diets”. Contrary to other prophylactic therapy studies, our premise is that if all other hemostatic and homeostatic factors are near normal through optimum nutrition, the over-all importance of Factor VIII and Factor IX deficiencies are less significant.Case reports of patients with Hemophilia A and B are presented, which indicate a comparative decrease in the plasma fraction requirements for the treatment of the bleeding episodes in these patients during long term therapy with megavitamin doses of choline (a refinement of Boudreaux’s “peanut factor”). One case (WFS) of severe Hemophilia A with less than 1% Factor VIII, under therapy for over 10 yeara has had periods of remission not requiring plasma factor infusions for almost 2 years.From our combined studies, we conclude that a long term nutritional prophylactic therapy program with emphasis on choline in Hemophilia A and B can result in a decrease in plasma needs. antibody formation and the occurrence of hepatitis.

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 677-685 ◽  
Author(s):  
Hideto Matsui ◽  
Masaru Shibata ◽  
Brian Brown ◽  
Andrea Labelle ◽  
Carol Hegadorn ◽  
...  

Abstract Under certain instances, factor VIII (FVIII) stimulates an immune response, and the resulting neutralizing antibodies present a significant clinical challenge. Immunotherapies to re-establish or induce long-term tolerance would be beneficial, and an in-depth knowledge of mechanisms involved in tolerance induction is essential to develop immune-modulating strategies. We have developed a murine model system for studying mechanisms involved in induction of immunologic tolerance to FVIII in hemophilia A mice. We used lentiviral vectors to deliver the canine FVIII transgene to neonatal hemophilic mice and demonstrated that induction of long-term FVIII tolerance could be achieved. Hemophilia A mice are capable of mounting a robust immune response to FVIII after neonatal gene transfer, and tolerance induction is dependent on the route of delivery and type of promoter used. High-level expression of FVIII was not required for tolerance induction and, indeed, tolerance developed in some animals without evidence of detectable plasma FVIII. Tolerance to FVIII could be adoptively transferred to naive hemophilia recipient mice, and FVIII-stimulated splenocytes isolated from tolerized mice expressed increased levels of interleukin-10 and decreased levels of interleukin-6 and interferon-γ. Finally, induction of FVIII tolerance mediated by this protocol is associated with a FVIII-expandable population of CD4+CD25+Foxp3+ regulatory T cells.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4319-4319
Author(s):  
Leonard A Minuk ◽  
Benjamin H Chin-Yee ◽  
Martha L Louzada ◽  
Lori Laudenbach ◽  
Ian H Chin-Yee

Abstract Abstract 4319 Background: Increasing life expectancy in individuals with hemophilia has lead to a higher prevalence of cardiovascular risk (CV) factors and disease in this aging population. Clinical guidelines recommend screening patients as early as age 35 for hypertension, dyslipidemia, diabetes, obesity and smoking and intervention to modify these risk factors. Antithrombotic agents (antiplatelet or anticoagulants) are beneficial in secondary prevention of CV events but no randomized controlled trials have studied these drugs in patients with hemophilia. The goal of this study was to identify the prevalence of CV risk factors and disease in patients with hemophilia over the age of 35, the use of antiplatelet agents and other drugs in the management of risk factors. Method: Retrospective chart review was conducted on all patients age 35 and older with Hemophilia A or B who attended the Southwestern Ontario Regional Hemophilia Program. This clinic services a population of approximately 1.5 million patients, following 139 patients with hemophilia A or B. Demographic information, severity of bleeding disorder, and CV risk factor and events were extracted from patient records as well therapeutic interventions and frequency of bleeding events. Result: A total of 46 out of 139 patients (33%), 37 with hemophilia A and 9 with hemophilia B, met inclusion criteria of age over 35. The majority of patients in this age group were classified as mild or moderate severity (40/46) based on factor levels (Factor VIII <0.01 = 4, Factor VIII >0.01–0.05 = 6, Factor VIII>0.06 = 27; Factor IX<0.01 = 2, Factor IX>0.01–0.05 = 6, Factor IX>0.06=1). Two patients had inhibitors, and 2 were on prophylaxis. Hypertension was identified in 22/46 (48%), dyslipidemia in 16/46 (35%), smoking in 16/46 (35%), and diabetes in 6/46 (13%). CV disease potentially requiring antithrombotic therapy for secondary prevention was identified in 5/46 patients (11%). Two had coronary artery disease, 1 had a transient ischemic attack, and 2 had atrial fibrillation. Of these patients, 2 patients underwent cardiovascular surgery for which they received factor replacement. One had an aortic valve replacement and coronary artery bypass graft. This patient did not receive any long-term antiplatelet treatment, but received heparin during surgery. The other patient underwent percutaneous coronary intervention with anticoagulation during the procedure, and received ASA and clopidogrel post-operatively, followed by ongoing ASA for 28 months. Of the remaining 3 patients with CV disease, 2 received ASA for 24 and 67 months. One patient received ASA after experiencing chest pain, but was discontinued after no underlying CV disease was found. No patients were given vitamin K antagonists. All 4 patients receiving antiplatelet agents were classified as mild (2) or moderate (2) hemophilia and no observed bleeding events were reported following the addition of these agents (median follow-up time 26 months, range 1–67 months). No factor prophylaxis was given while on long-term ASA. Conclusion: CV risk factors are prevalent in individuals with hemophilia and similar or higher to that reported in general population over age 35. Given the limited number of patients with CV disease in this study on antiplatelet agents, the safety of these drugs in patients with bleeding disorders cannot be determined. Although CV risk factors are prevalent in patients with hemophilia, the rarity, clinical heterogeneity and infrequent use of antithrombotic therapy suggest the need to develop a national or international registry to address the safety of these treatments for this population. Disclosures: No relevant conflicts of interest to declare.


1980 ◽  
Vol 44 (01) ◽  
pp. 039-042 ◽  
Author(s):  
Philip M Blatt ◽  
Doris Ménaché ◽  
Harold R Roberts

SummaryThe treatment of patients with hemophilia A and anti-Factor VIII antibodies is difficult. Between July 1977 and June 1978, a survey was carried out by an ad hoc working party of the subcommittee on Factor IX concentrates of the International Committee on Thrombosis and Hemostasis to assess the effectiveness of Prothrombin Complex Concentrates in controlling hemorrhage in these patients. The results are presented in this paper and, although subjective, support the view that these concentrates are not as effective in patients with inhibitors as Factor VIII concentrates are in patients without inhibitors.


2021 ◽  
Vol 22 (14) ◽  
pp. 7647
Author(s):  
E. Carlos Rodríguez-Merchán ◽  
Juan Andres De Pablo-Moreno ◽  
Antonio Liras

Hemophilia is a monogenic mutational disease affecting coagulation factor VIII or factor IX genes. The palliative treatment of choice is based on the use of safe and effective recombinant clotting factors. Advanced therapies will be curative, ensuring stable and durable concentrations of the defective circulating factor. Results have so far been encouraging in terms of levels and times of expression using mainly adeno-associated vectors. However, these therapies are associated with immunogenicity and hepatotoxicity. Optimizing the vector serotypes and the transgene (variants) will boost clotting efficacy, thus increasing the viability of these protocols. It is essential that both physicians and patients be informed about the potential benefits and risks of the new therapies, and a register of gene therapy patients be kept with information of the efficacy and long-term adverse events associated with the treatments administered. In the context of hemophilia, gene therapy may result in (particularly indirect) cost savings and in a more equitable allocation of treatments. In the case of hemophilia A, further research is needed into how to effectively package the large factor VIII gene into the vector; and in the case of hemophilia B, the priority should be to optimize both the vector serotype, reducing its immunogenicity and hepatotoxicity, and the transgene, boosting its clotting efficacy so as to minimize the amount of vector administered and decrease the incidence of adverse events without compromising the efficacy of the protein expressed.


2017 ◽  
Vol 11 (3) ◽  
pp. 774-779 ◽  
Author(s):  
Holger Schäffler ◽  
Astrid Huth ◽  
Georg Lamprecht ◽  
Olaf Anders

The treatment of inflammatory bowel diseases (IBD) can be challenging, especially in elderly multimorbid patients. Since incidence and prevalence rates of IBD are rising steadily, treatment of older patients with relevant and also rare comorbidities will be of increasing relevancy for caregivers. Here we report on a 74-year-old multimorbid patient with severe ulcerative colitis (UC) and hemophilia A. Because of the chronic active disease, therapy with a tumor necrosis factor-α inhibitor was started. He suffered from a severe infectious complication (pneumonia) under therapy with infliximab. The therapy was changed to vedolizumab, with which the patient stayed in long-term clinical and endoscopic remission. Because the patient had a non-ST-segment elevation myocardial infarction in April 2016, he received dual platelet inhibitor therapy with aspirin and clopidogrel. Because of consecutive aspirin intolerance, the therapy was changed to clopidogrel monotherapy. Although the UC was treated appropriately with vedolizumab and the patient was in endoscopic mucosal remission, recurrent bleeding episodes from multiple inflammatory pseudopolyps occurred. The bleeding episodes resolved quickly after immediate treatment with factor VIII (Kogenate®). In conclusion, we describe the first patient in the literature with UC and hemophilia A who stayed in long-term remission under therapy with vedolizumab. From our point of view, vedolizumab can be safely administered in the setting of UC and hemophilia A. Antiplatelet drugs which inhibit primary hemostasis must be used with caution in this setting. Bleeding episodes can be treated safely and effectively with factor VIII (Kogenate®).


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-17
Author(s):  
Dougald Monroe ◽  
Mirella Ezban ◽  
Maureane Hoffman

Background.Recently a novel bifunctional antibody (emicizumab) that binds both factor IXa (FIXa) and factor X (FX) has been used to treat hemophilia A. Emicizumab has proven remarkably effective as a prophylactic treatment for hemophilia A; however there are patients that still experience bleeding. An approach to safely and effectively treating this bleeding in hemophilia A patients with inhibitors is recombinant factor VIIa (rFVIIa). When given at therapeutic levels, rFVIIa can enhance tissue factor (TF) dependent activation of FX as well as activating FX independently of TF. At therapeutic levels rFVIIa can also activate FIX. The goal of this study was to assess the role of the FIXa activated by rFVIIa when emicizumab is added to hemophilia A plasma. Methods. Thrombin generation assays were done in plasma using 100 µM lipid and 420 µM Z-Gly-Gly-Arg-AMC with or without emicizumab at 55 µg/mL which is the clinical steady state level. The reactions were initiated with low (1 pM) tissue factor (TF). rFVIIa was added at concentrations of 25-100 nM with 25 nM corresponding to the plasma levels achieved by a single clinical dose of 90 µg/mL. To study to the role of factor IX in the absence of factor VIII, it was necessary to create a double deficient plasma (factors VIII and IX deficient). This was done by taking antigen negative hemophilia B plasma and adding a neutralizing antibody to factor VIII (Haematologic Technologies, Essex Junction, VT, USA). Now varying concentrations of factor IX could be reconstituted into the plasma to give hemophilia A plasma. Results. As expected, in the double deficient plasma with low TF there was essentially no thrombin generation. Also as expected from previous studies, addition of rFVIIa to double deficient plasma gave a dose dependent increase in thrombin generation through activation of FX. Interestingly addition of plasma levels of FIX to the rFVIIa did not increase thrombin generation. Starting from double deficient plasma, as expected emicizumab did not increase thrombin generation since no factor IX was present. Also, in double deficient plasma with rFVIIa, emicizumab did not increase thrombin generation. But in double deficient plasma with FIX and rFVIIa, emicizumab significantly increased thrombin generation. The levels of thrombin generation increased in a dose dependent fashion with higher concentrations of rFVIIa giving higher levels of thrombin generation. Conclusion. Since addition of FIX to the double deficient plasma with rFVIIa did not increase thrombin generation, it suggests that rFVIIa activation of FX is the only source of the FXa needed for thrombin generation. So in the absence of factor VIII (or emicizumab) FIX activation does not contribute to thrombin generation. However, in the presence of emicizumab, while rFVIIa can still activate FX, FIXa formed by rFVIIa can complex with emicizumab to provide an additional source of FX activation. Thus rFVIIa activation of FIX explains the synergistic effect in thrombin generation observed when combining rFVIIa with emicizumab. The generation of FIXa at a site of injury is consistent with the safety profile observed in clinical use. Disclosures Monroe: Novo Nordisk:Research Funding.Ezban:Novo Nordisk:Current Employment.Hoffman:Novo Nordisk:Research Funding.


Blood ◽  
1996 ◽  
Vol 87 (11) ◽  
pp. 4671-4677 ◽  
Author(s):  
S Connelly ◽  
JM Gardner ◽  
RM Lyons ◽  
A McClelland ◽  
M Kaleko

Deficiency of coagulation factor VIII (FVIII) results in hemophilia A, a common hereditary bleeding disorder. Using a human FVIII-encoding adenoviral vector, Av1ALAPH81, we have demonstrated expression of therapeutic levels of human FVIII in mice sustained for more than 5 months after vector administration. Administration of a high dose (4 x 10(9) plaque-forming units [pfu]) of Av1ALAPH81 to mice resulted in a peak expression of 2,063 ng/mL of human FVIII in the mouse plasma, with levels decreasing to background by weeks 15 to 17. Normal FVIII levels in humans range from 100 to 200 ng/mL and therapeutic levels are as low as 10 ng/mL. Alternatively, administration of 8- to 80-fold lower vector doses (5 x 10(8) pfu to 5 x 10(7) pfu) to normal adult mice resulted in expression of FVIII at therapeutic levels sustained for at least 22 weeks. Detailed analysis of vector toxicity indicated that the high vector dose caused a dramatic elevation of liver-specific enzyme levels, whereas an eight-fold lower vector dose was significantly less hepatotoxic. The data presented here demonstrate that administration of lower, less toxic vector doses allow long-term persistence of FVIII expression.


1999 ◽  
Vol 82 (08) ◽  
pp. 555-561 ◽  
Author(s):  
Douglas Jolly ◽  
Judith Greengard

IntroductionHemophilia A results from the plasma deficiency of factor VIII, a gene carried on the X chromosome. Bleeding results from a lack of coagulation factor VIII, a large and complex protein that circulates in complex with its carrier, von Willebrand factor (vWF).1 Severe hemophilia A (<1% of normal circulating levels) is associated with a high degree of mortality, due to spontaneous and trauma-induced, life-threatening and crippling bleeding episodes.2 Current treatment in the United States consists of infusion of plasma-derived or recombinant factor VIII in response to bleeding episodes.3 Such treatment fails to prevent cumulative joint damage, a major cause of hemophilia-associated morbidity.4 Availability of prophylactic treatment, which would reduce the number and severity of bleeding episodes and, consequently, would limit such joint damage, is limited by cost and the problems associated with repeated venous access. Other problems are associated with frequent replacement treatment, including the dangers of transmission of blood-borne infections derived from plasma used as a source of factor VIII or tissue culture or formulation components. These dangers are reduced, but not eliminated, by current manufacturing techniques. Furthermore, approximately 1 in 5 patients with severe hemophilia treated with recombinant or plasma-derived factor VIII develop inhibitory humoral immune responses. In some cases, new inhibitors have developed, apparently in response to unnatural modifications introduced during manufacture or purification.5 Gene therapy could circumvent most of these difficulties. In theory, a single injection of a vector encoding the factor VIII gene could provide constant plasma levels of factor in the long term. However, long-term expression after gene transfer of a systemically expressed protein in higher mammals has seldom been described. In some cases, a vector that appeared promising in a rodent model has not worked well in larger animals, for example, due to a massive immune response not seen in the rodent.6 An excellent review of early efforts at factor VIII gene therapy appeared in an earlier volume of this series.7 A summary of results from various in vivo experiments is shown in Table 1. This chapter will focus on results pertaining to studies using vectors based on murine retroviruses, including our own work.


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