The use of continuous infusion of factor concentrates in the treatment of hemophilia

Bolus infusion of clotting factor concentrates remains the most common approach to the treatment or prevention of bleeding in patients with hemophilia. Although successful use of continuous infusion of such concentrates has been reported by several groups, this alternative treatment method has not achieved widespread popularity. We report here our experience in one hemophilia center with the use of continuous infusion of factor VIII and factor IX concentrates in 13 patients, 11 with hemophilia A, and 2 with hemophilia B. All patients were treated successfully for bleeding episodes (e.g., hemarthroses, intracranial, or gastrointestinal bleeding) or for surgical procedures (appendectomy, thoracotomy, etc.). Three patients with low titer factor VIII inhibitors were treated successfully with constant infusion therapy, requiring a mean dose of factor VIII concentrate 2.3 fold (8.20 u/kg/h) higher than that of the patients without inhibitors (3.63 u/kg/h) to maintain a circulating plasma level of factor VIII of 1 u/ml. The use of constant infusion of clotting factor concentrates is safe, efficacious, and more convenient than bolus therapy of factor concentrates and should be considered for hospitalized hemophilia patients requiring replacement therapy.     

Arthritis in hemophilia

The severe and progressive permanent crippling defects that develop in the child with severe hemophilia are no longer inevitable. Although the prophylactic administration of deficient factor on a daily basis by intravenous injection to the young child suffering from hemophilia is economically and logistically prohibitive in most instances, the immediate administration of deficient factor at the onset of an acute bleeding episode will retard, if not totally prevent, the development of hemophilic arthritis. A continuous program of physical therapy for muscle strengthening increases the support of joints, improves coordination, and tends to lessen the number of bleeding episodes. It must be recognized that although deficient factor replacement, physical therapy, and other orthopedic measures are of utmost importance, optimal care of the child with hemophilia must also include attention to the social and psychological complications of this disease. The provision for a normal home and school experience, adequate participation in physical activities, and the use of appropriate disciplinary measures will allow the child with hemophilia to reach adulthood with a minimum of emotional and physical disability.     

Endoscopic sphincterotomy in adult hemophiliac patients with choledocholithiasis

BACKGROUND: The aim of this study was to investigate the risk of bleeding in adult hemophiliac patients undergoing endoscopic sphincterotomy for choledocholithiasis. METHODS: From 1983 to 2002, 7 patients with hemophilia A and two with hemophilia B were referred for endoscopic sphincterotomy and extraction of bile duct stones. The degree of hemophilia was mild in 4 patients, moderate in 3, and severe in two. Pre-admission levels of blood clotting factors ranged from less than 1% to 18%. Levels of the deficient factors were monitored carefully before and after sphincterotomy, and the relevant factor was replaced to achieve 100% activity before and for 24 hours after endoscopic sphincterotomy. OBSERVATIONS: Seven patients had factor replacement every 8 hours, and two received continuous infusions. No patient developed bleeding after sphincterotomy. At discharge, 48 hours after the procedure, patients who had received continuous infusions had a factor level of greater than 90%; those who had received intermittent replacement had levels of greater than 50%. After discharge, the patients were treated with regular infusion of the deficient factor for 15 days. CONCLUSIONS: With adequate preoperative and post-procedure monitoring of clotting factors, meticulous attention to hemostasis during sphincterotomy, careful post-procedure monitoring, and timely replacement therapy, patients with hemophilia can undergo endoscopic sphincterotomy without bleeding complications.     

The phenotypic heterogeneity of severe hemophilia

It has been long recognized that 10 to 15% of patients with "phenotypically characterized" severe hemophilia (< 1% clotting factor activity) have relatively mild disease clinically. Not all these patients have frequent spontaneous bleeding, and even among those who bleed, the extent of joint damage tends to vary considerably. The basis for this difference has not been completely understood. This article reviews the literature on possible determinants of phenotypic variation in patients with severe hemophilia. Apart from the well-recognized associations of the level of residual clotting factor activity, pharmacokinetics of administered clotting factor concentrates, and presence of prothrombotic markers, there is evidence to suggest that variations in other coagulation proteins as assessed in tests of global hemostasis as well as the fibrinolytic system can affect the clinical severity of bleeding. We also hypothesize that mediators of the inflammatory response in the synovium are likely to impact the severity of joint damage in these patients. One of the major issues in the management of hemophilia today is to decide on ways in which therapy, particularly the initiation and intensity of prophylaxis, can be individualized. A detailed understanding of all factors that may contribute to joint damage in severe hemophilia could help us in tailoring therapy for these individuals.     

Prevention of bleeds in hemophilia patients with inhibitors: emerging data and clinical direction

In patients with hemophilia, the development of high-responding inhibitors to factor VIII prevents adequate replacement therapy and results in increased risk of serious bleeding episodes, poor control of joint bleeding, and progressive, debilitating joint disease. Immune tolerance therapy can eradicate inhibitors, but it is not uniformly successful. Emerging data suggest that prophylaxis using activated prothrombin complex concentrates may be effective and safe in reducing the incidence of joint bleeding during immune tolerance therapy and for patients in whom immune tolerance induction fails. However, only controlled clinical trials will ultimately demonstrate whether prophylaxis can prevent joint bleeding and damage, and improve quality of life in patients with inhibitors.     

The literature on inhibitors: articles that influence my management of patients with hemophilia A and high-titer inhibitors

High-titer inhibitors represent the greatest management challenge faced by clinicians who treat patients with hemophilia A, as bleeding episodes no longer respond to standard factor VIII replacement therapy. Over the last seven decades, major strides have been made in inhibitor treatment. This article focuses on the seminal clinical observations and studies that provided the foundation for these advances in hemophilia care.     

A diagnosis of mild hemophilia A made by massive intraabdominal bleeding in a 13-year-old boy

We report a 13-year-old boy who had massive intra-abdominal bleeding without a history of bleeding episodes or traumatic cause of bleeding. The patient underwent surgical treatment because bleeding was not controlled after treatment with tranexamic acid and transfusions including fresh-frozen plasma. Bleeding was traced to the lower left lobe of the liver. The mother's side of the family had a history of bleeding episodes in the boy's grandfather, great uncle, and son of a great aunt. A low level of plasma factor VIII coagulant activity (22%) led to a diagnosis of mild hemophilia A. Compared with severe hemophilia, mild hemophilia is more difficult to diagnose because bleeding episodes are less frequent. Most cases are found after incidental trauma or uncontrolled surgery-related bleeding, there is rarely a family history of hemophilia and activated partial thromboplastin time is normal or slightly prolonged. However, bleeding episodes in mild hemophilia may result in excessive, sometimes life-threatening hemorrhage and require early diagnosis and replacement treatment with adequate amounts of factor VIII, as in severe hemophilia.     

Health economics of treating haemophilia A with inhibitors

Summary.  Haemophilia is a rare, inherited blood disorder in which blood clotting is impaired such that patients suffer from excessive internal and external bleeding. At present there is no cure for haemophilia A and patients require expensive, life-long treatment involving clotting factor replacement therapy. Treatment costs are perceived to be higher for patients who have developed inhibitory antibodies to factor VIII, the standard therapy for haemophilia A. However, initial cost analyses suggest that clotting factor therapy with alternative haemostatic agents, such as recombinant activated factor VII or activated prothrombin complex concentrate, is no more expensive for the majority of haemophilia A patients with inhibitors than for those without inhibitors. With the availability of effective alternative haemostatic agents, orthopaedic surgery for haemophilia A patients with inhibitors is now a clinical option, and initial cost analyses suggest this may be a cost-effective treatment strategy for patients with inhibitors whose quality of life (QoL) is severely impaired by joint arthropathy. In an era of finite healthcare resourcing it is important to determine whether new treatments justify higher unit costs compared with standard therapies and whether such higher costs are justified from an individual perspective in terms of improved QoL, and from a societal perspective in terms of improved productivity and reduced overall healthcare costs. This paper examines current data on the health economics of treating haemophilia A patients with inhibitors, focusing on the overall costs of clotting factor replacement therapy and the cost consequences of joint replacement.     

Successful endoscopic sphincterotomy for choledocholithiasis in a patient with severe hemophilia A and inhibitors

Endoscopic sphincterotomy (ES) is a standard procedure for bile duct stone removal. However, the safety of ES in patients with hemophilia remains unknown. We treated a 46-year-old man who had choledocholithiasis and severe hemophilia A with high-responding inhibitors during immune tolerance induction therapy. Since coagulation factor VIII inhibitors neutralize and inactivate endogenous and exogenous factor VIII, bleeding risk is higher in hemophilia A patients with inhibitors than in those without inhibitors. With adequate pre- and post-procedure monitoring of the clotting factor and supplemented clotting factor, the patient could safely undergo ES without bleeding complications. ES can be also an effective and safe first-line therapy for choledocholithiasis in patients with hemophilia and inhibitors under the condition of appropriate management.     

Effect of danazol on clotting factor levels, bleeding incidence, factor infusion requirements, and immune parameters in hemophilia

Several recent studies have reported conflicting results on the effectiveness of danazol, an attenuated androgen, in raising plasma levels of clotting factors VIII and IX in patients with hemophilia. We undertook a randomized, double-blind cross-over trial using 8 weeks' administration of danazol (D), 600 mg/d, and 8 weeks' administration of placebo (P) separated by 2 weeks of rest in 12 patients with hemophilia A and four patients with hemophilia B. Plasma factor VIII and IX levels, frequency and type of bleeding episodes, amount of factor concentrate infused, fibrinogen, fibrinolysis assays, antithrombin III, liver function, and immune parameters were followed. During the danazol phase a minimal increase was noted in the average clotting factor levels, an increase that, although statistically significant, was of hemostatically marginal magnitude. Significant increases in protein C and plasminogen levels, however, were observed during the danazol period, suggestive of danazol-mediated enhanced fibrinolysis. Clinically, bleeding frequency was significantly increased, and more clotting factor was consumed during the danazol period. Furthermore, eight episodes of hematuria and oral mucosal bleeding was reported during the danazol phase in contrast to only one episode of hematuria during the placebo phase, consistent with an enhancement of fibrinolytic activity with danazol. We conclude that danazol does not have a hemostatically significant effect on plasma levels of factor VIII and IX but may be associated with enhancement of fibrinolytic activity, resulting in increased bleeding frequency and requiring more clotting factor infusions. Therefore, danazol is not a viable alternative in the treatment of hemophilia.     

Setting the stage for individualized therapy in hemophilia: What role can pharmacokinetics play?

Replacement therapy with clotting factor concentrates (CFC) is the mainstay of treatment in hemophilia. Its widespread application has led to a dramatic decrease in morbidity and mortality in patients, with concomitant improvement of quality of life. However, dosing is challenging and costs are high. This review discusses benefits and limitations of pharmacokinetic (PK)-guided dosing of replacement therapy as an alternative for current dosing regimens. Dosing of CFC is now primarily based on body weight and based on its in vivo recovery (IVR). Benefits of PK-guided dosing include individualization of treatment with better targeting, more flexible blood sampling, increased insight into association of coagulation factor levels and bleeding, and potential overall lowering of overall costs. Limitations include a slight burden for the patient, and availability of closely collaborating, experienced clinical pharmacologists.     

The hope and reality of long-acting hemophilia products

Recombinant DNA technology and protein engineering are creating hope that we can address ongoing challenges in hemophilia care such as reducing the costs of therapy, increasing the availability to the developing world, and improving the functional properties of these proteins. Technological advances to improve the half-life of recombinant clotting factors have brought long-acting clotting factors for hemophilia replacement therapy closer to reality. Preclinical and clinical trial results are reviewed as well as the potential benefits and risks of these novel therapies.     

Clinical evaluation of recombinant human factor VIII (BAY w 6240) in the treatment of hemophilia A.

A pilot clinical trial was conducted in five patients with severe hemophilia A to evaluate the safety and efficacy of a recombinant human factor VIII preparation, BAY w 6240 (rFVIII). In a comparative pharmacokinetic study of rFVIII and a plasma-derived factor VIII preparation (pdFVIII), the mean t1/2 values for rFVIII at week 1 and week 13 were 16.8 and 14.4 h, while this value for pdFVIII at week -2 was 16.9 h. There were no statistical differences between these values. The mean in vivo recovery rates of rFVIII were comparable to those of pdFVIII. When rFVIII was administered prophylactically three times a week for 4 weeks, no bleeding episodes were observed. Seventy-four bleeding episodes were assessed during the 6-month treatment period. The efficacy rate of the hemostatic effect was confirmed to be 95.9%. No adverse reactions attributable to rFVIII were observed in a total of 178 infusions. Neither FVIII-inhibitors nor antibodies to foreign proteins were detected. Vital signs and laboratory findings showed no significant changes attributable to rFVIII. These results suggest that rFVIII is safe and efficacious as replacement therapy for hemophilia A.     

How we treat a hemophilia A patient with a factor VIII inhibitor

The most significant complication of treatment in patients with hemophilia A is the development of alloantibodies that inhibit factor VIII activity. In the presence of inhibitory antibodies, replacement of the missing clotting factor by infusion of factor VIII becomes less effective. Once replacement therapy is ineffective, acute management of bleeding requires agents that bypass factor VIII activity. Long-term management consists of eradicating the inhibitor through immune tolerance. Despite success in the treatment of acute bleeding and inhibitor eradication, there remains an inability to predict or prevent inhibitor formation. Ideally, prediction and ultimately prevention will come with an improved understanding of how patient-specific and treatment-related factors work together to influence anti-factor VIII antibody production.     

Sustained phenotypic correction of canine hemophilia A using an adeno-associated viral vector

Gene therapy for hemophilia A requires efficient delivery of the factor VIII gene and sustained protein expression at circulating levels of at least 1% to 2% of normal. Adeno-associated viral type 2 (AAV2) vectors have a number of advantages over other viral vectors, including an excellent safety profile and persistent gene expression. However, a major disadvantage is their small packaging capacity, which has hampered their use in treating diseases such as hemophilia A, cystic fibrosis, and muscular dystrophy, which are caused by mutations in large genes. Here we demonstrate that this can be overcome by using small regulatory elements to drive expression of a B-domain-deleted form of FVIII. The use of this vector for hepatic gene transfer in a canine model of hemophilia A resulted in the sustained (> 14 months) expression of biologically active FVIII. FVIII activity levels of 2% to 4% were achieved. These levels correlated with a partial correction in the whole-blood clotting time and cuticle bleeding time. In addition, immunoprecipitation analysis demonstrated the expression of canine FVIII of the predicted size in the plasma of injected animals. These data support the use of AAV2 vectors in human clinical trials to treat hemophilia A patients.     

Bleeding in carriers of hemophilia

A wide range of factor VIII and IX levels is observed in heterozygous carriers of hemophilia as well as in noncarriers. In female carriers, extreme lyonization may lead to low clotting factor levels. We studied the effect of heterozygous hemophilia carriership on the occurrence of bleeding symptoms. A postal survey was performed among most of the women who were tested for carriership of hemophilia in the Netherlands before 2001. The questionnaire included items on personal characteristics, characteristics of hemophilia in the affected family members, and carrier testing and history of bleeding problems such as bleeding after tooth extraction, bleeding after tonsillectomy, and other operations. Information on clotting factor levels was obtained from the hospital charts. Logistic regression was used to assess the relation of carrier status and clotting factor levels with the occurrence of hemorrhagic events. In 2004, 766 questionnaires were sent, and 546 women responded (80%). Of these, 274 were carriers of hemophilia A or B. The median clotting factor level of carriers was 0.60 IU/mL (range, 0.05-2.19 IU/mL) compared with 1.02 IU/mL (range, 0.45-3.28 IU/mL) in noncarriers. Clotting factor levels from 0.60 to 0.05 IU/mL were increasingly associated with prolonged bleeding from small wounds and prolonged bleeding after tooth extraction, tonsillectomy, and operations. Carriers of hemophilia bleed more than other women, especially after medical interventions. Our findings suggest that not only clotting factor levels at the extreme of the distribution, resembling mild hemophilia, but also mildly reduced clotting factor levels between 0.41 and 0.60 IU/mL are associated with bleeding.     

Thirty years of hemophilia treatment in the Netherlands, 1972-2001

Since the introduction of replacement therapy in the early 1960s by the infusion of plasma-derived factor VIII and IX preparations, important changes have occurred for hemophilia patients. We studied the medical and social developments over 30 years of hemophilia treatment. Since 1972, 5 cross-sectional national postal surveys among all hemophilia patients in the Netherlands were performed, the latest in 2001. The prestructured questionnaires included items on treatment, the presence of inhibitory antibodies against factor VIII or IX, the annual number of bleeding episodes, use of inpatient hospital care, and hepatitis C and HIV infections. Response rate in 2001 was 70%. Young patients (<16 years) with severe hemophilia showed the largest increase in use of prophylaxis, from 34% in 1972 to 86% in 2001. The occurrence of hemorrhages has gradually decreased. Hospital admissions decreased from 47% of all patients in 1972 to 18% in 2001. Our study shows that the treatment of patients with severe hemophilia in the Netherlands has focused on the use of prophylactic treatment, especially in children. This has resulted in a decrease in bleeding frequency and an improvement of the medical and social circumstances of patients.     

Inhibitor antibodies to factor VIII and factor IX: management

Inhibitor antibodies directed against factor VIII or factor IX present challenges to the clinician. Fortunately, several management options are available, although each has disadvantages as well as advantages. Alloantibodies against factor VIII (which develop in 25 to 50% of children with severe hemophilia A, as well as in a small percentage of children with mild or moderate hemophilia A) may be low titer and transient or may be high titer. Most patients with high-titer problematic inhibitors now try to eliminate the inhibitor by using one of several immune tolerance induction (ITI) regimens. For treatment of bleeding episodes in patients who have high-titer (> or = 5 Bethesda units) inhibitors, one can use a prothrombin complex concentrate (PCC) (preferably an activated PCC [APCC]), recombinant (r) factor VIIa, or porcine factor VIII. The choice of product is generally dependent on the type and severity of the patient's bleeding, degree of cross-reactivity of the patient's inhibitor with porcine factor VIII, physician familiarity with the product, product availability, and cost. In persons with hemophilia B, alloantibodies occur in only 1 to 3% of severely affected individuals. However, in roughly half of those who develop inhibitors, anaphylaxis or severe allergic reactions occur on infusion of any type of factor IX-containing product. This phenomenon usually develops after relatively few exposures to factor IX; thus it is recommended that the first 10 to 20 infusions of factor IX given to children with severe hemophilia B be given in a setting equipped for treatment of shock. For treatment of bleeding episodes in patients with severe allergic reactions, rF VIIa is the treatment of choice. ITI has been less successful in hemophilia B patients with inhibitors than in those with hemophilia A, and in a subgroup of patients with severe allergic reactions who were desensitized to factor IX and then tried on ITI, results were even poorer. Additionally, several developed nephrotic syndrome while on ITI. For hemophilia B patients with inhibitors who do not have allergic reactions to factor IX, bleeding episodes can be treated with PCC or APCC or with rF VIIa. Autoantibodies directed against factor VIII are rare but can occur in a variety of settings. They occur mainly in adults, and bleeding is often severe and life threatening. Although some factor VIII autoantibodies disappear spontaneously, most require immunosuppression. Corticosteroids and cyclophosphamide are generally recommended. For treatment of bleeding, therapeutic options include (human) factor VIII concentrates, porcine factor VIII, APCC, and rFVIIa. The choice of product is generally determined by the consulting hematologist's familiarity with the product, product availability and cost, as well as response to treatment.     

FEIBA prophylaxis for patients with haemophilia and inhibitors

Summary.  Prophylaxis with clotting factor concentrates has been shown to prevent bleeding episodes and improve quality of life in patients with severe haemophilia A or B. The benefits of long-term prophylaxis may also extend to patients with high-titre factor VIII or IX inhibitors who have failed or are not candidates for immune tolerance. Because the presence of an alloantibody makes it difficult to achieve haemostasis during a bleeding event, inhibitor patients are at increased risk for life-threatening haemorrhage and the development of arthropathy. Accumulating evidence suggests that prophylactic therapy with the bypassing agent FEIBA reduces bleeding episodes, including haemarthrosis, and maintains normal joints, although it does not halt established joint disease. Infections associated with central venous access devices are a frequent complication of prophylaxis in young children with haemophilia.     

Review of immune tolerance induction in hemophilia A

At first sight the bleeding disorder hemophilia A seems to have little in common with immune disorders, but immunology research intersects with other disciplines including hematology.Nowadays, the most important complication in the treatment of hemophilia A is the development of neutralizing antibodies (inhibitors) against exogenous administered factor VIII (FVIII), which occurs in approximately 30% of all patients with severe hemophilia A. This antibody response renders FVIII replacement therapy ineffective, thereby increasing the risk for uncontrollable bleeding and morbidity, decreasing quality of life and increasing healthcare costs. The only proven effective therapy to eradicate these inhibitors is immune-based. Using a protocol called “immune tolerance induction” (ITI), the repeated and frequent administration of FVIII under non-inflammatory conditions downregulates the established antibody response and induces immune tolerance.There has been progress in research clarifying the mechanisms that mediate tolerance induction using ITI, both from patient studies and from research in cell culture and animal-based models. Peripheral tolerance induction to FVIII involves the apoptosis of antigen-specific B-memory cells, anergy induction in antigen-specific effector T-cells (Teff), induction of regulatory T-cells (Treg) and the formation of anti-idiotypic antibodies. In this review hemophilia A will be used as an example to discuss current concepts of tolerance induction as they are applied in patient care. Where possible, we will extrapolate tolerance findings in hemophilia A to related pathways known to affect auto-immune disorders or allergy.