Continuous infusion of monoclonal antibody-purified factor VIII

Continuous intravenous infusion of wet and dry heat treated factor VIII products has been shown to be an effective, safe, and convenient alternative to pulse-dose therapy for the treatment of patients with hemophilia. We have used 12-hr, single-bottle continuous infusion of a factor VIII product purified from plasma sources by the use of monoclonal antibodies (Monoclate; Rorer Pharmaceutical Company) for the treatment of four bleeding episodes in three patients with severe hemophilia A. Patients required 2.1 U/kg/hr to attain an in vivo factor VIII level of 50 U/dl. Clinical hemostasis was achieved for all treatment episodes and no untoward effects of therapy were noted. Stability of the factor VIII:C levels in the product in vitro was also demonstrated. We conclude from this preliminary data that continuous infusion of factor VIII products purified by monoclonal antibody technology is a safe, effective, and practical approach to the treatment of patients with hemophilia A.     

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.     

Current status and future prospects for the prophylactic management of hemophilia patients with inhibitor antibodies

Inhibitor antibodies to factor VIII arise in a substantial minority of patients with hemophilia A treated with replacement therapy; factor IX inhibitors in treated hemophilia B patients are considerably less common. As replacement therapy is not feasible in most such patients, hemostasis can generally only be achieved with “inhibitor bypassing agents”, namely (activated) prothrombin complex concentrates and recombinant factor VIIa. These agents are widely used to treat active bleeding in inhibitor patients but they have been used relatively infrequently as prophylactic agents to prevent bleeding and its consequences, mainly progressive joint damage. This is in contrast to hemophilia patients without inhibitors, in whom prophylactic replacement with concentrates of factor VIII or IX has become widely accepted as the optimal strategy to prevent these adverse outcomes. This review addresses the current experience and evidence and the future prospects regarding prophylaxis in inhibitor patients.     

Acquired factor VIII inhibitors

Acquired hemophilia A is a rare bleeding diathesis caused by autoantibodies directed against clotting factor VIII and associated with an increased morbidity and mortality. This autoimmune disorder most commonly occurs in the elderly. Although it may be associated with several underlying pathologies, up to 50% of reported cases remain idiopathic. In contrast with congenital hemophilia, which is commonly characterized by hemarthroses, hemorrhages in patients with acquired hemophilia involve most frequently soft tissues. The 2 treatment priorities are to arrest the acute bleeding and to eradicate the factor VIII autoantibody. Acute bleeding episodes in patients with low-titer inhibitors can be treated using human factor VIII concentrates, whereas factor VIII bypassing agents, such as activated prothrombin complex concentrates or recombinant activated factor VII, are effective for the treatment of those with high-titer inhibitors. An analysis of the literature shows that the most effective first-line treatment for the eradication of factor VIII autoantibodies is the combination of steroids and cyclophosphamide. However, there is increasing evidence on the effectiveness of other treatment approaches, such as immune tolerance regimens and rituximab. If confirmed by large controlled studies, these innovative therapies might become a valid option for long-term eradication of factor VIII inhibitors.     

Acquired factor VIII inhibitors in nonhemophilic patients

 Antibodies against factor VIII occur in about 15–35% of hemophilia A patients and induce refractoriness to factor VIII substitution. In most cases, these antibodies are of the IgG class. Strategies to avoid or to treat such inhibitors are controversial. In very rare cases, factor VIII inhibitors also develop in nonhemophilic patients. Although there are anecdotal reports that these antibodies may disappear spontaneously without occurrence of bleeding tendencies, in the majority of patients the clinical course is characterized by severe hemorrhages. From 1980 to 1995, we observed ten nonhemophilic patients with acquired factor VIII inhibitors at our hospital. In most cases, a sudden bleeding tendency was observed shortly after an injury or surgery. Coagulation tests showed a prolonged aPTT and a decreased F VIII level. Other deficiencies of blood-clotting factors and acquired or hereditary von Willebrand's disease were excluded. Therapy with F VIII concentrates did not produce the expected increase. Measurement of F VIII inhibitor levels in Bethesda units/ml (BU/ml) revealed maximal values in the range of 2–128 BU/ml. Immunosuppressive therapy with azathioprine or cyclophosphamide in combination with methylprednisolone led to complete disappearance of the inhibitor, normalization of the coagulation tests, and complete remission of the bleeding tendency in seven treated patients within 6 weeks. Although the clinical course is not predictable and inhibitors may disappear spontaneously, combined therapy with methylprednisolone and azathioprine or cyclophosphamide is recommended for patients with bleeding tendency. In pregnancy, therapy should be started only with methylprednisolone; post-partum, azathioprine should be used additionally if methylprednisolone as a single drug does not lead to complete remission. In emergency situations, therapy with high doses of human factor VIII concentrate may be used. When bleeding does not cease, the additional use of activated prothrombin-complex concentrates or porcine factor VIII is indicated. Possible side effects may include hepatitis and short-lived intravascular thrombin production. Received: 23 January 1996 / Accepted: 11 November 1996     

Comparison of continuous and intermittent Factor VIII concentrate therapy in hemophilia A

Comparison of continuous versus intermittent (every 12 h bolus) infusion of a high-purity Factor VIII concentrate in 12 severe hemophilia A patients undergoing surgical procedures indicated that a higher (50 u/dl versus 35 u/dl) minimal plasma level was seen with the same amount of product when given continuously. A continuous VIII concentrate infusion of 2 u/kg/h produces a mean VIIIc level of about 50 u/dl or, alternatively, about 0.04 u/kg/h raises the VIIIc level by 1 u/dl (1%). None of the patients showed any abnormal bleeding. Higher plasma levels of VIIIc were noted by the two-stage VIIIc assay than by the one-stage VIIIc assay. Fibrinogen levels were normal or only slightly elevated, and the monomer test was consistently negative.     

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.     

Phage display technology: a tool to explore the diversity of inhibitors to blood coagulation factor VIII

Hemophilia A is a X-linked bleeding disorder that is caused by the functional absence of blood coagulation factor VIII. The bleeding tendency in hemophilia A patients can be corrected by the administration of plasma-derived or recombinant factor VIII concentrates. A serious complication in hemophilia care is the development of factor VIII neutralizing antibodies (inhibitors) that arise as a consequence of factor VIII replacement therapy. The majority of factor VIII inhibitors are directed toward epitopes located within the A2, A3, and C2 domains of factor VIII. In this article, we summarize current knowledge on the epitope specificity of factor VIII inhibitors. In addition, we will discuss recent information on the molecular characteristics of human anti-factor VIII antibodies generated by phage display technology.     

Continuous infusion of monoclonal antibody-purified factor VIII: Rational approach to serious hemorrhage in patients with allo-/autoantibodies to factor VIII

Hemorrhage in a patient with factor VIII inhibitor is associated with increased morbidity and mortality. Treatment with factor IX complex concentrates or recombinant factor VIIA (rVIIa) may not control bleeding and may induce thrombosis. In this study, continuous infusion of a monoclonal antibody-purified factor VII concentrate (Monoclate-P) was used successfully in two hemophilic patients with factor VIII alloantibodies and one nonhemophilic patient with a factor VIII autoantlbody. In two patients, hemorrhage was life-threatening, and, in one, bleeding did not stop with repeated infusions of activated factor IX complex concentrates. The patients' ages ranged from 4 to 15 years, and the inhibitor levels from 6 to 300 Bethesda units/ml. Clinical hemostasis was excellent, and In vivo recovery of infused factor VIII was achieved. When an excess of monoclonal factor VIII was added to the inhibitor plasma in vitro, a stable level of residual factor VIII activity was noted after an initial rapid loss. This second-order reaction occurs in plasmas of patients with type I factor VIII inhibitors. In one patlent, we showed that the saturation dose of the factor VIII inhibitor predicted in vivo recovery of factor VIII:C. These data emphasize the importance of characterizing the kinetic reactions of the factor VIII inhibitor. Furthermore, we confirm previous reports that continuous infusion of monoclonal factor VIII is a safe and effective treatment of patients with factor VIII inhibitors in whom hemorrhage Is either life-threatening or refractory to standard treatment. © 1994 Wiley-Liss, Inc.     

Immune Tolerance Therapy in Patients with Acquired Hemophilia

Acquired hemophilia is a rare disorder with an estimated annual incidence of 0.2-1 cases per million individuals. The etiology of the disorder remains obscure, although approximately half of all cases are associated with other underlying conditions. In acquired hemophilia, the severe hemorrhagic diathesis is caused by the development of autoantibodies directed against a clotting factor, most commonly factor VIII. These autoantibodies inhibit normal coagulation and lead to bleeding complications, which can be life-threatening in a high percentage of cases. Prompt diagnosis and appropriate management of the disorder enable effective control; the short- and long-term aims of therapy are to terminate the acute bleed and eliminate or reduce the inhibitor, respectively. Immune tolerance therapy has been shown to successfully eradicate or suppress inhibitors in patients with congenital hemophilia A and may be applicable to patients with acquired hemophilia. Here we present preliminary data on the use of immune tolerance therapy in patients with acquired hemophilia and discuss possible treatment strategies.     

Immune tolerance therapy in patients with acquired hemophilia

Acquired hemophilia is a rare disorder with an estimated annual incidence of 0.2-1 cases per million individuals. The etiology of the disorder remains obscure, although approximately half of all cases are associated with other underlying conditions. In acquired hemophilia, the severe hemorrhagic diathesis is caused by the development of autoantibodies directed against a clotting factor, most commonly factor VIII. These autoantibodies inhibit normal coagulation and lead to bleeding complications, which can be life-threatening in a high percentage of cases. Prompt diagnosis and appropriate management of the disorder enable effective control; the short- and long-term aims of therapy are to terminate the acute bleed and eliminate or reduce the inhibitor, respectively. Immune tolerance therapy has been shown to successfully eradicate or suppress inhibitors in patients with congenital hemophilia A and may be applicable to patients with acquired hemophilia. Here we present preliminary data on the use of immune tolerance therapy in patients with acquired hemophilia and discuss possible treatment strategies.     

The role of plasma-derived factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients

Besides preventing bleeding episodes, common goals of the treatment of hemophilia include integrating of patients into a normal social life and optimizing their quality of life. Sufficient amounts of factor VIII (FVIII) concentrates, whether recombinant or plasma-derived, are continuously needed. Guidelines for quality assurance of treatment will be a cornerstone to maintain optimal clinical management of patients especially considering financial aspects. Advances in manufacturing technologies have made possible general availability of modern concentrates for the management of hemophilia A patients. Safety, cost and continuous supply of concentrates must be considered when deciding on a product for replacement therapy. As todays' products have reached an excellent margin of safety with regard to virus transmission, the development and treatment of inhibitors is currently the main concern for physicians and patients. The incidence of inhibitors is influenced by various patient-related factors such as mutation type or severity of the disease. Plasma-derived FVIII concentrates containing von Willebrand factor (VWF) may have clinical advantages over pure FVIII concentrates with regard to inhibitor development and inhibitor eradication. Clinical trials comparing FVIII/VWF concentrates with pure FVIII concentrates are lacking, thus a lower inhibitor incidence has not yet been proven. Data from Germany on immune tolerance induction with FVIII/VWF concentrates indicate higher success rates with these than with pure FVIII concentrates. In addition FVIII/VWF concentrates are the therapy of choice when immune tolerance therapy with pure FVIII products is not successful.     

Continuous infusion of porcine factor VIII in the management of patients with factor VIII inhibitors

The effectiveness of continuous infusion porcine factor VIII (PFVIII) has been evaluated in the treatment of 7 consecutive patients with factor VIII(FVIII) inhibitors. Two patients had hemophilia A and five were nonhemophiliacs with acquired FVIII inhibitors. The median pretreatment anti-porcine FVIII titre was 0.2 (range: 0–15.0) Bethesda units (BU), and the anti-human FVIII titer was 12.0 BU (range: 2.4–50.0). All patients presented with major bleeding. Patients were given a bolus dose of PFVIII followed by continuous infusion. Six patients also received immunosuppressive therapy. Therapeutic FVIII levels (>0.5 U/ml) were achieved in 6 of 7 patients at a median time of 12.5 hr, and then maintained with continuous infusion PFVIII. Six patients were treated for more than 7 days, and in four of these there was a decline in FVIII recovery between days 7 to 11, presumably related to a rising antibody response to PFVIII. These four patients were plasmapheresed and the three patients with autoantibodies recovered therapeutic FVIII levels but this did not occur in the patient with hemophilia. Thrombocytopenia developed in 4 patients at days 18 to 24, with the platelet count falling to 11 to 87 × 10⁹/L, and the PFVIII was discontinued in 3 patients. All patients recovered from the acute bleeding events. With prolonged immunosuppressive therapy, the FVIII inhibitor disappeared in all patients with autoantibodies and there have been no relapses after a median follow-up period of 581 days. This study demonstrates that continuous infusion PFVIII is an effective therapy for patients with FVIII inhibitors, but that prolonged treatment is associated with the development of inhibitors to porcine FVIII and severe thrombocytopenia, which readily corrects with discontinuation of PFVIII. Am. J. Hematol. 56:112–118, 1997. © 1997 Wiley-Liss, Inc.     

Clinical Characteristics and Prognostic Factors in Hemophiliacs with Intracranial Hemorrhage: A Single-Center,Retrospective Experience

Intracranial hemorrhage (ICH) is the most serious bleeding event that occurs in patients with hemophilia; its estimated mortality rate is approximately 20 %, accounting for the largest number of deaths from bleeding. We conducted this single-center, retrospective study to examine the characteristics of and prognostic factors in patients with hemophilia. A comprehensive review of 12 cases of intracranial hemorrhage (ICH) among 10 patients. All 12 cases of ICH in the 10 patients were treated with clotting factor concentrates. Three patients had intracerebral hemorrhage that required neurosurgical intervention. After presenting with ICH, two pediatric patients developed antibodies to clotting factors. Two adult patients with intracerebral hemorrhage died, and the mortality rate was thus 20.0 % (2/10) in our clinical series. Prompt and intensive treatment with clotting factor concentrates may significantly lower the mortality rate among patients with hemophilia presenting with ICH. Our results showed a better prognosis in pediatric patients with intracerebral hemorrhage. Clinicians should pay special attention to the possible development of inhibitors after intensive treatment in pediatric patients. Further studies are needed to examine methods for administering clotting factor concentrates and to determine whether neurosurgical intervention is essential in each case.     

Acquired hemophilia A

Acquired hemophilia A is a rare but severe autoimmune bleeding disorder, resulting from the presence of autoantibodies directed against clotting factor VIII. The etiology of the disorder remains obscure, although approximately half of all cases are associated with other underlying conditions. A prompt diagnosis and appropriate management enable effective control of this acquired hemorrhagic disorder: the aims of therapy are to terminate the acute bleeding episode and eliminate or reduce the inhibitor. The recent availability of bypassing agents, first activated prothrombin complex concentrates and then recombinant activated factor VII, has significantly reduced mortality during the acute phase of the disease in patients with high titer inhibitors. On another front, immunosuppressive therapy (corticosteroids and cytotoxic agents, alone or in various combinations) has resulted in long-term inhibitor suppression in up to 70% of the cases. Moreover, new therapeutic strategies (anti-CD20 monoclonal antibody and immune tolerance protocols) are very promising and may further improve the prognosis of acquired hemophilia A.     

Continuous and intermittent infusion of coagulation factor concentrates in patients undergoing surgery: a single centre Australian experience

Background: Haemophilia patients require large doses of coagulation factor concentrates to optimise haemostasis at the time of surgery. The superior pharmacokinetic profile of continuous infusion over intermittent bolus administration may be more advantageous.
Aims: We report our experience using coagulation factor concentrates delivered by continuous infusion in patients undergoing surgery.
Methods: A retrospective case notes review of all patients treated by continuous infusion at Royal Prince Alfred Hospital (RPAH) over a two year period and a comparison of two cohorts of patients undergoing orthopaedic surgery using either continuous infusion or bolus factor VIII (FVIII) replacement therapy. Patients received a pre-operative bolus of factor concentrate (AHF, Immunine or Recombinate) followed by a continuous infusion calculated according to weight, clearance and target plasma concentration.
Results: Twenty-one (19 M, two F) with haemophilia or von Willebrand's disease underwent 26 surgical procedures between July 1995 and July 1997. The mean total consumption of concentrate per patient was 36,676 units (range 6750–82,000) infused over a mean period of 7.6 days (range one-16). One patient experienced minor surgical bleeding on treatment and one patient developed severe bleeding into the replaced joint off infusion requiring additional boluses of treatment. In a separate analysis, ten of these patients who underwent major orthopaedic surgery were compared to a historic cohort ( n =8) of patients who received bolus injections for similar types of operations.
Conclusions: Coagulation factor concentrates delivered by continuous infusion have major clinical and economic advantages in the surgical management of patients with haemophilia.     

Plasma clearance rates of coagulation factors VIII and IX in factor- deficient individuals

The plasma clearance rates of factors IX and VIII were determined in patients with hemophilia A and B who had received factor replacement by prolonged, continuous infusion of factor concentrates. The clearance rates were calculated by dividing the factor infusion rates by the steady-state plasma factor activities corrected for base-line factor activities. The mean factor IX clearance rate in eight factor IX- deficient patients was 233 mL/h (range 159 to 340 mL/h). The mean normalized clearance rate was 3.4 mL/h/kg. The mean factor VIII clearance rate in eight factor VIII-deficient patients was 294 mL/h (range 229 to 361 mL/h) and the mean normalized rate was 5.0 mL/h/kg. Both factors show linear relationships between the factor infusion rates and the steady-state plasma factor activities achieved.     

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.     

Desmopressin is not always effective in mild haemophilia Apatients undergoing urological surgery: the need of standardized protocols

Desmopressin may be an efficient haemostatic treatment for mild A haemophiliacs because its infusion raises plasma factor VIII level. We report the use of desmopressin in five mild haemophilia A patients undergoing urological surgery. They all received a preoperative infusion (0.3 microg kg(-1), i.v.) 1 h before incision followed by repeated injections at 12- or 24-h intervals according to the severity of the procedure. Nevertheless, four patients presented a postoperative bleeding requiring again surgery performed for 3 of them under clotting factor concentrate instead of desmopressin. The occurrence of haemorrhage was not always correlated with particularly low plasma factor VIII level. Surgical management of urological procedures with desmopressin in mild haemophilia A patients requires standardized protocols.     

Clinical heterogeneity of acquired hemophilia A: a description of 4 cases

Acquired hemophilia A is a rare but severe auto-immune bleeding disorder characterized by the presence of autoantibodies directed against clotting factor VIII. Acquired hemophilia A may be idiopathic or associated with several conditions, such as postpartum, autoimmune diseases, malignancies or drugs. The treatment modalities of bleeding episodes and eradication of the factor VIII auto-antibody depend on the titer of anti-factor VIII:C and may include desmopressin (DDAVP), prednisolone, prednisolone-cyclophosphamide, high dose intravenous gammaglobulin, FVIII-VWF concentrate and/or recombinant FVIIa (rFVIIa). In this study we report four cases of autoimmune factor VIII inhibitors (2 associated with autoimmune disorders, 2 idiopathic) demonstrating the heterogeneity of this disease from pathogenic, clinical, therapeutic and prognostic points of view.