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.     

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.     

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.     

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.     

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.     

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.     

Acquired hemophilia masked by warfarin therapy

People without hemophilia but with autoantibodies specifically directed against the procoagulant activity of factor VIII are known to have acquired hemophilia. The bleeding diathesis in these patients is often severe and life-threatening. The definite laboratory diagnosis of this disorder includes demonstration of low factor VIII levels in plasma with a high titer of factor VIII inhibitors, but the initial suspicion for its presence should rise in view of a prolonged partial thromboblastin time (PTT) and a normal prothrombin time associated with an acquired bleeding disorder. Oral anticoagulant treatment is known to prolong PTT as well, and the merger of these 2 situations may cause delayed diagnosis of acquired hemophilia with devastating consequences. We describe here the first reported case of acquired hemophilia diagnosed in a patient treated with warfarin. In such patients prolonged PTT may be ascribed to warfarin therapy rather than to acquired hemophilia, thus causing a dangerous delay in diagnosis.     

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.     

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.     

Acquired hemophilia A: Updated review of evidence and treatment guidance

Acquired hemophilia A (AHA) is a rare disease resulting from autoantibodies (inhibitors) against endogenous factor VIII (FVIII) that leads to bleeding, which is often spontaneous and severe. AHA tends to occur in elderly patients with comorbidities and is associated with high mortality risk from underlying comorbidities, bleeding, or treatment complications. Treatment, which consists of hemostatic management and eradication of the inhibitors, can be challenging to manage. Few data are available to guide the management of AHA‐related bleeding and eradication of the disease‐causing antibodies. Endorsed by the Hemostasis and Thrombosis Research Society of North America, an international panel of experts in AHA analyzed key questions, reviewed the literature, weighed the evidence and formed a consensus to update existing guidelines. AHA is likely underdiagnosed and misdiagnosed in real‐world clinical practice. Recommendations for the management of AHA are summarized here based on the available data, integrated with the clinical experience of panel participants.     

New approaches to using FEIBA in the treatment of inhibitor patients

Managing hemophilia becomes particularly difficult in patients with inhibitory antibodies, especially in those requiring surgery or with refractory bleeding events. Equally challenging are those patients who develop autoantibodies against factor VIII (FVIII) in the absence of a prior history of FVIII deficiency (acquired hemophilia). Physicians seeking both short- and long-term treatment strategies for bleeding events must often rely on FVIII-bypassing agents such as activated prothrombin complex concentrate (e.g., factor eight bypassing activity [FEIBA VH, Baxter BioScience, Westlake Village, CA]) or recombinant factor VIIa (rFVIIa [NovoSeven, NovoNordisk, Bagsvaerd, Denmark]). Surgical procedures in patients with inhibitors present a considerable challenge, from both a risk-benefit and a cost-benefit aspect. Hemostasis is difficult to achieve in these patients and new treatment options are being explored. Similarly challenging are refractory bleeds, the management of which is likely to benefit from a systematic treatment approach.     

Should hemophilia treaters switch to albumin-free recombinant factor VIII concentrates

PURPOSE OF REVIEW: To discuss the advantages and disadvantages of the albumin-free recombinant factor VIII concentrates in the treatment of hemophilia A. RECENT FINDINGS: The third-generation recombinant factor VIII product Advate has been found to be safe and effective in treating bleeding associated with hemophilia A. SUMMARY: Multiple issues must be considered when selecting a factor VIII concentrate for patients with hemophilia A including efficacy, availability, risk of transmission of infectious agents, risk of inhibitor development and cost. Third-generation recombinant factor VIII concentrates have been shown to be safe and effective. A theoretical improvement in risk of infectious agent transmission has been achieved by production of the products without human or animal plasma proteins. Controversy exists, however, with regard to a higher risk of inhibitor development with recombinant products. The higher cost of Advate can also potentially play a role in product choice. Overall every patient and their family must be presented with the advantages and disadvantages of all factor VIII concentrates, and be allowed to make an informed decision about which product to use for treatment.     

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     

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.     

Acquired hemophilia A: a concise review

Acquired hemophilia A is a rare but severe autoimmune bleeding disorder. It is more frequent in the elderly and results from the presence of autoantibodies directed against clotting factor VIII. In this review, we briefly report on the present state of knowledge regarding acquired hemophilia A, analyzing its epidemiology, pathogenesis, diagnostic, and clinical features. We also describe the main characteristics of this disorder according to its association with different conditions and the most important advances in the treatment of bleeding episodes and the eradication of the autoantibody.     

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.     

Spontaneous inhibitors to coagulation factors

Spontaneous inhibitors to coagulation factors are autoantibodies that usually appear in the elderly, but may also occur in patients with immunological disorders such as lupus, lymphoma, asthma or drug reactions. Most antibodies are directed against factor VIII, but any coagulation protein may be affected. They should be suspected in individuals who previously had normal haemostasis, but who now begin to experience bleeding into the skin and muscles, or suffer haemorrhages after routine procedures such as insertion of vascular catheters, intramuscular injections, or minor surgery. The haemostasis laboratory is critical in identifying the particular inhibitor and quantitating its potency. Factor VIII inhibitors prolong the partial thromboplastin time (PTT) but not the prothrombin time (PT), and incubating mixtures of patient plasma and normal plasma enhances the prolongation of the clotting time. The Bethesda assay provides a rough assessment of inhibitor potency. Inhibitors of von Willebrand factor prolong the bleeding time and impair ristocetin-induced platelet aggregation. Factor V inhibitors are associated with a prolonged PTT and PT, not correctable with normal plasma. Patients will often have a history of exposure to bovine thrombin in fibrin glue. The antibodies most difficult to recognize are those that alter fibrin polymerization or stabilization. Abnormal clot retraction or clot solubility in urea solutions are an important clue. The management of these disorders depends on characterization of the inhibitor, and using appropriate clotting factor concentrates to control acute bleeding. For example, recombinant human factor VIII or desmopressin may be effective for patients with low titre factor VIII inhibitors, whereas porcine factor VIII, recombinant factor Vlla, or prothrombin complex concentrates stem bleeding in those with high titres. Inhibitors of von Willebrand factor may be amenable to desmopressin, cryoprecipitate, or von Willebrand factor concentrates. Some patients with factor V inhibitors have responded to platelet transfusions, as the platelet factor V may be shielded from the autoantibody. Bleeding due to factor XIII inhibitors may be managed with fibrogammin, a factor XIII concentrate. All patients should be treated for underlying disorders and given drugs such as corticosteroids and cytotoxic agents to suppress inhibitor formation. Major advances in new immunosuppressive technologies, such as monoclonal B-cell antibodies, offer hope of more effective therapies for spontaneous inhibitors to coagulation factors.     

Postpartum acquired factor VIII inhibitors: Results of a survey

Postpartum factor VIII inhibitors are rare; thus, collecting clinical and treatment data may provide valuable information in guiding patient management. This paper reports the results of a survey of United States and Canadian hemophilia centers on 14 patients with postpartum acquired factor VIII inhibitors. Patients ranged in age from 23 to 40 years. Parity at diagnosis was most frequently the first gestation. Two patients were diagnosed prepartum, but two patients only up to one year postpartum. Initial inhibitor titers ranged from two to 550 Bethesda units (BU), and rose to five to 885 BU. The median duration of the inhibitor was 27 months, with two of the 14 inhibitors unresolved at the time of the survey. A total of 80 bleeding episodes occurred, five of which were life or limb threatening. Three patients received no blood products and were not hospitalized. Of those treated for hemostasis, activated prothrombin complex concentrates and porcine factor VIII were most often reported to be effective. For immunosuppression, all patients received steroids and most received additional treatment. Steroids were reported ineffective more frequently than cyclophosphamide. No adverse fetal events were noted and there was no maternal mortality. These results underline the clinical heterogeneity of the severity of postpartum factor VIII inhibitors, and provide treatment guidelines in the absence of prospective studies. Am. J. Hematol. 59:1–4, 1998. © 1998 Wiley-Liss, Inc.     

Diagnosis,laboratory aspects and management of acquired hemophilia A

Acquired hemophilia A (AHA) is a rare autoimmune disease, characterized by severe, often life-threatening hemorrhages in patients without a prior history of bleeding disorder. It most frequently occurs in the elderly, and may be associated with other clinical conditions, such as cancer, autoimmune diseases, pregnancy or without a relevant cause. Diagnosis and correct therapy are crucial for the patient’s outcome. Management of the disease consists of gaining immediate control of acute bleeding and the starting of an immunosuppressive therapy in order to eradicate the anti-factor VIII autoantibody. Factor VIII bypassing agents, such as prothrombin complex concentrates or recombinant activated factor VII, have proven effective in bleeding control, whereas the combined therapy of cyclophosphamide and corticosteroids seems to be, at present, the best immunosuppressive option. Other treatments including Rituximab, immunoadsorption or induction of immune tolerance are still experimental, and need to be validated through controlled clinical trials.