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.     

Complications associated with the treatment of haemophiliacs with inhibitors

To examine the safety profile of products used to treat inhibitor patients unresponsive to factor VIII, a review of published clinical experience was performed. The products evaluated were activated prothrombin complex concentrates (aPCCs), such as AUTOPLEX® T, porcine factor VIII and recombinant activated factor VII (rVIIa). Safety characteristics included potential for transmission of infectious agents, anamnesis, thrombogenicity, thrombocytopenia and allergic reactions. While viral transmission has been virtually eliminated, the risk is theoretically higher with plasma-derived products such as aPCC and porcine factor VIII than with rVIIa, although contamination of cultured cells is a concern. Anamnesis occurs with aPCCs and porcine factor VIII, and may induce resistance to further therapy with porcine factor VIII. Thrombosis and disseminated intravascular coagulation are very infrequently reported in patients exposed to aPCCs and rVIIa, and never with porcine factor VIII. The latter is occasionally associated with thrombocytopenia, but this uncommonly limits treatment with this agent. Lastly, allergic reactions occur with about equal frequency with all products, but anaphylaxis is mainly a concern after administration of porcine factor VIII. In conclusion, products currently available are reasonably safe. Considerations such as efficacy, availability, ease of administration and cost must also be considered in making treatment choices.     

Complications associated with the treatment of haemophiliacs with inhibitors

To examine the safety profile of products used to treat inhibitor patients unresponsive to factor VIII, a review of published clinical experience was performed. The products evaluated were activated prothrombin complex concentrates (aPCCs), such as AUTOPLEX® T, porcine factor VIII and recombinant activated factor VII (rVIIa). Safety characteristics included potential for transmission of infectious agents, anamnesis, thrombogenicity, thrombocytopenia and allergic reactions. While viral transmission has been virtually eliminated, the risk is theoretically higher with plasma-derived products such as aPCC and porcine factor VIII than with rVIIa, although contamination of cultured cells is a concern. Anamnesis occurs with aPCCs and porcine factor VIII, and may induce resistance to further therapy with porcine factor VIII. Thrombosis and disseminated intravascular coagulation are very infrequently reported in patients exposed to aPCCs and rVIIa, and never with porcine factor VIII. The latter is occasionally associated with thrombocytopenia, but this uncommonly limits treatment with this agent. Lastly, allergic reactions occur with about equal frequency with all products, but anaphylaxis is mainly a concern after administration of porcine factor VIII. In conclusion, products currently available are reasonably safe. Considerations such as efficacy, availability, ease of administration and cost must also be considered in making treatment choices.     

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.     

Choice of replacement therapy for hemophilia: recombinant products only?

In the early 1980s it was recognized that coagulation factor concentrates prepared from plasma pooled from thousands of donors transmitted the hepatitis and the human immunodeficiency viruses. The last 15 years have witnessed the development of methods that, applied during concentrate manufacturing, inactivate viruses escaping the screening procedures. The adoption of these measures has dramatically reduced the risk of transmission of bloodborne infections by plasma-derived coagulation factor concentrates. The production of recombinant factor VIII and IX and their availability for patient treatment epitomize progress in hemophilia care through DNA technology. No transmission of infectious agents has been documented and the small amount of residual animal proteins, particularly in the early products, has not been associated with any clinically significant adverse reaction. There is little doubt that recombinant factor VIII and IX are the products of choice for the treatment of patients with hemophilia, particularly the second-generation products containing no plasma-derived human protein and fewer and fewer animal proteins. However, availability and cost still oblige most physicians to ration recombinant products and prioritize certain patient groups (previously untreated, previously uninfected).     

Large scale studies assessing anti‐factor VIII antibody development in previously untreated haemophilia A: what has been learned,what to believe and how to learn more

Minimizing the risk of inhibitor development by acting on modifiable risk factors remains a sensible goal for treatment optimization in haemophilia A. By critically appraising published studies assessing inhibitor development, this review addresses the role of studies in previously untreated patients (PUPs) for establishing the immunogenicity of new concentrates, suggest novel research design to be adopted in future studies and discuss clinical practice implications of the reported differential immunogenicity of Kogenate Bayer and Advate factor VIII concentrates. Three considerations are relevant here: (i) all of the existing concentrates, when tested following the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee recommendation, were shown to be safe; as a consequence, (ii) when considering using any newly introduced product, one should be aware that it could, in future, turn out to be as immunogenic as Kogenate Bayer, and (iii) at the population level, it might be wiser not to use Kogenate Bayer in PUPs, if the choice is against Advate. When presenting the risk of developing inhibitors to the individual patient (or their family), the message remains that the risk can be as high as 40%, without any efficient instrument to predict individual inhibitor risk. Patients should be invited to enrol into a randomized registry trial, including random assignment to trials with new investigational products.     

Current status of hemophilia patients and recombinant coagulation factor concentrates in Japan

The first recombinant factor VIII concentrate was introduced in 1987 to treat hemophilia A patients, and the product was licensed in the United States in 1992. More than 10 years have passed since the recombinant products have been used for treatment of hemophilia A. The new therapeutic options seem to be safe and effective through the gathered experiences. Recently, recombinant factor VIIa concentrate has become available to treat hemophilia patients with inhibitor and factor VII deficiency patients in Europe and also recombinant factor IX for the treatment of hemophilia B has been licensed in the United States and Europe. The usage of recombinant coagulation factors has expanded the routine therapy for hemophilia in many countries. In Japan, the consumption of recombinant factor VIII is increasing year by year, because many patients have started to think that the recombinant technology seems to be safe. Unfortunately, though, the factor VIIa and factor IX products have not been licensed yet in Japan. This article discusses the current status of patients with hemophilia and recombinant coagulation factor products in Japan.     

Why Prescribe Highly Purified Factor VIII and IX Concentrates?

The aftermath of the HIV catastrophe and hepatitis virus transmission to hemophiliacs has been characterized by continuous efforts to improve the purity of factor VIII and factor IX concentrates, increasing sophistication of the virucidal methods used, and the introduction of recombinant factor VIII. The cost of hemophilia care is substantial and there is a large price difference between products depending on their purity; generally, the purer the concentrate, the higher the price. The use of expensive highly purified concentrates may be questioned if these products are not superior in terms of safety, efficacy or convenience. The properties of concentrates used in hemophilia care are discussed in this review, as are their safety and side effects. The available data do not clearly reveal any clinical difference between factor VIII concentrates, although the highly purified products may be of theoretical benefit. With regard to factor IX, purified products do not seem to carry any risk of the well-known thromboembolic complications which occur in certain situations after treatment with prothrombin complex concentrates.     

Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study

It has been suggested that plasma-derived factor VIII products induce fewer inhibitors than recombinant factor VIII products. We investigated the relationship of factor VIII product type and switching between factor VIII products with the risk to develop inhibitors. This multicenter retrospective cohort study included 316 patients with severe hemophilia A born between 1990 and 2000. The outcome was clinically relevant inhibitor development, defined as the occurrence of at least 2 positive inhibitor titers with decreased recovery. The risk of inhibitor development was not clearly lower in plasma-derived compared with recombinant factor VIII products (relative risk [RR], 0.8; 95% confidence interval [CI], 0.5-1.3). Among high-titer inhibitors, the possible reduction in risk was even less pronounced (RR, 0.9; CI, 0.5-1.5). Plasma-derived products with considerable quantities of von Willebrand factor (VWF) carried the same risk for inhibitor development as recombinant factor VIII products (RR, 1.0; CI, 0.6-1.6). Switching between factor VIII products did not increase the risk for inhibitors (RR, 1.1; CI, 0.6-1.8). In conclusion, our findings support neither the notion that plasma-derived factor VIII products with considerable concentrations of VWF confer a lower risk to develop inhibitory antibodies than recombinant factor VIII products, nor that switching between factor VIII product brands increases inhibitor risks in previously untreated patients with severe hemophilia A.     

Desmopressin in mild hemophilia A: indications,limitations, efficacy,and safety

Replacement therapy with blood products has long been the only available therapeutic option for patients with bleeding disorders. Plasma-derived cryoprecipitate and factor (F) VIII concentrates, which have been used for hemophilia A patients, involve the risk of transmitting blood-borne diseases. Both plasma-derived and recombinant FVIII concentrates are expensive, and there is a global shortage. The synthetic vasopressin analogue desmopressin acetate (1-deamino-[8-D-arginine]-vasopressin, DDAVP) increases plasma concentrations of coagulation FVIII and von Willebrand factor (vWF) two fold to six fold through endogenous release. The drug is an attractive therapeutic alternative because it carries no risk of transmission of infectious diseases. Desmopressin is today a widely used hemostatic agent not only in patients with mild hemophilia A or von Willebrand disease (vWD) but also in those with congenital or acquired platelet dysfunction. There is a long clinical experience with the drug because it has been used for prevention of bleedings in connection with invasive procedures and for treatment of bleedings since the mid-1970s. Not all hemophilia A patients can be treated. The clinical usefulness depends on the postdesmopressin plasma concentration of FVIII, which in turn depends on the patient's basal FVIII level. Therefore, a test dose is recommended in candidate patients. In general, only the mildest hemophilia A patients respond sufficiently. Optimal hemostatic effect is achieved with a dosage of 0.3 microg/kg given intravenously. An intranasal desmopressin spray is suitable for the home treatment.     

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.     

Is the Apparent Outbreak of Hepatitis A in Belgian Hemophiliacs due to a Loss of Previous Passive Immunity?

Several reports describing outbreaks of hepatitis A in hemophilia A patients transfused with solvent/detergent-treated factor VIII concentrates have raised concern about possible transmission of hepatitis A by these concentrates. We recently witnessed such an outbreak of hepatitis A in 6 hemophilia A patients; review of the clinical data did not disclose any increased risk factor for community-acquired hepatitis A. A case-control study comparing the prevalence of anti-hepatitis A IgG antibodies in hemophiliacs and age-matched controls showed a lower seroprevalence in hemophiliacs. This might be due to passive protection acquired through transfusion of the previously used immunoglobulin-containing cryoprecipitate. The outbreak of hepatitis A could be explained as a catch-up phenomenon linked to the loss of passive protection with the use of purer factor VIII concentrates.     

Cumulative inhibitor incidence in previously untreated patients with severe hemophilia A treated with plasma-derived versus recombinant factor VIII concentrates: a critical systematic review

Inhibitor development represents currently the most serious and challenging complication of clotting factor replacement therapy. A number of studies have analyzed the impact of the type of factor VIII (FVIII) replacement therapy (plasma-derived versus recombinant concentrates) on inhibitor development in hemophilia A patients with conflicting results. In order to shed light on this controversial issue, we performed a systematic review and meta-analysis on the published prospective studies evaluating the incidence rate of inhibitors in previously untreated patients (PUPs) with severe hemophilia A. Data from a total of 800 patients enrolled in 25 prospective studies published between 1990 and 2007 were included in this review. The quality of the studies was evaluated using two different systems: the Newcastle-Ottawa Scale (NOS) and STrengthening the Reporting of OBservational studies in Epidemiology (STROBE). Overall, the inhibitor incidence rate did not differ significantly between recipients of plasma-derived and recombinant FVIII concentrates (weighted means: 21%; 95% CI, 14-30 versus 27%; 95% CI, 21-33). Similarly, high titer inhibitors did not differ significantly between patients treated with plasma-derived (weighted means: 14%; 95% CI, 8-25) or recombinant FVIII concentrates (weighted means: 16%; 95% CI, 13-20). Thus, the main conclusion of this systematic review performed using selective criteria is that the type of FVIII product (i.e., plasma-derived versus recombinant FVIII concentrates) does not seem to influence the inhibitor rate in PUPs with severe hemophilia A.     

Recombinant factor VIIa versus aPCCs in haemophiliacs with inhibitors: treatment and cost considerations

For haemophiliacs with factor VIII inhibitor titres greater than approximately 5 Bethesda Units, haemostasis is best achieved with activated prothrombin complex concentrates (aPCCs, AUTOPLEX®T and FEIBA®) and the recently approved recombinant factor VIIa (rFVIIa). The optimal treatment should be determined by consideration of efficacy, safety, availability, cost and convenience. The current evidence does not allow definitive conclusions to be drawn regarding the relative efficacy of aPCCs and rFVIIa. The principal safety concerns are transmission of viral or other pathogens, thrombogenicity and immunogenicity. The two aPCCs are derived from human plasma and therefore carry the potential for transmitting viruses. This risk is negligible for rFVIIa, although this product could theoretically transmit animal pathogens. The aPCCs are clinically safe in most applications. Likewise, rFVIIa should be considered potentially thrombogenic, though with a low risk. The aPCCs contain detectable factor VIII and can therefore be immunogenic, but in practice this rarely affects their efficacy. The costs of single doses of aPCCs and rFVIIa are similar, but a treatment course of rFVIIa typically requires more doses. Treatment with rFVIIa may be more cumbersome owing to the requirement for more frequent administration. In addition, as for any product for which there is only a single supplier, availability could be vulnerable in some circumstances.     

Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A

Inhibitor development is the major treatment complication in children with severe hemophilia A. It is not clear whether the risk of inhibitors is higher with recombinant factor VIII or with plasma-derived factor VIII. We used multivariate analysis to compare 2 cohorts of previously untreated patients (PUPs) with severe hemophilia A: 62 patients treated with the same brand of high-purity plasma-derived FVIII (pFVIII) containing von Willebrand factor (VWF) and 86 patients treated with full-length recombinant FVIII (rFVIII). In addition to the usual end points (all inhibitors, high inhibitors), we also examined a third end point (high inhibitors and/or immune tolerance induction). The risk of inhibitor development was higher in patients treated with rFVIII than in patients treated with pFVIII, regardless of other risk factors (F8 genotype; nonwhite origin; history of inhibitors in patients with a family history of hemophilia; age at first FVIII infusion). The adjusted relative risk (RRa) for inhibitor development with rFVIII versus pFVIII was 2.4 (all inhibitors), 2.6 (high inhibitors), and 3.2 (high inhibitors and/or immune tolerance induction), respectively, depending on the end point (above). The pathophysiology of this large effect must be understood in order to improve the characteristics of recombinant products and to reduce the incidence of inhibitors to FVIII.     

Hemophilia: State of the Art of Hematologic Care 1988

Since 1982, when the World Federation of Hemophilia first published a document on the state of the art of hemophilia diagnosis and care, there have been lights and shadows in this field. Although the widespread infection of hemophiliacs with the human immunodeficiency virus (HIV) contaminating clotting factor concentrates is still a threatening and formidable shadow, the gloomy picture brought about by the AIDS epidemic is partially lightened by spectacular improvements in therapy and diagnosis. Carrier detection and first-trimester prenatal diagnosis can now be performed accurately in most kindreds by analysis of DNA of the factor VIII or IX genes. An important step forward towards the elimination of the risk of blood-borne infections transmitted by plasma products was recently made through the application of virucidal methods to clotting factor concentrates. Since HIV appears more vulnerable to such methods than the hepatitis viruses, currently available concentrates can be considered substantially free from the risk of transmitting HIV infection. Even though transmission of hepatitis is much reduced but not totally abolished, virucidal methods are continuously being improved, so that it can be foreseen that concentrates will become safer and safer. Finally, factor VIII produced by recombinant DNA technology is undergoing the first clinical trials in hemophiliacs. Hopefully, it will free from the risk of transmitting infections and will be available in sufficiently large amounts to meet the need of hemophiliacs worldwide. In 1982, the World Federation of Hemophilia published a message on the status of diagnosis and treatment of hemophilia. Since then, hemophilia care has been complicated by widespread infection of hemophiliacs with human immunodeficiency virus (HIV).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Antibodies reactive with human T cell leukemia viruses in the serum of hemophiliacs receiving factor VIII concentrate

The third member of the family of T cell leukemia viruses (HTLV III) has been proposed as the primary etiologic agent of the acquired immunodeficiency syndrome (AIDS). A high risk of AIDS has been reported among patients with hemophilia, particularly those with factor VIII deficiency who receive commercial clotting factor concentrates. In a prevalence survey conducted between September 1982 and April 1984, initial serum samples from 74% of hemophiliacs who had ever been treated with commercial factor VIII concentrate, 90% of those frequently treated with factor VIII concentrate, and 50% of those treated with both factor VIII and factor IX concentrates had antibodies reactive against antigens of HTLV III, compared with none of the hemophiliacs treated only with factor IX concentrate or volunteer donor plasma or cryoprecipitate. Two of the seropositive patients have developed AIDS-related illnesses, and a third patient died of bacterial pneumonia. One initially seronegative patient developed antibodies against HTLV III during the study and is currently well. The predominant antibody specificities appear directed against p24 and p41, the presumed core and envelope antigens of HTLV III, suggesting that factor VIII concentrate may transmit the p24 and p41 antigens of HTLV III. However, the presence of infectious retroviruses in clotting factor concentrates and the effectiveness of screening and viral neutralization procedures remain to be determined.     

Acquired hemophilia A with sigmoid colon cancer: successful treatment with rituximab followed by sigmoidectomy

Acquired hemophilia A is a rare and potentially fatal condition of coagulopathy caused by autoantibodies against clotting factor VIII (factor VIII inhibitor). We report a case of a 63-year-old woman, who presented with a sudden onset of severe hemorrhagic tendency with exclusively prolonged activated partial thromboplastin time (APTT). She was diagnosed with acquired hemophilia A due to a decrease in factor VIII activity and a high titer of factor VIII inhibitor. Hemorrhage was well controlled by recombinant activated factor VII. Although the level of factor VIII inhibitor did not decline with prednisolone and cyclophosphamide, it became undetectable with rituximab. In parallel with controlling hemorrhage, malignancy, which may cause acquired hemophilia A, was searched for and sigmoid colon cancer was found. After the eradication of factor VIII inhibitor, surgical resection was performed uneventfully. Thereafter, acquired hemophilia A has been in complete remission without any additional therapy. The present case suggests the efficacy of rituximab for refractory acquired hemophilia A and the importance of the identification of underlying diseases that can cause acquired hemophilia A.     

An update on the assessment and management of the risk of transmission of variant Creutzfeldt-Jakob disease by blood and plasma products

There have been four highly probable instances of variant Creutzfeldt-Jakob disease (vCJD) transmission by non-leucocyte depleted red cell concentrates and it is now clear that the infectious agent is transmissible by blood components. To date there in no reported evidence that the infectious agent has been transmitted by fractionated plasma products, e.g. factor VIII concentrate. This review outlines current and potential risk management strategies including donor deferral criteria, the potential for donor screening, blood component processing and prion reduction filters, plasma product manufacture and the difficulties in identification and notification of those considered 'at risk of vCJD for public health purposes'.