Plasma-derived Concentrates Research Articles

Markers of Blood Cell Activation and Complement Activation in Factor VIII and von Willebrand Factor Concentrates

Background: Preparations of commercially available clotting factor VIII are complex protein mixtures. Most of them contain either von Willebrand factor or human serum albumin as stabilizers. The aim of the study was to quantify further proteins in twelve concentrates either of recombinant origin or derived from human plasma. Methods: Proteins were separated by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Some proteins were quantified by ELISA. Results: Recombinant clotting factor preparations showed fewer protein spots in the 2D-PAGE, than plasma-derived preparations. Proteins identified in some of the plasma-derived concentrates included up to 90 ng/IU of the anaphylatoxin C3a, up to 40 ng/IU of the platelet Α-granule protein thrombospondin-1, up to 0.85 ng/IU of the platelet agranule protein platelet factor 4, 3.5 ng/IU myeloperoxidase secreted by leukocytes and up to 0.05 ng/IU of the leukocyte-secreted protein a-defensin. The protein content differed between concentrates from different manufacturers. Conclusion: The origin of the plasma used to prepare the factor concentrates might influence the protein impurities in these products. It is unknown whether the impurities observed have long-term consequences for chronic inflammatory conditions.

GUIDELINES FOR THE USE OF FRESH FROZEN PLASMA

Recommendations, which aim at standardising and rationalising clinical indications for the transfusion of fresh frozen plasma (FFP) in Belgium, were drawn up by a working group of the Superior Health Council. For this purpose the Superior Health Council organised an expert meeting devoted to “Transfusion Guidelines: Pathogen reduction, products and indications for the transfusion of plasma” in collaboration with the Belgian Haematological Society. The experts discussed the indications for the transfusion of FFP, pathogen reduction for FFP and the practical issues of administering FFP and plasma-derived concentrates. The recommendations formulated by the experts were validated by the working group with the purpose of harmonising FFP transfusion in Belgian hospitals.

Rare inherited disorders of fibrinogen

Fibrinogen, a hexameric glycoprotein encoded by three genes - FGA, FGB, FGG - clustered on chromosome 4q is involved in the final steps of coagulation as a precursor of fibrin monomers required for the formation of the haemostatic plug. Inherited disorders of fibrinogen abnormalities are rare and not as well clinically characterized as some other inherited bleeding disorders. To characterize the clinical manifestations, molecular defects and treatment modalities of these rare disorders, a Medline search from January 1966 to September 2007 for these disorders reported in large studies and registries was undertaken. Inherited fibrinogen disorders can manifest as quantitative defects (afibrinogenemia and hypofibrinogenemia) or qualitative defects (dysfibrinogenemia). Quantitative fibrinogen deficiencies may result from mutations affecting fibrinogen synthesis, or processing while qualitative defects are caused by mutations causing abnormal polymerization, defective cross-linking or defective assembly of the fibrinolytic system. Clinical manifestations vary from being asymptomatic to developing catastrophic life-threatening bleeds or thromboembolic events. Management of bleeds includes use of purified plasma-derived concentrates, cryoprecipitate or fresh frozen plasma. Use of some of these products carries risks of viral transmission, antibody development and thromboembolic events. Establishment of registries in Iran, Italy and North America has fostered a better understanding of these disorders with an attempt to explore molecular defects. Rare Bleeding Disorder Registries developed through the United States and international efforts hopefully will encourage development and licensure of safer, effective products.

Prophylaxis of bleeding episodes and surgical interventions in patients with rare inherited coagulation disorders.

Rare inherited coagulation disorders (RICD) represent a group of inherited deficiencies of clotting factors characterized by a low prevalence in the general population (usually around 1:1,000,000 inhabitants) and, in severe cases (homozygous or compound heterozygotes), by the invariable occurrence of bleeding after invasive procedures if not adequately treated. Furthermore, spontaneous or post-traumatic severe bleeding may occur, as usually observed in patients with haemophilia, although less frequently. The clinical picture of patients with RICD may, however, be complicated by particular situations not encountered in haemophiliacs, such as gynaecological bleeding. The availability of virally-inactivated plasma-derived concentrates of the missing factors, apart from factor V, has rendered surgery and prophylaxis more feasible in these disorders, thus reducing the risk of life-threatening episodes and significantly improving the quality of life of affected patients. The goal for the future is to render this treatment accessible to all patients with these disorders, also to those living in developing countries.

Emergency Department Care for Patients with Hemophilia and Von Willebrand Disease

Patients with bleeding disorders such as hemophilia A, hemophilia B, and von Willebrand disease (VWD) are routinely treated at home, with their care managed in specialized centers. In emergency situations, these patients often present to their local emergency department (ED), where their management can represent a challenge to the emergency physicians and staff who rarely encounter them. Delays in diagnosis and administration of replacement therapy are the factors most commonly identified as predictive of death. Patients and family members are often very well educated in the disease and its management, which can significantly reduce morbidity and mortality. Children with bleeding disorders confer different challenges to the emergency physician and staff: they may present with no obvious signs of trauma or they may present with bruises consistent with non-accidental injury. All possible causes of bruising/bleeding should be investigated, although treatment should be administered promptly. The initial presentation of a bleeding disorder in the pediatric population is often made in the ED. Treatment of hemophilia A and B requires rapid replacement of the deficient clotting factor, with the desired factor level and dosage dependent on the product used and the hemorrhagic situation encountered. In patients with VWD, the main treatments are desmopressin or intravenous infusion of plasma-derived concentrates containing factor VIII and von Willebrand factor. The aim of this review is to outline some of the issues facing emergency physicians and the options available for the treatment of patients with hemophilia A, hemophilia B, and VWD.

Postoperative deep venous thrombosis in a woman with congenital afibrinogenaemia treated with fibrinogen concentrates

Postoperative deep venous thrombosis in a woman with congenital afibrinogenaemia treated with fibrinogen concentrates

VWF/FVIII complex and the management of patient with inhibitors: from laboratory to clinical practice

We and others have previously shown that inhibitor containing plasma from patients with congenital haemophilia A sometimes reacts less with von Willebrand factor (VWF) containing concentrates compared with highly purified plasma-derived or recombinant factor VIII (FVIII) concentrates. To further substantiate the haemostatic role of a variation in inhibitor reactivity with different FVIII concentrates, we compared the inhibitor titres from 11 plasma samples against a panel of FVIII concentrates and correlated titre with the capacity to inhibit thrombin generation. Three plasma-derived concentrates were tested: Fandhi (Grifols) which contains VWF with a final ratio of approximately 1 (VWF IU per IU FVIII:C); Haemate (CSL Behring) with a ratio of 2.5 and Haemofil M (Baxter), a monoclonal antibody-purified concentrate containing only trace amounts of VWF. In addition, the recombinant FVIII concentrate Kogenate Bayer (Bayer) containing no VWF was included in the panel. A statistically significant difference in measured titres against the four concentrates was found. The inhibitor titre needed to inhibit 50% maximum thrombin generation was lowest for Kogenate Bayer and highest and similar for Fandhi and Haemate. This study confirms the results from previous research regarding variation of inhibitor reactivity against different concentrates and further shows that the VWF containing concentrates Fandhi and Haemate added to FVIII-deficient plasma with the presence of inhibitor generate more thrombin than do the purified concentrates Haemofil M and Kogenate Bayer. A further interesting aspect could be that bypass therapy may have an increased efficacy when infused together with FVIII concentrates containing VWF. However, the clinical implications of all these findings in vitro need to be established.

Highly purified VWF/FVIII concentrates in the treatment and prophylaxis of von Willebrand disease: the PRO.WILL Study

Two therapeutic approaches are available to manage patients with von Willebrand disease (VWD): (i) the release of endogenous von Willebrand factor (VWF) from endothelial compartments induced by desmopressin (DDAVP); (ii) the transfusion of exogenous VWF contained in VWF/FVIII plasma-derived concentrates. Only a few high-purity VWF/FVIII concentrates have been extensively evaluated in pharmacokinetic (PK) trials as well as in retrospective or prospective efficacy studies in VWD. The Alphanate Study Group published results of PK and clinical efficacy studies in 2002. Efficacy results showed that 75% of bleeding episodes were controlled with one or two infusions, and 71% of patients who received prophylactic treatment for surgeries or invasive procedures had good clinical responses. In another retrospective study, 22 VWD patients in Italy received Fanhdi, a VWF concentrate similar to Alphanate. Excellent-good clinical responses were seen in 92% of bleeding episodes and in 93% of surgical procedures. More recently, the efficacy and safety of Fanhdi have been evaluated retrospectively in a larger cohort of Italian patients (n = 103) with 97% (bleedings) and 99% (surgeries) of excellent/good clinical responses. The largest experience on secondary prophylaxis in VWD has been collected in Sweden in 35 patients with severe forms of VWD. Secondary prophylaxis was also implemented in a cohort of Italian patients with VWD. Prophylaxis was started because of GI bleeds in seven patients with types 3 (n = 1), 2A (n = 4), 2M (n = 1) and type 1 (n = 1) and for joint bleeds in four patients with type 3 VWD (n = 4). Prophylaxis prevented bleeding completely in eight patients and largely reduced hospitalization for blood transfusions in the remaining three. The cost-effectiveness of these prophylaxis regimens versus on demand therapy will be now investigated in one large prospective study (PRO.WILL) organized in Italy.

Clinical use of Haemate(R) P in inherited von Willebrand's disease: a cohort study on 100 Italian patients

Plasma-derived concentrates containing von Willebrand factor and factor VIII (VWF/FVIII concentrates) are the mainstay of treatment of patients with inherited von Willebrand's disease (VWD) who are unresponsive or have a contraindication to desmopressin (DDAVP) therapy. Only a few clinical studies are available on the use of these VWF/FVIII concentrates in large numbers of cases and within the same country. The aim of our study was to collect retrospective data on the efficacy and safety of Haemate P (CSL Behring, Marburg, Germany) in a large cohort of well-characterized VWD patients after the introduction of the guidelines for VWD management in Italy. A retrospective survey of data records was organized among ten Italian Hemophilia Centers in order to retrieve information on the clinical use of Haemate P. Data on 100 VWD patients (44 males and 56 females, median age 41.5, range 2-87 years) were available relating to the period from January 2002 to December 2004. All patients were diagnosed according to the criteria proposed by the Italian guidelines for VWD management. Of the 100 VWD patients enrolled, 23 had type 1 VWD, 40 had type 2 (2A=7, 2B=11, 2M=9, 2M Vicenza=13) and 37 had type 3. Seventy-one percent were severely affected, as shown by VWF:RCo levels <10 IU/dL. Fifty-nine patients were treated with Haemate P because of 280 spontaneous bleeding episodes. These patients required 1,003 infusions of Haemate P with a median daily dose of 72 (27-135) VWF:RCo IU/kg. In ninety-five per cent of patients, clinical responses were rated as excellent/good. Fifty-six patients underwent major surgery (n=17), minor surgery (n=28), invasive procedures (n=9) or dental procedures (n=19), with a total consumption of 1.97x10(6) IU of VWF:RCo through 366 infusions of Haemate P. The median daily dose was 80 (range, 27-146) VWF:RCo IU/kg, with clinical responses rated as excellent/good in 97% of patients. Twelve patients (type 1=1, type 2B=1, type 2M Vicenza=1, type 3=9, with a median age of 34.5, range 11-71 years) also underwent 17 long-term secondary prophylaxis regimens to prevent recurrent bleeding at the same site (47% in the gastrointestinal tract, 35% in joints). During the 4,358 days of prophylaxis, the patients received 1,424 infusions of Haemate P, given three times (53%) or twice (47%) a week, with clinical responses rated as excellent/good in 100%. No serious adverse events, including thrombosis, were reported in the 370 evaluated treatments. Based on this retrospective study conducted in a large cohort of Italian patients (n=100) and covering a long period of observation (36 months), Haemate P was shown to be effective and safe for the clinical management of patients with VWD, whether given on demand or as prophylaxis.

Use of Recombinant Factor VIIa for Hip Surgery in a Patient with Factor-VII Deficiency

F actor-VII deficiency is a rare autosomal recessive disorder affecting approximately one in 500,000 persons1. The risk of bleeding complications depends on the factor-VII level, and patients with factor-VII activities of 5% are mildly affected2. As a result of its short half-life of six hours, factor-VII-replacement strategies require frequent infusions of factor preparations. Historically, options for treatment of or prophylaxis against bleeding in factor-VII-deficient patients included use of fresh-frozen plasma and plasma-derived concentrates of vitamin K-dependent coagulation factors (prothrombin complex concentrates). Potential complications associated with these products include infection with blood-borne pathogens as well as volume overload with fresh-frozen plasma and thrombotic events with prothrombin complex concentrates. Recombinant activated factor VII (recombinant factor VIIa) (NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) was approved by the United States Food and Drug Administration (FDA) in 1999 for treatment of bleeding in patients with hemophilia A or B who have inhibitors to factors VIII and IX, respectively. On the basis of limited clinical experience, recombinant factor VIIa appears to also have beneficial hemostatic effects in bleeding situations complicated by coagulopathies due to liver disease, massive hemorrhage, qualitative and quantitative platelet disorders, oral anticoagulation, and congenital factor-VII deficiency3,4. We present a case of off-label use of recombinant factor VIIa to prevent perioperative bleeding complications in association with a major hip procedure in a patient with congenital factor-VII deficiency. The patient's wife granted permission for us to submit data concerning the case for publication, as the patient had died of chronic cardiac disease. I n 2003, a seventy-six-year-old man had major bleeding after a primary right …

Impact of different inhibitor reactivities with commercial factor VIII concentrates on thrombin generation

In order to describe the haemostatic role of a variation in inhibitor reactivity with different factor VIII (FVIII) concentrates, we have compared inhibitor titres against a panel of FVIII concentrates and correlated titre with the capacity to inhibit thrombin generation. Three plasma-derived concentrates were tested in vitro in mixing experiments with inhibitor plasmas from 11 patients with severe haemophilia A: Fanhdi, which contains von Willebrand factor (VWF) with a final ratio of approximately 1:1 (VWF IU per IU FVIII:C); Haemate-P with a ratio of 2.5:1 and Hemofil-M containing only trace amounts of VWF. In addition, the recombinant FVIII concentrate Kogenate Bayer containing no VWF was included. Inhibitor titres and the capacity to generate thrombin were measured. A statistically significant difference in measured titres was found with the highest titres recorded against Hemofil-M. The inhibitor titres needed to inhibit 50% maximum thrombin generation were the lowest for Kogenate Bayer and the highest and similar for Fanhdi and Haemate-P with intermediate titres needed for inhibition of Hemofil-M. In this study, the thrombin generation assay provides additional indications for the role of VWF in the treatment of patients with inhibitors. The VWF-containing concentrates Fanhdi and Haemate-P, added to FVIII-deficient plasma with the presence of inhibitor, generate more thrombin than do the purified concentrates Hemofil-M and Kogenate Bayer.

Occurrence of inhibitors in previously untreated or minimally treated patients with haemophilia A after exposure to a plasma‐derived solvent‐detergent factor VIII concentrate

A solvent-detergent virus-inactivated plasma-derived FVIII concentrate (SD-pdFVIII) has been employed for treatment of Italian patients with haemophilia A for 15 years. This product is a non-monoclonally purified, high purity FVIII concentrate, containing large amounts of von Willebrand factor (VWF). A retrospective survey was carried out in Italy in order to evaluate the immunogenicity of SD-pdFVIII in previously untreated patients (PUPs) or in minimally treated patients (MTPs), i.e. previously exposed for up to 5 days only to other plasma-derived concentrates. The survey included 99 patients with ages ranging from 6 to 64 years (median=21.3) of whom 31 PUPs and 68 MTPs, the latter with a median of four exposure days (EDs; range 1-5) to other plasma products. Surveyed patients had been exposed to SD-pdFVIII for a median of 83 EDs (range 21-1580). Seven patients (three PUPs and four MTPs), all with severe haemophilia, had developed inhibitors [7.1%, 95%; confidence interval: 3-14%] after a median of 11 EDs (range 4-22). Of them, two were low responders (<or=5 BU mL-1) and five high responders. Two low responders and one high responder tolerated inhibitors spontaneously; one high responder underwent immunotolerance treatment with complete, long-standing response. These findings show that SD-pdFVIII is at low risk of inhibitor development in PUPs and MTPs with severe and moderate haemophilia, the risk of inhibitor development being similar to that previously reported for other plasma-derived VWF-containing FVIII products.

Treatment of von Willebrand disease

The bleeding tendency in von Willebrand disease (VWD) is heterogeneous and some patients with the mildest form of the disease have no significant bleeding symptoms throughout their lives. In some cases, the most difficult task for a clinician is to decide whether any treatment is actually required. However, cases with moderate to severe factor VIII (FVIII) and von Willebrand factor (VWF) deficiency usually require treatment to stop or prevent bleeding. Increasing autologous FVIII/VWF by desmopressin administration or providing normal allogeneic VWF through the infusion of plasma-derived concentrates can correct FVIII and VWF deficiencies and normalize or shorten bleeding time (BT). FVIII levels are the best predictors of soft tissue or surgical bleeding, while BT normalization, reflecting the correction of platelet-dependent functions of VWF, is considered a reliable indicator of an effective treatment of mucosal bleeding. Recombinant concentrates of FVIII are not indicated (apart from cases with alloantibodies against exogenous VWF), since they are devoid of VWF and lack its stabilizing effect on circulating FVIII. A very-high-purity concentrate of VWF has recently been made available, but its advantages over conventional concentrates containing both FVIII and VWF moieties are not obvious. The best way to select the appropriate treatment is to perform a test infusion with desmopressin in any patient with clinically significant VWD, provided that he/she has no contraindication to the compound or belongs to subtype with an anticipated lack of response (for example, type 3 VWD with FVIII/VWF lower than 5%).

Effectiveness of DDAVP in Von Willebrand's Disease.

Objective: Of the inherited bleeding disorders von Willebrand's disease (VWD) is the most common, with a prevalence of one in 10,000. Desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]) and a variety of plasma-derived concentrates of Factor VIII (FVIII) and von Willebrand factor (VWF) have been used to treat VWD. A prospective multicenter European study recently reported the effectiveness of DDAVP to be 27% in type 1 VWD and 18% in all type 2, which suggests that DDAVP is less effective than previously thought. Here we report our experience in a retrospective analysis of patients with known VWD challenged with DDAVP.Methods: Intranasal DDAVP was administered to 20 patients with known VWD who were studied before and 2 hours after dosing. A response to DDAVP was defined by a 2-fold increase in both FVIII concentration and ristocetin cofactor activity (VWF:RCo) as well as attainment of a level of at least 30 IU/dL. In addition, 6 subjects had bleeding time (BT) tests performed. Statistical analysis was performed using one-tailed multivariate Student's t-test.Results: Three of the 20 patients were excluded from the study: 2 had acquired VWD and 1 inadequate data. Of the 17 evaluable patients, 13 were type 1 and four type 2 (confirmed by multimer analyses). Overall response in the 17 patients was 59% (p<0.001); 13 subjects had FVIII levels that increased to more than 80 IU/dl, and 9 subjects had VWF:RCo levels of more than 50 IU/dl. Responses were observed in 8 of the 13 (62%, p<0.001) subjects with type 1 disorder and 2 of the 4 with type 2. The BT was >10 min prior to DDAVP and decreased significantly, to ≤7.5 min, in 5 of the 6 patients after DDAVP. Even when more stringent requirements for defining a response were used (a 3 fold increase and a level of at least 30 IU/dL of both FVIII and VWF:RCo activity, as used by the European multicenter study), 5 of 13 (39%, p=0.01) of the type 1 patients had a response. The average increase in responders in VWF:RCo was 3.33 fold and FVIII, 4.43 fold.Conclusions: The majority of patients with VWD have a significant biological response to intranasal DDAVP; a challenge test with intranasal drug identifies responders who should be considered for treatment with this agent.

Transfusion‐transmitted virus is not present in factor IX concentrates commonly used to treat haemophilia B

Transfusion-transmitted virus (TTV) is a potential cause of post-transfusion hepatitis in patients with haemophilia. Plasma-derived clotting factor concentrates currently undergo processes that are effective in removal and inactivation of viruses such as HIV, hepatitis B and C; however, their effectiveness with respect to TTV is unknown. To determine if TTV DNA is present in plasma-derived concentrates of factor IX, we tested 14 lots of Mononine and compared the results with BeneFix. Nucleic acid isolation, followed by a two-round polymerase chain reaction (PCR) and agarose gel analysis indicated that all 17 lots were negative for TTV. Although TTV may be considered an emerging pathogen, no evidence of the virus was detected in the commercially available plasma-derived concentrate of FIX most commonly used to treat haemophilia B.

Recombinant Factor VIIa concentrate versus plasma derived concentrates for the treatment of acute bleeding episodes in people with Haemophilia A and inhibitors.

In some people with haemophilia, therapeutic clotting agents are recognised as a foreign protein and anti-FVIII antibodies, known as 'inhibitors', are produced. This review investigates which treatment most effectively arrests acute bleeding in people with haemophilia A and inhibitors. To determine the clinical effectiveness of recombinant FVIIa concentrate in comparison to plasma-derived concentrates for the treatment of acute bleeding episodes in people with haemophilia A and inhibitors. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group trials register which comprises of references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. Date of the most recent search of the Group's trials register: September 2003. Randomised (RCTs) and quasi-randomised controlled clinical trials comparing Recombinant FVIIa concentrate to human plasma-derived concentrates (high-dose human or recombinant FVIII concentrate; prothrombin complex concentrates (PCCs); activated prothrombin complex concentrate (aPCC)) in people with haemophilia A. Comparisons with animal derived products were excluded. No studies were found that were eligible for inclusion in this review. A total of four studies were identified by the searches, however, none of these were eligible for inclusion in this review. No RCTs on the relative effectiveness of Recombinant FVIIa concentrate compared to human plasma-derived concentrates in people with haemophilia A and inhibitors were identified for inclusion in this review. The research evidence on which to base clinical decisions is therefore limited to case reports, and other less robust evidence. There is need for a well-designed, adequately-powered randomised controlled trial to assess the relative benefits and risks of using Recombinant FVIIa concentrate compared to human plasma-derived concentrates in people with haemophilia A and inhibitors.

Factor replacement therapy in haemophilia--are there models for developing countries?

Successful models for factor replacement in severe haemophilia involves prophylactic or on-demand administration of large quantities (1500-9000 IU kg-1 year-1) of very high purity factor concentrates starting early in life. The prohibitive cost of these protocols make them completely impractical in developing countries where the quantity of factor used for replacement therapy is much lower and varies considerably (25-500 IU kg-1 year-1). At this level of treatment, as some joint damage is inevitable, the aim of therapy shifts to preventing disability and preserving reasonable joint function rather than perfect architecture. There are no carefully recorded data on long-term outcome of musculo-skeletal function on these doses. Appropriate studies are needed to document such data. With regard to products for factor replacement, economic compulsions lead to the use a variety of factor concentrates and blood-bank products for replacement therapy. Most patients in the developing world do not have access to adequate replacement therapy. Among the rest, some get limited quantities of plasma-derived concentrates while others use cryoprecipitate, fresh frozen plasma or even whole blood. Since the superiority of virus-inactivated purified factor concentrates in achieving the aims of replacement therapy is well established, the aim should be to provide this for all people with haemophilia. This can be achieved by production of such concentrates locally or by importing them. Different models are possible depending on the circumstances in each country.

Characterization of inhibitors to FVIII with an ELISA in congenital and acquired haemophilia A.

Different methods can be used for the detection and quantification of inhibitors or antibodies to coagulation factor VIII (FVIII). Traditionally, clotting assays have been used, in particular the Bethesda assay. These assays have, however, several shortcomings, due to the complex reaction kinetics of some inhibitors and a low sensitivity to low-titre antibodies. In addition, a universal FVIII inhibitor standard is lacking. Furthermore, clotting assays do not detect noninhibitory antibodies. Use of ELISAs has been described and FVIII from various commercially available FVIII concentrates has been used as target antigen in the assays. In the present study, we systematically explored the influence of different FVIII concentrates on the performance of an ELISA for detection of FVIII antibodies. The described ELISA was also used for further characterization of FVIII inhibitors in patients with acquired and congenital haemophilia A. We found that the source of FVIII had a substantial impact on the frequency of antibody detection. Albumin-free recombinant FVIII as target antigen gave the highest sensitivity for the assay, whereas plasma-derived concentrates containing a high level of von Willebrand factor (vWF) gave the lowest sensitivity. Presumably vWF interferes with the binding of antibodies to FVIII. We suggest that albumin-free recombinant FVIII should be used as target antigen when ELISAs are used for detection of FVIII antibodies.

Evolving perspectives in product safety for haemophilia.

The past decade has seen a consolidation of the safety measures built into the manufacture of coagulation factor concentrates for people with haemophilia. The scientific developments of the 1980s have been fully reflected in the manufacturing principles and the regulatory control of concentrate production, so that the safety of concentrate therapy now exceeds the safety of normal blood transfusion. A clear understanding of the epidemiology of the transfusion-transmitted viruses allows the selection of donors with a satisfactory safety profile. Source material for plasma-derived concentrates is now screened with sensitive tests that detect viral infection in donors at a very early phase in the viral life cycle. This decreases the potential viral load to levels that are easily eliminated by well-accredited viral inactivation procedures. These measures have ensured a high level of assurance regarding the safety of products from the traditional transfusion-transmitted infections. However, testing for some transfusion-transmitted viruses does not yet form part of mainstream blood screening; alternative strategies based upon the particular needs of pooled plasma product recipients may be more feasible. Whereas the risk of emerging pathogens has to be kept constantly under review, four such viruses identified over the 1990s have proven to be of little relevance to plasma product recipients and the need for measures specifically directed against them is debatable. The risk of variant Creuzfeldt-Jakob Disease (vCJD) is a special case of an emerging infection that is insufficiently well characterized to allow a conclusive assessment of its role in the safety of concentrates; however, data regarding the capacity of concentrate manufacturing methods to clear the putative agent are encouraging. The relative uncertainty surrounding vCJD has caused the influential regulatory authorities of North America to take a precautionary approach regarding the selection of blood donors. This is having an effect on the supply of factor VIII concentrates and has possibly affected the rate at which developed countries have switched to recombinant products. The safety of recombinant products continues to be supported through patient monitoring, and the new generation of plasma protein-free products will further enhance the role of these products as the treatment of choice with people with haemophilia. However, their cost-effectiveness relative to the current generation of plasma-derived products makes it unlikely that they will be accessible by developing countries. The dependence of most of the world's population of people with haemophilia on a safe and sufficient blood supply will therefore continue into the foreseeable future, and with it the need to maintain constant vigilance on blood safety matters.

Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study: Presented in part at the meeting of the International Society of Thrombosis and Haemostasis in Washington, DC, August 1999.

AbstractAmong patients with von Willebrand disease (VWD) who are unresponsive to desmopressin therapy, replacement with plasma-derived concentrates is the treatment of choice. Because prospective studies are lacking, such treatment has been largely empirical. A multicenter, prospective study has been conducted in 81 patients with VWD (15 patients with type 1, 34 with type 2, and 32 with type 3 disease) to investigate the efficacy of a high-purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate for treatment of bleeding and surgical prophylaxis. Two preparations of the concentrate—one virally inactivated with solvent detergent, the other with an additional heat-treatment step—were evaluated. Pharmacokinetic parameters were similar for both preparations. Using pre-established dosages based on the results of pharmacokinetic studies, 53 patients were administered either preparation for the treatment of 87 bleeding episodes, and 39 patients were treated prophylactically for 71 surgical or invasive procedures. Sixty-five (74.7%) and 10 (11.5%) of the bleeding episodes were controlled with 1 or 2 infusions, respectively. Patients with severe type 3 VWD typically required more infusions and higher doses, at shorter time intervals, than did patients with generally milder types 1 and 2. Among patients undergoing surgical procedures, blood loss was lower than that predicted prospectively, and losses exceeding the predicted value did not correlate with the postinfusion skin bleeding time. In conclusion, the concentrate effectively stopped active bleeding and provided adequate hemostasis for surgical or invasive procedures, even in the absence of bleeding time correction.