Pharmacokinetics of von Willebrand factor and factor VIII coagulant activity in patients with von Willebrand disease type 3 and type 2.

Nine patients with von Willebrand disease type 3, six with type 2B, one with type 2A, and one patient with type 1/2N were infused with one dose of approximately 50 or 100 IU ristocetin cofactor activity (RCoF) per kg body weight of von Willebrand factor (vWF) (Human), a product with a very low content of factor VIII (FVIII). Blood samples were collected over 96 h. The data for RCoF and vWF antigen (vWF:Ag) were fitted to a 1-compartment model decay. The data for FVIII:C were fitted to a model with a linear time 'synthesis' term and a 1-compartment decay. Results in von Willebrand disease type 3 patients (nine patients; 10 infusions) indicated a volume of distribution of 39.9 and 39.8 mL kg-1 for RCoF and vWF:Ag, respectively. The FVIII:C rate of synthesis was 6.4 U dL-1 h-1 (range: 4.4-8.8). The decay rates for FVIII:C, RCoF, and vWF:Ag were 0.041 (h-1) [t1/2: 16.9 h]; 0.061 (h-1) [t1/2: 11.3 h] and 0.006 (h-1) [t1/2: 12.4 h], respectively. In patients with von Willebrand disease type 2 (n = 8) the RCoF mean volume of distribution was 46 mL kg-1. The factor VIIIC mean rate of synthesis was 5.5 U dL-1 h-1 and the decay rate 0.043 (h-1) [t1/2: 16.1 h]. The rate of decay for RCoF and vWF:Ag were 0.050 (h-1) [t1/2: 13.9 h] and 0.044 (h-1) [t1/2: 15.7 h], respectively.

New treatments of von Willebrand disease: plasma derived von Willebrand factor concentrates.

During the past 10 years the quality of plasma derived virus inactivated products containing von Willebrand factor (vWF) has improved and the ratios of ristocetin cofactor activity (vWF:RCo) to von Willebrand factor antigen (vWF:Ag) have increased. There are, however, considerable variations in AHF-vWF products with ranges from 0.25 to 1.4 unit of vWF:RCo for each unit of vWF:Ag, and 0.5 to 5.3 units of vWF:RCo for each factor VIIIC (FVIIIC) unit. The availability of a vWF product depleted of FVIII has allowed pharmacokinetic studies of the vWF protein. There have been no dose response studies, dosage regimens remain empirical and are still, except in rare instances, based on FVIIIC dosage. Current concentrates are as effective as cryoprecipitate in the management of patients with vWD non responsive to DDAVP. These concentrates should be preferred to cryoprecipitate which carries a risk of virus transmission.

Pharmacokinetics of von Willebrand factor and factor VIIIC in patients with severe von Willebrand disease (type 3 VWD): estimation of the rate of factor VIIIC synthesis. Cooperative Study Groups.

Nine patients (10 infusions) with a confirmed diagnosis of type 3 VWD were infused with von Willebrand factor (human), a preparation of von Willebrand factor (VWF) with a very low factor VIII content. Each patient was infused with one dose of approximately 50 or 100 iu ristocetin cofactor activity (VWF:RiCoF) per kg body weight. Bleeding times were performed during the 24 h period after infusion. Plasma samples were obtained over the 96 h period after infusion and were analysed for factor VIII coagulant activity (FVIIIC), VWF:RiCoF, von Willebrand factor antigen (VWF:Ag), and multimers. The FVIIIC data were analysed by non-linear least-squares analysis assuming constant FVIIIC 'synthesis' and exponential decay. The VWF data were fitted for exponential decay. The average decay rates for FVIIIC, VWF:RiCoF and VWF:Ag were 0.041, 0.061 and 0.056 respectively. The average calculated 'synthesis' rate for FVIIIC was 6.4 u/dl/h. The synthesis of FVIIIC was slightly faster and the decay slightly slower following the infusion of 100 iu VWF:RiCoF/kg than of 50 iu VWF:RiCoF/kg. Correction of the bleeding time was strongly dose dependent. At 4 h post infusion the median bleeding time was 9 min following a dose of 50 iu VWF:RiCoF/kg versus 3 min with a dose of 100 iu VWF:RiCoF/kg. There was no decrease in the bleeding time until the level of VWF:Ag or VWF:RiCoF reached > 100 u/dl.

Creutzfeldt-Jakob disease: current U.S. policy to further reduce the possible risk of transmission by transfusion.

Because the results of epidemiological and subhuman primate studies conducted over the last quarter of a century have failed to show a statistically significant risk of transmission of CJD by transfusion of blood components or plasma derivatives, the FDA's position is that only a theoretical low risk of CJD transmission cannot be excluded at this time. Consequently, FDA issued two memoranda on 8 August 1995 as updated interim policy documents recommending: (1) permanent deferral from donating blood or plasma for all persons who state at the time of donation, or for whom post donation information becomes available, that they have ever received pit-hGh, a dura mater transplant graft, or have a blood relative history of CJD, unless this increased risk for CJD is excluded on the basis of genetic analysis testing; (2) the quarantining of all undistributed in-date units of blood or blood components collected from either of these three groups of donors together with notification of all consignees of such in-date units so that distributed units also can be quarantined and recipient tracing and notification may be effected, and (3) the withdrawal from distribution and quarantining of in-date plasma derivative products derived from plasma pools containing a unit from either of these three groups of donors at known high risk for CJD, or donors subsequently diagnosed as having CJD. Consignees of these products are to be notified in order that they, in turn, may inform physicians or other qualified personnel responsible for the care of product recipients to provide counseling as deemed medically appropriate. The 'family history of CJD' criterion was further clarified to mean a 'history of CJD in 2 or more family members' during the BPAC meeting of 14 December 1995. In a workshop meeting on 29 January 1996 the FDA urged that additional laboratory animal data be generated by plasma derivative manufacturers in order to ascertain if the sterilization steps used in their production of plasma derivatives further reduce the risk of transmission of CJD.

Safety monitoring and epidemiological surveillance of blood transfusion in the United States.

Safety monitoring and epidemiological surveillance of blood transfusion in the United States is complex and involves government agencies and independent organizations. Several systems of control are in place nationwide to ensure that blood, blood components, and plasma derivatives meet prescribed standards. Control and surveillance of drugs that are biologics, which include human blood, blood components and plasma derivatives, are exercised by the Food and Drug Administration. Epidemiological surveillance involves several agencies and organizations that constitute a network capable of rapidly detecting unusual adverse events.

Antithrombin III concentrates.

The general characteristics of antithrombin III (AT III) concentrates available in the United States are described in this article. The effectiveness of AT III concentrates in the prevention and treatment of thrombotic episodes in patients with hereditary AT III deficiency are summarized, and the use of this product in various conditions with acquired AT III deficiency are reported.

Evaluation of the safety, recovery, half-life, and clinical efficacy of antithrombin III (human) in patients with hereditary antithrombin III deficiency. Cooperative Study Group.

Antithrombin III (Human) (AT III) was administered to 18 patients with documented hereditary AT III deficiency. In eight patients with no ongoing clinical symptoms of thrombosis, the percent increase per unit AT III infused per kilogram of body weight ranged from 1.56% to 2.74%, and the half-life from 43.3 to 77.0 hours. No significant difference was noted between patients receiving and those not receiving coumarin therapy. In clinically ill patients, the in vivo recovery was significantly lower and ranged from 0.64% to 1.90% increase per unit AT III infused/kg. Efficacy of AT III was evaluated in 13 patients for the prevention or treatment of thrombosis. AT III was efficacious as assessed by the absence of thrombotic complications after surgery and/or parturition, and the nonextension and nonrecurrence of thrombosis in patients exhibiting an acute thrombotic episode. No side effects were noted. Follow-up studies indicated no hepatitis B seroconversion and no alanine aminotransferase elevations in patients who were not transfused with other blood products.

Thrombogenicity of factor IX complex: in vivo investigation.

Factor IX Complex therapy has been associated with thrombosis when used in patients with liver disease, hemophilia B and hemophilia A with inhibitors to Factor VIII when administered repetitively and in high doses. Three mechanisms for inducing thrombogenicity have been proposed: activated coagulants, coagulant-active phospholipid content and/or the high zymogen level attained in recipients. A new animal model using Russel Viper Venom (RVV) as an in vivo stimulus of coagulation has been used to investigate the role of high levels of zymogens in the induction of thrombosis. The quantity of RVV tolerated by rabbits infused with Factor IX Complex is reduced 100-fold. Infusion of Factor X or prothrombin also reduces the lethal dose of RVV. In contrast, Coagulation Factor IX devoid of other coagulants has little effect. However other animal data indicate that the amount of activated coagulants can play a role in the in vivo thrombogenicity of Factor IX Complex.

[PPSB]. / Le PPSB.

PPSB, the plasma derivative which contains the vitamin K-dependent clotting factors, was first produced in 1959 at the Centre National de Transfusion Sanguine in Paris under the leadership of Jean-Pierre Soulier. Today over 20 such products are manufactured around the world. All production methods take advantage of the common adsorption and elution properties of all the vitamin K-dependent clotting factors due to the presence of gamma carboxy residues. Although the clinical use of PPSB has been extended to all congenital and acquired deficiencies of the vitamin K-dependent clotting factors and more recently to treat hemorrhagic episodes of hemophilia A patients with antibody to Factor VIII, the major clinical indication remains hemophilia B. The major complication associated with the use of PPSB is the occurrence of viral diseases, particularly non-A, non-B hepatitis of unknown etiology and specifically associated with the use of PPSB is the occurrence in some patients of thromboembolic complications. Current research is oriented toward the production of a safer product.