Infusion Of FVIII Research Articles

Can haemophilic arthropathy be prevented?

Can haemophilic arthropathy be prevented?

A Case of Acquired Idiopathic Hemophilia Successfully Treated with Immunosuppressive Drugs and Factor VIII Concentrates

The appearance of circulating factor VIII:C (FVIII:C) inhibitors in nonhemophilic patients represents a rare condition characterized by spontaneous and often life-threatening bleeding. We describe a patient with ac quired idiopathic hemophilia in whom immunosuppres sive therapy associated with human FVIII infusion deter mined a prompt and complete disappearance of the inhib itor. Given the very low number of patients with acquired hemophilia and the lack of prospective randomized clin ical trials published, we hope to contribute to a better definition of the therapeutic strategy in these patients.

Changes in factor VIII binding capacity of von Willebrand factor and factor VIII coagulant activity in two patients with type 2N von Willebrand disease after hemostatic treatment and during pregnancy.

The changes of the FVIII binding capacity of vWF after the infusion of FVIII/vWF concentrate was studied in two patients with type 2N vWD, and also during pregnancy in one of them. After infusion of FVIII or DDAVP to the patients, FVIII:C in plasma increased as expected, but it then decreased, with a markedly short half-life, of about 2 h, due to the defect in the FVIII binding capacity of vWF in plasma. However, after infusion of FVIII/vWF concentrate (40 U of FVIII:C/kg), FVIII:C increased, from 4-6 to 100-160 U/dl, more than the expected values, and decreased with the half-life expected. The FVIII binding capacity of vWF in plasma changed in parallel with the concentration of exogenous normal vWF, with a half-life of more than 24 h. During pregnancy, no increase of FVIII:C was observed, although vWF:Ag increased from 40 (before pregnancy) to 90 U/dl in plasma at 35th week of gestation. The FVIII binding capacity of vWF in plasma showed no increase during pregnancy. Accordingly, the administration of FVIII/vWF concentrate to the patient at delivery resulted in adequate hemostasis.

Strategy for pre-clinical evaluation of factor VIII concentrates.

A series of methods and assay systems was designed, using both mouse monoclonal antibodies and purified human polyclonal antibodies, by which alterations in the antigenic properties, and potentially therefore in the immunogenic properties, of FVIII concentrates could be identified. Those methods could be applied to the pre-clinical evaluation of FVIII concentrates. It has become evident that very subtle alterations in FVIII can have dramatic effects on its antigenicity and immunogenicity and it is suggested that an analysis of FVIII preparations, using reagents such as mouse monoclonal antibodies, should be carried out as a pre-clinical evaluation. It is also thought that any haemophiliac patient is at risk of developing anti-FVIII antibodies, even though he had been considered as tolerant to the infusion of FVIII. The diversity of FVIII concentrates now available on the market has multiplied the chances of encountering a product that would give an immune response in some patients and this further stresses the need for a careful check of FVIII concentrates.

Expression of the Blood-Clotting Factor-VIII cDNA Is Repressed by a Transcriptional Silencer Located in Its Coding Region

Hemophilia A is caused by a deficiency of factor-VIII procoagulant (fVIII) activity. The current treatment by frequent infusions of plasma-derived fVIII concentrates is very effective but has the risk of transmittance of blood-borne viruses (human immunodeficiency virus [HIV], hepatitis viruses). Use of recombinant DNA-derived fVIII as well as gene therapy could make hemophilia treatment independent of blood-derived products. So far, the problematic production of the fVIII protein and the low titers of the fVIII retrovirus stocks have prevented preclinical trials of gene therapy for hemophilia A in large-animal models. We have initiated a study of the mechanisms that oppose efficient fVIII synthesis. We have established that fVIII cDNA contains sequences that dominantly inhibit its own expression from retroviral as well as from plasmid vectors. The inhibition is not caused by instability of the fVIII mRNA (t1/2, > or = 6 hours) but rather to repression at the level of transcription. A 305-bp fragment is identified that is involved in but not sufficient for repression. This fragment does not overlap the region recently identified by Lynch et al (Hum Gene Ther 4:259, 1993) as a dominant inhibitor of RNA accumulation. The repression is mediated by a cellular factor (or factors) and is independent of the orientation of the element in the transcription unit, giving the repressor element the hallmarks of a transcriptional silencer.

Adverse Effects of Treatment with Porcine Factor VIII

In the last 10 years 63 courses (283 infusions) of porcine FVIII were given to 25 hemophiliacs with high titer alloantibodies and to 5 patients with autoantibodies to factor VIII. Although the product was in general clinically efficacious, adverse effects of treatment were more frequent and severe than previously reported. After 63 courses there was a median percentage fall in baseline platelet count of 54% (range 8-86%); for 10 courses (16%), thrombocytopenia was severe or moderately severe (less than 100 x 10(9)/l), with nadirs of platelet count ranging from 10 to 99 x 10(9)/l (median 67). Allergic reactions were seen in 15 of 30 patients (50%), in 20 of 63 courses (32%), more frequently but not exclusively after the first infusion. Relatively mild symptoms (fever, flushing, urticaria, shivering) occurred in 15 courses; 5 courses, however, were accompanied by more severe anaphylactoid reactions, 2 of which required resuscitation therapy. Allergic reactions were observed both in patients pretreated with steroids or anti-histamines (in 7 of 18 courses, 39%) and in nonpretreated patients (in 13 of 45 courses, 29%). In conclusion, adverse reactions are frequent after porcine FVIII (in 30 of 63 courses, 47%), and can occur also with infusions subsequent to the first. Hence, the recently proposed use of porcine FVIII as home treatment should be implemented with caution.

Treatment of bilateral fracture of the mandible in a hemophilic patient with inhibitor to factor VIII

Among patients with hemophilia A, approximately 15% develop inhibitors to Factor (F) VIII, and management of bleeding becomes a major problem.' The management of hemophiliacs with inhibitors has recently been reviewed by Lusher, t Eyster et al.,2 and Penner.' Penner proposed that hemophilic patients with low inhibitor levels «40 Bethesda Units (BU) of inhibitor per ml of plasma) who are to undergo surgery should be treated by plasmapheresis until the inhibitor level is below IO BUlml of plasma and then receive infusion of FVIII concentrate for six days followed by infusion of activated prothrombin complex concentrates (PCC). In patients with inhibitor levels above 40 BUlml of plasma who require surgery, 75-100 units of activated PCC per kg bodyweight at four to eight hour intervals is advocated.' Dental extractions performed in hemophiliacs with inhibitors have previously been reported. Nilsson et al. described the use of cyclophosphamide, F-IX concentrate, and tranexamic acid for dental extractions in two hemophilia B patients with inhibitors to F-IX. Several case reports of dental extractions in patients treated with a combination of activated PCC and systematically administered antifibrinolytics (epsilon-arninocaproic acid (EACA) or tranexamic acid (AMCA» have been presented [Agrestini et al.,5 four patients), Hanna et al.,6 three patients), Scharrer. (one patient),