Further evidence for recessive inheritance of von willebrand disease with abnormal binding of von willebrand factor to factor VIII

Abstract

A new family with a bleeding diathesis and FVIII deficiency secondary to abnormal binding of von Willebrand factor (vWF) to factor VIII (FVIII) is described. Two propositi of this family, an 18-year-old male and a 33-year-old female, both with a history of epistaxis, bruising, bleeding from the gums, epistaxis, hemarthrosis, and hematoma, were analyzed. Also additional members of the same family with no bleeding history were also studied. The propositi showed normal vWF activities, low FVIII activity; one of them had been diagnosed as having hemophilia A and the other was a hemophilia A carrier. Both showed a very poor response to treatment with FVIII concentrates and desmopressin (DDAVP) but a good clinical response to cryoprecipitate. APTT was prolonged and no inhibitory activity was noticeable in their plasmas. Thirty-five units per kilogram body weight of Hemofil M was infused to both propositi and FVIII reached basal level within 60 minutes of the infusion. No FVIII response at all was observed in the female after intravenous DDAVP administration. However, the male who received the infusion of 35 U/kg body weight of Humate-P achieved a normal FVIII level that was maintained for 12 hours. Multimeric analysis of vWF was normal in all the members studied. Von Willebrand factor domain for FVIII binding was assayed in the two propositi and in six other members of the same family by using a non-isotopic and sensitive method, a modification of the one previously described, using the Hemofil M concentrate as exogenous FVIII. The data obtained showed that both propositi had similar binding to that observed by using plasma of a patient with severe von Willebrand disease. Furthermore, five siblings had a decreased binding of vWF to FVIII, when compared with plasma from normal individuals or patients with hemophilia A. We also observed that, for screening purpose, the ratio of bound FVIII/immobilized vWF (at saturation of the anti-vWF and offering of 1 U/ml of exogenous FVIII) distinguished two levels of abnormality (normal range 0.70-1.15, propositi 0.004-0.007, and remaining members affected 0.25-0.42). The most probable explanation is that the propositi are homozygous or double heterozygous, the other five siblings affected being heterozygous for a recessive vWF defect. This more accessible assay presented here may be of help in routine analysis for diagnosing this type of von Willebrand disease, which has important implications for therapy and genetic counseling.

Investigation of the Anti-HIV Properties of Oxihumate

“…The possible application of coal-derived humic acid and fulvic acid as antimicrobials has been investigated by Cloete et al [10] and van Rensburg et al [11], whereas the anti-inflammatory properties of coal-derived fulvic acid have recently been described by van Rensburg et al [12]. More recently, humate has been used in the treatment of von Willebrand disease [13]. Patients were treated with an infusion of 35 mg/kg body weight after which normal factor VIII levels were achieved.…”

von Willebrand disease update: diagnostic and treatment dilemmas

“…The diagnosis depends mainly on the measurement of the affinity of VWF to FVIII (VWF:FVIIIB) which is markedly decreased. The original assay is a solid phase immunoassay [15] but several modifications have enabled simplification and even automation of the assay [26][27][28][29]. In France, the test is now carried out using only commercially available reagents [30].…”

“…The gene has 52 exons, 12 of which (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) are duplicated with 3% variation in a partial VWF pseudogene on chromosome 22. While several positive and negative transcriptional regulatory elements have been characterized in the 5¢ flanking region of the gene, the mechanisms regulating expression of VWF in vivo remain poorly defined.…”

Phase I trial with oral oxihumate in HIV‐infected patients

“…Humic acids (sold under the trade name of Huminit) have been used in medicines for the treatment of hyperacidity and other gastric disturbances in humans [Gramsch, 1961;Reichert, 1966]. Humic acids have also been used as antiinflammatory agents because of their local antiinflammatory, hyperemic, and analgesic properties [Brandt, 1964;Eichelsdö rfer, 1976] and in the treatment of anemia, hypercholesterolemia [Soloveyva and Lotosch, 1984], and Von Willebrand's disease [Lopez-Fernandez et al, 1992]. No unfavorable side effects have been observed at dosages of up to 1.8 g per day.…”