Evidence for a von Willebrand factor defect in factor VIII binding in three members of a family previously misdiagnosed mild haemophilia A and haemophilia A carriers: consequences for therapy and genetic counselling

Abstract

A plasma von Willebrand factor (vWf) defect limited to its failure to bind factor VIII (FVIII) was previously characterized in a woman with FVIII deficiency and normal primary haemostasis. By using in vitro tests we found a similar pattern in three siblings of another family previously thought to be affected with mild haemophilia A. Furthermore, a decrease in vWf ability to bind FVIII was found in the parents and the brother of the three patients. This decrease was consistent with heterozygous expression of a recessive vWf gene abnormality. FVIII deficiency was corrected by infusion with a vWf concentrate almost devoid of FVIII coagulant activity. FVIII recovery and half-life thus obtained showed that this treatment was more effective than a FVIII infusion performed by way of comparison. These results indicate that this vWf defect may account for FVIII deficiency in patients without the usual laboratory and clinical features of von Willebrand's disease. Changes in therapy and genetic counselling following the new diagnosis in this family emphasize the need to search for such a vWf defect in patients in whom FVIII deficiency is not obviously X-linked.

Type 2N von Willebrand disease: Characterization and diagnostic difficulties

“…19 Type 2N exhibits FVIII levels from 1 to 40 U/dL, associated with normal or reduced VWF levels, but a low FVIII/VWF:Ag ratio, 20 in a phenotype that may prompt a misdiagnosis of mild haemophilia A. 21 Here we report on our 15-year experience of diagnosing type 2N…”

von Willebrand disease update: diagnostic and treatment dilemmas

“…As a consequence, the FVIII:C to VWF:Ag ratio is reduced (<0.5) in all the patients with type 2N VWD. Type 2N may be misdiagnosed as moderate and mild haemophilia A [24,25]. The diagnosis depends mainly on the measurement of the affinity of VWF to FVIII (VWF:FVIIIB) which is markedly decreased.…”

“…Spontaneous bleeding manifestations are generally mild (ecchymosis, epistaxis, excessive bruising). Haemarthrosis and gastrointestinal bleeding are rare and observed mainly in patients with low FVIII:C levels (<5 IU dL )1 ) [14,24]. Rare patients with a low VWF:Ag level or abnormal VWF multimeric pattern may exhibit additional mucous membrane bleeding characteristic of primary haemostasis defects.…”

“…A patient with a low FVIII:C level (6 IU dL )1 ) who received a single infusion of an immunopurified FVIII concentrate (with no VWF) demonstrated a very short FVIII:C half-life (approximately 2.5 h), much shorter than that measured in haemophilia A patients treated with the same product. By contrast, another patient from the same family received a single injection of a VWF concentrate almost devoid of FVIII [24] and displayed a delayed but sustained rise in FVIII:C characteristic of the FVIII:C response observed in patients with severe VWD [38]. Although there are some anecdotal reports in the literature of patients with type 2N VWD treated with recombinant FVIII [39], replacement therapy with VWF is the only way to efficiently stabilize the FVIII:C activity because of the absence of endogenous VWF.…”

“…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.…”